A retirement article on MarketWatch argues we should plan to live to be 100.
Consider: According to the mortality tables, there’s a two-thirds chance that a male who’s age 55 today will live to age 80. Imagine if you play the odds as if you were at a Blackjack table — and plan on being among those who die before age 80, but don’t.
If you do not smoke, are not obese, don't have high blood sugar or high blood pressures, or other major risk factors then your odds of reaching 80 are much higher.
My take on the mortality tables: they are excessively pessimistic. The mortality tables assume a fairly static biomedical treatment environment in which only small incremental improvements to medical care are possible. No discontinuities are part of the forecast. This seems a very big mistake. On the horizon we can see the approach of effective gene therapies, cell therapies, and other treatments that attack the underlying mechanisms of aging. The scientists doing research on these treatments will succeed. Once they do we will have biotechnology that enables us to repair aged tissue.
For a long time mortality has declined fairly slowly. That's because we've had no tools for attacking the underlying mechanisms of aging. Our bodies gradually wear out just like bodies 50 or 100 years ago. We've got medical treatments that reduce the consequences of failing tissue (e.g. blood pressure medicine) and treatments that slow the rate of development of some types of problems (e.g. cholesterol lowering drugs). But we can't do much about the rate at which we accumulate mutations or the rate at which a href="http://www.futurepundit.com/archives/008684.html">we accumulate toxic intracellular junk.
We aren't going to stay helpless against aging tissues. The legions of scientists experimenting with pluripotent stem cells, tissue engineering, gene therapies, and other promising therapies will succeed and they will succeed in the first half of the 21st century. Once we can fix and replace failing parts the mortality tables go out the window as we gain the ability to do what we can now do to old cars: replace parts and keep on going. At some point in the 21st century we will reach actuarial escape velocity where the rate at which we can repair the body exceeds the rate at which pieces of the body wear out and fail. Our rejuvenated bodies will then go on for many more decades and eventually centuries.
In a nutshell: If you are in your 30s or below I think your odds of dying of old age are remote. Whether folks in their 40s, 50s, and beyond will live to benefit from rejuvenation therapies probably depends on how long they will live naturally. Someone who is 50 years old and has 40 years to go even without biomedical advances will certainly live long enough to enjoy the benefits of biotechnologies that will enable them to live well beyond 90 years.
When cells get old some of them die. But unfortunately other cells live on what's called a senescent state in which they produce toxins that harm neighboring cells and the whole body. Got some aches and pains? You can probably at least partially blame them on senescent cells. Mayo Clinic researchers working with genetically engineered mice showed that by killing off senescent cells they delayed the development of age-related diseases such as muscle loss and cataracts. Killing off bad cells enabled the good cells in muscles to function better. I want this treatment in a human-usable form. The sooner the better.
ROCHESTER, Minn. — Researchers at Mayo Clinic have shown that eliminating cells that accumulate with age could prevent or delay the onset of age-related disorders and disabilities. The study, performed in mouse models, provides the first evidence that these "deadbeat" cells could contribute to aging and suggests a way to help people stay healthier as they age. The findings appear in the journal Nature, along with an independent commentary on the discovery.
These mice were genetically engineered to make their senescent cells more vulnerable. For us adults perhaps gene therapy could add the genetic mechanism needed to kill off our old cells. But it will be a big challenge to get genes delivered into all the cells in the body.
It is hard to selectively kill off just certain types of cells as cancer treatment side effects and failures have shown. Though in some ways killing senescent cells is easier than killing cancers. First off, to cure cancer the dead rate of cancer cells has to be near 100%. By contrast, the killing of just half of all senescent cells would cut the toxin load to the body in half and leave room for healthier cells to divide and take the place of sicker cells. Second, since a single course of treatment doesn't have to kill all senescent cells there's a lot more time in which to do successive waves of treatments to kill off the surviving senescent cells.
A co-author of this study talks in terms of potential benefits in terms that begin to approach the radical rhetoric of biogerontologist Aubrey de Grey. Aubrey advocates the outright defeat of aging (reversal of aging with youth lasting thousands of years). One of the major planks in Aubrey's platform for aging defeat is the killing off of senescent cells.
"By attacking these cells and what they produce, one day we may be able to break the link between aging mechanisms and predisposition to diseases like heart disease, stroke, cancers and dementia," says co-author James Kirkland, M.D., Ph.D., head of Mayo's Robert and Arlene Kogod Center on Aging and the Noaber Foundation Professor of Aging Research. "There is potential for a fundamental change in the way we provide treatment for chronic diseases in older people."
Human bodies become more inflamed as they get old in large part due to senescent cells.
Five decades ago, scientists discovered that cells undergo a limited number of divisions before they stop dividing. At that point the cells reach a state of limbo — called cellular senescence — where they neither die nor continue to multiply. They produce factors that damage adjacent cells and cause tissue inflammation. This alternative cell fate is believed to be a mechanism to prevent runaway cell growth and the spread of cancer. The immune system sweeps out these dysfunctional cells on a regular basis, but over time becomes less effective at "keeping house."
Note the point about the immune system becoming less able to sweep away dysfunctional cells. Immune system rejuvenation would reduce the incidence of cancer. If we can kill off both cancer cells and senescent cells we could add decades to our life expectancies.
The scientists genetically engineered the mice to cause their senescent cells to die in the presence of a compound that is non-toxic to normal cells.
Dr. van Deursen and colleagues genetically engineered mice so their senescent cells harbored a molecule called caspase 8 that was only turned on in the presence of a drug that has no effect on normal cells. When the transgenic mice were exposed to this drug, caspase 8 was activated in the senescent cells, drilling holes in the cell membrane to specifically kill the senescent cells.
The great result: killing off senescent cells delayed the onset of age-related diseases.
The researchers found that lifelong elimination of senescent cells delayed the onset of age-related disorders such as cataracts and muscle loss and weakness. Perhaps even more importantly, they showed that removing these cells later in life could slow the progression of already established age-related disorders.
The findings support a role of senescent cells in the aging process and indicate that chemicals secreted by these cells contribute to age-related tissue dysfunction and disease.
This is a very exciting report.
This report reminds me of work done by Thomas Rando and Irina Conboy at Stanford (and Conboy later elsewhere) showing that blood from old mice suppresses cell growth in young mice. This suggests that stem cell therapies would work far better if senescent cells were killed off since they are probably (I am guessing) the source of the growth-suppressing blood chemicals in the old. Other work earlier this year by Tony Wyss-Coray at Stanford found a chemokine secreted by cells was at least partially responsible for suppressing neurogenesis (the creation of new neurons).
Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory.
The ability to kill off senescent cells will probably boost brain function as well as other parts of the body. Gotta love that.
Update: Nicholas Wade looks at the benefits and harm from cells becoming senescent.
And despite being termed senescent, the cells are very active: They convert themselves into factories that churn out 100 different kinds of growth factors, along with cytokines, the inflammatory agents that stimulate the immune system. The evolutionary reason for this activity may be to provoke the immune system to attack patches of premalignant and malignant cells.
It is not certain that wiping out senescent cells will provide an unalloyed blessing. Killing them might up cancer risk. Effective cures for cancer would therefore reduce the risk of treatments that kill senescent cells.
Scientists at the Dana Farber Cancer Institute found that engineering mice to suppress the telomerase enzyme (which makes telomere caps on chromosomes) caused the mice to prematurely age and activating the enzyme in prematurely aged mice caused some of their aging to reverse. But read on for why we can't easily exploit this insight.
Scientists at Dana-Farber Cancer Institute say they have for the first time partially reversed age-related degeneration in mice, resulting in new growth of the brain and testes, improved fertility, and the return of a lost cognitive function.
In a report posted online by the journal Nature in advance of print publication, researchers led by Ronald A. DePinho, MD, said they achieved the milestone in aging science by engineering mice with a controllable telomerase gene. The telomerase enzyme maintains the protective caps called telomeres that shield the ends of chromosomes.
I wasn't going to do a post on this report because it was pretty much along the lines of my expectations. Also, it does not suggest any obvious easy ways to do full body rejuvenation. But since enough people have asked me here's my take:
If we found a way to turn on telomerase to make all our telomeres longer we'd increase the amount of repair done in our bodies. Lengthened telomeres would at least slow and, for a time, partially reverse aging in some parts of the body. That sounds great. But doing this might not cut all cause mortality. Why? Longer telomeres in aged cells will increase our odds of developing and dying from cancer.
The problem is that telomere shortening is an anti-cancer strategy for the body. Using drugs or gene therapy to lengthen telomeres would enable dormant cancer cells or pre-cancerous cells to grow. Whether the net result would be longer or shorter life would depend on each individual. But probably on average the net result would be shorter life because otherwise we'd already have more active telomerase (since longevity-lengthening mutations would be selected for, all else equals). In other words, our telomeres get shorter as we age in order to stop cancer cells. But their shortening also prevents other cellular division which accelerates aging. So telomere shortening with each division of a cell is a trade-off.
In spite of the cancer risk from longer telomeres I would be more excited by a study that found a way to activate telomerase in human cells in the body. Why? Because some people who have degenerative conditions face such high risks of death from organ failure that for most of them telomere lengthening would cut their death risk from organ failure by more than they'd increase their death risk from cancer. Basically, they face a bigger risk of death from unrepaired failing tissue than they do from cancer. So the trade-off for them comes down on the side of greater benefit from lengthening their telomeres.
When telomeres get too short their shortness tells cells to die or at least to stop dividing. But you need a constant supply of dividing cells in your skin and intestinal tract among other places. So widespread telomere shortening in an organism causes shrinking organs and declining function as cells die and are not replaced.
Loss of telomeres sends a cascade of signals that cause cells to stop dividing or self-destruct, stem cells to go into retirement, organs to atrophy, and brain cells to die. Generally, the shortening of telomeres in normal tissues shows a steady decline, except in the case of cancer, where they are maintained.
The experiments used mice that had been engineered to develop severe DNA and tissue damage as a result of abnormal, premature aging. These animals had short, dysfunctional telomeres and suffered a variety of age-related afflictions that progressed in successive generations of mice.
Among the conditions were testes reduced in size and depleted of sperm, atrophied spleens, damage to the intestines, and shrinkage of the brain along with an inability to grow new brain cells.
In order to do full body rejuvenation we need a cure for cancer that has mild side effects. Given a reliable way to wipe out or normalize cancer cells the risks of telomerase activation would go way down.
We could use telomere lengthening for a wider range of people sooner if the telomere lengthening therapy could be delivered more selectively to single organs or cell types. Figuring out ways to do that will take a while. Stem cell therapies where newer undamaged cells with long telomeres are introduced might become workable sooner.
Also check out some of my earlier posts on telomeres and aging: Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, and Sedentary Lifestyles Age Chromosome Telomeres Faster.
Intercytex is pursuing development of a rejuvenation therapy near and dear to the hearts of hundreds of millons of men the world over. Hair follicles can be removed, replicated in culture, and then reimplanted to eliminate baldness.
Intercytex has successfully tested a method of removing hair follicles from the back of the neck, multiplying them and then reimplanting the cells.
The treatment was initially tested on seven men with male pattern baldness, five of whom grew hair, and is now being tested on a further 20.
During a 30-minute operation, hair follicles are taken from the back of the neck, then grown in culture until they number in the thousands.
They are then injected under the skin where the hair needs to grow back.
They expect the therapy to work against male pattern baldness due to dihydrotestosterone and also alopecia in women.
Cambridge, UK, 6th October 2006 – Intercytex (LSE: ICX) and its partner, The Automation Partnership (TAP), announce today that they have been awarded a £1.85 million grant by the UK Department of Trade and Industry (DTI) through the Technology Programme to develop an automated manufacturing process for ICX-TRC, Intercytex’ novel hair regeneration therapy. Intercytex is a leading cell therapy company developing products to restore and regenerate skin and hair and The Automation Partnership is a private company specialising in the automation of life science processes.
The grant will be used primarily to develop a dedicated robotic system to support the commercial-scale production of dermal papilla (DP) cells, the main cells involved in hair regeneration and the key component of ICX-TRC.
The Intercytex approach to hair regeneration centres on extracting an individual’s DP cells from a small hair follicle biopsy at the back of the head, multiplying the cells in a proprietary aseptic culture system and then re-implanting the cells back in the head to induce new hairs. It is vital that each patient’s cells remain isolated throughout the multiplication process.
Since the treatment of hair loss is optional and typically paid for by the individual the cost is an important consideration. So robotic automation to get the cost down makes sense.
I am convinced that rejuvenation therapies that improve outward appearances will hit the market much more rapidly than therapies that make inner organs young again. There are at least four reasons for that. First and most obviously, the skin and hair follicles are easier to reach. Second, people care (however unwisely) more about their outsides than the age of their livers or kidneys. They want to look young and that desire is pretty intense. Third, at least in the United States plastic surgery therapies do not appear to be as tightly regulated as most therapies. Fourth, people spend their own money on plastic surgery and other appearance enhancing therapies. Conservative insurance company rules for which therapies are legitimate do not hold back the introduction of new therapies.
Another area of human enhancement with biotechnology where I expect a lot of early action is with athletic enhancement. But the prospects there are not as good because for many athletes the use of such therapies must be kept secret. Most professional and amateur sports associations do not want athletes enhancing their performance with biotechnological treatments such as gene therapies. Governments tend to side against athletic enhancement too.
The widespead bans on gene therapies and other biotech therapies for athletes is unfortunate for those who want rejuvenation therapies. If gene therapies, cell therapies, and other cutting edge therapies were allowed by sports associations then the incentive to develop them would be much greater and we'd get those therapies sooner. Many of the therapies that would help athletes would also help aging bodies. A treatment that enhances muscle growth? Old folks suffer from atrophying muscles. A therapy that enhances circulation? Old folks suffer from poor circulation too.
A drug made to enhance memory appears to trigger a natural mechanism in the brain that fully reverses age-related memory loss, even after the drug itself has left the body, according to researchers at UC Irvine.
Professors Christine Gall and Gary Lynch, along with Associate Researcher Julie Lauterborn, were among a group of scientists who conducted studies on rats with a class of drugs known as ampakines. Ampakines were developed in the early 1990s by UC researchers, including Lynch, to treat age-related memory impairment and may be useful for treating a number of central nervous system disorders, such as Alzheimer’s disease and schizophrenia. In this study, the researchers showed that ampakine drugs continue to reverse the effects of aging on a brain mechanism thought to underlie learning and memory even after they are no longer in the body. They do so by boosting the production of a naturally occurring protein in the brain necessary for long-term memory formation.
I am surprised this was so easy to do. Some aspects of brain aging will require gene therapy, cell therapy, and other techniques to reverse. But this study's results strongly suggest that conventional drugs will play an important role in preventing and reversing brain aging.
Ampakines boosted a protein involved in memory formation and improved quality of connections between nerve cells.
The researchers treated two groups of middle-aged rats twice a day for four days with either a solution that contained ampakines or one that did not. They then studied the hippocampus region of the rats’ brains, an area critical for memory and learning. They found that in the ampakine-treated rats, there was a significant increase in the production of brain-derived neurotrophic factor (BDNF), a protein known to play a key role in memory formation. They also found an increase in long-term potentiation (LTP), the process by which the connection between the brain cells is enhanced and memory is encoded. This enhancement is responsible for long-term cognitive function, higher learning and the ability to reason. With age, deficits in LTP emerge, and learning and memory loss occurs.
Significantly, restoration of LTP was found in the middle-aged rats’ brains even after the ampakines had been cleared from the animals’ bodies. The drug used in the injections has a half-life of only 15 minutes; the increase in LTP was seen in the rats’ brains more than 18 hours later. According to the researchers, this study suggests that pharmaceutical products based on ampakines can be developed that do not need to be in the system at all times in order to be effective. Most drugs used to deal with central nervous system disorders, such as Parkinson’s disease, are only effective when they are in the body. Further studies will be needed to determine exactly how long the effect on LTP will be maintained after the ampakines leave the system.
The economic impact of drugs that reduce and reverse brain aging will be huge. People in their 50s, 60s, and 70s will be far more economically productive when brain aging can be reduced and even reversed. The question isn't whether this can be done but when it will be done.
The idea that stem cells will be used to rejuvenate aged bodies shows signs of becoming the conventional wisdom among stem cell researchers. Writing in the journal EMRO reports of the European Molecular Biology Organization two recent articles address this prospect. First, researcher Nadia Rosenthal examines "Youthful prospects for human stem-cell therapy" for both disease prevention and life extension.
It is the year 2053. A mere century after James Watson and Francis Crick resolved the structure of DNA, scientists at the forefront of medical research have just announced the first successful regeneration of a human heart. After re-routing the blood of Jón Sigurdsson, a terminal heart-failure patient, to an advanced cardiac assist device and removing most of the damaged organ, doctors thawed a frozen tube of Jón's personalized stem cells—established in 2013 from embryonic stem cells created through somatic nuclear transfer—and injected them into his chest. Thanks to a sophisticated cocktail of growth factors, the new stem cells target the damaged area and rapidly get to work, perfectly rebuilding a youthful heart. Several weeks later, Jón is discharged in excellent health. Regenerative medicine provided him with a new kidney ten years ago, and subsequent double knee regeneration gave him renewed mobility. Now his new heart will soon have him running a six-minute mile again. Jón Sigurdsson is 100 years old.
Rosenthal foresees a future in which stem cell-based therapies rejuvenate aged parts of the body and allow much longer lifespans. Stem cell research seems inevitably to lead to such thoughts. Stem cell researchers want to develop youthful, genetically undamaged, and flexible stem cells. Once they accomplish this for a wide range of stem cell types it is hard to avoid the conclusion that many parts of the body could be repaired by sending in youthful cells to gradually replace the old cells. She even discusses the future use of stem cells to dissolve scar tissue and build new 3 dimensional scaffolding for tissue types which have suffered decay in larger scale structures.
Most of the rest of the article is a tour through recent advances in stem cell research and what they portend
Reproductive cloning is not envisioned in humans, but the lessons learned from cloned animals may be important for therapeutic applications of nuclear transfer. Large deletions involving millions of base pairs have been found in ageing post-mitotic tissues, such as the heart (Vijg, 2004), thus removing large numbers of genes, which leads to cellular degeneration. If such defective nuclei from senescent tissue were used to generate personalized stem cells for therapy, they could cause more harm than good. Moreover, nuclei from patients with inherited diseases, such as haemophilia or muscular dystrophy, may first need to be manipulated to correct the genetic defect before they can be used in clinical settings.
Such a transfer, with subsequent manipulation of genes in human ES cells using human viral vectors and other techniques, could be used on aged nuclei to avoid creating stem cells with dangerous mutations. Any strategy for introducing genetic changes must be applied with care, however, due to the possibility of these genes randomly integrating into the host genome, causing even more serious mutations. To circumvent this danger, techniques for gene-specific modifications that are routinely performed in mouse ES cells have recently been applied to human ES cells, thereby providing the opportunity to correct genetic mutations in stem cells derived from nuclear transfer before administering them to patients.
Adult stem cells are being found an increasing number of locations the human body and in other mammals. At the same time, the tools we have for identifying adult stem cells still leave much to be desired.
In parallel with studies on ES cells, a concerted search for similar adult stem-cell lineages has yielded a flood of recent publications. These challenge the classical concept that stem cells in the adult are present in only a few locations, such as the skin or bone marrow, and are committed to differentiate into the tissue in which they reside. Nevertheless, rigorous criteria are required to distinguish an adult stem cell from partially committed cells with limited potential. True stem cells are self-renewing during the lifetime of an organism and they undergo asymmetric division, so that one daughter cell maintains the stem-cell lineage while the other daughter cell matures into a specialized cell type. The criteria for defining stem cells in the adult are still difficult to satisfy experimentally. There is no predictable location for stem cells in most adult tissues, and we still have only limited tools for identifying them.
For purposes of regeneration we need to know a lot more about adult stem cells. Most obviously adult stem cells are an important source of cells for use in regeneration therapies. However, less obviously, we need to know all the types of adult stem cells and all their locations in the body in order to develop and deliver youthful replacement adult stem cells into all the reservoirs that hold them. Therefore we absolutely need to delineate all the differences between the many different kinds of adult stem cells.
The emotional political debate about the limitations and advantages of embryonic stem cells versus adult stem cells and ethical arguments about embryonic stem cells tend to distract attention from the fact that we need to solve many problems in adult stem cell manipulation. Regardless of how replacement stem cells are made they have to get converted into the various adult stem cell types in order to replace aged stem cells of each type with more youthful cells. Well, how to create adult stem cells of each needed type? How to grow them in sufficient number? How to cheaply and easily test to know that a conversion to a needed cell type succeeded? Then the created cells must get delivered to all the many (and probably mostly still undiscovered) stem cell reservoirs in the adult body. How to get stem cells to go just where we want them to go? Will they have affinity for their natural habitats? Or will they require methods of injection or ways to tag them to give them affinity for the desired target areas? All these problems need solutions.
We need many new technologies to make manipulation of all stem cell types easier. We need automated ways to separate out the many stem cell types from other cell types and to nurture and grow them. We need ways to rejuvenate stem cells. Stem cell research does not exist in a vacuum separate from other avenues of advance in biological sciences and biotechnology. We need advances in DNA sequencing technology to make it cheap and easy to test the DNA of stem cell lines for correctness and completeness. We need gene therapy techniques that can repair and improve the genome of stem cell lines.
Rosenthal's article reviews many recent reports on adult and embryonic stem cell research. In is worth reading in full.
Another article in EMRO reports by Anthony D. Ho, Wolfgang Wagner & Ulrich Mahlknecht of the University of Heidelberg, Germany is entitled "Stem cells and ageing" with the provocative subtitle "The potential of stem cells to overcome age-related deteriorations of the body in regenerative medicine".
Although the vulnerability to infectious disease and cancer is caused by a decline of the immune system, the latter is in turn a product of interactions among haematopoietic stem cells and the microenvironments in the bone marrow and the thymus, as well as in the mucous lining of the bronchus and gut systems. Hence, all ageing phenomena—tissue deterioration, cancer and propensity to infections—can be interpreted as signs of ageing at the level of somatic stem cells. As the regenerative prowess of a living organism is determined by the ability and potential of its stem cells to replace damaged tissue or worn-out cells, a living organism is therefore as old as its stem cells.
These researchers outline a number of technical obstacles which make identification and study of non-embryonic stem cells difficult.
Lab tests which can measure a stem cell line's regenerative potential are needed.
Furthermore, by contrast to ESCs, which can be derived from cell lines established from 4- to 7-day-old embryos, somatic stem cells are elusive. The need for in vitro assays to identify human haematopoietic progenitors increased with the advent of haematopoietic tissue transplantation to treat leukaemia. Any assay to measure stem cells must compare the properties of the cells analysed in vitro with those of repopulating units tested in vivo after a lethal dose of irradiation—an experimental approach that is obviously not possible in humans (Ho & Punzel, 2003).
The problem with stem cells in older bodies does not appear to be so much diminished numbers as diminished abilities in those stem cells which remain.
Various studies have indicated that even though similar HSC concentrations could be found in young and old bone marrow, it is the functional ability per cell in the repopulation model that shows a significant reduction with increasing donor age. HSC senescence is regulated by several genetic elements mapped to specific chromocytes (Chen, 2004). These elements may differ among species, strains and even individuals in the mouse model. In humans, HSC senescence and related pathological effects might not be as obvious as in the mouse model because individual primitive HSC clones can produce progeny that sustain life-long mature blood cell production, which is especially obvious after bone marrow or HSC transplantation.
The older the donor of bone marrow cells for transplantation (e.g. for leukemia) the worst the chances of success.
The success of any bone marrow transplantation correlates with the quantity of HSCs in the graft, which are able to reconstitute the blood and immune system after myeloablation. On the basis of our extensive experience in HSC transplantation since 1984, we have found that age represents the main variable and worst prognostic factor for clinical outcome of transplantation. Recent evidence indicates that there is a decline with age in the quantity and quality of the CD34+ cells harvested. There is also a change in the ratio of fat to cellular bone marrow with age, which has been well known since the turn of the twentieth century. One way to overcome this problem would be to expand the human HSC population ex vivo before transplantation. There have been numerous such attempts, but progenitors with self-renewal capacity are very demanding. Reports of successful expansion of HSCs derived from human marrow in the laboratory have thus far been controversial. By contrast, CD34+ cells derived from umbilical cord blood have been shown to be expandable to a limited extent, which is another indication that the potency of HSCs declines with ontogenic age.
As we age we all would benefit from infusions of youthful stem cells carefully selected to have few DNA mutations. We'd gain stronger immune systems, less risk of anemia, and probably stronger bones as well. More generally, the development of genetically sound and youthful stem cells for all the stem cell reservoirs of the body would partially reverse aging and substantially increase life expectancies.
STANFORD, Calif. - Any older person can attest that aging muscles don't heal like young ones. But it turns out that's not the muscle's fault. A study in the Feb. 17 issue of Nature shows that it's old blood that keeps the muscles down.
The study, led by Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences at the Stanford University School of Medicine, built on previous work showing that old muscles have the capacity to repair themselves but fail to do so. Rando and his group studied specialized cells called satellite cells, the muscle stem cells, that dot muscle tissue. These normally lie dormant but come to the rescue in response to damaged muscle-at least they do in young mice and humans.
In older mice the satellite cells hold the same position, but are deaf to the muscle's cry for help. In the Nature study, Rando and his group first attached old mice to their younger lab-mates in a way that caused the two mice to share a blood supply. They then induced muscle damage only in the older mice. Bathed in the presence of younger blood, the old muscles healed normally. In contrast, when old mice were connected to other old mice they healed slowly.
In similar work, the group examined the livers of older mice connected to younger lab-mates. The cells that help liver tissue regenerate are less active in older animals, but again the cells responded more robustly when the livers in older mice were bathed in the younger blood. Clearly, something in the youthful blood revived the regenerative cells in muscle and liver.
Of course another possibility is that something in the aged blood is suppressing stem cells and repair mechanisms. Does their work rule out that possibility? I don't see that it does. But I haven't read the original paper.
It would be interesting to know how the effect of the young versus old blood scaled as they were blended in different ratios. For example, does one quarter young blood mixed with three quarters old blood have a quarter the effect of pure young blood or more or less than a quarter of the effect?
There is a potential bright side to this report: If blood could be made young again then possibly cells thoroughout the body in many tissue types would act young again.
"We need to consider the possibility that the niche in which stem cells sit is as important in terms of stem cell aging as the cells themselves," said Rando, who is also an investigator at the Veterans Affairs Palo Alto Health Care System. It could be the chemical soup surrounding the cells, not the cells themselves, that's at fault in aging.
One clue to what might be going on also comes from previous work. Rando had found that satellite cells in younger muscles begin producing a protein dubbed Delta in response to muscle damage. Older muscles maintained the same pre-injury levels of Delta even after muscle damage. However, in the current study he found that satellite cells in elderly mice joined to younger partners ramped up Delta production to youthful levels after an injury.
However, there is a less optimistic interpretation to this result: The body may have evolved to produce stem cell growth suppressor compounds as the body ages in order to suppress cell divisions that could produce cancer cells. So blood that causes old stem cells to grow and repair tissue more vigorously might increase the risk of cancer. My guess is young blood would do that to older people.
The young blood effect was confirmed using cells grown in culture.
The group confirmed their results by putting satellite cells from old and young mice in a lab dish with either old or young blood serum. Old satellite cells in old serum and young satellite cells in young serum both behaved as expected. But when old satellite cells were bathed in young serum they cranked up their production of Delta and began dividing. Likewise, young satellite cells decreased the amount of Delta they produced when in a dish with older serum and divided less frequently.
Rando said that it may be a general phenomenon that a person's inability to repair tissues with age-whether it's muscle, liver, skin or brain-is a matter of the regenerative cell's environment rather than the cells themselves.
Rando said that finding the youth-promoting factors in the blood is no small task. "It's as big a fishing expedition as you can possibly imagine," he said. With thousands of proteins, lipids, sugars and other small molecules in the blood serum, deciding where to look first would be tantamount to a roll of the dice. What's more, there's no evidence that the same blood component is responsible for reviving the different types of cells.
"Another approach is to pick factors that are good candidates and see if any of them or some combination recapitulate the effect of the younger blood," Rando said. His group is now looking for likely targets. He said that for some degenerative diseases such as Alzheimer's or muscular dystrophy, such blood-borne factors may be able to reactivate the regenerative cell's ability to repair tissue that has been damaged.
This is an important report. But I repeat my caution above: If the presence or absence of some compound(s) in the blood is reducing the repair ability of a variety of tissue types (and it seems likely other tissue types will also be found to be affected by young versus old blood) then there is a decent chance that this reduction in repair ability was selected for to achieve some benefit, most likely a reduction in cancer risk.
Having stated the caution the ability to turn up repair capabilities could still be therapeutically useful for people who have dire needs for repair of some organ or tissue type. For example, turning up repair temporarily after major surgery or an accident could be worth the increased risk of cancer in some cases.
Suppose that changes in levels (either increases in suppressor molecules or decreases in cell growth stimulating molecules) of one or more compounds in the blood as we age happens in order to reduce the risk of cancer. Well, this is problematic for hopes to derive maximal benefits from replacing aged stem cell reservoirs with youthful stem cells. The old stem cells could be replaced with younger cells. There'd be immediate gains from lowered risk of cancer and relative improvements in the vigor and health of adult stem cells. So that is still worth doing. Yet the young replacement stem cells would still be restrained by levels of compounds in the aged blood. Here's the problem: If some but not all stem cell reservoirs have their stem cells replaced with younger stem cells it might not be safe to change the blood to make it more like young blood. It might be necessary to rejuvenate all stem cell reservoirs before the blood can safely be made more like young blood.
Here is an analogy: Imagine you have a car. It is old and it has 4 bad axles that will fall off if the car is driven too fast as well as a steering column that will fall apart at high speeds. Suppose you know how to replace the 4 axles but not the steering column. Well, if you replace only the 4 axles you still can't safely drive your car at high speeds. But with humans this problem is even tougher because there are many stem cell reservoirs located near every muscle and organ that would need to be rejuvenated before they could all have their level of stimulation by the blood safely raised to youthful levels.
Once really effective anti-cancer treatments (even treatments that kill all precancerous cells) are developed then most (all?) safety worries from making blood young again would go away. Any cancers that popped up in response to having youthful and growth-stimulating blood could quickly be slain or they could be slain even before the blood was rejuvenated. So great cancer-slaying treatments would make rejuvenation treatments easier to implement.
The Methuselah Foundation has awarded its first prize to a scientist for extending life-spans of middle aged mice. (same article here and here)
Dr. Aubrey de Grey, Chairman of The Methuselah Foundation (www.Mprize.org), awarded the first ever Methuselah Mouse Rejuvenation Prize to Dr. Stephen Spindler, who lead the first experiment to achieve rejuvenation in middle-aged mice, making them biologically younger while extending their lifespans.
The award was presented on November 21st during the 2004 Gerontological Society of America Conference in Washington, D.C.
Dr. Spindler's research was astounding because it began with mice that were in middle age. This research, first reported in Proceedings of the National Academy of Science achieved decisive increases of 15% average and maximum lifespan, AND was accompanied by significant early reductions of deaths from cancer. The fact that mice actually became younger was verified by genetic microarray analysis. Video showing that mice were more active and vibrant than their years can be found at http://www.biomarkerinc.com/html/video1-hi.htm
The Methuselah Foundation has attracted a number of notable donors and sponsors.
The Methuselah Foundation is supported by individuals who are no longer willing to stand by and do nothing while the diseases of aging disable and then take their irreplaceable loved ones away. They are taking matters into their own hands and inviting others to join with them to cure and reverse aging. Among the over 100 donors and sponsors, including the X PRIZE Foundation, Foresight Institute, the Life Extension Foundation, Dr. William Haseltine -- Founder of Human Genome Sciences and Dr. Raymond Kurzweil -- noted futurist and entrepreneur.
In addition to extending the lives of middle aged miced another one of Spindler's notable and useful achievements was showing that most of the gene expression changes caused by long term and life extending calorie restriction diets occur in mice which are first put on calorie restriction when they are elderly.
Finally, we investigated the effects of CR in mouse heart. Eight weeks of CR reproduced many of the long-term effects of CR on gene expression and physiology. CR rapidly decreased natriuretic peptide B and collagen I and III expression. CR reduced perivascular collagen accumulation and cardiomyocyte size in the left ventricle. These results suggest that hearts of LT-CR mice are physiologically younger than those of control mice. Switching CR mice to control feeding rapidly returned 91% of the CR responsive genes to control expression levels. Thus, CR rapidly and reversibly induced genomic changes associated with reduced cardiovascular pathology.
Importantly, these results suggest that it should be possible to use rapid treatments with pharmaceuticals and other compounds to identify agents that mimic the rapid changes in gene expression caused by caloric restriction. The gene expression biomarkers of caloric restriction can also be used to develop pharmaceuticals targeted to its genomic effects.
The usefulness of this result is that it can be used to more rapidly scan for drugs that act as calorie restriction (CR) mimetics which are capable of putting an organism's metabolism in the same state that is seen in animals or humans on calorie restricted diets. The calorie restriction extends average life expectancy. But consistently eating a small amount of calories every day is beyond the will power of most people and most people do not want the gaunt appearance seen in many CR practitioners. A drug that could induce the same metabolic state without requiring a constant fight against eating would appeal to a lot of people as a far easier way to extend their lives.
Recently, studies have shown that three dwarf mice mutations are capable of extending life span by approximately 40% through a molecular mechanism that may be different from that found in CR animals. These mutations also delay and ameliorate the effects of age-related diseases. BioMarker scientists--in collaboration with other scientists--are identifying the gene expression biomarkers associated with this model of life span extension.
Dr Stephen R. Spindler, scientific co-founder of BioMarker, studied longevity-related expression in 12,000 genes in mice using cDNA microarray chips. Gene expression data from these experiments indicate that even a brief period of caloric restriction produces about 70% of the changes associated with life span extension. These gene changes are correlated with a number of significant cellular changes including destruction of pre-cancerous cells (apoptosis), protection of cells from toxins and carcinogens, reduction in inflammation and improvements in cardiovascular health.
The bit about CR inducing pre-cancerous cells to die holds out the possibility that one could reduce one's risk of cancer by periodically going to a low calorie diet. Imagine doing a CR diet one month a year. One might kill off some pre-cancerous cells that otherwise would develop into a fatal cancer. It would be interesting to see whether periodic CR could increase average life expectancy of mouse strains by reducing the incidence of cancer. A CR mimetic drug holds out the possibility of doing the same thing.
As the inaugural Rejuvenation Prize, Spindler's award sets the bar for other teams competing to reverse aging in mice, including the six teams already enrolled. To win, these teams must beat Spindler's record using groups of at least 20 mice that show rejuvenation in at least five different markers of aging.
The Methuselah Foundation has announced that their Methuselah Mouse Prize award offered to scientists who break records in lab mouse longevity has reached the half million dollar mark in funding.
Lorton, VA. September 1, 2004. The Methuselah Foundation, creators of the Methuselah Mouse Prize, the world's first scientific prize for research on extending longevity, today announced that it has secured $500,000 in funding commitments and a long term support commitment from an anonymous supporter making his donation in the name of the X PRIZE Foundation, the multi-million-dollar bounty which has successfully encouraged the development of private passenger space travel.
"We've seen how prizes such as the X PRIZE and the Methuselah Mouse Prize can dramatically increase competition and innovation, and create interest for the public," said Dr. Peter H. Diamandis, Founder and Executive Producer of the X PRIZE. "With this contribution, we're signaling our belief that Prizes can not only take us into space, but help bring about breakthroughs in the way we live and age."
"We're thrilled to have the support of the X PRIZE, said David Gobel, Director of the Methuselah Foundation and the Methuselah Mouse Prize. "This landmark contribution will further swell the size of the Prize, and encourage scientific research teams around the world to develop breakthrough techniques for extending the healthy human lifespan. It will create a needed impetus and focus for the development of new rejuvenation therapies."
The Methuselah Mouse Prize is being offered to scientific research teams who develop the longest living Mus musculus, the breed of mouse most commonly used in scientific research. This is a critical precursor to the development of human anti-aging techniques. Currently, six teams around the world are vying for the prize, and this new contribution is expected to swell that number.
"By encouraging the development of technologies that enable sustainable human rejuvenation, the Methuselah Foundation is the first and most developed organization directly promoting the development of human "Projuvenation" technology." Said the Methuselah Foundation's Chief Science Officer - Dr. Aubrey de Grey. "The focus of the Methuselah Foundation is not simply extending human life; it is discovering ways to limit and eventually eliminate the destructive effects of human aging, promoting not only longer life but freedom from the effects of aging-related conditions and diseases."
Your support of the Methuselah Mouse Prize is the best and most effective way that you can help ensure that human biological rejuvenation technologies are developed and widely available as quickly as possible. The future return on your investment is a longer, healthier, and ultimately better quality of life for yourself and your loved ones."
There is an obvious parallel here with the $10 million X Prize for private groups to launch humans into space. The X Prize has been very successful in attracting private groups to make a serious effort to build craft that can fly into orbit. In the latest turn in that fierce competition the Scaled Composites SpaceShipOne may have a leg up over the da Vinci Project due to a parts shortage affecting the latter.
I understand the appeal of building rockets to get into space. It is great to watch the unfolding of the competition to build private space launch vehicles. But priorities seem out of whack when the Ansari X Prize has $10 million now available to the winners whereas the Methuselah Mouse Prize has a mere half million. Look at it this way: Once we can achieve an indefinite state of youth (basically until we die by accident, murder, or suicide) using Strategies for Engineered Negligible Senescence (SENS) we will have centuries to migrate into space.
Of course, what is far more out of whack is that NASA has billions of dollars to spend per year while the Ansari X Prize is achieving far more per dollar spent with their prize offering. Similarly, many individual diseases get funding per year of hundreds of millions or even billions of dollars whereas eternal youth research advances with literally orders of magnitude less money spent on it.
Instapundit megablogger Glenn Reynolds interviews Aubrey de Grey for Tech Central Station on the subject of our future ability to reverse aging.
Q: Some people regard aging research, and efforts to extend lifespan, with suspicion. Why do you think that is? What is your response to those concerns?A: I think it's because people don't think extending healthy lifespan a lot will be possible for centuries. Once they realise that we may be able to reach escape velocity within 20-30 years, all these silly reasons people currently present for why it's not a good idea will evaporate overnight. People don't want to think seriously about it yet, for fear of getting their hopes up and having them dashed, and that's all that's holding us back. Because of this, my universal response to all the arguments against curing is simple: don't tell me it'll cause us problems, tell me that it'll cause us problems so severe that it's preferable to sit back and send 100,000 people to their deaths every single day, forever. If you can't make a case that the problems outweigh 100,000 deaths a day, don't waste my time.
By "escape velocity" Aubrey means the point at which we will be able to repair the damage of aging faster than it accumulates so that the odds of dying decrease rather than increase each year. As it stands now a 50 year old has a higher chance of dying than a 49 year old in the course of a year and a 51 year old has a higher chance of dying in a year's time than a 50 year old. As our bodies get older the odds go up of anything going wrong badly enough to kill us in the space of a year. Aubrey thinks we may reach the "escape velocity" point of aging reversal treatments in the 2020s or 2030s. I share this view and one reason I share it is that the rate of advance of biologicals sciences and biotechnology is accelerating. In fact, the reason I have a category archive entitled Biotech Advance Rates is to demonstrate that we can not use past rates of advance as an indicator of how fast we will advance in the future.
Aubrey recommends reading a fable written by Nick Bostrom, a British Academy Research Fellow at Oxford University, about aging called The Fable of the Dragon-Tyrant which is about to be published in The Journal of Medical Ethics.
Next to speak was the king’s chief advisor for morality, a short and shriveled man with a booming voice that easily filled the auditorium:“Let us grant that this woman is correct about the science and that the project is technologically possible, although I don’t think that has actually been proven. Now she desires that we get rid of the dragon. Presumably, she thinks she’s got the right not to be chewed up by the dragon. How willful and presumptuous. The finitude of human life is a blessing for every individual, whether he knows it or not. Getting rid of the dragon, which might seem like such a convenient thing to do, would undermine our human dignity. The preoccupation with killing the dragon will deflect us from realizing more fully the aspirations to which our lives naturally point, from living well rather than merely staying alive. It is debasing, yes debasing, for a person to want to continue his or her mediocre life for as long as possible without worrying about some of the higher questions about what life is to be used for. But I tell you, the nature of the dragon is to eat humans, and our own species-specified nature is truly and nobly fulfilled only by getting eaten by it...”
This advisor for morality sounds like George W. Bush's advisor Leon Kass.
Here's a point I emphatically agree with: Glenn Reynolds thinks there is nothing beautiful about aging and dying.
I've watched people I love age and die, and it wasn't "beautiful and natural." It sucked. Aging is a disease. Cataracts and liver spots don't bring moral enlightenment or spiritual transcendence. Death may be natural -- but so are smallpox, rape, and athlete's foot. "Natural" isn't the same as "good."As far as I'm concerned, I'd rather see my tax dollars spent on longevity research than, well, most of the other things they're spent on. I wonder how many other people feel that way.
Looking at how things have worked out in American society, I'm not too worried. The tendency in America seems to be toward more turnover, not less, in major institutions, even as lifespans grow. CEOs don't last nearly as long as they did a few decades ago. University presidents (as my own institution can attest) also seem to have much shorter tenures. Second and third careers (often following voluntary or involuntary early retirements) are common now. As a professor, I see an increasing number of older students entering law school for a variety of reasons. And we've seen all of this in spite of the abolition of mandatory retirement ages by statute over a decade ago. It's more dynamism, not less.Of course, that may not be true everywhere. In societies that are already stagnant, like the Egypt of the Pharaohs, or the Central Committee of Leonid Brezhnev's time, death is the main source of dynamism, and the young (and middle-aged) often do wind up in sour apprenticeships waiting for their elders to die. In capitalist democracies, other forces play a far greater role. So it seems to me that we have little to fear from extending human lifespans in our own society. And to the extent that lifespan-extension robs dictatorships of what little dynamism they possess, it probably makes them less dangerous, too.
I certainly agree with him about free societies. Though imagine a Joseph Stalin or a Mao Tse Tung given eternal youth. There are countries that have begun to go down the path away from totalitarianism because their dictator died from old age. Still, we shouldn't all be forced to grow old and die in every country of the world just in order to cause the death of a Stalin or a Pol Pot. The greatest murderers in history have killed only a very fraction of the number of people that aging has killed.
For more on Aubrey and the prospects for reversing aging see my previous posts Aubrey de Grey Decries Entrenched Timidity Of Aging Research Funding, Aubrey De Grey: We Could Triple Mouse Lives In 10 Years, Aubrey de Grey: First Person To Live To 1000 Already Alive, Wanted: Half Billion Dollars To Jumpstart Eternal Youthfulness Research and my entire Aging Reversal category archive.
Update: Writing in PLoS Biology Aubrey de Grey has a review of Coping With Methuselah: The Impact of Molecular Biology on Medicine and Society where he discusses the potential nearness of the point where we will reach 'actuarial escape velocity’ (AEV) and become less likely to die from one year to the next.
Unfortunately, they didn't discuss what would happen if age-specific mortality rates fell by more than 2% per year. An interesting scenario was thus unexplored: that in which mortality rates fall so fast that people's remaining (not merely total) life expectancy increases with time. Is this unimaginably fast? Not at all: it is simply the ratio of the mortality rates at consecutive ages (in the same year) in the age range where most people die, which is only about 10% per year. I term this rate of reduction of age-specific mortality risk ‘actuarial escape velocity’ (AEV), because an individual's remaining life expectancy is affected by aging and by improvements in life-extending therapy in a way qualitatively very similar to how the remaining life expectancy of someone jumping off a cliff is affected by, respectively, gravity and upward jet propulsion (Figure 1).
The escape velocity cusp is closer than you might guess. Since we are already so long lived, even a 30% increase in healthy life span will give the first beneficiaries of rejuvenation therapies another 20 years—an eternity in science—to benefit from second-generation therapies that would give another 30%, and so on ad infinitum. Thus, if first-generation rejuvenation therapies were universally available and this progress in developing rejuvenation therapy could be indefinitely maintained, these advances would put us beyond AEV
Aubrey believes that policymakers may well try to accelerate the development of rejuvenation therapies once they see that such therapies will provide a way to escape from the crushing burden of retirement benefits. I also have argued that rejuvenation therapies would solve demographic problems including the financial burdens of an aging population.
Reason of the Fight Aging! blog has additional commentary on Aubrey's PLoS Biology review. But be sure to read Aubrey's article first. He makes a number of excellent points and I had a hard time choosing what to excerpt.
David Stipp of the business magazine Fortune has an article about biogerontologist Aubrey de Grey and his radical views about the feasibility of halting and reversing aging.
Even if he's right, de Grey is well aware that scientific feasibility doesn't equal political will. In fact, he says his own starting point in gerontology was his recognition in the mid-1990s of an institutional "fatalism logjam." Since there have been few signs of progress in the quest for anti-aging therapies, funding agencies generally dismiss such work as a waste of resources, or worse, as attempts to brew up snake oil. They won't pay for research, so no progress is made—which, in turn, keeps the impression of intractability in place. Thus, serious scientists have long avoided the pursuit of anti-aging therapies for fear of being labeled flaky dreamers or aspiring charlatans. The closest approach to such work is the relatively modest quest for medicines that prolong good health during old age. This entrenched timidity "just makes me spit," says de Grey. Many researchers on aging privately agree, he adds, but can't afford to be as outspoken as he is because it might hurt their chances to get grants. (A problem he doesn't have, thanks to his genetics job.) Breaking the vicious circle, he adds, will require a big, bold stroke.
It is great that a mainstream business magazine is publicizing these ideas. As anyone who has been reading FuturePundit for a while must know by now, I share Aubrey's views about what is possible to achieve in human rejuvenation. Also, he is right to argue that we are not trying anywhere near as hard as we should to develop rejuvenation therapies given the excellent prospects for success within the lifetimes of many people now alive. So big is the potential pay-off that the failure to make the big push for rejuvenation is surely the biggest mistake in science policy now being made by the United States and the other developed countries.
On the bright side, some of the problems being worked on with the goal of treating various diseases are going to contribute toward the set of therapies that Aubrey has outlined as Strategies for Engineered Negligible Senescence. For instance, all the work on stem cells and tissue engineering builds toward the ability to grow replacement organs and to send in stem cells to replace cells lost from the accumulation of damage that comes with aging. Also, the continued development of a large range of technologies that accelerate the rate of advance of biological science and biotechnology are making it easier to develop rejuvenation therapies. So there are rays of hope in spite of the pessimistic and obviously wrong conventional wisdom that still guides biomedical research funding policy in the United States and other developed countries.
Aubrey is arguing for $100 million per year for a 10 year project to triple the life expectancies of bioengineered mice as a way to test out rejuvenation therapies for humans. To put that amount in perspective the US National Institutes for Health (NIH) is currently funded at $28 billion for Fiscal Year 2004. We are failing to spend even chump change amounts to pursue rejuvenation treatments that would obsolesce the need for the development of most disease treatments. Most disease is the result of general aging. Parts wear out and begin to act in ways that cause symptoms of disease. If the parts could be rejuvenated, if they could be replaced, if built up toxins could be removed then the vast bulk of diseases would never develop in the first place.
Update: The Fight Aging blog has a post with additional commentary about the Fortune article and mentions the Methuselah Mouse Prize which Aubrey and Dave Gobel have organized to provide incentives to researchers to develop longer lived mice.
In an interview with the MIT Technology Review biogerontologist Aubrey de Grey states that treatments that would tripe mouse life expectancy could be developed within 10 years.
TR: You believe that tripling the remaining lifespan of two-year old mice is as little as 10 years away.
De Grey: That’s right, with adequate funding. The sort of funding that I tend to talk about is pretty modest, really—less than the amount the United States already spends on the basic biology of aging. I’m talking about a maximum of $100 million per year for 10 years. With that sort of money, my estimate is we would have a 90 percent chance of success in producing such mice.
Aubrey advocates use of an animal model to demonstrate that rejuvenation therapies could be developed for humans and he has founded the Methuselah Mouse Foundation to provide awards to scientists who break new records in mouse longevity.
It is very unfortunate that more money is not flowing into rejuvenatiion therapy development. With a level of funding for rejuvenation therapy develop which is less than 3% of the current yearly NIH budget tens or hunfreds of millions more of us would have a chance to eventually become young again.
Aubrey has given previous interviews about reversing the aging process here and here. My Aging Reversal archive has many other posts about Aubrey's views on why we can reverse aging within the lifetimes of many people who are currently alive and why we ought to try much harder to do the research that will let us reverse aging. Also see Aubrey's website about Strategies for Engineered Negligible Senescence (SENS) and how bodies could be treated so that they do not become older from one year to the next.
Update: A dwarf mouse named Yoda has turned 4 which is equivalent to about 136 human years.
ANN ARBOR, MI -Yoda, the world's oldest mouse, celebrated his fourth birthday on Saturday, April 10, 2004 . A dwarf mouse, Yoda lives in quiet seclusion with his cage mate, Princess Leia, in a pathogen-free rest home for geriatric mice belonging to Richard A. Miller, M.D., Ph.D., a professor of pathology in the Geriatrics Center of the University of Michigan Medical School.
Yoda was born on April 10, 2000 at the U-M Medical School . At 1,462-days-old, Yoda is now the equivalent of about 136 in human-years. The life span of the average laboratory mouse is slightly over two years.
“Yoda is only the second mouse I know to have made it to his fourth birthday without the rigors of a severe calorie-restricted diet,” Miller says. “He's the oldest mouse we've seen in 14 years of research on aged mice at U-M. The previous record-holder in our colony died nine days short of his fourth birthday. 100-year-old people are much more common than four-year-old mice.”
Genetic modifications of his pituitary and thyroid glands along with a reduced production of insulin make Yoda a dwarf who gets cold easily. Most of us have already reached our full sizes and so even when analogous forms of genetic engineering can be done to humans Yoda's modifications are not going to do us any good. However, every type of intervention that extends life provides insights that may lead to interventions that could be done to extend the lives of adult humans.
To put into perspective Yoda's human-equivalent of 136 years of life consider that the record for longest lived human is generally accepted to be French woman Jeanne Calment who lived over 122 years. But attempts to convert mouse years into human years have to be taken with a grain of sand. Genetically Yoda is not a natural mouse and the genetic engineering done to create his strain effectively makes the entire strain have an average life expectancy that is higher than that of regular mice. So why use natural mouse life expectancies to translate Yoda's age into human years?
The most important lesson demonstrated by Yoda's new mouse longevity record is that genetic manipulations can extend life expectancy. It may seem obvious to some readers to expect that, yes, life expectancy ought to be able to be improved by genetic manipulations. Still, scientists who demonstrate that mouse life extension can be done with today's biotechnology add weight to the argument that we can develop techniques to extend the lives of humans currently living rather than in some diistant future.
University of Cambridge biogerontologist Aubrey de Grey says the first person who will live to be 1000 is 45 years old right now.
The first person to hit 150, he believes, is already 50 now. And the first individual to celebrate 1,000 -- imagine the candles on that birthday cake -- is just five years younger, he contends.
Aubrey thinks aging is barbaric. Aubrey is right.
"Aging is fundamentally barbaric, and something should be done about it," said de Grey, who has published research in Science and other peer-reviewed journals. "It shouldn't be allowed in polite society."
Aubrey believes there will be a sea change in public opinion about the reversibility of aging once genetic engineering, stem cell therapies, and several other aging-reversal therapies allow mice to live much longer. Toward this end Aubrey is one of the founders of the Methuselah Mouse Foundation which offers cash prizes to scientists who develop techniques that allow them to set new records for mouse longevity. This work will lead to the development of a combination of treatments which will allow the attainment of engineered negligible senescence where the body effectively ceases to age from one year to the next. The major categories of approaches to reverse aging are called Strategies for Engineered Negligible Senesence or SENS for short.
A form of adult stem cells called endothelial progenitor cells in the blood are inversely correlated with arterial damage that leads to heart disease.
NEW ORLEANS -- Duke University Medical Center researchers have uncovered a strong relationship between the severity of heart disease and the level of endothelial progenitor cells circulating in the bloodstream. This relationship, if confirmed by ongoing studies, could represent an important new diagnostic and therapeutic target for the treatment of coronary artery disease, they said.
These endothelial progenitor cells (EPC) are produced in the bone marrow, and one of their roles is to repair damage to the lining of blood vessels. Duke cardiologists believe that one cause of coronary artery disease is an increasing inability over time of these EPCs to keep up with the damage caused to the arterial lining, or endothelium.
"In our study we found that patients with multi-vessel disease had many fewer EPCs, which supports our hypothesis that these cells play an important role in protecting blood vessels," said cardiologist Geoffrey Kunz, M.D., of the Duke Clinical Research Institute. "If you don't have enough of the cells, the ongoing damage to the endothelium from traditional risk factors occurs faster than the body's ability for repair."
EPC levels are independently correlated with heart disease incidence.
"We found that the patients with multi-vessel disease had significantly lower EPC counts than those without -- 13 CFU vs. 41.7 CFU," Kunz said. "Additionally, for every 10 CFU increase in EPC level, a patient's likelihood for multi-vessel disease declined by 20 percent."
While the EPC levels did not vary significantly by age, gender or other risk factors, the researchers found that the levels were lower for diabetics (19 CFU vs. 36 CFU) and for patients who had suffered a recent heart attack (23 CFU vs. 34 CFU).
"These findings demonstrate a strong inverse relationship between circulating EPCs and coronary artery disease, independent of traditional disease risk factors," Kunz said.
The researchers said that it might ultimately be possible to forestall or even prevent development of atherosclerosis by injecting these cells into patients or by retraining the patient's own stem cells to differentiate into progenitor cells capable of arterial repair.
While the direct clinical use of stem cells as a treatment might be many years off, the researchers said it is likely that strategies currently used to reduce the risks for heart disease -- such as lifestyle modifications and/or different medications -- preserve these rejuvenating cells for a longer period of time, which delays the onset of atherosclerosis.
This latest result in humans illustrates yet again how important it is to develop stem cell therapies to replace aged adult stem cell reservoirs with rejuvenated stem cells. Duke researchers have already successfully shown that replacement bone marrow stem cell therapies reduce the development of atherosclerosis in mice. See my previous post Bone Marrow Stem Cell Aging Key In Atherosclerosis. Also, this latest result is not the first indication that the aging of stem cells in humans is a heart disease risk. See my previous post Aged Blood Stem Cells Indicator For Cardiovascular Disease Risk. These results demonstrate that we do not need to develop a greater understanding of aging in order to start developing rejuvenation therapies. The major challenge now is to develop effective treatments that will repair and replace aged tissue. Research aimed at developing useful stem cell therapies is a key piece of the rejuvenation puzzle.
In a far-ranging interview with the Better Humans web site biogerontologist Aubrey de Grey outlines the reasons why so few scientists are currently working on rejuvenation therapies even though biological science and biotechnology have advanced far enough for such work to begin in earnest.
The fatalism problem can be dissected into three separate problems that form a sort of triangular logjam, each perpetuating the next. The public thinks nothing can be done. So, the state only funds very unambitious work -- very reasonably they feel that to fund stuff that their constituency thinks is a pipedream would jeopardize re-election. (Parallel logic holds for shareholders and directors in industry.)
So, scientists -- also very reasonably -- don't even submit grants to do ambitious stuff, even if they want to (of which more in a moment), because it's a waste of time -- the grant will be turned down. So, when scientists go on the television to talk about their work, they talk about the cautious stuff that they're actually doing, not about the ambitious stuff that they're not doing, and indeed this encourages them to the mindset that they don't really want to do the ambitious stuff anyway.
So, the public -- again very reasonably -- continues to view curing aging as very, very far away, because the scientists with the best information are telling them that (not in as many words, but by what they're not saying). So each of these three communities is behaving very reasonably in its own terms, but the result is stasis.
Aubrey lays out his 7 major categories of therapies that will, once they become available, make it possible for humans to have youthful bodies for decades longer than is now possible. He believes there are concrete steps that could be taken now in mice models to test out versions of those therapies and that the results could be available from mouse studies within 10 years if $100 million per year was spent to develop all these major categories of therapeutic approaches. Therapies for humans that would add years and perhaps even decades to life could be available by the 2020s if a big push was started now. Then more therapies introduced in the later 2020s and 2030s could so extend life that anyone still alive at that point who doesn't die from an accident will effectively be able to become young again.
There are enough multimillionaire and billionaire philanthropists that all the work could be done with private money if only enough wealthy people became interested. If you know any wealthy people then do us all a favor and send them Aubrey's interview and some of the articles from his web site.
Speaking of Aubrey's web site, if you haven't already been there be sure to visit Aubrey's home page for Strategies for Engineered Negligible Senescence (SENS) and read some of his articles about how to stop and reverse aging.
Satellite cells are a type of adult stem cells that can become myocytes, adipocytes or osteocytes. By becoming myocytes satellite cells help to repair injured muscle. Satellite cells do not divide as rapidly in older animals and as a result muscles do not heal as rapidly as humans and animals age. Some Stanford University School of Medicine researchers have discovered that a compound that mimicks the effect of a satellite cell regulatory protein can cause satellite cells to repair older muscles more rapidly.
In previous work, Rando found that satellite cells spring into action when a protein on the cell surface called Notch becomes activated, much like flicking the cell’s molecular “on” switch. What flips the switch is another protein called Delta, which is made on nearby cells in injured muscle. This same combination of Delta and Notch also plays a role in guiding cells through embryonic development.
Having found this pathway, Rando and Conboy wondered whether slow healing in older muscles resulted from problems with signaling between Delta and Notch – failing either to make enough Delta or to respond to the Delta signal.
In their initial experiments, Rando and Conboy found that young, middle-aged and older mice all had the same number of satellite cells in their muscles and that these cells contained equivalent amounts of Notch.
“It doesn’t seem as if there’s anything wrong with the satellite cells or Notch in aged muscle,” Rando said. That left Delta as the suspect molecule.
To test whether older muscles produce normal amounts of Delta, the researchers looked at the amount of protein made by mice of different ages. Young and adult mice, equivalent to about 20- and 45-year-old humans, both had a large increase in Delta after an injury. Muscles in older mice, equivalent to a 70-year-old human, made much less Delta after an injury, giving a smaller cry for help to the satellite cells. In response, fewer satellite cells were activated to repair the muscle damage.
A further set of experiments showed that slow repair in older muscles can be overcome. When the team applied a molecule to young muscles that blocked Delta, those satellite cells failed to divide in response to damage. Conversely, when they applied a Delta-mimicking molecule to injured, older muscles, satellite cells began dividing much like the those in younger muscle. The older muscles with artificially activated satellite cells had a regenerative ability comparable to that of younger muscle.
Although the studies focused on muscle regeneration after injury, Rando said similar problems with the interplay between Delta and Notch may cause the gradual muscle atrophy that occurs in older people, in astronauts or in people whose limbs are immobilized in a cast or from bed rest.
There might be cancer risks from taking a Delta-mimicking drug as a long-term treatment to avoid the muscle atrophy that comes with age. It is likely that the satellite cells really are aging and the down-regulation of Delta might be an evolutionary adaptation to reduce the risk that mutated and damaged pre-cancerous satellite cells might be stimulated to divide and become cancerous. This result does not eliminate the need to develop cell therapies to replace satellite cells with more youthful replacements.
The other reason that lower Delta activity with age might have been selected for as an evolutionary adaptation is again age related: this might have been done to conserve the cells by reducing the number of times they divide. The satellite cells probably can divide only a limited number of times. By reducing the production of Delta with age the satellite cells might be conserved for higher priority uses. Upregulating Delta or delivering a Delta agonist might simply wear out the satellite cells too rapidly providing a short-term benefit but a longer term greater harm.
What is needed is a process that can easily isolate aged adult stem cells from one's own body and basically refurbish and rejuvenate them. It is not too hard to see the broad outlines of what such a rejuvenation process might look like. One step has got to be a way to sort through different stem cells isolated from the body to choose ones that have little damage to their chromosomes and, in particular, little or no damage to genes that regulate cell growth. An accumulation of mutations to genes that regulate cell growth is what produces cancers. Rejuvenation of stem cells that are close to becoming cancerous would pose a substantial health risk. Gene therapy applied to carefully selected adult stem cells would elongate their telomeres and perhaps do other rejuvenating repairs. Then the rejuvenated cells would be grown up in large numbers and reinjected back into various appropriate locations of the body that they were originally isolated from.
The New York Times has an article by James Gorman about University of Cambridge biogerontologist Aubrey de Grey's appearance at the Pop!Tech conference.
Getting old and dying are engineering problems. Aging can be reversed and death defeated. People already alive will live a thousand years or longer.
He was at pains to argue that what he calls "negligible senescence," and what the average person would call living forever, is inevitable. His proposed war on aging, he said, is intended to make it happen sooner and make it happen right.
Aubrey says he only needs a half billion dollars to start the coming explosion in anti-aging research.
Mr. de Grey has no illusions about the challenge he faces. He wants to establish an institute to direct research, he said, adding that he probably needs $500 million to achieve the goal of using mouse research to kick-start a global research explosion on human aging. That includes the prize fund.
If anyone is in the Washington DC area be aware that on November 5, 2003 Aubrey de Grey will be debating the prospects for rolling back aging at an AAAS meeting.
WASHINGTON, DC, Nov. 1, 2003 (PRIMEZONE) -- The Methuselah Foundation is proud to announce a landmark debate between two pioneering scientists on not just how, but when, science will reverse the aging process -- hosted by the AAAS and funded by the Alliance for Aging Research.
In a November 5th debate at the American Association for Advancement of Science, 1200 New York Ave, 11 AM, Dr. Aubrey de Grey, University of Cambridge, will discuss the very real possibility of a modern day medical fountain-of-youth with Dr. Richard Sprott, Executive Director of the Ellison Medical Foundation. Dr. de Grey is a Pioneering Biogerentologist, the Senior Science Advisor to the Methuselah foundation, and serves on the Board of Directors of the International Association of Biomedical Gerontology and the American Aging Association.
These two leading biogerontologists will debate the implications of recent advances in aging and anti-aging research, and set forth a timeline for reversal of aging and its associated diseases. Morton Kondracke, Executive Editor of Roll Call and author of Saving Milly, a personal chronicle of his wife's battle with Parkinson's disease, will moderate.
Some people claim that we can't extend human life by hundreds or thousands of years because biological systems are too complicated or the problems are too complicated. The term "complicated" in this context means several separate things and it is worth it to try to break them apart. Here is my first stab attempt to describe what might be meant by the term "too complicated" when used by anti-aging therapy pessimists:
Aubrey argues that we don't really need to understand everything that goes wrong in aging. We just need to be able to fix it. He is quite right to argue that we should be approaching the problem of human aging with a mentality more like that of an engineer or an auto mechanic. We can develop techniques to fix things without understanding every last detail. Therefore the "too complicated to understand" argument is even less of an objection.
Still, even if we just want to fix things there is value in developing greater understanding in particular areas. The ability to measure what goes on in cells as they differentiate is very important for developing the ability to fix and replace old parts because we need a way to measure the results of our attempts to turn cells into other cell types. But advances in measuring epigenetic information and gene expression promise to make the study of cellular differentiation progressively easier to do. If we can measure something then we can test out ways to manipulate it. Instrumentation advances are very important for the advance of biological science and biotechnology. Fortunately, the steady advances in semiconductors and nanotechnology assure that the instrumentation advances will continue to come at a fairly rapid pace.
Update: It is also possible to watch the debate remotely as a webcast.
October 15, 2003 -- (BRONX, NY) -- Researchers at the Albert Einstein College of Medicine of Yeshiva University and colleagues have discovered that a gene mutation helps people live exceptionally long lives and apparently can be passed from one generation to the next. The scientists, led by Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein, report their findings in the October 15, 2003 issue of the Journal of the American Medical Association (JAMA).
The mutation alters the Cholestryl Ester Transfer Protein (CETP), an enzyme involved in regulating lipoproteins and their particle size. Compared with a control group representative of the general population, centenarians were three times as likely to have the mutation (24.8 percent of centenarians had it vs. 8.6 percent of controls) and the centenarians' offspring were twice as likely to have it.
CETP affects the size of "good" HDL and "bad" LDL cholesterol, which are packaged into lipoprotein particles. The researchers found that the centenarians had significantly larger HDL and LDL lipoprotein particles than individuals in the control group. The same finding held true for offspring of the centenarians but not for control-group members of comparable ages.
Evidence increasingly indicates that people with small LDL lipoprotein particles are at increased risk for developing cardiovascular disease, the leading cause of death in the United States and the Western world. Dr. Barzilai and his colleagues believe that large LDL particles may be less apt than small LDL particles to penetrate artery walls and promote the development of atherosclerosis, a major contributor to heart disease and stroke. Their study found that HDL and LDL particles were significantly larger in those offspring and control-group members who were free of heart disease, hypertension and the metabolic syndrome (a pre-diabetic condition that increases risk for cardiovascular disease).
The research team studied people of Ashkenazic (Eastern European) Jewish descent because of the group's genetic homogeneity -- it had a small number of "founders" and was socially isolated for hundreds of years. Studying a group of genetically similar people speeds the identification of significant genetic differences and limits the amount of genetic "noise" that can result when examining more heterogeneous groups. (The research team also included scientists from the University of Maryland School of Medicine; Tufts University; Boston University School of Medicine; and Roche Molecular Systems Inc.)
To identify the biological and genetic underpinnings of exceptional longevity, the researchers studied 213 individuals between the ages of 95 and 107, along with 216 of their children. For comparison, they looked at 258 spouses of the offspring and their neighbors.
"These results are significant because they mean that the mutation of the CETP gene is clearly associated with longevity," says Dr. Barzilai. "Furthermore, finding this mutation in both the centenarians and their offspring suggests that the mutation may be inherited."
Keep in mind that slightly over half of the long-lived did not have this cholesterol size boosting genetic variation. Likely there are a number of genetic variations in a variety of genes that affect longevity.
"Large particle size seems to give people an extra 20 years of life, with very little disability to go along with it," said Dr. Nir Barzilai, who directed the study at the Albert Einstein College of Medicine in the Bronx.
Another 20 years would be great. During those 20 additional years more medical advances will happen that will increase your odds of living even longer. How could this be done? CETP is made in the liver and released into the blood. Possibly a drug could be developed to either mirror the effects of CETP in the blood or interact with it to change its shape or to increase its synthesis and release from the liver. But another strong possibility would be the development of a gene therapy to do to liver cells to provide one's body with the variation of Cholestryl Ester Transfer Protein that increases cholesterol particle size. One thing you can do now: exercise.
One caveat: A person who has large cholesterol particles from birth is going to age more slowly from the very start. A person first getting a treatment to increase cholesterol particle size at age 50 will already have 50 years of aging at a faster rate due to smaller cholesterol particles. So the benefit will not be as great for anyone who gets some future cholesterol particle boosting treatment later in life.
When people who have been sedentary start performing regular exercise, their L.D.L. particles grow bigger, as shown by Dr. William E. Kraus, a cardiologist at the Duke University Medical Center, and his colleagues a year ago in a study of people 40 to 65.
Though Barzilai doesn't endorse smoking, he noted that the cholesterol mutation exerted such a powerful protective effect that many of his volunteers never developed lung disease despite decades of puffing cigarettes and cigars.
Among his volunteers was a 95-year-old woman who had smoked since she was 8 and who - not coincidentally- has a 100-year-old sister and a brother who's 97.
Expect more reports of this sort where life-extending genetic variations are identified. Each one will become a target of either drug development, gene therapy development, or both.
Dr. Linda Patridge and colleagues of University College London have discovered that the effects of calorie restriction for life extension on fruit flies is remarkably short-lasting.
In a detailed demographic analysis of life and death among 7,492 fruit flies, published today in Science magazine, Dr. Partridge and her colleagues discovered that the protective effect of dieting snaps into place within 48 hours, whether the diet starts early in life or late. Flies that dieted for the first time in middle age were the same as flies that had been dieting their whole lives. But the effect can be lost just as quickly. Flies that dieted their entire lives and then switched, as adults, to eating their fill were the same two days later as flies that had never dieted.
It has been thought that Calorie Restriction must work to increase life expectancy by slowing the gradual accumulation of damage. Therefore the length of time on the Calorie Restriction diet was expected to determine its total life-extending effects. At least in fruit flies there do not appear to be extended benefits once the fruit flies are taken off the diet. This is surprising.
"If this works in humans, then it means that from the time a person starts on a restricted diet, they'll be like individuals of the same age who were always on that diet. Their prospects of survival are the same."
A few of our more radical experts believe that, in the next 50 years, 90-year-olds could look like 30-year-olds and feel as fit as a 45-year-old thanks to an explosion in regenerative medicine, genetic research and biotechnology.
And today's children could live to 120 - or longer. The Centre for Strategic and International Studies in Washington predicts that a female born today will have a 40 per cent chance of surviving until she is 150 years old.
I don't see how someone can do a calculation to come up with a percent odds. What is more likely the case is that at some point we will reach the ability to keep people perpetually young and then life expectancy predictions will be based chiefly on non-aging related causes of death. The mystery is just when will we reach the point where we can reverse aging?
Nicholas D. Kristof of the New York Times quotes a much more radical prediction by biogerontologist Aubrey de Grey.
"Our life expectancy will be in the region of 5,000 years' in rich countries in the year 2100, predicts Aubrey de Grey, a scholar at Cambridge University. (This is, of course, a great prediction to make, because none of us will be around in 2100 to mock him if he's wrong.)
Kristof is wrong on his last point. The year 2100 is only 97 years away as of this writing. Barring the end of human civilization (which is a distinct possibility) even without advances in medicine there are already many people alive now who will be alive then. Even under the most conservative estimates of the rate of biomedical research advance it seems likely that average life expectancy will increase by decades in this century. So tens or hundreds of millions of people alive right now should live to the year 2100.
Aubrey expects that within 100 years we will have total mastery of technology for growing replacement organs, making youthful replacements of adult stem cell reservoirs in the body, the ability to eliminate accumulated of intracellular aggregate junk, and still other parts of the rejuvenation puzzle.
In an interview with The Speculist after listing what he considers to be the 7 most promising approaches for rejuvenation Aubrey says that those 7 rejuvenation approaches could all be tried in mice within a decade's time.
What do you consider a realistic timeframe for putting treatments in place that address all seven?
That's hard to say, because some of them need really good gene therapy, which is still rather black magic. I won't stop there, though, because I feel that biogerontologists have a duty to give their best guess at timescales. What I can say is that we should be able to implement all seven in mice within a decade. This is because gene therapy in mice is a lot easier, for the simple reason that we don't have to worry about safety. And the thing is that as soon as we do implement them in mice, and presuming that they give the sort of life-extension benefits I predict, the general public will realize that aging is not inevitable after all, and will push incredibly hard for more work on human gene therapy etc. to get the therapies working in humans as fast as possible.
This is key. Aubrey's attitude is that we don't have to wait for every single molecular mechanism of aging to be elucidated in excruciating detail before we start trying to role back the clock. If we take more of an angineering approach and just start trying to replace or repair what most likely needs to be replaced or repaired we can get useful anti-aging therapies much sooner.
Aubrey thinks that on the outside we will achieve engineered negligible senescence within 60 years.
Assuming you live to be 100, what will be the biggest difference be between the world you were born into and the world you leave?
Um, do you mean if I die aged 100? I fully intend not to leave the world at such a paltry age. But even if I died aged 100, that's still 60 years away — far too long to be able to make such predictions. Hmm, well, in 60 years we'll definitely have aging under complete control — I guess it would be difficult to imagine a bigger difference than that.
Aubrey has a lot more on his website about strategies of engineered negligible senescence.
Leonid A. Gavrilov of the University of Chicago Center on Aging has kindly sent me notice of a paper he has just published with Natalia S. Gavrilova on the importance of redundancy loss in redundant systems as a cause of aging.
Reliability Theory Explains Human Aging And Longevity
Our bodies backup systems don't prevent aging, they make it more certain. This is one offshoot of a new "reliability theory of aging and longevity" by two researchers at the Center on Aging, NORC at the University of Chicago.
The authors presented their new theory at the National Institutes of Health (NIH) conference "The Dynamic and Energetic Bases of Health and Aging" (held in Bethesda, NIH). Their theory of aging is published this month by the "Science" magazine department on aging research, Science's SAGE KE ("Science of Aging Knowledge Environment").
The authors say, "Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components."
"Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are REDUNDANT in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy."
In their paper, "The quest for a general theory of aging and longevity" (Science's SAGE KE [Science of Aging Knowledge Environment] for 16 July 2003; Vol. 2003, No.28, 1-10. http://sageke.sciencemag.org ), Leonid Gavrilov and Natalia Gavrilova offer an explanation why people (and other biological species as well) deteriorate and die more often with age.
Interestingly, the relative differences in mortality rates across nations and gender decrease with age: Although people living in the U.S. have longer life spans on average than people living in countries with poor health and high mortality, those who achieve the oldest-old age in those countries die at rates roughly similar to the oldest-old in the U.S.
The authors explain that humans are built from the ground up, starting off with a few cells that differentiate and multiply to form the systems that keep us operating. But even at birth, the cells that make up our systems are full of faults that would kill primitive organisms lacking the redundancies that we have built in.
"It's as if we were born with our bodies already full of garbage," said Gavrilov. "Then, during our life span, we are assaulted by random destructive hits that accumulate further damage. Thus we age."
"At some point, one of those hits causes a critical system without a back-up redundancy to fail, and we die."
As the authors puts it, "Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as inevitable consequences of REDUNDANCY EXHAUSTION at extreme old ages."
All those who have achieved the oldest-old age have very few redundancies remaining, therefore they can't accumulate many more defects: They simply die when the next random shock hits a critical system. Hence, the mortality rates tend to level off at extreme old ages, and people all over the world die at relatively similar rates on average. The initial differences in body reserves (redundancy) eventually disappear.
In the authors' words, "The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age, and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels."
This fundamental theory of aging and longevity is grounded in a predictive mathematical model that accounts for questions raised by previous models addressing the mechanisms of aging, mortality, survival and longevity.
The authors are research associates at the Center for Aging at the University of Chicago's National Opinion Research Center. Their research was sponsored by the National Institute on Aging.
Let's think about this intuitively. We have many subsystems which are each critical to our survival. Also, there is a lot more redundancy in them than it first appears. We know we have 2 lungs and 2 kidneys and can survive with only one of them. But there are many redundancies at lower levels. For instance, we also have many little air sacs in each lung and can survive if only some of them get damaged. Also, there any many nerves innervating the heart telling it to beat and if a small fraction of them die off for most people the surviving nerves can still send enough messages to keep the heart beating well. Or how about the skin? Many cells are dying all the time and we can even experience a burst of cell deaths due to a sunburn and still survive. The same redundancy at the cellular level happens in many parts of the body. Half the cells in the liver can die off for some reason and yet the liver can usually function well enough in the short term with the rest of the cells to have time to grow back the lost cells.
An example of loss of redundancy playing a role in the development of diseases of old age was the report post here recently Bone Marrow Stem Cell Aging Key In Atherosclerosis. Once the pool of replacement cells for artery repair becomes depleted we become far more susceptible to atherosclerosis. It is possible that at the start of life that people differ with regard to the total number of replacement cells that their pool of bone marrow stem cells are capable of supplying.
The Pub Med abstract and the full text of the paper (in PDF format) are available online. Also see the web site of the authors for a lot more information about their work on theoretical models of aging.
University of Cambridge biogerontologist Aubrey de Grey was kind enough to respond to my request for some comments on the signficance of this work:
This work is certainly good work in its own terms, i.e. the mathematics is novel and rigorous. Whether it implies/motivates (or the opposite) any particular approach to life extension is a bit less clear, because the discovery of a mathematical model that fits observed data doesn't tell us anything in the Popperian sense, i.e. it doesn't falsify any hypothesis. This turns out to be true for essentially all analyses of actual and hypothetical survival patterns: even with very big datasets it turns out to be rather easy to fit the observed data to within statistical non-significance with more or less any theory. Occasionally people fool themselves into thinking they have falsified one or other of the major mortality models (eg Michael Rose's paper in April's Exp Gerontol), but it tends to take about a day before the flaw in their logic is exposed (in that case by me, correspondence out any day now in August's Exp Gerontol).
However, this really means a great deal more in terms of competition between hypotheses than you might think, because of what happens if you think of the issue the other way around. What work like this can show very robustly is that hypotheses which we might have thought WERE obviously falsified by known data are in fact not falsified at all. In the case of this work, what they show is that we may in fact be shot through with "defects" - things that make us live less long than if we didn't have them - even by birth. It is very counterintuitive that this should be consistent with observed mortality patterns, i.e. almost no mortality until say 2/3 of the life expectancy and then a sharp acceleration -- certainly I would think that that implies very nearly no defects at birth. If we THEN ask what the practical upshot may be, we can come up with quite interesting answers. First off, this is extremely relevant to the rather neglected area of epigenetic influences on aging that are laid down prenatally, of which the only well-known one is the relationship between birth weight and lifespan (and the total absence of such a relationship in the case of twins -- a real first-class mystery, that one) but of which there are lots of examples surveyed in Finch and Kirkwood's "Chance, Development and Aging" of a few years ago. So it certainly highlights the importance of prenatal care and the potential relevance of identifying aspects of damage that are already present at birth.
Think about that. There are certainly people walking around (in some cases not even able to walk) with obvious diagnosed birth defects. However, if this model is correct we might all be born shot through with "defects".
One cause of the differences in life expectancy between people may be random differences in the distribution of defects. Imagine two organs A and B which are each critical to survival (could be the heart and the liver for instance). If on average we are each born with 5 defects per organ just due to random events that happen during embryonic development then some may be born with only 2 defects per organ while others may be born with 8 defects per organ. Also, one person might be born with 10 total defects with 5 in each organ while another person might be born with 2 defects in A and 8 defects in B. If each organ tends to accumulate defects at the same rate and each fails with the same total number of defects then we'd be better off born with 5 in each organ rather than 2 in one organ and 8 in another since the failure of just one critical component is enough to cause death.
Random processes are just one source of defects. Genetic inheritance, maternal diet, maternal stress, maternal exposure to toxins, and other factors contribute to how well or poorly a fetus develops.
It would be valuable to have ways to measure the amount of redundancy still existing in each person from birth on throughout life. If one had some way of knowing which of one's subsystems were most lacking in redundancy one could pursue strategies designed to minimize stresses and damage to those subsystems.
The basics of what we have to do to reverse aging remain the same. We need to be able to supply rejuvenated replacement stem cells and grow replacement organs. We need to be able to do gene therapy to deliver various forms of revitalizing genes such as replacements for damaged mitochondrial genes and also genes that code for enzymes that can break down accumulated intracellular junk. See Aubrey de Grey's longer list of potential rejuvenation therapies. See my Aging Reversal archive for more on promising approaches for reversing aging.
Age-Related Stem Cell Loss Prevents Artery Repair And Leads To Atherosclerosis
DURHAM, N.C. – Aging has long been recognized as the worst risk factor for chronic ailments like atherosclerosis, which clogs arteries and leads to heart attacks and stroke. Yet, the mechanism by which aging promotes the clogging of arteries has remained an enigma.
Scientists at Duke University Medical Center have discovered that a major problem with aging is an unexpected failure of the bone marrow to produce progenitor cells that are needed to repair and rejuvenate arteries exposed to such environmental risks as smoking or caloric abuse.
The researchers demonstrated that an age-related loss of particular stem cells that continually repair blood vessel damage is critical to determining the onset and progression of atherosclerosis, which causes arteries to clog and become less elastic. When atherosclerosis affects arteries supplying the heart with oxygen and nutrients, it causes coronary artery disease and puts patients at a much higher risk for a heart attack.
The researchers' novel view of atherosclerosis, based on experiments in mice, constitutes a potential new avenue in the treatment of one of the leading causes of death and illness in the U.S., they said. Just as importantly, they continued, this loss of rejuvenating cells could be implicated in a broad range of age-related disorders, ranging from rheumatoid arthritis to chronic liver disease.
The results of the Duke research were posted early (July 14, 2003) on the website of the journal Circulation, (http://circ.ahajournals.org). The study will appear in the July 29, 2003, issue of the journal.
At issue is the role of stem cells, which are immature cells produced in the bone marrow that have the potential to mature into a variety of different cells. The Duke team examined specific stem cells known as "bone-marrow-derived vascular progenitor cells" (VPCs).
What we need is a way to take cells from our bodies and manipulate them into becoming youthful VPC stem cells. This will likely become a key treatment for reversing the process of aging.
The researchers believe that it might ultimately be possible to forestall or even prevent the development of atherosclerosis by injecting these cells into patients, or to induce the patient's own stem cells to differentiate into progenitor cells capable of arterial repair.
"Our studies indicate that the inability of bone marrow to produce progenitor cells which repair and rejuvenate the lining of the arteries drives the process of atherosclerosis and the formation of plaques in the arteries," said Duke cardiologist Pascal Goldschmidt, M.D., chairman of the Department of Medicine. "For a long time we've known that aging is an important risk factor for coronary artery disease, and we've also known that this disease can be triggered by smoking, bad diet, diabetes, high blood pressure and other factors.
"But if you compare someone who is over 60 with someone who is 20 with the same risk factors, there is obviously something else going on as well," he continued. "The possibility that stem cells may be involved is a completely new piece of the puzzle that had not been anticipated or appreciated before. These findings could be the clue to help us explain why atherosclerosis complications like heart attacks and strokes are almost exclusively diseases of older people."
Doris Taylor, Ph.D. a senior member of the research team, sees these findings leading researchers into new areas of investigation.
"For the first time we are beginning to an insight into how aging and heart disease fit together -- we've know they go hand-in-hand – but we haven't understood why," she said. "Understanding that we either run out of progenitor cells or that they don't work as well is a big molecular clue to what might be going on in the whole aging process.
"We are excited that as we unravel the mechanisms of this process, we will be able to look deeper into heart and vascular disease, as well as other disease," she added. "These studies form the basis of future collaborations."
In their experiments, the Duke team used mice specially bred to develop severe atherosclerosis and high cholesterol levels. The researchers injected bone marrow cells from normal mice into these atherosclerosis-prone mice numerous times over a 14-week period. As a control, an equal of number of the same kind of atherosclerosis-prone mice went untreated.
After 14 weeks, the mice treated with the bone marrow cells had significantly fewer lesions in the aorta, despite no differences in cholesterol levels. Specifically, the researchers detected a 40-60 percent decrease in the number of lesions in the aorta, the main artery carrying blood from the heart.
Using specific staining techniques on the aortas, the researchers were able to determine that the donor bone marrow cells "homed in" on areas where atherosclerotic lesions are most common, especially where smaller vessel branches take off from larger vessels. These areas tend to experience "turbulence" of blood.
When the researchers examined the vessels under a microscope, it appeared that the bone marrow cells not only migrated to where they were needed most, but that they differentiated into the proper cell types. Some turned into endothelial cells lining the arteries, while others turned into the smooth muscle cells beneath the endothelium that help strengthen the arteries.
To further prove that the donor bone marrow cells were responsible for rejuvenating arteries, the scientists measured in the endothelial cells the lengths of structures known as telomeres at the end of chromosomes. They found that the telomeres in the endothelial cells were longer in the treated mice than the untreated mice. Over time, telomeres are known to shorten as the organism ages.
Note that researchers at Stanford have developed a technique for lengthening telomeres. However, in order to rejuvenate aged cells it is likely that additional modifications besides telomere lengthening will be needed. It would be desireable to have ways to select out cells that have less accumulated mutational damage to DNA so that the risks of cancer development in rejuvenated cells would be lowered. Cells that are restored to a state that allows them to divide more rapidly would be a cancer risk if they contained mutations to regulatory genes that control cell division.
The researchers also injected these atherosclerotic mice with donor cells from older mice as well as from younger, pre-atherosclerotic mice."We found that the bone marrow cells from the young mice had a nearly intact ability to prevent atherosclerosis, while the cells from the older mice did not," Goldschmidt explained. "This finding suggests that with aging, cells capable of preventing atherosclerosis that are normally present in the bone marrow became deficient in the older mice that had developed atherosclerosis."
Note that many of the risk factors of heart disease may exert their influence by causing a continual stream of injuries to arteries that essentially cause VPCs in the bone marrow to divide so many times that they get worn out. Every time a cell divides its telomeres get shorter. One effect of shortened telomeres is that they are an obstacle to normal cell division. So a diet and health habits that reduce the demand for VPCs may allow them to function for more years repairing arteries.
Once the repair cells from the marrow become deficient, inflammation develops and leads to increase in inflammation markers (such as CRP). By providing competent bone marrow cells, the investigators were able to suppress the inflammation and its blood markers.
While the direct use of stem cells as a treatment may be many years off, the researchers said it is likely that strategies currently used to reduce the risks for heart disease – such as lifestyle modifications and/or different medications – preserve the collection of these rejuvenating stem cells for a longer period of time, which delays the onset of atherosclerosis.
For Goldschmidt, a major question is whether researchers can somehow use these cells to restore the integrity of the circulatory system of patients who already have a lifetime of atheroslerosis.
"We need to look at the possibility of re-training stem cells that would otherwise be targeted to a different organ system to help repair the cardiovascular system," he said. "Another interesting question is whether rheumatoid arthritis, as an example of chronic inflammatory disorders, causes stem cell loss, since such arthritis is a risk factor for coronary artery disease. The chronic process of joint disease could consume stem cells that could otherwise be used for the repair of the cardiovascular system. We are just beginning to appreciate the links between stem cells and cardiovascular disease."
The research was supported by the National Heart Lung Blood Institute and the Stanley Sarnoff Endowment for Cardiovascular Science.
Other members of the Duke team include: Frederick Rauscher, M.D., Bryce Davis, Tao Wang, M.D., Ph.D., Priya Ramaswami, Anne Pippen, David Gregg, M.D., Brian Annex, M.D., and Chunming Dong, M.D.
This study demonstrates the importance of developing the ability to replenish stem cell reservoirs as a rejuvenation therapy. Progress on methods for how to take cells from the body and turn them into youthful VPCs is essential for extending life and avoiding heart disease and stroke.
This latest result is not that big of a surprise. See my previous post Aged Blood Stem Cells Indicator For Cardiovascular Disease Risk to see how this latest result is consistent with earlier research.
A mutation in the gene daf-2 in the worm Caenorhabditis elegans (generallly referred to as C. elegans) doubles life expectancy by turning on a large number of other genes which serve a variety of functions.
Tracing all the genetic changes that flow from a single mutation, UCSF scientists have identified the kinds of genes and systems in the body that ultimately allow a doubling of life span in the roundworm, C. elegans. Humans share many of these genes, and the researchers think the new findings offer clues to increasing human youthfulness and longevity as well.
Using DNA microarray technology, the researchers found that the single life-extending mutation -- a change in the gene known as daf-2 -- exerts its influence through antimicrobial and metabolic genes, through genes controlling the cellular stress response, and by dampening the activity of specific life-shortening genes.
"This study tells us that there are many genes that affect life span, each on its own having only a small effect," said Cynthia Kenyon, PhD, UCSF professor of biochemistry and senior author on a paper in Nature reporting the research.. "The beauty of the daf-2 gene is that it can bring all of these genes together into a common regulatory circuit. This allows it to produce these enormous effects on lifespan." Kenyon is also director of the Hillblom Center for the Biology of Aging at UCSF's Mission Bay campus.
Lead author on the paper is Coleen Murphy, PhD, a postdoctoral scientist in Kenyon's lab.
By partially disabling one gene at a time, either in daf-2 mutants or in wild-type worms, through a technique known as RNA interference, the scientists were able to discover that no single gene by itself determines lifespan. Of the key genes, each can increase life span by 10 to 30 percent, the research shows. But when daf-2 engages the whole army of genes, they can produce huge changes in lifespan.
Because any individual gene appears to have a relatively small effect on life span, identifying the key players would have been difficult in a standard genetic screen, the scientists say, underscoring the power of DNA microarray analysis for teasing apart complex systems.
Kenyon's team discovered ten years ago that a single mutation in the daf-2 gene, which encodes a hormone receptor similar to the human receptors for the hormones insulin and IGF-1, doubled the worms' life span. The same or related hormone pathways have since been shown to affect life span in fruit flies and mice, and therefore are likely to control life span in humans as well. Her lab found that daf-2 affects lifespan through a second gene, known as daf-16, whose function was known to control the expression of other genes.
But the finding left unanswered just how longevity is achieved. What are the genes that daf-16 regulates? The new research shows that several key systems are involved. Many of the genes that affect lifespan code for antioxidant proteins, the researchers found; others code for proteins called chaperones that help repair or degrade damaged proteins. This is especially interesting, Kenyon says, because many diseases of aging involve oxidative damage or protein aggregation.
Other longevity genes found active in the long-lived mutants make proteins that help ward off bacterial infections, the researchers found. Kenyon's lab showed earlier that infections are the likely cause of death for the worm; recent research from others has shown that the long-lived animals are known to be resistant to bacterial infection. The current study shows that without these genes activated, the long-lived worms die sooner. In humans, too, infections pose a serious health problem for the aged.
"Maybe one day we will be able to tweak the insulin/IGF-1 systems in humans to produce many of the same benefits that we see in the worm," Kenyon says.
The scientists also found longevity genes affecting lipid transport and energy metabolism, as well as a host with unknown functions.
"The diversity of these life span gene functions is just remarkable" said Kenyon.
The long-lived worms, as well as mice with similar changes in the same genes, also are disease resistant, and the study suggests possible mechanisms for this finding. The antimicrobial response could protect against infections, and the antioxidant response can protect against diseases that involve oxidative damage. Many researchers suspect stroke and a number of neurological diseases in humans are hastened by oxidative damage.
Earlier this year, Kenyon's lab showed in C. elegans that the damage-repairing chaperone proteins not only increase lifespan, but also delay the onset of protein-aggregation diseases similar to Huntington's disease.
"The marvelous thing about this new study is that it provides an explanation not only for the remarkable longevity of these animals, but also for their ability to stay healthy so long," Kenyon says.
"They just turn up the expression of many, many different genes, each of which helps out in its own way. The consequences are stunning, and if we can figure out a way to copy these effects in humans, we might all be able to live very healthy long lives," she adds.
Co-authors on the Nature paper are Cornelia Bargmann, PhD, professor of anatomy and Howard Hughes Medical Institute investigator at UCSF; Steven McCaroll, a graduate student; Hao Li, PhD, UCSF assistant professor of biochemistry; and Andrew Fraser and Ravi Kamath at the Welcome CRC Institute and Department of Genetics, University of Cambridge.
You might be thinking, if a single mutation in a single gene can increase life expectancy why doesn't this mutation exist naturally? The most likely explanation is that the mutation in daf-2 somehow decreases reproductive fitness. In other words, it exerts some effect that decreases the number of viable offspring that a C. elegans organism will produce in at least some environments.
One reason why upregulation of repair and other systems might be selected against is that there are energy costs and other costs to making and operating enzymes. Just increasing the amount of a particular type enzyme in a cell has the effect of taking up room that would otherwise be used for other enzymes that serve other purposes. A cell that has more repair enzymes floating around in it can do a better job of repairing itself but at the cost of not being able to do some other functions as well.
An organism has to first survive in the short term in order to even be around to grow old in the long term. If a mutation helps short term early life survival enough to allow the organism to reproduce where it otherwise wouldn't have lived long enough to reproduce then that mutation will tend to be selected for. We can see in a large number of design trade-offs in cells that natural selection has acted to put limits to how much of a cell's metabolism is dedicated to dealing with longer term threats.
Research into genetic variations that influence life expectancy is certainly valuable because it produces a better understanding of the aging process and may point the way toward therapies that will slow or, in some cases, even reverse some changes that cause aging. Drugs will eventually be developed that will intervene in gene expression regulatory mechanism to turn up expression of genes for repair, antioxidant, immune, and other systems related to longevity. But keep in mind that there are limits to how much can be accomplished by turning up existing biological subsystems that extend because all of these systems have the effect of only slowing the process of aging. They do not reverse the process of aging.
The really radical anti-aging therapies of the future will use Strategies for Engineered Negligible Senescence (SENS) to rejuvenate cells and whole organisms by repairing and replacing cells and organs that existing human genes do not know how to repair or replace.
OTTAWA, ON (June 26, 2003) - A research team from the Ottawa Health Research Institute (OHRI), led by Dr. Michael Rudnicki, has published a groundbreaking study that demonstrates how a novel population of adult stem cells resident in muscle tissue plays an important role in muscle regeneration.
For the first time, the research also identifies details of the molecular signals that direct these adult stem cells to form new muscle, offering hope for millions of people with neuromuscular disorders.
The Rudnicki team's findings are published in the June 27 issue of the prestigious scientific journal Cell.
This landmark research shows that a class of adult muscle stem cells, called CD45+ cells, play a natural role in regeneration when they receive signals in the form of a secreted protein known as Wnt. Wnt proteins are secreted in response to tissue damage and act to trigger the stem cells to divide and then develop into highly specialized muscle cells.
"Why is this important?" asks Dr. Rudnicki, who is a Professor of Medicine at the University of Ottawa. "A central question in the application of stem cells to repair damage has been 'what are the switches that trigger the stem cells to make new tissue of a specific type?' Now that this question has been answered for muscle tissue, we can exploit this knowledge to potentially benefit people with neuromuscular diseases such as muscular dystrophy or diseases that involve muscle wasting such as multiple sclerosis, ALS, and cancer." However, he cautions, clinical applications are still some time away.
A focus of future research will be to develop drugs that target the Wnt signaling pathway as new treatments for neuromuscular diseases and muscle injury.
The ability to instruct stem cells to become muscle cells also has future application in therapies to reverse the effects of aging. Aging humans lose muscle cells from the heart and from muscles throughout the body. While the ability to do this is still some years away the ability to send in cells to serve as replacements will be a valuable rejuvenation therapy.
The fact that muscle cells die will eventually even be exploitable to enhance human muscles. Any form of genetic engineering that has the effect of increasing efficiency or capacity of muscles will be deliverable by adding genetic modifications to stem cells. The fact that older muscle cells have died basically will provide an opening to bring in new cells which will have enhanced functionality.
A study in rats matching the activity of 146 genes with brain aging and impaired learning and memory produces a new picture of brain aging and cognitive impairment. The research, by scientists at the University of Kentucky, uses powerful new gene microarray technology in a novel way to match gene activity with actual behavioral and cognitive performance over time, resulting in the identification of this wide range of aging- and cognition-related genes (ACRGs). Importantly, the changes in gene activity had mostly begun in the mid-life of the rats, suggesting that changes in gene activity in the brain in early adulthood might set off cellular or biological changes that could affect how the brain works later in life.
The report (embargoed for release until May 7, 2003, at 5 p.m. ET) appears in the May 2003 issue of The Journal of Neuroscience. It provides more information on genes already linked to aging, including some involved in inflammation and oxidative stress, and also describes additional areas in which gene activity might play a role in brain aging. These include declines in energy metabolism in cells and changes in the activity of neurons (nerve cells) in the brain and their ability to make new connections with each other. In addition, other areas in which genes appear to play an influential role involve increases in cellular calcium levels which could trigger cell death, cholesterol synthesis (also implicated in Alzheimer's disease in other research), iron metabolism and the breakdown of the insulating myelin sheaths that when intact facilitate efficient communication among neurons.
Note that this study does not explain why energy metabolism declines. Is the decline caused by damage to the genes that code for proteins involved in energy metabolism? Does junk accumulate in the cells and crowd out the space which would otherwise be used for energy metabolism? Does the circulatory system decline in its ability to deliver the nutrients needed to feed the machinery of energy metabolism in the mitochondria. Or it could be that the energy metabolism be getting down-regulated because there is too much oxidative stress on the aged cells for other reasons (e.g. accumulated junk in the cells could be reacting with compounds in the cell to create free radicals). There might be a regulatory mechanism in cells to down-regulate energy metabolism when there is a lot of oxidative stress so that the cell no longer has to handle the additional free radical stress caused by high levels of energy metabolism. There are a lot of other possibilities. Some of those possibilities are a lot more likely than others and there are obvious experiments that could be tried to test them.
One obvious avenue of investigation would be experiments to try to introduce replacement genes for the mitochondrial genes involved in energy metabolism. If the replacement genes helped then one explanation for declining energy production might be accumulated damage to mitochondrial DNA.
The study was conducted by a team led by Philip W. Landfield, Ph.D., and colleagues Eric M. Blalock, Kuey-Chu Chen, Keith Sharrow, Thomas C. Foster, and Nada M. Porter at the University of Kentucky, Lexington, and James P. Herman at the University of Cincinnati, Ohio. It was supported primarily by the National Institute on Aging (NIA). Additional support was provided by the National Institute of Mental Health (NIMH). Both are parts of the National Institutes of Health at the U.S. Department of Health and Human Services.
"Gene microarrays, which can measure activity of thousands of genes simultaneously, provide the most advanced genomics technology. This has allowed us to do what no other study has done before – use large numbers of microarrays to relate genes and behavior over the lifespan of the animals on a scale that can identify most of the important players," says Landfield. "The good news is that we have a new, more comprehensive model of brain aging at the genetic level; the downside is that this model shows just how very complex that process may be." "This study makes it very clear that it is not a single gene or even several genes that are responsible for brain aging. Here, we are presented a picture of age-related changes in multiple cellular pathways and systems which interact with one another to change the brain's structure and how it functions," notes Brad Wise, Ph.D., Program Director, Fundamental Neuroscience, NIA.
This fellow's phrasing is unfortunate and can leave readers with a misimpression of the meaning of these results. Just because the expression of a large number of genes changes as we age does not mean that all those genes are contributing to the process of aging. The expression of many of those genes may be changing in order to compensate for changes that aging is causing. The changing of the gene expression might simply be symptoms rather than causes of aging. This is why gene microarray studies to study changes in gene expression by themselves provide only a very incomplete picture of what causes aging.
The microarrays do not provide an indication of what is causing each gene to be turned on or off in the cells in the sample. The biggest missing element in this kind of study is a way to measure what molecules are turning each gene on and off and, in turn, what molecules are regulating those molecules. Gene arrays do not show the chains of cause-and-effect that are responsible for the levels of gene expression that they measure.
In the study, young, middle-aged, and aged rats were trained on two memory tasks, learning to navigate a water maze and remembering familiar objects in their cages. After training, the scientists examined the brain tissue of the rats, specifically the hippocampus, an area associated with memory and cognition. RNA (ribonucleic acid, which carries out the DNA's instructions for making proteins) was isolated from each rat and selectively bound to a separate chip containing over 8,700 fragments of genes to generate gene expression, or activity, profiles. One important step was further refining of the analyses to reduce false positives and false negatives while statistically assessing changes in gene activity. The researchers then homed in on genes that changed with aging and, finally, on genes involved in age-related changes in the performance of the rats on the two memory tests. Ultimately, they zeroed in on 146 ACRGs (aging- and cognition-related genes), which were then assigned to functional categories representing different cellular processes in the brain. A complete listing of the genes and what they do appears in the original journal article.
Offering one model of brain aging, the researchers suggest that loss of neuronal processes and the compromise of their insulating myelin sheaths may trigger brain inflammation, eventually leading to loss of the cells' function. The changes in gene expression for the most part were seen in mid-life, before cognition was impaired, suggesting that changes in gene activity in the brain in early adulthood might initiate cellular or biological changes that could lead to functional changes later in life.
An increase in the expression of genes that are involved in inflammation responses is characteristic of other aged cell types that have been studied with gene microarrays. I think these guys are just guessing that the inflammation might be causing the loss of myelin sheath. My guess is that the inflammation is causing a number of other problems in neurons as well.
The NIA leads the Federal effort to support and conduct basic, clinical, and social and behavioral studies on aging and on age-related memory change and dementia. It supports the Alzheimer's Disease Education and Referral (ADEAR) Center, which provides information on research on age-related memory change and Alzheimer's disease. ADEAR's website can be viewed at www.alzheimers.org. ADEAR may also be contacted at 1-800-438-4380. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information website www.nia.nih.gov.
What we need are experiments that try a variety of interventions to find ways for aged cells to be repaired. As mentioned above, genes could be introduced to try to replace mitochondrial genes that are more susceptible to damage. Also, genes that code for “xenohydrolases” could be introduced in animal models to see if clearing out the accumulated junk in neurons would allow them to function more like younger cells. A number of other approaches are possible. What we need, as Aubrey de Grey explains, is a shift toward more of an engineering mindset to develop tools and techniques that can undo the damage caused by aging (PDF file).
If you want to get up to speed on the most radical thinking on how to stop and reverse human aging then take the time to read all of Aubrey de Grey's publications on Strategies for Engineered Negligible Senescence.
The tangled up pieces of protein fragments (known as neurofibrillary tangles) seen in Alzheimer's Disease patients also occur to a lesser extent in aging brains in people who do not develop Alzheimer's.
The researchers found tangles in all of the brains. However, the number of tangles was higher in those with mild cognitive impairment.
The researchers also found a direct link between the number of tangles and scores from memory tests carried out on the eight people before they died.
You might see this as bad news. Our brains are accumulating protein tangles that are causing cognitive decline as we age. Well, the cognitive decline is already happening regardless of its cause. But if you look at this latest research in the right light it is good news. Why? A lot of money and effort are going into discovering the causes of Alzheimer's and how to treat it. These latest results suggest that those future treatments developed for Alzheimer's which work by ridding the brain of neurofibrillary tangles will probably be of benefit to us all regardless of whether we are going to develop Alzheimer's.
Neurofibrillary tangles are far from the only harmful compounds that accumulate in the body as we age. One key class of therapies designed to repair and reverse the effects of aging throughout the body will be the development of techniques for the removal of assorted classes of junk that accumulate within cells. One place in cells where junk or waste accumulates as cells age are the lysosomes. Lysosomes are intracellular organelles that specialize in breaking down cellular waste. But some forms of waste (notably lipofuscin - which is actually an assortment of different kinds of compounds) can not be broken down by lysosomal enzymes and hence these forms of waste accumulate. Lipofuscin and other accumulating forms of waste are suspected of contributing to the formation of a number of degenerative diseases of old age.
University of Cambridge biogeronotologist Aubrey de Grey has proposed the development of cellular rejuvenation therapies using gene therapy to transfer bacterial or fungal enzymes into cells to break down lipofuscin and other accumulated cellular waste products. (PDF file)
Here I consider the feasibility of a hitherto unexplored approach to this problem: augmentation of the lysosomal catabolic machinery with “xenohydrolases”, enzymes identified in other organisms that can degrade material that our existing apparatus cannot. Such enzymes should only need to break down a small minority of the molecular structures present in these aggregates to have a substantial effect because by doing so they will create and/or expose previously inaccessible substrates for enzymes we already have. Lysosomal function seems to be impaired by such aggregates , but not abolished, indicating that new hydrolases are continually (albeit ineffectively) targeted to aggregate-laden lysosomes.
The neurofibrillary tangles which are linked to cognitive impairment may also be accumulating in lysosomes. Therefore therapies aimed at introducing “xenohydrolases” (xeno in this context referring to enzymes whose genes are transferred from other species) may also be able to be adapted to work against neurofibrillary tangles.
The development of gene therapies that give cells the ability to synthesize enzymes that can "throw out the trash" promises to extend longevity, make cells throughout the body to perform in more youthful ways, and to contribute to the eventual ability to reverse aging and make aging humans young again. Gene therapies to break down toxic accumulated waste in cells will play an essential part in efforts to achieve Engineered Negligible Senescence. If you want to read more about Engineered Negligible Senescence and the coming ability to make aged humans young again then check out the FuturePundit Aging Reversal archive. Also, see the Strategies for Engineered Negligible Senescence (SENS) web site.
Biogerontologist Aubrey de Grey argues that if people had longer life expectancies they'd be far more supportive of measures that would improve the environment of the planet Earth 100 years and longer from now. After all, if people are going to be around to deal with the long term consequences of what happens now they are going to be far more likely to care about the environmental consequences of what happens.
Writing in the Usenet group sci.life-extension Aubrey sees life extension as beneficial to the environment.
If you *expect* to live another century or two, you probably *will* act (at least somewhat) to make sure this planet does too.
If you want to make sure this planet lives another century or two, your best bet is probably to make people alive today do so too.
I try to make a habit of pointing this out to environmentalists, and especially to environmentalists who focus on overpopulation as a reason to eschew life extension. My mileage varies...
Aubrey also thinks that the public would be far more supportive of the development of life extending therapies if scientists were more willing to discuss just how soon they believe significant life extension therapies could be developed.
I'm saying that even though a healthy proportion of educated/thinking people think as you (and me) about the long-term future of the planet, the same cannot be said for the public at large. Really this is no more than a generalisation of the reason there is such widespread apathy about life extension research: scientists' perpetual refusal to discuss timescales just reinforces the view that no serious breakthrough is likely within the lifetime of anyone presently alive, and with that mindset it is no surprise that the public don't agitate for such research to be expedited.
I am firmly in Aubrey's camp in terms of believing that dramatic extensions of human life are achievable in a time frame that would benefit most of those living today in industrialized countries. The only reason most of us may not end up living long enough to benefit from these therapies is that scientists are not currently asking for the money to make a serious push to develop them.
While many fear that extended life will simply mean extended old age the most promising ways for extended life involve a return of an organism's body to a much more youthful state using "Strategies for Engineered Negligible Senescence" (SENS).
On August 12th 2001, a small roundtable meeting was held at UCLA, Los Angeles, to discuss a wide range of issues surrounding the possibility that, within a few decades, biotechnology might be developed that would enable us to reverse all the key lifespan-limiting components of human aging. The meeting was a sequel to one held in Oakland in October 2000 entitled "Strategies for Engineered Negligible Senescence" (SENS), so the UCLA meeting was entitled "SENS 2". Full funding was generously provided by the Maximum Life Foundation (see http://www.maxlife.org/).
The October meeting, SENS 1, gave rise to a highly controversial and provocative article, "Time to Talk SENS: Critiquing the Immutability of Human Aging", which is to be published in the Annals of the New York Academy of Sciences as part of the Proceedings of the 9th Congress of the International Association of Biomedical Gerontology . (More details of that meeting, including a transcript, are online at http://research.mednet.ucla.edu/pmts/sens/index.htm .) The central conclusion of that article was that there is a substantial possibility that, within about ten years, we could take a mouse aged about two years (i.e., with a remaining life expectancy of six months or so) and restore it to sufficiently youthful physiology that it would live a year longer than otherwise.
Part of the problem is that many of the scientists who have skills needed to develop the Methuselah Mouse (mice would effectively serve as testbeds to try out prospective therapies) have a bigger focus on figuring out how things work. What is needed is more of an engineering mindset. With an engineering mindset the focus would not be to wait until every mechanism of aging is figured out in detail. Engineers ask if they have the tools needed to do a job and if they do they start working on a solution. Well, we have the tools needed to start now to develop therapies to reverse aging. What we need is the proper mindset and for money to be allocated to the attempt.
In spite of the lack of an ambitious engineering effort to reverse aging some pieces of the puzzle are being worked on. All the work to develop stem cell therapies is applicable. The same is true for tissue engineering efforts and attempts to grow replacement organs. But there are many other pieces that are not getting a lot of effort devoted to them. For instance, a lot of work needs to be done to develop the means to clear the junk out of cells - particularly post-mitotic cells - that accumulates as cells age. But the effort in this area is still pretty minimal. Also, work should be done to create a mouse that has all its mitochondrial DNA moved to the nucleus. Such a mouse line could be used to check whether putting mitochondrial DNA in a safer location will prevent or delay either a decline in energy output or conversion of some cells into major sources of free radicals or both.
The public needs to begin demanding major research efforts to develop therapies to reverse aging. Absent those demands the development of anti-aging and rejuvenation therapies will take many years longer than is necessary.
A new study provides evidence that a form of a common vitamin plays a key role in regulating the response of cells to calorie restriction. Calorie restriction is the only reliable way to extend maximal lifespace of a large range of species and a great deal of work is going in to trying to figure out how calorie restriction does that.
Keep in mind while reading this article that nicotinamide is another name for niacinamide and nicotinic acid is another name for niacin. Niacin is the form of vitamin B3 that causes the flushing effect of hot red skin because it causes the release of histamine from mast cells into the bloodstream. Niacin also has a cholesterol lowering effect. Niacinamide is the form of vitamin B3 that people take if they want to avoid the flushing effect but niacinamide does not lower cholesterol.
Also, the NAD mentioned in the article is an acronym for Nicotinamide Adenine Dinucleotide. NAD (sometimes called NADH) is involved in mitochondrial metabolism for breaking down sugars and serves as an energy-carrying molecule. There has been a lot of speculation that calorie restriction may lengthen lifespan in part by causing changes in the regulation of mitochondrial operation that reduce the amount of free radical species generated and therefore reduces the rate of accumulation of damage that leads to old age. However, there has also been speculation that calorie restriction turns on repair systems. In the latter hypothesis calorie restriction makes cells respond as if they are under environmental stress and to take better care of themselves perhaps at the expense of performing at a lower level.
One of the take-home lessons from this article is that large doses of niacinamide taken regularly might either reduce lifespan in general or at least it might block the lfespan-extending effects of calorie restriction.
BOSTON, MA-- Researchers at Harvard Medical School (HMS) have discovered that a gene in yeast is a key regulator of lifespan. The gene, PNC1, is the first that has been shown to respond specifically to environmental factors known to affect lifespan in many organisms. A team led by David Sinclair, assistant professor of pathology at HMS, found that PNC1 is required for the lifespan extension that yeast experience under calorie restriction. A yeast strain with five copies of PNC1 lives 70 percent longer than the wild type strain, the longest lifespan extension yet reported in that organism. Their findings are reported in the May 8 Nature.
The PNC1 protein regulates nicotinamide, a form of vitamin B3. Sinclair's group previously found that nicotinamide acts as an inhibitor of Sir2, the founding member of a family of proteins that control cell survival and lifespan. Sir2 extends lifespan in yeast by keeping ribosomal DNA stable. PNC1 converts nicotinamide into nicotinic acid, a molecule that does not affect lifespan. In doing so, it keeps nicotinamide from inhibiting Sir2, allowing the yeast to live longer.
The finding implies that lifespan is not simply dependent on accumulated wear and tear or metabolism, as some researchers have suggested, but is at least partly controlled by an active genetic program in cells--one that could theoretically be boosted. "In contrast to the current model, we show that the lifespan extension from calorie restriction is the result of an active cellular defense involving the upregulation of a specific gene," Sinclair said.
For decades researchers have known that severe calorie restriction extends the lives of many organisms like yeast, fruit flies, worms, and rats, and it also slows the aging process and prevents cancer in rats. But why less food seems to help organisms live longer has been puzzling. While Sir2 is a necessary part of the equation, calorie restriction does not affect Sir2 levels, indicating that Sir2 must be regulated by another protein that does respond to calorie restriction.
Some researchers have speculated that NAD, a cofactor of Sir2 and a common metabolite in the cell, acts as a regulatory mechanism. Because NAD levels vary with rates of metabolism in yeast, this model suggests that calorie restriction might lengthen lifespan by lowering metabolism. However, Sinclair's group showed that the effect of PNC1 was independent of NAD availability. They believe that the real regulator of Sir2 is nicotinamide, which is one of the products of the reaction between Sir2 and NAD.
PNC1 levels are highly sensitive to environmental cues like calorie restriction, low salt, and heat that are known to make yeast live longer. Sinclair's team believes that the PNC1/nicotinamide pathway provides a genetic link between the environment of an organism and its lifespan, allowing an organism to actively change its survival strategies according to the level of environmental stress it senses.
In humans, the picture is undoubtedly more complicated; for one, humans have seven Sir genes, not just Sir2. The nicotinamide pathway is also different in humans, but Sinclair's group has shown that nicotinamide inhibits human SIRT1, a homologue of Sir2. His group is now investigating human genes that may play the same role as PNC1.
One of the immediate implications of the work is that it emphasizes the functional difference between nicotinamide and nicotinic acid. Nicotinic acid (niacin) is a known anticholesterol treatment, while nicotinamide (or niacinimide) is sometimes touted for anti-aging abilities and is in clinical trials as a therapy for diabetes and cancer. However, the two substances are sometimes sold interchangeably as supplements under the name vitamin B3. "Our study raises the concern of taking high doses of nicotinamide," Sinclair said, because nicotinamide puts a damper on Sir2's actions in the cell.
An obvious follow-up to this study would be to try giving large doses of nicotinamide to mice on calorie restriction to see if the nicotinamide prevents the metabolic changes that calorie restriction causes. In particular, it would be interesting to look at gene expression changes as measured by gene arrays. Stephen Spindler and his group have already argued for using gene arrays to test for calorie mimetic drugs But they'd also work for testing compounds that blocked the beneficial effects of calorie restriction.
Some Congresscritters in the US House of Representatives are trying to be clever.
A bill pending in the House of Representatives would allow businesses with union workers to reduce their company pension obligations by billions of dollars, because statistics show that most blue-collar workers do not live as long as other Americans.
US corporations spent the better part of the 1990s raising their estimates for long term expected rates of return on their pension fund investments. When they got up to 9 and 10 percent as long term expected rates of return they entered the lunacy zone. Many have lowered their estimates somewhat but are still excessively optimistic. Markets do not grow in earnings over the long term faster than the economy grows as a whole. In fact, John Maudlin argues that public stock returns actually underperform the overall economy by about 1 percent. The US economy is not going to grow at 6 or 7 percent over the long term let alone 9 or 10 percent. Therefore actuarial assumptions about future earnings for many corporate pension funds are already unrealistic. We don't need the US Congress stepping in to provide companies another way to make their pension fund actuarial assumptions even worse.
One critic of this proposal quoted by The New York Times says that the bill does not require companies with lots of white collar workers to raise their assumptions of retiree life expectancy to adjust for the fact that white collar workers live longer. Therefore the net effect of this bill for corporations would be to lower the average assumed life expectancy they use for workers overall. If the bill really has that effect it is foolish.
There is an even more serious problem with the actuarial assumptions made by pension funds about life expectancy: the rate of advance of biomedical science is accelerating. As a consequence of the acceleration of the advance of biological science and technology the gradual rise in life expectancy which has characterized the last century will not be repeated in the 21st century. In the next few decades big killer diseases such as cancer which for decades medical science has made only slow progress against will be defeated entirely. Also, and more importantly, cell and gene therapies will be developed which have rejuvenating effects and successful techniques for growing replacements for most types of organs will be developed as well.
Simply put, the historical model of slow steady rise in life expectancy is going to be shattered by the development of revolutionary biotechnologies which will cause large rapid increases in human life expectancy. Linear actuarial extrapolations of past trends will not provide a useful guide to future trends in human life expectancy. Biogerontologists, equipped with the increasingly powerful tools of molecular biology such as DNA sequencing machines, microfluidics chips, gene array chips, and other tools and techniques will increasingly turn toward the pursuit of Strategies for Engineered Negligible Senescence to end human aging entirely. The tools at the disposal of biological engineers are already powerful enough to start working in earnest toward such an ambitious goal. Using the current armament of laboratory tools and techniques biologists now have the ability to start to develop and test some of the major types of rejuvenating therapies in mouse models. Within 20 years and perhaps even sooner many of those therapies could be ready for human trials. Therefore it seems unreasonable to expect a continuation of past trends of slowly rising human life expectancy.
Scientists may have discovered why the brain’s higher information-processing center slows down in old age, affecting everything from language, to vision, to motor skills. The findings may also point toward drugs for reversing the process.
A brain chemical called GABA helps neurons stay finicky about which signals they respond to – a must for the brain to function at its peak. Certain neurons in very old macaque monkeys lose their pickiness, researchers have found, seemingly because they don’t get enough GABA. These results appear in the journal Science, published by the American Association for the Advancement of Science (AAAS).
If a lack of GABA is indeed responsible for the old neurons’ indiscriminate firing, this problem may be simple enough to treat. Existing drugs, such as Xanax, increase GABA production, according to author Audie Leventhal of the University of Utah School of Medicine. These drugs haven’t been carefully tested on the elderly, though.
"The good news is there are a lot of drugs around that can facilitate GABA-ergic function and maybe some of them will help," said Leventhal.
Leventhal and his colleagues studied visual function in monkeys he believes are the oldest in the world. The monkeys live in a colony in Kunming, China, established as part of a Chinese and Russian experimental program in the 1950s. At 30 years old (around 90 in people years), these animals have lived around twice as long as they do in the wild.
“They really do sort of look like grandpa. They have thinning hair and wrinkles,” Leventhal said.
In monkeys, as well as humans, visual function declines with age. While the eye itself does degenerate, this decline also involves the vision-related section of the cerebral cortex, which is responsible for many “higher-order” brain functions.
What the researchers discovered about the visual system likely applies to age-related declines in other parts of the cerebral cortex, according to Leventhal,
"If it's going on in the visual cortex, it's probably going on in other parts of the cortex," he said.
In the visual cortex, each so-called “V1 neuron” responds only to the sight of objects at a specific orientation or moving in a certain direction. GABA probably restricts the V1 neurons from responding to any other types of stimuli. This process helps the brain make sense out of the vast quantities of visual information coming in through the eyes.
"It’s like New York City or Boston during a blackout,” Leventhal said, describing what would happen if neurons weren’t restricted to specific responses. “With all the gating mechanisms like the stoplights out, you’d think traffic would move faster. But it doesn’t."
The researchers recorded the activity of individual neurons in the visual cortex of old and young macaque monkeys, while showing the monkeys various images on a computer screen. The devices that monitored the neurons also held small glass tubes of substances that could be released directly onto the neurons. The substances were GABA, a GABA-enhancing compound called muscimol, and a GABA-blocking compound called bicuculline.
The GABA blocker made the neurons less selective in the young monkeys, but had no significant effect in old monkeys. Presumably, that’s because the older neurons had already lost much of their selectivity, according to the researchers.
GABA and the GABA-enhancer had a relatively small effect in the young monkeys, moderately increasing the percentage of cells that were selective for particular orientations and directions. In the old monkeys, however, GABA and the GABA-enhancer had a much stronger effect, significantly increasing the percentage of highly selective cells.
Thus, the visual cortex of the older monkeys seemed to function less effectively, because GABA wasn’t limiting the neurons to specific responses. Exactly how this change occurred isn’t completely clear. In their Science paper, the researchers speculate that perhaps GABA production decreases in older brains.
Leventhal is hoping that more researchers will begin study aging in monkeys.
“It’s absolutely remarkable to me that my lab is the only lab in the world studying higher brain function in old monkeys. Old monkeys are rare, but the world is full of old human primates,” Leventhal said. “Hopefully we can drum up a little interest, and encourage other people who are trying to figure out how come their kids are smarter than they are now.”
The effect lasted only as long as GABA levels were maintained. When the chemical was removed, the brains of the old monkeys reverted to their aged confusion within a few minutes, Leventhal said. Added GABA appeared to have no effect on the young.
"It may be that already approved GABA (boosting drugs) have a positive effect on mental decline in the brains of older adults, but nobody has ever looked," he told Reuters Health.
The next logical step is to test the effects of known GABA-increasing drugs on older brains.
Dr Richard Harvey of the UK's Alzheimer's Society says new drugs with fewer side-effects may need to be developed to make best use of this discovery.
"The benzodiazepines, which include Xanax (alprazolam) and Valium (diazepam) affect the GABA system in the brain. "However they are highly addictive, and any benefits you might get from enhancing GABA are mitigated by the significant problems of physical and psychological dependence.
"Brain function gets worse as we get older, pure and simple. It's not whether it will get worse, it's a matter of how much worse it will get," Leventhal said. "The ramifications of this are to correct brain degradation in the elderly. That is significant to every human being."
What will be interesting to discover is why GABA levels decline with age. Do GABA-producing cells die off? Or are there signals that inhibit the production or release of GABA in aged brains? Or do old cells have insufficient energy output from their mitochondria to support the production of GABA?
Leventhal believes the aging phenomenon that causes these results is happening throughout the brain.
Leventhal believes a lack of GABA as people age will not just affect vision but all higher brain functions.
The boosting of GABA with drugs will not be as safe and effective as the natural production of GABA by young healthy nerve cells. Still, this discovery points the way for drug development and further research into how the brain ages. This research brings closer the day when we know how to slow and even reverse brain aging.
Update: Leventhal learned about the Rhesus Macaque monkeys in China during a sabbatical in China.
He also is an honorary professor at the University of Science and Technology in Anhui, China, a connection that came about because a number of his graduate students have been Chinese and he did a sabbatical there.
Mice fed every other day had their rate of aging decreased in ways analogous to a calorie restriction diet.
Eating double portions one day and nothing the next delivers the same health benefits to mice as seen in animals whose lifespan has been extended by restricting their calorie intake.
Eat every other day and live longer. The rats fed every other day experienced lower blood glucose and blood insulin just as happens when on calorie restriction diets. But the rats fed every other day had normal body weight.
This might be doable with the development of an appetite suppression drug. One could take it before going to bed and then not eat the next day. Then wake up the following day and pig out.
Update: Mark Mattson, the NIH National Institute of Aging scientist who conducted the study, says skipping meals is probably beneficial.
Nevertheless, Mattson said, "I would be very confident in saying that healthy adults don't need three full meals a day and would be better off skipping one or two. When you go without food, there are benefits. Your cells become more efficient. I haven't eaten breakfast for 20 years."
Mattson said a study is being planned to test the effect of fasting on people. The plan is to compare the health of a group of people fed the normal three meals a day with a similar group, eating the same diet and amount of food, but consuming it within four hours and then fasting for 20 hours before eating again.
Here is the original press release from the NIH/National Institute On Aging on Meal Skipping Helps Rodents Resist Diabetes, Brain Damage.
A new mouse study suggests fasting every other day can help fend off diabetes and protect brain neurons as well as or better than either vigorous exercise or caloric restriction. The findings also suggest that reduced meal frequency can produce these beneficial effects even if the animals gorged when they did eat, according the investigators at the National Institute on Aging (NIA).
"The implication of the new findings on the beneficial effects of regular fasting in laboratory animals is that their health may actually improve if the frequency of their meals is reduced," says Mark Mattson, Ph.D., chief of the NIA's Laboratory of Neurosciences. "However, this finding, while intriguing, will need to be explored further. Clearly, more research is needed before we can determine the full impact that meal-skipping may have on health."
In the study*, published in the Proceedings of the National Academy of Sciences Online Early Edition the week of April 28, 2003, Dr. Mattson and his colleagues found mice that were fasted every other day but were allowed to eat unlimited amounts on intervening days had lower blood glucose and insulin levels than either a control group, which was allowed to feed freely, or a calorically restricted group, which was fed 30 percent fewer calories daily than the control group. Despite fasting, the meal-skipping mice tended to gorge when provided food so they did not eat fewer calories than the control group. This finding in mice suggests that meal-skipping improves glucose metabolism and may provide protection against diabetes, Dr. Mattson says.
In the same study, mice on these three diets were given a neurotoxin called kainate, which damages nerve cells in a brain region called the hippocampus that is critical for learning and memory. (In humans, nerve cells in the hippocampus are destroyed by Alzheimer's disease). Dr. Mattson's team found that nerve cells of the meal-skipping mice were more resistant to neurotoxin injury or death than nerve cells of the mice on either of the other diets.
Previous studies by Dr. Mattson and his colleagues suggested that nerve cells in the brains of rodents on a meal-skipping diet are more resistant to dysfunction and death in experimental models of stroke and other neurological disorders including Parkinson's, Alzheimer's and Huntington's diseases. Dr. Mattson also has found that meal-skipping diets can stimulate brain cells in mice to produce a protein called brain-derived neurotrophic factor (BDNF) that promotes the survival and growth of nerve cells.
Dr. Mattson and his colleagues are currently studying the effects of meal-skipping on the cardiovascular system in laboratory rats. The findings of this study, which compares the resting blood pressures and heart rates of rats that were fasted every other day for six months with rats allowed to eat unlimited amounts of food daily, should be available soon.
The NIA leads the Federal effort supporting and conducting biomedical, clinical, social, and behavioral research on aging. This effort includes research into the causes and treatment of Alzheimer's disease, Parkinson's disease, stroke and other neurodegenerative disorders associated with age. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information Web site, www.nia.nih.gov.
*RM Anson, Z Guo, R de Cabo, T Iyun, M Rios, A Hagepanos, DK Ingram, MA Lane, MP Mattson, "Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from caloric intake," Proceedings of the National Academy of Sciences Online Early Edition the week of April 28, 2003 http://www.pnas.org/cgi/doi/10.1073/pnas.1035720100
It would be surprising to see pharmaceutical companies try to develop drugs that either stimulate the production of BDNF or that mimic the effects of BDNF.
Carogero Caruso, Professor of Biopathology and Biomedicine at the University of Palermo in Italy, has found a link between high levels of anti-inflammatory cytokine InterLeukin-10 (IL-10) and longevity.
Professor Caruso, whose research is published in this month's Journal of Medical Genetics, said: "Longevity is definitely more easily controlled by those who can counter inflammatory disease."
Long term low grade inflammation has has been linked to the development of a large assortment of degenerative and chronic illnesses. Anti-inflammatory drugs have been found to decrease the incidence of heart disease, cancer (both breast cancer and colon cancer), and other illnesses. Therefore it is not too surprising to find that people who live longer have more anti-inflammatory IL-10 and less inflammation promoting hormone TNFa.
To investigate this further, the research team examined the frequency of genes coding for IL-10 and TNFa in 72 men and 102 women, all of whom had reached the age of 100. Similar DNA testing was also carried out in 115 men and 112 women aged between 22 and 60.
The results showed that significantly more centenarian men expressed genes encoding for high levels of the anti-inflammatory IL-10 than did younger men, although there were no differences in the levels of the pro-inflammatory TNFa among the various age groups.
And significantly more centenarian men expressed genes for the combination of high IL-10 and low TNFa production than did their younger peers. There were no differences in levels of the cytokines, either separately or in combination, among the women.
This latest work builds on previous work by Caruso's group showing that there is a genotypic variation that increases IL-10 production and is associated with longevity.
The presence of -1082GG genotype, suggested to be associated with high IL-10 production, significantly increases the possibility to reach the extreme limit of human lifespan in men. Together with previous data on other polymorphic loci (Tyrosine Hydroxylase, mitochondrial DNA, IL-6, haemochromatosis, IFN-), this finding points out that gender is a major variable in the genetics of longevity, suggesting that men and women follow different strategies to reach longevity. Concerning the biological significance of this association, we have not searched for functional proves that IL-10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. However, recent data on IL-6 and IFN- genes suggest that longevity is negatively associated with genotypes coding for a pro-inflammatory profile. Thus, it is intriguing that the possession of -1082G genotype, suggested to be associated with IL-10 high production, is significantly increased in centenarians.
This latest result is another example of how inflammation response affects longevity. Yet another example is the recently discovered link between Parkinson's Disease and COX-2 enzyme levels. Many of the newer non-steroidal anti-inflammatory drugs (NSAIDs), such as Celebrex and Vioxx, work by blocking just the COX-2 enzyme while the older generation NSAIDs inhibit both COX-1 and COX-2 enzymes. It is possible that COX-2 inhibitors may delay the development of Parkinson's Disease. More generally, expect to see a continued stream of reports on the results of studies that investigate how anti-inflammatory hormones and drugs slow or prevent a number of diseases of old age.
A March 2003 staff working paper of the US President's Council on Bioethics reflects its chairman Leon Kass's lack of enthusiasm for the prospect of preventing and reversing the aging process.
4. Attitudes toward Death and Mortality: An individual committed to the scientific struggle against aging and decline may be the least prepared for death, and the least willing to acknowledge its inevitability. Therefore, given that these technologies would not in fact achieve immortality, but only lengthen life, they would in effect make death even less bearable, and make their beneficiaries even more terrified of it and, in a sense, obsessed with it. The fact that we might die at any time could sting far more if we were less attuned to the fact that we must die at some time. In an era of age-retardation, we might, in practice, therefore live under an even more powerful preoccupation with death, but not one that leads us to commitment, engagement, urgency and renewal.
5. The Meaning of the Life Cycle: There is also more to the question of aging than the place of death and mortality in our lives. Not just the specter of mortality, but also the process of aging itself affects our lives in profound ways. Aging, after all, is a process that mediates our passage through life, and that gives shape to our sense of the passage of time and our own maturity and relations with others. Age-retardation technologies at once both make aging more manipulable and controllable as explicitly a human project, and sever age from the moorings of nature, time, and maturity. They put it in our hands, but make it a less intelligible component of our full human life. In the end, they could leave the individual unhinged from the life-cycle. Without the guidance of our biological life-cycle, we would be hard-pressed to give form to our experiential life-cycle, and to make sense of what time, age, and change should mean to us.
Kass and company apparently believe that if our bodies don't grow old we will become even more fearful of death. He also thinks we will feel unhinged and lack the sense of purpose that supposedly comes with growing old. I don't personally derive a sense of meaning and purpose from growing old (except that as more years go by I try harder and harder to encourage others to support anti-aging research - so maybe he's right). Aging seems like an entirely undesireable process. Wisdom and understanding would come with the passing of the years even of one didn't grow old.
What would be wrong with having many generations at the prime of their lives for many decades? These ethicists are arguing as if we need really old and the children around to give the middle aged people someone to boss around. Oh great. Couldn't this need be satisfied by getting really obedient dogs, border collies perhaps?
1. Generations and families: Family life and the relations between the generations are, quite obviously, built around the shape of the life cycle. A new generation enters the world when its parents are in their prime. With time, as parents pass the peak of their years and begin to make way and assist their children in taking on new responsibilities and powers, the children begin to enter their own age of maturity, slowly taking over and learning the ropes. In their own season, the children bring yet another generation into the world, and stand between their parents and their children, helped by the former in helping the latter. The cycle of succession proceeds, and the world is made fresh with a new generation, but is kept firmly rooted by the experience and hard-earned wisdom of the old. The neediness of the very young and the very old put roughly one generation at a time at the helm, and charge it with caring for those who are coming, and those who are going. They are given the power to command the institutions of society, but with it the responsibility for the health and continuity of those institutions. In a society reshaped by age-retardation, generation after generation would reach and remain in their prime for many decades. Sons would not surpass their fathers in vigor just as they prepared to become fathers themselves. One generation would have no obvious reason to make way for the next as the years passed. The succession of generations would be obstructed by a glut of the able. The old would think less of preparing their replacements, and the young would see before them only layers of their elders blocking the path, and no great reason to hurry in building families or careers. Families and generational institutions would surely reshape themselves to suit the new demographic form of society, but would that new shape be good for the young, the old, the familial ties that bind them, the society as a whole, or the cause of well-lived human lives?
2. Innovation and change: The same glut would likely affect other institutions, private and public. From the small business to the city council, from the military to the Fortune 500 corporation, generational succession would be disrupted, as the rationale for retirement diminished. With the slowing of succession cycles might well also come the slowing of the cycles of innovation and adaptation in these institutions. Innovation is often the function of a new generation of leaders, with new ideas to try and a different sense of the institution’s mission and environment. Waiting decades for upper management to retire would surely stifle this renewing energy and slow the pace of innovation—with costs for the institutions in question and society as a whole.
They also bring up a fallacy about a loss of the ability to innovate with the passing of the years. If a person's mind didn't age and it stayed as keen as a mind is when it is young then the person will have a longer run at being creative. With no loss in the ability to concentrate or to form new memories will come a greater ability to sustain creative output in many fields.
If there are too many people in a corporation at the top who never retire then one can just change jobs to a company that is growing and promoting people. Or one can become self-employed. Most people aren't going to become senior managers anyway and yet the failure to reach senior management level does not rob a life of meaning.
Along with aging reversal therapies will come the ability to boost intelligence. With youthful smarter minds and energetic bodies people will become far more creative. The result will be a cultural renaissance.
People who think like Leon Kass are fighting a losing battle. Biotechnology will continue to advance and its rate of advance will accelerate. The only question is how long will we have to keep ourselves alive before the technology becomes available to make our bodies young again? Will the technology come soon enough to help those who otherwise will die of old age in 20 years? Or do you need to make it another 30 or 40 years to survive to see the day when it becomes possible to have one's body rejuvenated and returned to a state of youthfulness?
The ethics of using biotech enhancements to slow the aging process were a focus of the Council's March 6 meeting. "Is it reasonable to think that the biological processes of aging are rightly regarded as analogous to a model of disease, to be studied and modified?" chairman Leon Kass asked to launch the topic.
Members chewed over his question and most agreed that aging is a natural part of the life cycle, not a disease.
The problem with this line of reasoning is that many conditions that are now called diseases are essentially the product of aging processes. For instance, what is heart disease? If cells in a heart are very aged the heart will show the symptoms of heart disease.
In fact, as University of Idaho gerontology researcher Steven Austad explained to this bioethics panel the vast bulk of diseases increase in incidence with age.
And the last point is that slowing aging is really a much more effective approach to preserving health, than is the treatment of individual diseases, and I'll give you the rationale for that in this slide here, which shows that these are major causes of death. And you can see that virtually all of them increase exponentially with age. And one of the consequences of the analyses that Jay Olshansky will, no doubt, talk about later, is that curing each of these individual diseases has a surprisingly small impact on life expectancy. But more important, curing one of those diseases does not take care of all of the other disabilities that may be associated with aging, because of other disabilities, such as chronic arthritis, the decline in sensory capacity. These things also increase exponentially in aging, getting rid of one cause at a time, basically leave people who may be alive, but may be very disabled. By slowing down the aging rate, we basically delay the onset and the progression of a whole host of mortal and debilitating diseases.
Slow aging and the onset of a large number of illnesses will be delayed. Reverse aging and the onset of many illnesses will be entirely avoided. Can a biological process lead to disease and yet not be a disease process itself? One can debate the question philosophically but regardless of whether aging is classified as a disease the most effective way to prevent most diseases is to slow and reverse aging.
University of Utah aging researcher Richard Cawthon makes a similar argument.
According to some estimates, slowing the rate of aging just enough to postpone the age of onset of multiple age-related chronic diseases by two to three years would save hundreds of billions of dollars in health care costs. Furthermore, lowering age-specific mortality rates from multiple causes by slowing the rate of aging may be easier to achieve than lowering them to the same extent by developing a separate, more specific intervention for each of a multitude of age-related life-threatening diseases of which atherosclerotic heart disease, cancer, stroke, lung infections, and chronic obstructive pulmonary disease are among the most common.
The levels of a type of adult stem cells called endothelial progenitor cells are inversely correlated with cardiovascular disease risk.
Levels of a type of adult stem cell in the bloodstream may indicate a person's risk of developing cardiovascular disease, according to a study supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health in Bethesda, MD.
The study looked at the blood level of endothelial progenitor cells, which are made in the bone marrow and may help the body repair damage to blood vessels. Scientists from NHLBI and Emory University Hospital in Atlanta, GA, found that cardiovascular disease risk was higher in persons with fewer endothelial progenitor cells. The cells of those at higher risk also aged faster than those at lower risk, as determined by the Framingham Heart Study risk factor score, a standard measurement of cardiovascular risk. Additionally, the study found that blood vessels were much less likely to dilate and relax appropriately in persons with low levels of the cells.
Results of the study, which involved 45 healthy men aged 21 and older, some of whom had standard cardiovascular risk factors, appear in the February 13, 2003, issue of The New England Journal of Medicine. The two main forms of cardiovascular disease are heart disease and stroke. Standard heart disease risk factors are age, family history of early heart disease, smoking, high blood pressure, high blood cholesterol, overweight/obesity, physical inactivity, and diabetes.
"Past research on cardiovascular disease has often focused on what causes the damage to the blood vessels," said Dr. Toren Finkel, chief of NHLBI's Cardiology Branch and coauthor of the study. "We looked at the other part of the equation: How does the body repair damaged blood vessels? What does that tell us about the cause of the disease?
"We believe that these endothelial progenitor cells patch damaged sites in blood vessel walls," he continued. "When the cells start to run out, cardiovascular disease worsens. We don't yet know what causes their depletion but it may be related to the fact that the risk of cardiovascular disease increases as people age. For instance, the cells may be used up repairing damage done by other risk factors or those risk factors could directly affect the survival of the endothelial cells themselves.
"Much more research needs to be done to better understand this finding," Finkel added. "But it's possible that, some day, doctors may be able to test a person's risk of cardiovascular disease by taking a blood sample and measuring these cells. If the level is too low, an injection of endothelial cells might boost the body's ability to repair itself and prevent more blood vessel damage."
The decline in endothelial progenitor cells may be due an aging process that has left those stem cells less able to divide and make new cells for blood vessel repair.
In order to test their hypothesis that endothelial progenitor cells age prematurely in individuals with higher cardiovascular risk factors, the investigators studied endothelial progenitor cells from subjects with either high or low Framingham risk scores. After seven days in culture, a significantly higher number of cells from the high-risk subjects had characteristics of senescence, or aging.
"Cardiovascular health is dependent on the ability of the blood vessels to continually repair themselves," says Arshed Quyyumi, MD, professor of medicine at Emory University School of Medicine, formerly of the NHLBI, and a member of the research team. "Evidence has shown that cardiovascular risk factors ultimately lead to damage to the endothelial layer of blood vessels. We can now speculate that continuing exposure to cardiovascular risk factors not only damages the endothelial layer, but may also lead to the depletion of circulating endothelial progenitor cells. Thus, the net damage to blood vessels and hence the risk of developing atherosclerosis depends not only on the exposure to risk factors, but also on the ability of the bone marrow-derived stem cells of endothelial origin to repair the damage.
"We will need larger studies to determine a definite cause and effect relationship between a decrease in these cells and adverse cardiovascular events. Our study did demonstrate, however, a correlation between endothelial progenitor cells, cardiovascular risk factors, increased senescence of endothelial progenitor cells, or stem cells, and vascular function. We are hopeful that further research will show that endothelial progenitor cells are a useful marker for cardiovascular disease risk."
Here's part of what might be going on here: in someone who has cardiovascular risk factors the endothelial progenitor cells (which are a type of non-embryonic stem cell) may need to divide at a faster rate in order to repair the damage being done to cells in the endothelial layer of blood vessels. The need to divide at a faster rate basically may be causing the endothelial progenitor cells to age more rapidly.
If the endothelial progenitor cells divide more rapidly in response to damage caused by cardiovascular risk factors then the telomeres on their chromosomes shrink more rapidly and the cells will lose the ability to divide sooner. Short telomeres are a marker for increased risk of mortality. This latest result suggests one reason why: blood vessels can not be repaired as well and this will increases the risk of heart disease and stroke.
Another reason why some people have lower levels of endothelial progenitor cells may be because they started life with shorter telomeres. Whether the telomeres are shrinking more rapidly or starting out shorter it is likely that short telomeres are at least one of the causes of the senescence of endothelial progenitor cells. It would be very interesting to test the cells of those with lower and higher Framingham heart disease risk scores and see if those with higher risk scores have shorter telomeres in their endothelial progenitor cells and in other blood cell types.
What can be done about this? A direct approach would be to remove stem cells, lengthen their telomeres, and then return those cells into the body. This approach might increase the risk of cancer unless accompanied with other techniques to assure that the cells so treated do not have any mutational damage that makes them prone to become cancerous. Another approach would be to use stem cells from embryos to replace host blood stem cells. But that approach elicits strong ethical objections from some quarters. Its not clear that therapeutic cloning or the harvesting of stem cells from aborted embryos will ever be allowed i the United States.
This latest result is further evidence for the idea that reseeding non-embryonic stem cell reservoirs with more youthful stem cells will be an essential technique for reversing aging.
Quyyumi noted a class of drugs called statins, used to lower high cholesterol levels and reduce the risk of developing heart disease, have been shown to triple the levels of these stem cells.
This is an interesting twist. If telomere shortening was causing the stem cells to become senescent then one wouldn't expect a drug that lowers cholesterol to boost the levels of these cells.
A mutation in mitochondrial DNA appears to be linked to longer life expectancy.
Mitochondrial DNA is the portion of the cell DNA that is located in mitochondria, the organelles which are the "powerhouses" of the cell. These organelles capture the energy released from the oxidation of metabolites and convert it into ATP, the energy currency of the cell. Mitochondrial DNA passes only from mother to offspring. Every human cell contains hundreds, or, more often, thousands of mtDNA molecules.
It's known that mtDNA has a high mutation rate. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and other colleagues found what Attardi described as a "clear trend" in mtDNA mutations in individuals over the age of 65. In fact, in the skin cells the researchers examined, they found that up to 50 percent of the mtDNA molecules had been mutated.
Then, in another study two years ago, Attardi and colleagues found four centenarians who shared a genetic change in the so-called main control region of mtDNA. Because this region controls DNA replication, that observation raised the possibility that some mutations may extend life.
Now, by analyzing mtDNA isolated from a group of Italian centenarians, the researchers have found a common mutation in the same main control region. Looking at mtDNA in white blood cells of a group of 52 Italians between the ages of 99 and 106, they found that 17 percent had a specific mutation called the C150T transition. That frequency compares to only 3.4 percent of 117 people under the age of 99 who shared the same C150T mutation.
To probe whether the mutation is inherited, the team studied skin cells collected from the same individuals between 9 and 19 years apart. In some, both samples showed that the mutation already existed, while in others, it either appeared or became more abundant during the intervening years. These results suggest that some people inherit the mutation from their mother, while others acquire it during their lifetime.
The mitochondria contain DNA that code for a subset of all the proteins that get used in mitochondria. Most of the genes for mitochondria are coded for in the nucleus. Those genes that are part of the miticondrial DNA (mtDNA) are more vulnerable to oxidative damage as cells age because the mitochondria produce a lot of free radicals as a side effect of how they do energy metabolism. The presence of mtDNA within mitochondria is rather like an Achilles Heel for how eukaryotic organisms are designed. Therefore a mutation in the mtDNA that affects longevity is not surprising.
Is news of this mutation useful for devising anti-aging therapies? Possibly. It might point to a method to slow aging by development of pharmaceutical means of enhancing mtDNA replication. However, the most optimal way to deal with the accumulation of damage to mtDNA would be a gene therapy that moved the mtDNA genes into the nucleus. Such a therapy would essentially move the mtDNA genes out of harm's way and therefore the genetic variations that help those genes survive better in mitochondria would become irrelevant.
Techniques to do gene therapy to a large portion of the cells in the body is probably the ability most needed to be able to turn back the biological clock on aged cells. While some cells and organs will some day be replaced via cell therapy and organ replacements there are parts of the body where replacement is really not a good idea. Most notably, the central nervous system defines who we are. Even if brain replacement was possible that would replace who we are with someone else. Gene therapy is most needed for brain rejuvenation so that the cells that constitute our brains can be made youthful again.
The abstract for the PNAS research paper that reports these results is available online.
Sheep normally live to be 11 or 12. Dolly was 6 and a half and lame with arthritis. She was euthanised due to a lung condition.
The institute's Dr. Harry Griffin said Dolly had suffered from a virus-induced lung cancer that was also diagnosed in the past few months in other sheep housed with Dolly
She might not have gotten the infection and cancer as a result of being a clone. It is not clear that being a clone contributed to her early death. Though one scientist who was involved in research on Dolly says her clone status did contribute to her early death.
Professor Rudolf Jaenisch, who in March 2001 co-wrote an article with Dolly's creator Professor Ian Wilmut for the journal Science titled "Don't Clone Humans!" said that the death "is exactly what was expected: clones will die early".
How could her status as a clone contribute to her early death? Dolly had short telomere caps on her chromosomes.
The researchers found that Dolly's telomeres were shorter than other 3-year-old sheep, suggesting she is genetically older than her birth date.
The telomeres of chromosomes shrink with age losing 100-200 base pairs in length every time a cell divides. Shorter telomeres have recently been demonstrated to correlate with shorter life expectancy in humans. This strongly suggests that Dolly's problems stem from her shorter telomeres. Certainly her immune system would be less vigorous as a result of shortened telomeres.
However, as scientists cloning cows at Advanced Cell Technology have demonstrated, cloning of cells from an older organism does not always lead to shorter telomeres in the cloned offspring.
Moreover, when the scientists examined skin cells from the clones, they found that the telomeres were longer than those of the original senescent cells and even longer than those of typical newborn calves. One cloned cow that's now 2 years old has the telomeres of a calf, says Lanza.
ACT might be using a technique that is part of their proprietary cloning technology to achieve better cloning outcomes.
Worcester, MA, November 22, 2001 – Advanced Cell Technology, Inc. (ACT) and its subsidiary Cyagra, Inc. today reported that its proprietary cloning technology has been used to produce healthy and normal adult animals. ACT evaluated 30 cattle cloned from proliferating skin cells. Twenty-four (80%) of the clones were vigorous and remained alive and healthy one to four years later (by comparison, survival to adulthood normally ranges from 84% to 87%). Results of general health screens, physical examination and immune function were normal for all clones, including laboratory analysis on blood and urine, biochemistry, and behavioral responses. "We haven't observed any of the genetic defects, immune deficiencies or other abnormalities reported in the popular or scientific press," said Robert Lanza, M.D., Vice-President of Medical & Scientific ACT. "All of the data collected reinforce the view that these animals were clinically and phenotypically normal." The report will be published in next week's issue of SCIENCE (November 30, 2001), titled "Cloned Cattle Can Be Healthy and Normal" by ACT and its collaborators at the Mayo Clinic, Trans Ova Genetics, Em Tran and the University of Pennsylvania.
ACT has also done therapeutic cloning experiments where they cloned old cows, extracted cells from the embryo, and then injected the embryo cells back into the old cattle. These cells became major sources of blood immune system cells in the old cattle.
He said that 170 days later the injected cells had survived and were thriving in the blood of the cattle. When put into lab dishes, they grew abundantly, much as young fetal cells do.
This is an important experiment because ACT was able to take cells from an old cow and from them make cells that were much younger that could be injected back into the same cow to rejuvenate the cow's aged immune system. The problem with this approach is that since it involves the creation of an embryo it is considered morally objectionable by many and quite possibly will be outlawed by the US Congress.
An experiment with fetal cells was recently done in the UK where instead of cloning to create a source of cells aborted fetuses were used. The fetuses provided eye stem cells that improved the eyesight of sufferers of retinitis pigmentosa.
Transplants of fetal eye tissue seem to have improved the vision of two out of four people with a degenerative eye disease. It is too early to be sure the improvements are real and lasting, but on the strength of the results the team pioneering the surgery has asked regulators for permission to carry out further operations.
The ACT therapeutic cloning experiment to rejuvenate aged cow immune systems and the experiment with aborted fetus eye stem cells both demonstrate the therapeutic potential of cells derived from embryos (whether pluripotent or not). Work on adult stem cells so far has not produced cell lines with all the same advantages. On the bright side these experiments are demonstrating the enormous future therapeutic potential for cell therapies. However, regardless of how one feels personally about the use of therapeutic cloning or aborted fetuses stem cell sources, enough people have ethical objections to these approaches that the quickest way scientifically to the development of many useful cell therapies is likely to be legally blocked in at least some countries.
There has been considerable debate for years as to whether the shortening of telomere length that happens each time cells divide is linked to mortality. Skeptics have argued that people were dying of other factors before telomeres became short enough to become a rate-limiting factor on longevity. However, recent research by Richard Cawthon has found a correlation between telomere length and longevity in humans.
Dr. Richard M. Cawthon and his colleagues at the University of Utah in Salt Lake City discovered that initially healthy people older than 60 with shorter telomeres--snippets of genetic material that cap chromosomes--are more likely to die than people of the same age with longer caps at the end of the chromosomes, which are long strings of coiled DNA found in cells.
Risk of death from both infection and heart disease was higher for those with shorter telomeres.
In all, 101 donors died. People with shorter telomeres showed an 86 percent higher death rate. They ran a threefold higher risk of dying from heart disease and an eight-fold higher risk of death from infectious disease, almost entirely pneumonia.
The higher rate of death from infection involved only a small fraction of the total set of people in the study. Most people die from things other than infection. Still, the results may demonstrate that the immune system requires a lot of cell replication to handle pathogens and over the years immune cells may have their telomeres wear down a lot as a result.
Telomere length matters for cells that have to divide. Heart muscle cells do not normally divide. Also, while regular muscle has a type of muscle stem cell that can generate replacement muscle cells the heart muscle does not have stem cells closely associated with them (at least not to my knowledge). Therefore the higher heart disease death rate for people with shorter telomeres brings up the question of why. Is it that people with shorter telomeres can't easily grow new blood vessels to keep the heart muscle cells well fed? Or do stem cells come from other parts of the body travel to the heart to form replacements for damaged and dead heart muscle cells?
The reduction in the ability of immune cells to rapidly divide is probably what causes the big increase in mortality from infection.
This was associated with a 3.18-fold increase in risk of death from heart disease for those in the bottom half of telomere length, to an 8.54-fold increased risk of death from infectious diseases for people in the bottom quartile of telomere length.
A blood test for telomeres could make longevity predictions more accurate. The implications of these results is dramatic for medical insurance and life insurance.
The test, which can produce a result in less than six hours from one drop of blood, could revolutionise the life insurance and health industries.
That means higher insurance rates for people with shorter telomeres or even denial of coverage while those with longer telomeres would get lower rates. Are you curious to find out for yourself how short or long your telomeres are?
There are even more subtle effects that could flow from a more accurate way of predicting longevity. Suppose you are an administrator for a defined benefit pension plan. You could reasonably argue that people with longer telomeres should have to work longer than people with shorter telomeres to earn a given level of benefits once retired.
Why do telomeres get short as we age? Why don't cells just turn on their telomerase enzymes and grow their telomeres? Once telomeres get short enough they prevent cells from dividing. Why would cells be designed to get to a point where they can no longer divide? One theory is that shortening of telomeres prevents old cells which are accumulating damage from becoming cancerous.
Judith Campisi of the Lawrence Berkeley Laboratory has a more sophisticated version of the popular theory that cellular aging evolved in part as a defense against cancer.
Epidemiologists and practicing physicians have long noted that cancer rates soar in people over 50, an observation usually attributed to the build-up of deleterious genetic mutations with age. But Dr. Campisi puts at least part of the blame on the accumulation of cells with a senescent phenotype, which hang around in certain tissues long after they've undergone changes in morphology, behavior and function. They secrete many different molecules, some of which appear to have a "field effect" that promotes malignant changes in nearby cells.
Support for this idea comes from a series of experiments in which preneoplastic epithelial cells were grown either on a lawn of presenescent stromal cells or one where 10-15% of cells were senescent. Dr. Campisi and her colleagues saw significantly more premalignant changes in cells exposed to senescent neighbors. The investigators obtained similar results in nude mice, where they observed a direct relationship between exposure to senescent cells and the size and number of tumors that developed. In mice, a neoplastic mutation was needed as a starting point for oncogenesis; after that, senescence appeared to drive tumor development.
Dr. Campisi speculates that cellular senescence evolved as a cancer suppression mechanism at a time when the life expectancy for humans was far shorter than it is today. Now that people live so much longer, senescence may be an example of antagonistic pleiotropy: a trait selected to optimize fitness early in life turns out to have unselected deleterious effects later on. Although this may sound like depressing news, Dr. Campisi sees it differently. She believes that additional research will discover small molecules that can counteract damaging secretions from old cells that have overstayed their welcome.
An implication of Campisi's work is to make aging rejuvenation harder to do. The senescent cells need to either be induced to die or somehow (drugs or gene therapy perhaps) induced to not secrete the kinds of molecules that they make that drive tumor development. A lot of cancers show up in organs. One way to get rid of the senescent cells that are driving tumor development is to get rid of the organs that contain them. So one more radical strategy for reducing the risk of cancer would be to grow replacements for those organs that posed the greatest cancer risk for each individual.
BOSTON - Scientists at Dana-Farber Cancer Institute and their colleagues have found that much of the widespread damage that the rare genetic disease ataxia telangiectasia, or AT, wreaks on the body results from the progressive shortening of telomeres, the structures that cap the ends of a cell's chromosomes.
In genetically altered mice, the researchers found that the shortening of telomeres led to a "crisis" that disrupted chromosomes "like a hand grenade thrown into the cell," as one scientist put it. The resulting cellular chaos was manifested throughout the rodents' bodies by the loss of reparative stem cells that different organs normally have in reserve, producing symptoms of premature aging such as hair loss and slow wound healing, and early death.
The report by Kwok-Kin Wong, MD, PhD, and Ronald A. DePinho, MD, of Dana-Farber and their collaborators was posted by Nature today on its website as an advance online publication, and it will appear in a forthcoming print issue of the journal."There are significant implications for humans" in the discovery, said DePinho, whose laboratory has made a number of fundamental findings about telomeres and their role in aging, cancer and problems like liver cirrhosis. "It suggests that much of the problems in AT are related to eroding telomeres. It provides us with a point of attack." For example, it might be possible someday to restore telomere function with drugs and potentially reduce some of the ravages of the disease, DePinho says.
Short telomeres are harmful in all sorts of ways. Long telomeres are a cancer risk.
Aside from perhaps providing for a new blood test to predict longevity does this latest result provide any sort of guide for the development of anti-aging treatments? To put it another way: Does it make sense to try to develop treatments that will lengthen telomeres? One potential risk of such treatments is cancer. The cells that have short telomeres are probably more at risk of becoming cancerous than cells in the same body that have longer telomeres (cells in the same body and cell type will not all have the same telomere length). Whether telomere lengthening would be a net benefit is hard to know and would probably depend on each individual's risk factors.
If a therapy (probably a gene therapy though not necessarily) to lengthen telomeres is delivered in the body then many different cells will get their telomeres lengthened. Some of the cells will be ones which have accumulated mutations that put them at risk for becoming cancerous. This argues against generalized therapies to lengthen telomeres throughout the body.
One less risky approach is to develop the ability to make high quality rejuvenated cells with lengthened telomeres outside of the body and then to deliver those cells back into the body as cell therapies. Cells taken out of the body could be treated to increase telomere length. A further step would be needed in order to reduce the risk of cancer due to accumulation of mutations. Individual cells whose telomeres were lengthened could be grown up into much larger numbers of cells. From that larger number of cells some could be sacrificed to do integrity testing of the genes that are most crucial for prevention of cancer. In other words the DNA could be sequenced or otherwise checked for mutations - especially in genes that regulate cell division. Cell lines that were found to have no mutations in crucial areas could then be further developed to eventually be injected back into the body to provide rejuvenated cells of the desired type.
In order to do the most thorough possible testing to screen out harmful mutations the development of much faster and cheaper DNA sequencing technology is needed. See the FuturePundit category archive for Biotech Advance Rates for a number of posts on the development of technologies that promise to reduce the cost of DNA sequencing by orders of magnitude.
Gene therapy to cell lines would also be helpful. There are naturally occurring genetic variations that increase the risk of cancer. More genetic risk factors for cancer will be found with time. Gene therapy to cell lines could be done to change cancer risk factor genes of cells to versions that make the cells less likely to turn cancerous.
In summary, short telomeres are probably a mortality risk. But telomere lengthening will bring risks as well as benefits. Development of therapies that increase telomere length for cells in the body (i.e. in situ therapies) might be beneficial for some portion of the population. The benefit would be greater if the therapy could be targeted to specific cell types. It would be greater still if it could be applied to cells outside of the body which are then carefully screened and treated in order to reduce the cancer risk before the cells are returned to the body. Telomere lengthening is unlikely to be applied systemically to increase telomere lengths for all the cells in the body or for all people.
Update: Illustrating the importance of short telomeres as a way to prevent cancer some scientists have recently discovered a regulatory site that controls telomerase expression. The suspicion is that this site gets mutated to enable the growth of cancers. They hope their finding can be used to develop a drug that will turn off telomerase in cancer cells.
The scientists, whose findings are reported in the journal Cancer Research, believe that a drug that targets the gene and the way it is packaged could switch off telomerase in cancerous cells.
Because telomerase is active in about 85-90 percent of cancers, a drug that blocks its production could potentially be effective against many different types of cancer.
From the BBC report Professor Robert Newbold of Brunel University and lead researcher for this study says blocking the expression of telomerase could stop cancer growth.
"Now we understand more fully how tumours activate telomerase we can begin to develop drugs that target this process to restore mortality to cancer cells and stop them from growing and dividing indefinitely."
As people age chemical bonds built using glucose molecules connect proteins to each other in ways that are harmful. The resulting compounds are called Advanced Glycosylation End-products or AGEs. This is a bit confusing since AGE the chemical bond sounds like age which is how old something is. As we age we get more AGEs. The neat thing about AGEs is that they are a type of bond that is fairly easily reversible by a whole class of chemical compounds. A company called Alteon has been developing an AGE-breaker drug called ALT-711 for several years. They've had trouble getting funded in part because some in the pharmaceutical industry fear that if ALT-711 gets approved for market it will be very easy for competitors to see that it works and then to rapidly to develop other drugs from the same class of chemicals to compete with it.
A lot of anti-aging enthusiasts have wanted to take ALT-711 for years in hopes that it would generally break AGE bonds throughout the body and by doing so reverse one aspect of aging. While Alteon's low level of funding has slowed its development of ALT-711 it has recently been able to complete a phase IIa trial of ALT-711 with promising results.
Alteon has announced positive results for its developmental agent, ALT-711, from a preliminary analysis of the phase IIa DIAMOND trial in diastolic heart failure. The first 17 patients in the trial, who received ALT-711 for 16 weeks, experienced a statistically significant reduction in left ventricular mass, and the drug had a positive effect on their quality of life.
The results of ALT-711 trials for other medical conditions, importantly including high blood pressure, will be announced in the first half of 2003.
But the real tests of the drug's potential are still to come. Alteon says the results of clinical trials testing ALT-711 in 450 patients with high blood pressure will be available in the first half of this year. Data on another 180 patients with a thickening of the heart's left ventricle will be available at the same time.
Alteon is developing ALT-711 for a wide range of conditions related to aging.
These compounds have an impact on a fundamental pathological process caused by protein-glucose complexes called Advanced Glycosylation End-products (A.G.E.s). The formation and crosslinking of A.G.E.s lead to a loss of flexibility and function in body tissues, organs and vessels and have been shown to be a causative factor in many age-related diseases and diabetic complications. Alteon is initially developing therapies for cardiovascular and kidney diseases in older or diabetic individuals.
The ability to break the AGE bonds may provide many benefits to the aging body. In addition to improving the cardiovascular system it might make skin less wrinkly and possibly it might make kinks in muscles (if there's some medical term for this I'd be curious to know it) less likely to happen. Connective tissue might become more supple and older folks might regain some of the ability to stretch more easily like when they were younger. The awareness that AGE breakers could deliver these kinds of benefits has kept anti-aging enthusiasts as a sort of cheering section for Alteon's progress over the years.
Anti-aging enthusiasts want to see ALT-711 to be approved for just one disorder so that it is available on the market. In the United States once a drug is approved doctors who are willing to do so can prescribe it for off-label uses (i.e. for purposes other than why the US Food and Drug Administration approved it). Alteon will probably not try to get the ALT-711 approved for its broad anti-aging effects. The FDA would be reluctant to approve a drug for that purpose and it would be hard (and rather more expensive) to design a clincal trial that would demonstrate that a drug had broad anti-aging effects. Alteon is smart to pursue ALT-711 approval for a really big market such as high blood pressure treatment. However, once its approved for a single purpose such as for high blood pressure treatment expect to see hard core anti-aging enthusiasts go shopping around for doctors willing to prescribe it for off-label uses.
Even though the rodents ate more food than normal mice they had less fat and lived longer.
Clever genetic detective work may have pinpointed the reason why a near-starvation diet prolongs the life of many animals.
Ronald Kahn at Harvard Medical School in Boston, US, and his colleagues have been able to extend the lifespan of mice by 18 per cent by blocking the rodent's accumulation of fat in specific cells. This suggests that leanness - and not necessarily diet - promotes longevity in "calorie restricted" animals.
The experiment was done by knocking out (ie disabling or removing) a gene that codes for the insulin receptor found on fat cells. Without this receptor the fat cells had no way of being told by insulin to pick up sugar from the blood. Hence the fat cells couldn't get the raw materials they needed in order to be able to make and store fat. The consequence was a substantial boost in life expectancy.
As a consequence of this modification, they cut off the fuel supply that enables the body to lay down fat.
These "Firko" (fat-specific insulin receptor knock-out) mice ate normal diets but had reduced fat mass and lived 18 per cent longer on average than normal mice. Even when they were made to overeat, they stayed lean.
While calorie restriction (CR) typically boosts life even more (30% in some cases) this result tends to suggest that one mechanism by which CR works is by reducing the amount of stored fat. Recent research results on the risks of intra-abdominal fat suggests a number of mechanisms by which a reduction in fat will increase life expectancy.
Reducing intra-abdominal, or visceral, fat is important because in addition to increasing the risk of cardiovascular disease and diabetes, among other conditions, such fat can raise insulin levels, which promotes the growth of cancer cells.
People with high levels of intra-abdominal fat may not even know it, McTiernan said, because it is hidden, deposited around the internal organs within the abdomen. "Most women don't know about intra-abdominal fat, but they should, since it is the most clinically significant type of fat and it's where women tend to store fat after menopause."
Although it is known that so-called "apple-shaped" people who store their fat around the stomach are at higher risk for conditions such as diabetes, hypertension and stroke than "pear-shaped" people who store their fat in their buttocks and thighs, visceral obesity is not necessarily correlated with body shape, McTiernan said. The only accurate way to determine the presence and extent of intra-abdominal fat is with imaging procedures such as CT or MRI scans.
Will it some day be possible to be rejuvenated, to become physically young once again? Yes. Barring an asteroid strike, nanotech goo, robot revolt, or biowar that wipes out the human race the day will come when bodies can be restored to a youthful state. Not only is this day coming but it is coming in this century. Many of us may live to see it. Stem cells topics to cover: - stem cells - embryonic and adult - cloning - what the clone egg does to the nucleus - youthful stem cells outcompete older stem cells - stem cell reseeding as method for rejuvenation and restoration of youthfulness - engineered negligible senescence - The cow experiment is important for a number of reasons. Should you care about stem cell research progress? Yes. Why? Stem cells are great. Stem cell reservoir reseeding will be one of the major rejuvenation therapies for turning back the aging clock so that some day we can become young again. The younger readers may not yet appreciate what a drag it is getting old: poorer eyesight, less endurance, poorer memory, more aches, easier to get kinks in muscles, less ability to bounce back from a night of debauched partying, you name it. As we get older there are more things that we could do when we were younger that we become less able to as we get older.
Current investigations include the evaluation of stem cells to treat incontinence in animal models. In research to date stem cell tissue engineering has been used to restore deficient urethral sphincter muscles in animal models. "These findings are exciting on many levels. First this is the first time that stem cell tissue engineering has been used to restore deficient sphincter muscles. Secondly, it lays the foundation for further investigation into methods of using stem cells to treat stress urinary incontinence," said Michael Chancellor, M.D., Professor of Urology and Gynecology. Chancellor and his colleagues have isolated muscle-derived stem cells (MDSC) from normal rats, transduced them with a reporter gene and injected the stem cells into allogenic denervated proximal urethral sphincters. After two weeks, they prepared urethral muscle strips from normal, denervated and denervated-MDSC injected rats. Fast twitch muscle contractions were recorded after electrical field stimulation. The amplitude of fast twitch muscle contractions decreased in denervated sphincters, and improved in denervated sphincters injected with MDSC by approximately 88 percent. Histological evaluation revealed the formation of new skeletal muscle fiber at the urethral sphincter injection sites.
By producing mice that have only one copy of the gene that codes for insulin-like growth factor type 1 (IGF-1) researchers produced mice that lived on average 26% longer.
When the researchers looked at the effects of deleting one copy of the gene in male and female mice, they found that the impact was different for the sexes. Males with one copy of the IGF-1 receptor lived 16% longer than normal male mice, while their female counterparts lived 33% longer than normal females.
The same effect might turn out to be achieveable either by blocking the production of IGF-1 or by creating a drug that bocks the IGF-1 receptor or by creating a drug that suppresses the production of IGF-1. But what is important here is that it demonstrates how the ability to genetically engineer mice allows scientists to test hypotheses and theories about the processes that cause aging and to test intervention strategies to slow it down or reverse it. The sequencing of the mouse genome provides scientists with the locations of many more genes to manipulate to conduct these types of studies.
Update: The researchers were building on work done in invertebrates that suggested a link between IGF-1 levels and longevity.
"These results show that a general decrease in IGF-1 receptor levels can increase lifespan in a mammalian species. Thus, the genetic link between insulin-like signaling and longevity, originally discovered in non-vertebrates, also seems to exist in higher vertebrates", conclude the authors.
Ray Kurzweil reviews the talks given by participants of the Fifth Annual Alcor Conference on Extreme Life Extension.
Robert Freitas is a Research Scientist at Zyvex, a nanotechnology company, and in my view the world's leading pioneer in nanomedicine. He is the author of a book by the same name and the inventor of a number of brilliant conceptual designs for medical nanorobots. In his first major presentation of his pioneering conceptual designs, Freitas began his lecture by lamenting that "natural death is the greatest human catastrophe." The tragedy of medically preventable natural deaths "imposes terrible costs on humanity, including the destruction of vast quantities of human knowledge and human capital." He predicted that "future medical technologies, especially nanomedicine, may permit us first to arrest, and later to reverse, the biological effects of aging and most of the current causes of natural death."
Freitas presented his design for "respirocytes," nanoengineered replacements for red blood cells. Although much smaller than biological red blood cells, an analysis of their functionality demonstrates that augmenting one's blood supply with these high pressure devices would enable a person to sit at the bottom of a pool for four hours, or to perform an Olympic sprint for 12 minutes, without taking a breath. Freitas presented a more complex blueprint for robotic "microbivores," white blood cell replacements that would be hundreds of times faster than normal white blood cells.
Freitas has the full text of his conference lecture entitled "Death Is An Outrage" on his web site.
The end result of all these nanomedical advances will be to enable a process I call “dechronification” – or, “rolling back the clock.” I see no serious ethical problems with this. According to the volitional normative model of disease that is most appropriate for nanomedicine, if you’re physiologically old and don’t want to be, then for you, oldness and aging are a disease, and you deserve to be cured. After all, what’s the use of living many extra hundreds of years in a body that lacks the youthful appearance and vigor that you desire? Dechronification will first arrest biological aging, then reduce your biological age by performing three kinds of procedures on each one of the 4 trillion tissue cells in your body.
* First, a respirocyte- or microbivore-class device will be sent to enter every tissue cell, to remove accumulating metabolic toxins and undegradable material. Afterwards, these toxins will continue to slowly re-accumulate as they have all your life, so you’ll probably need a whole-body cleanout to prevent further aging, maybe once a year.
* Second, chromosome replacement therapy can be used to correct accumulated genetic damage and mutations in every one of your cells. This might also be repeated annually.
* Third, persistent cellular structural damage that the cell cannot repair by itself such as enlarged or disabled mitochondria can be reversed as required, on a cell by cell basis, using cellular repair devices.
We’re still a long way from having complete theoretical designs for many of these machines, but they all appear possible in theory, so eventually we will have good designs for them.
Freitas links to another article of his that further expounds on the coming ability of nanobots to repair bodies and reverse aging:
Artificial "biobots" could be in our bodies within five to 10 years. Advances in genetic engineering are likely to allow us to construct an artificial microbe - a basic cellular chassis - to perform certain functions. These biobots could be designed to produce vitamins, hormones, enzymes or cytokines in which the host body was deficient, or they could be programmed to selectively absorb and break down poisons and toxins. A new company called engeneOS, Inc., founded in late 2000, has already announced plans to develop artificial Engineered Genomic Operating Systems using the techniques of molecular biology. These systems will comprise a library of component device modules and proprietary modular components. This will allow the engineering and construction of programmable biobots with novel form and function.
Unfortunately, Kurzweil says little about Aubrey de Grey's presentation at the conference and yet de Grey is proposing the development of some fairly specific rejuvenation techniques that show a lot of promise. What is important about the techniques that Aubrey advocates is that they can be made to work many years before nanomedicine becomes possible. In fact, Aubrey argues (and I agree), that we know enough now about the molecular mechanisms of aging and that we already have sufficently advanced biochemical tools and techniques to start developing some forms of aging-reversal intervention. The candidate methods of intervention and aging reversal could be tested using the tools that biochemists and molecular biologists already possess and the results of the tests would show how much various interventions may help.
Aubrey also holds the radical view (and is having success in convincing a number of noted biologists on this) that it will be faster to the develop aging reversal therapies to avoid the diseases of old age than it will be to continue to try to develop treatments for those diseases to deal with the disorders of old age once they appear. His argument is that it is the processes of aging that are increasing the incidence of the many disorders of old age and so if we make our bodies younger we will avoid many of the diseases that inflict people as they grow older.
Aubrey has co-authored a paper with a prominent list of biologists (Aubrey D. N. J. de Grey, Bruce N. Ames, Julie K. Andersen, Andrzej Bartke, Judith Campisi, Christopher B. Heward, Roger J. M. McCarter and Gregory Stock) which describes some of the techniques that could be used to reverse aging. The paper is entitled Time to Talk SENS: Critiquing the Immutability of Human Aging.
Aging is a three-stage process: metabolism, damage and pathology. The biochemical processes that sustain life generate toxins as an intrinsic side-effect. These toxins cause damage, of which a small proportion cannot be removed by any endogenous repair process and thus accumulates. This accumulating damage ultimately drives age-related degeneration. Interventions can be designed at all three stages. However, intervention in metabolism can only modestly postpone pathology, because production of toxins is so intrinsic a property of metabolic processes that greatly reducing that production would entail fundamental redesign of those processes. Similarly, intervention in pathology is a "losing battle" if the damage that drives it is accumulating unabated. By contrast, intervention to remove the accumulating damage would sever the link between metabolism and pathology, so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging – which we term "engineered negligible senescence" – may be within sight. Given the major demographic consequences if it came about, this possibility merits urgent debate.
The term "negligible senescence" was coined1 to denote the absence of a statistically detectable increase with organismal age in a species’ mortality rate. It is accepted as the best operational definition of the absence of aging, since aging is itself best defined as an increase with time in the organism’s susceptibility to life-threatening challenges. It has been compellingly shown to exist only in one metazoan, Hydra;2 certain cold-blooded vertebrates may exhibit negligible senescence but limitations of sample size leave the question open;1 and it has not been suggested that any warm-blooded animal (homeotherm) does so. Indeed, humans are among the slowest-aging homeotherms.
Since Gilgamesh, civilization has sought to emulate Hydra – to achieve a perpetually youthful physiological state – by intervention to combat the aging process. Such efforts may appropriately be termed "strategies for engineered negligible senescence" (SENS). This phrase makes explicit the inevitable exposure to extrinsic, age-independent causes of death (which is blurred by more populist terms such as "immortality" or "eternal youth"), while also stressing the goal-driven, clinical nature of the task (in contrast to the basic-science tenor of, for example, "interventive biogerontology"). Here we discuss the feasibility, within about a decade, of substantive progress towards that goal.
Click thru and read the full paper. If you don't have college level training in biology it might be a bit hard to follow on some points. But most of it can be understood by the interested layman.
In a large number of species it has been found that a calorie restriction (CR) diet increases lifespan. Scientists have been looking for a clue as to what molecular mechanisms are at work in CR that cause a slowing in the rate of aging. A possible clue has been found in experiments on fruit flies:
In a report in Friday's edition of the journal Science, researchers said studies with fruit flies, which have many genes similar to mammals, showed that an enzyme called Rpd3 histone deacetylase likely is a key to longevity.
"If you decrease the level of enzyme without eating less, you still get life span extension," said Stewart Frankel, a Yale research scientist and the study's senior author.
This result needs to be repeated in a warm blooded mammalian species. Another avenue of investigation would be to try to find pharmacological agents that will block the activity of Rpd3 histone deacetylase in mammals.
Recall the recent post about how youthful stem cells from embryo livers outcomputed older adult stem cells in cows. It is not known what exactly about the youthful stem cells made them more competitive. One possibility is that their telomeres are longer and hence they can divide more times. A recent report of a group at Stanford provides a way to more easily lengthen telomeres:
Writing in the Nov. 18 Proceedings of the National Academy of Sciences (PNAS), Stanford researchers described how newly created circles of synthetic DNA - called "nanocircles" - could help researchers learn more about the aging process in cells.
"In the long run, we have this dream of making laboratory cells live longer," said Eric Kool, a professor of chemistry at Stanford and co-author of the PNAS study. "We thought of this pie-in-the-sky idea several years ago, and we've been working toward it ever since."
All cells carry chromosomes - large molecules of double-stranded DNA that are capped off by single-strand sequences called telomeres. In their study, the research team successfully used synthetic nanocircles to lengthen telomeres in the test tube.
"The telomere is the time clock that tells a cell how long it can divide before it dies," Kool noted. "The consensus is that the length of the telomere helps determine how long a cell population will live, so if you can make telomeres longer, you could have some real biological effect on the lifespan of the cell. These results suggest the possibility that, one day, we may be able to make cells live longer by this approach."
Cellular death Human telomeres consist of chemical clusters called "base pairs" that are strung together in a specific sequence known by the initials TTAGGG. This sequence is repeated several thousand times along the length of the telomere. But each time a cell divides during its normal lifecycle, its telomeres are shortened by about 100 base pairs until all cell division finally comes to a halt.
"Suddenly there's a switch in the cell that says, 'It's time to stop dividing,'" Kool explained. "It's still not completely clear how that works, but it is clear that once telomeres reach the critically short length of 3,000 to 5,000 base pairs, they enter senescence and die."
In nature, a chromosome can be lengthened by the enzyme telomerase, which adds new TTAGGG sequences to the end of the telomere. But because telomerase is difficult to produce in the lab, Kool and his co-workers decided to create synthetic nanocircles that mimic the natural enzyme.
Each nanocircle consists of DNA base pairs arranged in a sequence that is complementary to the telomere. When placed in a test tube, the nanocircles automatically lengthen the telomeres by repeatedly adding new TTAGGG sequences.
"Nanocircles are so simple they're amazing," Kool observed. "Each nanocircle acts like a template that says, 'Copy more of that sequence.' In the test tube, we start with very short telomeres and end up with long ones that are easy to see under the microscope with fluorescent labeling. This suggests the possibility that one day we may be able to make cells live indefinitely and divide indefinitely, so they essentially become refreshed, as if they were younger."
Aging and cancer Kool pointed out that most cells have a limited lifespan, which is part of the normal aging process.
"The link between organism aging and cell aging is less clear, but there very likely is a link," he noted. "On the other hand, it is pretty clear that telomere length governs how long an individual cell lives."
In some diseases, such as premature aging (progeria) and cirrhosis, patients have cells with unusually short telomeres, Kool said. Cancer is another disease closely associated with telomere size.
"In order for a cell to become cancerous, one of the things it has to do is switch on the telomerase gene which makes the telomeres longer," he said. "The body has decided that the best way to keep an organism alive is to keep telomerase turned off, because otherwise you can get mutations and cancer too easily."
Because researchers need to study cells that live a long time, many labs rely on tumor-derived cells, which continuously divide and therefore are immortal. Kool predicted that nanocircle technology could one day provide an alternative method that would allow researchers to use healthy cells in their experiments instead of cancerous ones.
This is a very useful technique for aging research. For example, to test why younger stem cells can outcompete adult stem cells one could take adult bone marrow blood-forming stem cells, lengthen their telomeres, and then test to see if they can do just as well as clone embryo liver stem cells to outcompete adult stem cells that have not had their telomeres lengthened.
Even if telomere lengthening makes adult stem cells more able to replicate and even if this results in better body repair that doesn't mean that telomere lengthening would become a generally good thing to do to all adult stem cells in a human body. It is possible that telomere lengthening will allow cells that have otherwise damaged DNA to survive and to become cancerous. It is theorized that telomere shortening is a safeguard mechanism to help prevent cells from turning into cancer cells.
Another part of the puzzle needed to make a safe and effective rejuvenation therapy is the ability to sort thru adult stem cells and separate out the ones that have the least amount of DNA damage. Then one could take the better less damaged cells and extend the telomeres and reimplant them into the body. These more carefully selected cells would present less risk of becoming cancerous. To further reduce the risk of cancer from stem cells that have had their telomeres lengthened it will some day be possible to apply gene therapies that would repair a small number of locations in the genome where mutations contribute to the conversion of cells into cancers.
To summarize the significance of this latest report: This new technique for telomere lengthening will initially be useful to investigate the relative contribution that telomere shortening makes to cellular senescence. In the longer run it may also be useful in adult stem cell rejuvenation therapies and as part of organ replacement growth methods.
U Cambridge biogerontologist Aubrey de Grey has just delivered a presentation to the Fifth Alcor Conference on Extreme Life Extension. The conference proceedings are not online but an abstract of Aubrey's presentation is very intriguing:
Cancer: why it is now the main barrier to extreme life extension, and a revolutionary new approach to defeating it indefinitely
The genomic instability that underlies cancer makes it enormously harder to combat indefinitely than any other aspect of aging. Its only clear-cut "Achilles heel" is the absolute need to stabilise telomeres (usually with telomerase); if this can be prevented with total certainty by deleting (not just suppressing) a vital gene, cancer will be prevented. However, many of our normal cells need telomerase for their normal function. I will explain why existing anti-cancer approaches are unlikely ever to postpone cancer by more than a decade or two, and then present a radical, feasible solution, involving the periodic re-seeding of our various stem cell pools with cells whose telomeres have been re-lengthened ex vivo.
Adult stem cells are considered by some researchers to be a major source of cancer. Adult stem cells divide much more than most other cell types. Therefore they accumulate more damage from errors in replication. At the same time, since they do divide (they are mitotic in biological terms) the settings of their genetic switches are closer than the settings of post-mitotic (ie cells that never divide) cell types to the settings that allow cancers to divide without control.
The replenishment of aged adult stem cells with younger adult stem cells would serve multiple purposes. First, the youthful adult stem cell replacements would be more vigorous and hence would serve as better sources of replacement cells when fully differentiated cells die. Also, I'm guessing that Aubrey is arguing that the replacement stem cells would have fewer genetic defects and longer telomeres and hence be less prone to become cancer cells.
For a general scientific discussion of aging also see Aubrey de Grey's book The Mitochondrial Free Radical Theory of Aging.
Update: On a related subject see this report of the work of Stanford biological chemist Eric Kool on a newer faster method to elongate telomeres.
There is an important report out in New Scientist about therapeutic cloning and the relative vigor of different stem cell types. But it is difficult to puzzle out exactly what this report is saying. If anyone with relevant knowledge can go read the full article in New Scientist I'd appreciate your feedback in the comments for this post: (or email me)
Now New Scientist has uncovered a patent application that claims cloned stem cells have a big advantage over other stem cells. A team at Advanced Cell Technology (ACT) in Massachusetts, working with Malcolm Moore of the Memorial Sloan-Kettering Cancer Center in New York, cloned skin cells from two cows. They then injected blood-forming stem cells (which also give rise to immune cells) from the cloned fetuses back into the cows. One cow had its immune systems suppressed with drugs.
The cloned cells seemed to have an amazing ability to take over from adult ones, replacing up to 50 per cent of the cows' blood stem cells after just one infusion, even in the cow whose immune system was untouched.
UPDATE: Upon reflection, my interpretation: First, they took skin cells from the cows. Then they cloned them by putting their nucleuses into unfertilized eggs (from the same or different cows?). Then they grew cow fetuses to the 100 day point. Then they harvested blood stem cells from the fetuses. Then they injected those blood stem cells back into the adult cows that had been cloned. These cloned stem cells outcompeted the existing blood stem cells. Okay, then how did they know that the cloned cells outcompeted the existing stem cells that were already in the adults? Did they inject each cow's clone-derived stem cells into the other cow in the pair? They would need some genetic marker that would let them tell the cloned cells apart from the native cells of the cow. Possibly they used mitochondrial DNA for that purpose by using a different cow as the egg donor for the cloning.
While this article doesn't convey the details of these experiments with sufficient clarity the article does seem to be claiming that the cloned stem cells were in some sense younger than the more adult stem cells. If this is what the ACT researchers found then this is very important. Many scientists are trying to coax adult stem cells into becoming various differentiated cell types and some successes are even being reported. However, the cells in the adult stem cell reservoirs in the body age along the rest of the body. This latest result underscores this point. As scientists find ways to coax adult stem cells into becoming various assorted differentiated cell types will they find that the adult stem cells will be too old and tired to become enough of each needed cell type to be useful? Or will they find that the differentiated cells so produced are too old to function properly?
Old People Most Need Replacement Cells. The Old people are the group who have the most amount of illness and who are most in need of having their stem cells coaxed into making various kinds of differentiated replacement cells. Yet the adult stem cells of old people are also going to be old and therefore less vigorous than those of younger adults.
Youthful adult stem cells are not just useful for treating illnesses. If the adult stem cell reservoirs could be replenished with youthful cells then we could become at least partially youthful again. Just as embryonic stem cells (whether created by classical fertilization or by cloning) can be converted into fully differentiated cells it ought to be possible to find ways to coax them into becoming each of the specialized adult stem cell types. This is desireable because adult stem cells are creating differentiated cells throughout our bodies every day. They are making new skin cells, blood cells, neurons, and assorted other cell types.
However, coaxing embryonic stem cells to become adult stem cell types may not turn out to be any easier than coaxing a given adult stem cell type into becoming other different adult stem cell types. We need to understand in far more detail what makes each adult stem cell type be that type and not some other adult stem cell type or the embryonic stem cell type. It is a lot easier to find indications that one has created a differentiated cell type because differentiated cell types have unique proteins that are well known and used for doing what they do and they make various chemicals that can be tested for. But to stop differentiation at an intermediate step (ie at the adult stem cell step) is harder.
While this latest report may demonstrate an advantage of stem cells created by cloning it doesn't answer the question of why those cells are more vigorous. If the report really did find that adult skin fibroblast cells, when cloned, became stem cells that were more vigorous than existing adult stem cells in the same animal then why? One potential explanation is that the cloning process presented the differentiated adult fibroblast's genome with chemical signals that induced it to grow its telomeres. However, there are other possibilities. One big one is that the cloning procedure may just have selected for less damaged DNA. If the scientists had to clone many nucleuses in order to get one that worked then the scientists may have just been selecting for a cell that had the least amount of accumuation of aging-related damage to its genome.
Fixing Telomere Length: If telomere length is the problem a technique may be found to take adult stem cells out of the body, bath them with in genes or drugs that induce telomerase to make long telomeres, and then to transfer the reinvigorated stem cells back into the body. There is a caution here. Even if such a procedure worked and the stem cells became more vigorous the cells might still have a dangerous amount of accumulated DNA damage in them as well. The risk of cancer and metabolic disorders might be increased.
Fixing Accumulated DNA Damage: However, if adult stem cells become old due to accumulation of DNA damage then that becomes a much harder problem to fix. The genome is 3 billion base pairs lone. It will some day be possible to locate and identify all the mutations in an extracted line of adult stem cells. But then all the mutations (or at least all the important ones) would need to be fixed. Gene therapy to fix that amount of damage is far in advance of where gene therapy is today.
Select Cells With Less Damaged DNA: Another possible approach would be to take out large numbers of adult stem, let each cell divide, and take one of each pair and sequence its DNA. Look for cells that have the least amount of DNA damage. Then fix their telomeres and/or do gene therapy to fix the damage that the chosen cells do have. This approach depends on DNA sequencing technology that is under development but not yet available. It also depends on gene therapy technology that is not yet available.
Some people have ethical objections to using embryonic stem cells in to develop medical therapies. Embryonic stem cells can be created by fertilizing an egg with a sperm to make an embryo and then letting the embryo divide. However, cloning has now been demonstrated (at least in other species besides humans) as a way to create a viable embryo. This is done by taking an unfertilized egg, taking out its nucleus and putting an adult nucleus into it. Do that enough times and some small percentage of the resulting cells will be capable of developing into a fetus and then baby and then adult. But since cloning can create viable embryos (at least some small percentage of the time) many of the same people who object to using fertilized eggs to create stem cells also object to the use of cloning to make stem cells as well. In their view the fact that a cell has the potential to become a full human adult should imbue that cell with special rights and legal protections.
Note that it is not the objective of this essay to argue for or against the various positions taken in the ethics debate about various forms cloning and stem cell research. My goal here is to show why this latest report about ACT's research is pertinent to those who are making supporting arguments.
Many who argue against embryonic stem cell research claim that ways will be found to induce adult stem cells to do anything that embryonic stem cells can do. One objection to that line of argument is that it may take longer to find ways to tell adult stem cells to become less differentiated and then to differentiate down a different path. For instance, find a way to make blood stem cells to become not just locked into being blood stem cells so that they can then be told to become muscle stem cells. But this latest report strengthens another argument against adult stem cells as competitors to embryonic stem cells: adult stem cells are older and therefore generally less able to do any job they can be coaxed into doing. Therefore adult stem cells may be less able to replace embryonic stem cells for many therapeutic purposes.
Will ACT be able to do anything with the results that were the occasion for this discussion? There is reason to doubt on that score. ACT is not doing too well:
Advanced Cell, based in Worcester, Mass., temporarily suspended Cibelli's human cloning efforts for lack of money, and also sold its cattle-cloning subsidiary, Cyagra LLC, to raise cash.
Geron, the Menlo Park, Calif.-based industry leader, laid off a third of its work force and cut research spending to bolster its lagging stock price.
At least in some cases there may be a way to get relatively younger stem cells without either using embryos or cloning. One way to do it is to take stem cells from the umbilical cord of a newborn bady. The umbilical cord is going to be thrown out anyway. Using it for this purposee does not cost any real or potential life. Most kinds of ethical objections that are raised about cloned and embryo stem cells don't really apply to umbilical stem cells because umbilical stem cells are more differentiated than embryo stem cells (ie they are not at the point in development where a cell is at when it is ready to become a full fetus). The problem with umbilical stem cells up to now has been that they are few in number and haven't been easy to grow. However, here's a recent report of a better way to get stem cells from umbilical cords:
One obstacle to using cord blood more routinely as a source of stem cells in transplantation patients is the amount of blood required. Clinical trials have established that higher numbers of blood cells per kilogram of body weight of the recipient are associated with improved transplantation outcome. However, the amount of blood cells collected from cords is often not sufficient for an adult recipient. Scientists have therefore attempted to culture and expand cord blood-derived cells before transplanting them into patients. As they report in the October 21 issue of the Journal of Clinical Investigation, Irwin Bernstein and colleagues (Fred Hutchinson Cancer Center, Seattle, and University of Washington, Seattle), have been successful in doing so. Exposing human cord blood to a particular molecule called Delta-1 under defined culture conditions resulted in an over 100-fold increase in the number of the most immature stem cells. Other progenitors that maintained the potential to differentiate into multiple different blood cell types were also expanded.
On one hand the stem cells in a new born's umbilical cord should be very young and vigorous. On the other hand, these umbilical cord cells are already partially differentiated stem cells that are good at making blood cell types. Therefore it may be much more difficult to coax them to become all the other cell types that embryonic stem cells can become.
Here's another short report that again is not sufficiently detailed. Some sort of stem cell is induced to become a more differentiated neuron.
In November 11 advanced online Nature Neuroscience, Ping Wu and colleagues at the University of Texas Medical Branch, Galveston, Texas, USA, show that a novel priming procedure for fetal human neural stem cells (hNSCs) can transform them into cholinergic neurons in adult rat CNS (Nature Neuroscience, DOI:10.1038/nn974, November 11, 2002).
Did they take a fairly advanced rat fetus and extract already partially differentiated stem cells from the hippocampus to use to perform this procedure? Or did they take stem cells out of a fetus that was at a much earlier stage in development? Were the extracted stem cells more like embryonic stem cells or where they as differentiated as the sorts of stem cells that are found in adult brains?
Regardless of the type of stem cell these researchers started out with there is one note of caution to bear in mind when reports are made that stem cells have been converted into differentiated cells: It is not a certainty that the conversion was done perfectly accurately. Since we do not know exactly what pattern of genetic regulatory state characterises each cell type we don't know whether some attempt to make, say, a cholinergic neuron really made exactly that and nothing more or nothing less. Each cell type needs large sets of genes turned on and off in a pattern unique to that cell type. Its possible that some of these experiments are yielding cells that have a few extra genes turned on or a few genes turned off that shouldn't be turned on or off.
Scientists are gradually identifying and elucidating the function of the genes that control embryonic development and cellular differentiation:
Philadelphia, PA – In the search to understand the nature of stem cells, researchers at the University of Pennsylvania School of Medicine have identified a regulatory gene that is crucial in maintaining a stem cell's ability to self-renew. According to their findings, the Foxd3 gene is a required factor for pluripotency – the ability of stem cells to turn into different types of tissue – in the mammalian embryo. Their research is presented in the October 15th issue of the journal Genes and Development.
"Stem cells represent a unique tissue type with great potential for disease therapy, but if we are to use stem cells then we ought to know the basis of their abilities," said Patricia Labosky, PhD, an Assistant Professor in the Department of Cell and Developmental Biology. "Among the stem cell regulatory genes, it appears that Foxd3 gene expression keeps stem cells from quickly differentiating – that is, developing into different types of tissue – holding back the process so that an embryo will have enough stem cells to continue developing normally."
This latest report about Foxd3 adds to an existing list of genes that control embryonic development:
"Our findings implicate Foxd3 as one of the few genes serving as a 'master switch' of the developing embryo," said Labosky. "These genes determine the fate of cells by turning on or off other genes in response to signals in the embryo."
Foxd3 joins previously identified genes, such as Oct4, Fgf4, and Sox2, which control the pluripotency of embryonic stem cells in the early stages of embryogenesis. In their experiments, Labosky and her colleagues found that these genes are still expressed despite the lack of Foxd3. This suggests Foxd3 functions either downstream of Oct4, Fgf4 and Sox2, or along a parallel pathway.
At a molecular level what makes an embryonic cell different than an adult stem cell is probably just a different set of proteins and methyl groups bound at different places on the genome on different genes and regulatory sites. It should eventually become possible to change an adult stem cell (or, for that matter, a fully differentiated cell of any number of cell types) into an embryonic cell by sending in the right kinds and sequences of signals (hormones, drugs that will be discovered, gene therapy) to change the pattern of bound proteins and methyl groups on the DNA. At that point it should be equally possible to change an adult stem cell of one type into an adult stem cell of another type.
The development of a full understanding and the ability to fine tune control of all the genes that govern development could take a long time (10 years? 15 perhaps? my guess is 20 years max). Many scientists who are working with embroynic and adult stem cells are basically hoping that without first taking the time to understand all the details of how genes control cellular growth and differentiation they will be able to find ways to make these cells grow into needed replacement cell types and organs. So the debate about the use of human embryonic stem cells is about what approaches are ethically acceptable as ways to develop new therapies in the short and medium term.
My guess is that most of the people who hold that it is immoral to use embryonic stem cells in experiments are motivated by a spiritual definition of a human life. In their minds the moment of fertilization is a moment when a spirit enters the fertilized egg. As has already been demonstrated in other species, it is possible to put an adult cell nucleus into an unfertilized egg and the chemicals in the unfertilized egg cytoplasm somehow (as yet not understood) causes changes in the DNA in the nucleus of the adult cell genome that converts it into a state is similar enough to that of a freshly fertilized egg that the cloned cell can develop into an adult of that species. Therefore there is already a method other than fertilization that allows the creation of a new life. These will not remain as the only two methods for creating cells that are capable of developing into mature adults.
Some day we will have the knowledge and techniques to allow us to manipulate adult stem cells into all other types of cells. This would allows us to bypass the use of embryonic stem cells. But it would be a mistake to think this ability would allow us to entirely avoid the need to confront the ethical issues that cause some to oppose the use of embryonic stem cells. The ability to make adult stem cells into increasing numbers of other cell types will eventually extend to include the ability to make adult stem cells into embryonic stem cells. When the details come out about what makes embryonic stem cells different from adult stem cells the bright line that separates them in the minds of many opponents of embryonic stem cell use will become intellectually untenable. If the difference between embryonic and adult stem cells is just a set of molecular switches turned to different states then how can the opponents of embryonic stem cell use define the type of cell that deserves special legal protections? One could start with an adult stem cell and flip just one switch at a time to make it more and more like the switch settings that are characteristic of embryonic stem cells. How many of the switches will have to be flipped into the state that embryonic stem cells have them in before we would have to start treating the cells as embryonic and therefore entitled to special legal protection? Would they all have to be exactly as they are in an embryonic cell in order to warrant legal protection?
Advances in biotechnology promise to obsolesce the historical definitions of how we determine that something has enough of the characteristics of a human to be eligible for some degree of legal protection. The embryonic stem cell and cloning debates are just bush league warm-ups for much larger debates to come. The distance that has historically separated all manner of existing life forms from what we recognize as a human is going to narrow as it becomes possible to create humans in new ways, to give other species some of the qualities of what makes us unique (eg raise the intelligence of other species), and by methods of creating parts and keeping parts alive. We already have the problem of brain-dead humans and humans who are born with brains so defective they lack the thinking abilities that we associated with what it means to be a human. But as it becomes possible to create creatures that possess various subsets of the qualities that define humanity the question of what is a human will grow steadily more difficult to answer. Theoretical philosphical questions will become practical questions needing immediate answers. The debate over such basic questions promises to be highly divisive both within and between different human societies.
The oldest rodents living in captivity are the naked mole-rats (Heterocephalus glaber), the oldest of which are now at least 26 years old. Because of their living conditions they are less at risk of being killed by predators or accidents in the wild than are other rodent species. Therefore their longer natural lifespans are predicted by the evolutionary theory of aging. There was no big selective pressure for them to be more vigorous when younger and instead the selective pressure on all the genes that affect aging was toward longer lasting compoents.
In nature, naked mole-rats are known to live at least 10 years. "We think they live longer in the laboratory than they do in the wild because they're safer here, but they're pretty safe in nature, too," Sherman says. One of the factors contributing to the evolution of longer life spans is reduced extrinsic mortality, which Sherman defines as causes of death that are outside an animal's control, such as drowning in a flash flood or being devoured by a snake. In nature, naked mole-rats are largely protected from sources of extrinsic mortality by inhabiting subterranean burrows in extremely hard soils. Protection is enhanced by cooperative defense against predators. As a result, naked mole-rats have evolved genetic traits that make them more resistant to senescence than similar-sized, solitary, surface-dwelling rodents. Indeed, the only rodent known to live as long as the naked mole-rat is the African porcupine Hystrix brachyura , which is protected by its large body size and quills.
The diminutive naked mole-rat has something else going for it: greater fecundity with advancing age. "A large, old breeding female mole-rat gives birth to an incredible number of young and continues to do so year after year," Sherman says. "Our record for a laboratory female is 28 pups in one litter and more than 900 pups in a lifetime." Fecundity seems related to body size, Sherman adds, noting that mole-rat queens, like queens in honeybees and termites, are considerably larger than workers in their colonies. Fecundity is important because if old individuals can make disproportionate reproductive contributions, there will be strong selection to postpone senescence.
While naked mole-rats are models that support senescence theory, they are not perfect role models for humans. Senescence occurs, simultaneously, on all aspects of any organism, which means there is no single gene for aging or for youth. "Senescence theory," says Sherman, "tells us why the fountain of youth still eludes us -- and probably always will."
It isn't clear exactly what argument Paul Sherman is making when he claims that the fountain of youth will always elude us. It will be very hard to redesign out bodies in a way that totally precludes aging from happening. But that is not what is necessary. We will be able to repair and improve our bodies to make them young again. What we really need are techniques for repairing the accumulating damage and to slow the rate of accumulation. When biotechnology advances far enough we can repair the damage with periodic medical treatments (eg organ replacements, gene therapy, cell therapy) then we will get effective rejuvenaton and be able to feel and be young again. Rejuvenation by repair and replacement will be achieveable within the next 20 to 40 years.
New research on the Drosophila melanogaster fruit fly species yields results that support the mutation accumulation (MA) theory of ageing:
The other, more widely accepted theory of antagonistic pleiotrophy (AP) says that aging occurs when genes that offer help during the reproductive years -- those that produce estrogen, for example -- take on harmful roles later in life. Selection under AP theory favors the early life effects because these lead to the production of offspring but does not oppose the deleterious effects in late life, Hughes said. Building on her theoretical study of age-related inbreeding depression and genetic variability (PNAS, June 1996) while a doctoral student at the University of Chicago, Hughes and colleagues raised fruit flies to test the effect of delayed mutations.
The new study found that the deleterious effects of mutations on reproduction rose dramatically with age during the reproductive years in both genotypes -- homozygous (those with many identical genes, or inbreeding) and heterozygous (those having a variety of genes present). Reproductive success declined more rapidly, however, in the homozygous lines, as predicted by the MA theory.
"This study allowed us to detect certain kinds of genetic effects called dominance variance that are predicted to increase with age only under the MA theory," Hughes said. "The power to detect these effects is critical to tests of evolutionary aging theories, because an age-related increase appears to be a unique prediction of the MA theory, while other kinds of genetic effects can increase under either model."
There are other explanations for aging aside from the mutation accumulation (MA) theory. It is likely that aging is caused by an assortment of changes. For instance, cells accumulate trash molecules (eg lipofuscin) that the cells are unable to break down or expel. One way to solve assorted aging problems for cells that can be replaced is to replace them with younger cells. If an organ or reservoir of cells is replaced then all the aging effects for that group of cells are eliminated until the damage accumulates again. However, there are cell types for which it is far more preferable to repair than to replace (eg brain cells). So treatments utilizing both approaches will be developed.
Calorie Restriction (CR) is the only known consistent reliable way to extend life expectancy of a large variety of animals using wild type strains of animals (ie leaving aside in-bred lab strains that have special health problems). This latest result is not surprising but does suggest that CR's benefit may lie in its ability to reduce accumulation of genetic damage.
The hearts of mice on the low-calorie diets showed nearly 20% fewer age-related genetic changes and also appeared to have less DNA damage than those of mice on regular diets. Restricting calories also inhibited potentially disease-causing changes in the immune system, and suppressed apoptosis, or programmed cell death.
Numerous studies on animals have shown nutritious diets low in calories can result in significant health benefits, slow ageing and extend longevity. In some cases, the life-spans of animals in experiments have been increased by as much as a third. Even when calorie intake was not restricted until middle age, the life-span of mice increased by 20 per cent.
"Based on our finding, it appears that if people reduce their current calorie intake between 20 and 40% -- even starting in middle age -- they may delay the development of heart disease or possibly even prevent it," professor of genetics Tomas Prolla, PhD, tells WebMD.
In the August 2002 issue of Reason science writer Ron Bailey has written an excellent article surveying the prospects for various anti-aging techniques to slow and even reverse aging. He covers everything from the efficacy of antioxidants to the future prospects for gene therapy, artificial chromosomes, organ replacements, cell therapy, and nanotechnology.
I'm including a couple of excerpts to whet your appetites for the full article. In the first excerpt the discussion is about cell therapy to reseed cell populations. Note that there are adult stem cell reservoirs throughout the body used for everything from new memory formation, tissue repair, to immune cell generation. The stem cells in all those reservoirs age. Replacement of those aged cells with rejuvenated cells would partially restore youthfulness of the body:
Stem cells have been found in adult tissues, in umbilical cord blood from newborns, and in embryos. All have shown some promise. William Haseltine, the CEO of Human Genome Sciences, recently predicted in The Washington Post that it will one day be possible to "reseed the body with our own cells that are made more potent and younger, so we can repopulate the body." But stem cell transplants are at least 10 years away -- or even longer, if Leon Kass and his allies succeed in banning therapeutic cloning. Since the chorus calling for a ban includes President Bush, the prospects for research in this area are not as bright as they ought to be.
Aubrey de Grey's suggestion here is to use some form of gene therapy to move the mitochondrial DNA (mtDNA) genes into the nucleus where they are no longer close to the pathways that produce ATP energy molecules. Those pathways are responsible for a large fraction of the total number of free radicals generated in the body (by throwing off superoxide) and are a major cause of aging.
The Cambridge gerontologist Aubrey de Grey wants to genetically engineer mitochondrial genes into the nuclei of cells, where they would be better protected from the ravages of free radicals. He believes that once those genes are better protected they will not be so quickly mutated into the free radical death spiral. Once the vicious circle of mitochondrial mutations producing ever more free radicals is broken, longer life should result, he argues.
Aubrey's suggestion can be combined with the idea of reseeding adult stem cell reservoirs. Some day it will be possible to take some tired old adult stem cells from the body, do gene therapy to repair and rejuvenate them and also perform the gene therapy that also moves the mtDNA genes into the nucleus. Then reintroduce the rejuvenated adult stem into the body, The advantage of this approach is that as the adult stem cells gradually reproduced and differentiated into other cell types various portions of the body would gradually become the improved younger and more slowing aging cell types. Other genetic improvements besides the mtDNA-to-nucleus improvement could be introduced using this approach.
One of the lessons here is that while it will certainly become possible to genetically engineer progeny to be more resistant to aging those of us already alive with our own flawed genomes are not stuck with the hand that nature initially dealt us. Most of the genetic improvements that will be doable to progeny will also be doable to us if we can only live long enough to be around when the techniques become available. Gene therapy to make youthful replacement adult stem cells is not the only way this will be done. Another way would be thru organ replacement. It will some day be possible to take a cell sample from a person, apply rejuvenating and repair gene therapies and gene therapies that make the cells more resistant to aging. Then grow a new liver, stomach, or other organ from the rejuvenated cells and surgically put in the newer and longer lasting organ.
If you want to read even more then a great place to start is Aubrey de Grey's book The Mitochondrial Free Radical Theory of Aging.
P.S. I'm not going to post any more FuturePundit articles today because your time would be better spent reading Ron's full article if you haven't already read it. ;)
The only consistently reliable way found to slow the aging process across a large number of species is calorie restriction (CR). Cut calorie content of a diet to 30% less than an organism naturally eats and max and average lifespans will typically go up by 20% or 30%. CR is practiced by relatively few people because it is difficult to do and has some side effects (eg a gaunt appearance). A human study of the long term effects of CR has not been done because it would take a very long time to prove that CR really does increase lifespan (though shorter term studies have been done). The life extending effects have only been demonstrated in shorter lived species because its much easier (ie it takes a lot less time) to do lifespan experiments on shorter lived species. However, the physiological effects that happen during CR in other species (eg lower blood insulin and other factors easily measured in blood tests) also happen to humans on CR and human metabolism has enough in common with other species that it is reasonable to expect that CR will increase human life span.
As Scientific American reports in a lengthy interesting article, species more like humans are being studied on CR regimes and preliminary results look promising:
The rat findings have been replicated many times and extended to creatures ranging from yeast to fruit flies, worms, fish, spiders, mice and hamsters. Until fairly recently, the studies were limited to short-lived creatures genetically distant from humans. But long-term projects under way in two species more closely related to humans--rhesus and squirrel monkeys--suggest that primates respond to caloric restriction almost identically to rodents, which makes us more optimistic than ever that CR mimetics could help people.
The monkey projects--initiated by our group at the National Institute on Aging in the late 1980s and by a separate team at the University of Wisconsin- Madison in the early 1990s--demonstrate that, compared with control animals that eat normally, caloric-restricted monkeys have lower body temperatures and levels of the pancreatic hormone insulin, and they retain more youthful levels of certain hormones (such as DHEAS, or dehydroepiandrosterone sulfate) that tend to fall with age.
Some scientists believe that it may be possible to use a pharmacological agent to flip metabolism into the mode that CR puts the into. As this article indicates, the search is on for compounds that will emulate the metabolic changes that CR causes. The most thoroughly investigated compound to date is 2-deoxy-D-glucose. The problem with it is that its therapeutically effective dose in rats is very close to its toxic dose. If a safe and effective compound can be found then it will be possible to achieve most of the benefit fhat CR provides in terms of slowing aging without the need to feel hungry or have a gaunt appearance.
The researchers found that the median life span--the age by which half of the dogs had died--was nearly 2 years longer among the calorie-restricted dogs (13 years, versus 11.2 years). The dieting dogs also tended to go longer without needing treatment for chronic conditions--age 12, on average, compared with age 10. In both groups of animals, osteoarthritis was the most common medical problem, but the calorie-restricted dogs developed the condition an average of 3 years later than their litter-mates.