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.
They now plan to automate the process to get the costs down.
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.
Ampakines reverse some aspects of brain aging in rats.
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.
Young blood makes old cells act younger.
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.
Also see the Better Humans coverage of this story.
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.
Glenn Reynolds dismisses concerns that rejuvenation will cause society to become too static.
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.
Want another 20 years of life?
"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."
Some see youthful rejuvenation as something that can be accomplished within 50 years.
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.