Because immune cells circulate in the blood they strike me as great early candidates for development of rejuvenating stem cell therapies. The cells in the blood are accessible and replaceable than cells which living in complexly shaped organs. A great target for youthful cell development are the naive T cells which age and become less able to divide.
PORTLAND, Ore. – Researchers at Oregon Health & Science University have uncovered new information about the body’s immune system in a study that suggests new strategies may be in order for protecting the country’s aging population against disease. The research is published in the current edition of the Proceedings of the National Academy of Science.
The research focused on an important component of the body’s immune system, a certain type of white blood cell called naïve T-cells. These cells are called naive because they have no experience of encountering germs. However, once they encounter germs, they learn and adapt to become strong defenders of the organism. The cells play an important role in the vaccination process because vaccines, which contain either weakened or dead viruses, teach naïve T-cells how to recognize germs and prepare the body for fighting infectious diseases at a later date. Previous research shows that an individual’s supply of naïve T-cells diminishes over their lifetime, meaning that in old age a person is more susceptible to infections such as the flu.
“Our research identified one actual process by which naïve T-cells are lost later in life,” explained Janko Nikolich-Zugich, Ph.D., a senior scientist at the OHSU Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center and a professor of molecular microbiology and immunology in the OHSU School of Medicine.
“Throughout our lives, naïve T-cells divide very slowly in our bodies. This helps maintain sufficient numbers of naïve T-cells while we are young. As we age, naïve T-cells are lost and the remaining ones speed up their division to make up for the losses in their numbers. Interestingly, after a certain point, this actually causes the numbers of naïve T-cells to dwindle over time. Our data shows that once the number of naïve T-cells drops below a critical point, the rapidly dividing naïve cells are very short lived. Based on this finding and other information, research suggests that some of the aging Americans may be better protected against disease by finding a way to jumpstart production of new naïve T-cells instead of through revaccination.”
Infectious disease kill a lot of elderly people because their immune systems become too weak to hold off infections. But that is not the only way that immune system aging costs us. Aged immune systems are less able to fight off cancer and immune system aging might even be the biggest cause of the increasing incidence of cancer seen as people age.
We need to find a way to create youthful naive T cells to inject into us. Such cells would at least partially rejuvenate our immune systems and by doing so reduce our risk of cancer and infectious diseases.
Here is yet another reason brain aging is something we should figure out how to stop and reverse. The part of the brain that regulates thirst becomes inaccurate and underestimates water needs as we age.
Florey researchers Dr Michael Farrell, A/Prof Gary Egan and Prof Derek Denton discovered that a region in the brain called the mid cingulate cortex predicts how much water a person needs, but this region malfunctions in older people.
Dr Farrell said they infused old (age 65 to 74) and young (age 21 to 30) research participants with salty water to make them thirsty and then allowed them to drink as much water as they wanted.
“Although all participants had the same level of thirst, the older people only drank half as much water as the younger subjects,” Dr Farrell said.
“Using PET imaging we found in the older people, the mid cingulate cortex was ‘turned off’ much earlier by drinking small volumes.”
“This discovery helps explain why the elderly can become easily dehydrated,” he said.
As you age many processes in your brain start going awry. We need to develop biotechnologies to rejuvenate our brains. We'd become more productive, happier, and less hobbled by assorted maladies.
Your heart squeezes and relaxes more slowly every year as you get older.
Researchers at Johns Hopkins have evidence to explain why the supposedly natural act of aging is by itself a very potent risk factor for life-threatening heart failure.
In a study to be presented Nov. 4 at the American Heart Association’s (AHA) annual Scientific Sessions in Orlando, Fla., the Hopkins team analyzed more than a half-dozen measurements of heart structure and pumping function to assess minute changes in the hearts of 5,004 men and women, age 45 to 84, of different ethnic backgrounds and with no existing symptoms of heart disease.
Researchers found that each year as people age, the time it takes for their heart muscles to squeeze and relax grows longer, by 2 percent to 5 percent.
Test results were obtained from study participants who had undergone high-tech magnetic resonance imaging of the heart - tagged MRI - which measures individual muscle segment changes with each heartbeat.
We need stem cell therapies and other therapies that can reverse the changes that happen as our hearts age.
Our hearts eject less blood on every beat each year we get older.
The current gold standard, he says, is the heart’s ejection fraction, a ratio of the amount of blood pumped out with each heartbeat to the total volume of blood available for pumping. An ejection fraction of 50 percent to 65 percent is considered normal.
Study results showed that ejection fraction actually rose by 0.01 percent with every year. But Lima calls this figure misleading because the total amount of blood available for pumping, the bottom number in the ratio, decreases as the size of the heart cavity shrinks and heart walls thicken, falsely boosting test results when heart function is actually failing.
When researchers separated the numbers, the actual amount of blood pumped out by the heart fell by 8 milliliters per year, says Lima, an associate professor at The Johns Hopkins University School of Medicine and its Heart Institute.
All of these changes will become reversible. The aging process is not set in stone. The changes that come with aging will some day be reversed with gene therapies, cell therapies, and other treatments.
Ghrelin, which appears to stimulate appetite, also prevents or slows shrinkage of the thymus (a key organ for regulating the immune system) which occurs with increasing age.
The deterioration in immune function that occurs as an individual ages is thought to occur because the thymus involutes with age, causing a dramatic decrease in T cell output. New data generated by Dennis Taub and colleagues from the National Institutes of Health, Baltimore, suggest that in mice, thymic involution is caused by a decrease upon aging in thymic expression of both a hormone that is better known as a stimulator of food intake (ghrelin) and its receptor. These results led them to caution that care should be taken when considering blocking ghrelin as a potential approach for treating individuals who are obese and to suggest that harnessing this pathway might provide a new approach to boost immune function in individuals who are elderly or immunocompromised.
The physiological relevance of the decrease, with age, in expression in the mouse thymus of both ghrelin and its receptor was highlighted by the observation that infusion of ghrelin into old, but not young, mice markedly increased thymic mass, improved thymic architecture, and increased thymocyte and thymic epithelial cell numbers. These changes were associated with increased T cell output and increased diversity of the TCR repertoire of the peripheral T cell population. Consistent with these observations, age-associated thymic involution was accelerated in mice lacking either ghrelin or its receptor.
This poses a quandary: Use ghrelin which will likely increase the fat and boost the immune system? Or cut the fat and reduce the immune system? The story is actually more complex than that. See this review of how ghrelin and leptin influence appetite for the details.
This reminds me of the potential risks of older people taking growth hormone and androgens. We have a hard time trying to use hormones to boost various metabolic processes without incurring some costs of bigger problems in other areas. We need orders of magnitude more information about how human metabolism really works so that we can know how and where to intervene to achieve desired changes in metabolism without producing dangerous and unpleasant side effects.
The abstract of the paper provides a helpful clue to the ghrelin quandary. Ghrelin promotes thymopoiesis (poiesis means creation or production) during aging - but leptin (an appetite suppressor) does too.
We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow–derived Lin–Sca1+cKit+ cells, while ghrelin- and growth hormone secretagogue receptor–deficient (GHS-R–deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice.
So maybe we could use leptin to boost thymus size without boosting appetite. Then again, maybe boosting leptin would cause problems we don't even know about yet.
DALLAS — Sept. 4, 2007 — A simple imaging technique developed by UT Southwestern Medical Center researchers has revealed fat buildup in the hearts of pre-diabetic people long before symptoms of heart disease or diabetes appear.
This discovery fits a larger trend: in the future you'll be told sooner when parts of your body start breaking down. In fact, sensors will become so powerful that you'll be able to get daily measures (if you can stand to watch) of the many many small steps of your gradual decay into old age. This sort of advance will shift public perceptions about aging and cause younger people to see their bodies as gradually accumulating lots of small bits of old age. This will make people a lot more conscious of the aging process and reduce the feeling of invulnerability that younger people feel when looking at older people. I'm expecting this development and others like it to build support among younger people for a faster rate of research into techniques to slow, stop, and reverse the aging process.
Yet another impressive advance in scanning technology.
The technique detects fat accumulation in cells of the beating heart in a way no other clinical method can, the researchers said, and may provide a way to screen patients for early signs of heart disease in diabetes.
“Hearts beat; people breathe; and magnetic resonance imaging is very sensitive to motion, so we had to find a way to electronically ‘freeze’ the image of the heart,” said Dr. Lidia Szczepaniak, assistant professor of internal medicine at UT Southwestern and senior author of a study appearing in the Sept. 4 issue of Circulation.
“We wanted a noninvasive method to study the beating human heart,” Dr. Szczepaniak said.
Dr. Szczepaniak and her colleagues developed a technique that captures the signal from a beating heart as a person lies in an ordinary magnet used for MRI scanning.
The ability to detect the early stage development of insulin resistant (type 2) diabetes will serve the useful purpose of telling people to change their diets and lose weight. This capability should be more powerful than telling people they have high cholesterol and lipids in their blood since the report of fat build-up in heart muscle cells seems scarier. This MRI scan technique measures the early stage malfunction of a heart. Will you want to know about that?
The key to the whole process is Wnt, a protein traditionally thought to help promote maintenance and proliferation of stem cells in many tissues. But in this instance, Wnt appears to block proper communication.
"That was a total surprise," said Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences. "We had no idea that the Wnt signaling pathway would have a negative effect on stem cell function." Rando, who also does research and clinical work at the Veterans Affairs Palo Alto Health Care System, is senior author of the research that will be published in the Aug. 10 issue of Science.
Rando previously discovered (and the link below is to a previous post I did on that report) that old stem cells will act younger if exposed to younger blood. That's very troubling news for efforts to develop rejuvenating cell therapies. If the whole body is full of chemical signals that suppress growth then just replacing older stem cells with younger stem cells won't yield as much increase in healing and repair as our aging bodies need.
Rando had already discovered that old muscle stem cells, if placed in a youthful environment, had just as great a capacity for repairing acutely damaged tissue as do young cells.
It was while the researchers were testing the opposite situation - how the repair capabilities of young muscle stem cells were affected by being placed in an aged environment - that the Wnt pathway came to light. The work was done with live mice whose circulatory systems were joined, and in lab dishes with young cells immersed in serum from old blood.
As expected, the young muscle stem cells were influenced negatively by the aged environment, repairing damaged muscle tissue just as slowly and poorly as old stem cells in the same surroundings. This confirmed their earlier research showing that the ability of muscle stem cells to regenerate tissue depends on the age of the cells' environment (including the age of the blood supplying the tissue), not the age of the stem cell.
The stem cells exposed to too much Wnt failed to produce needed replacement muscle cells. Worse yet, the muscle stem cells formed scar tissue instead.
Rando also found that the misdirected stem cells - the ones that failed to generate new muscle cells in the old environment - were instead differentiating into scar-tissue-producing cells called fibroblasts. The stem cells weren't just failing to respond to the garbled instructions, they were actually giving rise to daughter cells that turned into the wrong thing. The consequence of muscle stem cells producing fewer muscle cells (myoblasts) and more fibroblasts is that the healing muscle had more scar tissue, also known as fibrosis.
"That says something about how cells decide who they're going to be. Even if they start off knowing they're supposed to be a muscle cell, they can change," said Rando. "If you're exposed to the wrong environment, it will change your fate."
Rando said the type of fibrosis that occurs in the aging muscle tissue is the same type seen in muscular dystrophy. He is already exploring how inhibiting Wnt signaling might help provide therapy for that disease.
So as you age your muscles accumulate scar tissue. We need ways to get rid of that scar tissue and replace it with youthful muscle cells produced from youthful and properly instructed stem cells.
Another research group has just discovered that Wnt is able to suppress mouse stem cell activity because as mice age their bodies make less of another protein called klotho. Well, klotho restrains Wnt and the absence of klotho causes Wnt to suppress stem cell division.
Wnt has also popped up unexpectedly in work by researchers at the National Institutes of Health, published in the same issue of Science, who were studying the effects of a deficiency of a hormone called klotho. Klotho deficiency causes a syndrome that resembles extremely rapid aging in mice, which end up dying very young compared with normal mice. In seeking to understand why that happens, the NIH researchers discovered that klotho inhibits Wnt activity. The hypothesis is that klotho production declines with age, and thus its effectiveness against Wnt decreases, allowing Wnt activity to pick up and disrupt the normal signaling to the stem cells in a variety of tissues studied.
You might think hey, why not deliver klotho hormone replacement therapy to slow or reverse cellular aging? Good question. Let me put the question another way: Why does klotho production decline with age? Is it just due to accumulation of damage to klotho-making machinery? My guess: the decline of klotho happens in order to reduce the risk of cancer. As cells age they accumulate mutations that could become cancerous. By slowing cell division by reducing klotho the body reduces healing but on average that reduction in healing becomes a net benefit due to avoided cancer.
Here is the abstract of that NIH study that Rando mentioned. Klotho suppresses Wnt whereas continuous exposure to Wnt causes cells to go into a senescent (old, much lower level of function) state.
The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.
We need to know whether other genes signal klotho's gene to stop expressing itself. We also need to know what upstream event starts the sequence of gene activations and deactivations that lead to too little klotho.
Wnt is an obvious candidate for drug development. A drug that binds to Wnt and blocks its action will probably have the effect of making your stem cells divide more vigorously and to form more types of needed cells. Though such a drug probably would increase your risk of cancer. For someone who is suffering from, say, life threatening cardiovascular disease the trade-off from drug use of getting more repair cell activity with more cancer risk would probably be worth it.
We need much more progress toward the goal of understanding how stem cells interact with aging bodies. In spite of all the news above about Wnt and klotho it seems likely that replacing aged stem cells with more youthful stem cells will yield many therapeutic benefits. The aged stem cells are at greater risk of becoming cancerous. Their replacement by stem cells that have far fewer accumulated genetic defects will reduce the risk of cancer from stem cells as well as provide stem cells that can divide more times. Older stem cells have shortened telomeres that become obstacles in the way of stem cell division.
If we could only find ways to keep stem cells active as the years go by we would develop degenerative diseases of old age much less frequently.
Despite the popular notion that antioxidants, such as vitamins C and E, offer health-promoting benefits by protecting against damaging free radicals, a new study in the August 10 issue of the journal Cell reveals that, in fact, balance is the key. The researchers show in mice that an overload of natural antioxidants can actually lead the heart to failure.
There is plenty of evidence about the damaging effects of oxidative stress, but “there is another side to the coin,” said Ivor Benjamin of the University of Utah, Salt Lake City. “There has been so much emphasis on free radicals to the exclusion of the potential consequences of reductants. Our study provides the first bona fide example of the role that reductive stress can play in disease.”
Reductants, sometimes referred to as antioxidants, are elements or compounds that easily give up an electron to become “oxidized,” while oxidizing agents readily accept electrons. In the body, such oxidation-reduction (redox) reactions are integral to the release and storage of energy. Many cellular pathways are also sensitive to the prevailing redox condition.
In a nutshell: A human mutation that causes muscle damage was added to mice. The scientists discovered that in mice this mutation causes an excess amount of glutathione in reduced form. They think that reductive stress (the opposite of oxidative stress) causes the protein clumping and muscle damage which accompany this mutation.
In the current study, the researchers examined mice carrying a human mutation earlier linked to so-called protein aggregation skeletal myopathies and cardiomyopathies, in which weakening skeletal and heart muscle contain clumps of proteins. Although the genetic basis for the disease had been linked to mutations in one of two genes, the mechanism responsible remained mysterious.
The researchers now show that mice with one of the mutant genes, áB-crystallin, specifically in the heart develop the same symptoms seen in human patients, including heart enlargement, progressive heart failure, and an early death. They further show that the animals’ hearts are under reductive stress.
The find initially took Benjamin by surprise, he said. They had conducted a test traditionally used to measure the level of oxidative stress in the animals, expecting they might see higher than normal levels. Instead, they found the mice had “markedly reduced” oxidative stress levels due to an abundance of a natural antioxidant known as glutathione.
The mutant mouse hearts exhibited a heightened stress response, including higher activity of heat shock proteins that have been documented in human heart failure, Benjamin explained. Such stress responses yield reactive oxygen species, triggering antioxidative pathways to kick in. In the diseased animals, however, that pathway—in which oxidized glutathione is recycled to its reduced, antioxidant form—soon got out of hand, producing excess levels of the reduced glutathione and a condition of reductive stress.
Too much of a good thing becomes a bad thing.
Less of an enzyme involved in generation of reductive compounds allowed the mice to avoid heart disease.
Moreover, they showed that the offspring of the heart-diseased animals and mice with lower levels of one of the antioxidant enzymes, glucose-6-phosphate dehydrogenase (G6PD), were relieved of their symptoms.
G6PD appears to help restore glutathione back to its reduced state. So a reduction in G6PD likely shifts glutathione back toward its reduced form. Cutting back G6PD lowered the amount of reduced glutathione in cells and doing that avoided heart disease.
Biogerontologist Aubrey de Grey has long argued that antioxidant vitamins would provide little life extension benefit. Why? Because antioxidant compounds are easy for cells to synthesize and if more of the antioxidant (aka reductant) compounds provided a net benefit then very likely selective pressures would have caused us to make more of these antioxidants.
There's no easy magic bullet to slow down the rate of aging. We need treatments that will repair the damage caused by aging. Those rejuvenating repair treatments will come in the form of cell therapies, gene therapies, and replacement organs.
Telomeres, pronounced TEE-low-meres, are DNA caps. They protect genes at the tips of chromosomes — all 23 pairs that reside in the nucleus of each of our trillions of cells. They are kind of like the tips that keep your shoelaces from unraveling.
A handful of studies indicate that telomeres are shorter in the immune cells of older people in comparison with the young. Now, a research team led by UCSF’s Wen-Chi Hsueh, MPH, PhD, suggests that telomere length might be associated with life span itself. Hsueh and colleagues published their very preliminary findings in the July 17 issue of the Proceedings of the National Academy of Sciences (PNAS).
The PNAS study co-authors believe they are the first to report an association between telomere length and life span. But the finding needs to be confirmed, Hsueh says, as more data on life span become available. Only 35 study participants have died so far.
Telomeres are caps on the ends of chromosomes. Current thinking is that every time a cell divides its telomere caps get shorter. Once the telomeres get short enough cells have a hard time dividing and perhaps become senescent. The telomere cap length shortening might be a mechanism for reducing the incidence of cancer. So if we could find a way to lengthen telomere caps of cells in our bodies any resulting rejuvenation might come at the expense of greater incidence of cancers. So you die from your cells not dividing enough or you die from your cells dividing too much.
At least in this Old Order Amish population the telomere lengths in fathers appear to correlate with the telomere lengths in their offspring.
The researchers discovered that average telomere length in fathers — but not mothers — was related to telomere length in children. Moreover, the researchers found an association between daughters’ telomere length and how long their fathers lived. This suggests that life span and telomere length may share some genetic determinants.
“It’s very rare to observe such a paternal inheritance phenomenon for complex traits, so I was very surprised,” Hsueh says.
The likely explanation is a biological phenomenon known as imprinting, Hsueh says. In imprinting, the activity of certain genes depends on whether they were passed down through one’s mother or one’s father. The maternal gene copies are not active. The exact mechanism by which imprinting might affect the inheritance of telomere length remains mysterious, Hsueh says.
I'm even more interested in the "Why?" than the "How?" about this effect. What advantage is there (if any) to having the father's telomere lengths exert a stronger influence on offspring than the mother's telomere lengths? Does some adaptive advantage come from this? Or is it a side effect of something else that was selected for?
The study was done on Old Order Amish in Pennsylvania because they are genetically fairly homogeneous and live very similar lifestyles to each other.
The Amish fit the bill. They have a small number of ancestors — about 200 Amish families came to the United States from Europe about 14 generations ago, during the early to mid-1700s. Now, there are about 30,000 Old Order Amish living in Lancaster County. They do not marry outsiders. As a result, they have little variability in their genes — a small gene pool. That reduces the complexity of finding genetic variants that may be associated with particular traits or diseases within the population.
There also is little variation in lifestyle and environment to complicate the study of genetic influences on aging, Hsueh notes. Amish women do not smoke or drink, and those behaviors also are very rare among Amish men. The Amish eat together in large groups and have similar schedules.
Highly homogeneous populations are very handy for teasing out various potential causes of differences in development and diseases.
Even though telomere lengthening would probably increase risk of cancer that will not always be the case. Picture, say, 10 or 20 years from now. Suppose an effective and controllable technique for telomere lengthening is found (probably a gene therapy that includes telomerase genes). How can telomere lengthening get used to increase life expectancy without increased death from cancer?
First off, we might have 100% effective cures for cancer 20 years from now. Certainly we will sooner or later. Whenever we develop the ability to cure cancer we'll be able to make use of many treatments that have the side effect of increasing cancer risk.
Second, we will gain the ability to selectively apply telomere lengthening only to cells which have no mutations that increase risk of cancer. Hiow? Take a bunch stem cells out of a body. Put each individually in a small tube with nutrients. Send in gene therapy to fix each cell's telomeres. Let each cell divide. Take just one cell out of each tube. Test for DNA mutations that increase cancer risk. Go back to the small tubes that contain cells which have no detectable cancer risk and let them replicate in much larger numbers. Then reinject those stem cells back into the body.
Third, repair the genes that have accumulated mutations that contribute to cancer. The third approach is similar to the second approach except more extensive gene therapy will get placed into each cell in order to repair the genes that have dangerous mutations. Basically, repair all the mutations that could contribute to cancer. Then telomere lengthening could be done safely without boosting cancer risk.
We need greater efforts to start testing out stem cell rejuvenation therapies such as telomere lengthening. This work could get done in rats, mice, and other non-human species and would provide useful indications on what kinds of stem cell rejuvenation therapies will work best.
If we could find a way to rejuvenate stem cells without boosting cancer risk then we could probably prevent and even reverse many degenerative old age diseases. See, for example, my previous post Bone Marrow Stem Cell Aging Key In Atherosclerosis.
Also see my previous posts "Telomere Length Indicates Mortality Risk" and "Chronic Stress Accelerates Aging As Measured By Telomere Length" and New Telomere Lengthening Technique Developed and Telomeres Wear Down Quicker In Men Than Women and Aged Blood Stem Cells Indicator For Cardiovascular Disease Risk.
Stuart Chambers, Margaret Goodell, and their colleagues investigated the molecular mechanisms underlying aging of stem cells by looking at the gene expression profiles of aging hematopoietic stem cells (HSCs), the precursors of blood cells. They found that genes involved in the inflammatory and stress response became more active with age, while genes important for regulating gene expression and genomic integrity became less active. These results lend strong support to the notion that HSCs succumb to the wear and tear of aging, just like other cells, and shed light on the mechanisms of aging.
To study HSCs’ regenerative capacity over time, Chambers et al. isolated HSCs from young (aged 2 months) and old (aged 21 months) mice and then transplanted either young or old cells into mice whose bone marrow cells had been destroyed by radiation. The young and old HSCs gave rise to new marrow cells at roughly the same pace 4 weeks after transplantation. But at 8 and 16 weeks after transplantation, the old HSCs’ contributions had dropped considerably, suggesting that aging HSCs lose their repopulating capacity. Yet, because HSCs increased in number, overall blood production from HSCs remained stable.
This is good news. Our stem cells grow old. Youthful stem cells perform better than older stem cells in the same sorts of organisms. The development of techniques to create youthful stem cells will yield cells that make great rejuvenation therapies. Youthful stem cells probably will not create as much inflammation in the body.
The finding that genes involved in the inflammatory response are expressed more (called up-regulation) as HSCs age fits with evidence linking inflammation and aging in the kidney, brain, and arteries. It may also help explain why HSCs lose function. One of the up-regulated genes, P-selectin, encodes a cell surface adhesion molecule. Because transplanted HSCs depend on cell adhesion to colonize bone marrow properly, the researchers explain, inappropriate up-regulation of genes encoding P-selectin may interfere with this process.
This result illustrates why Aubrey de Grey calls for development of youthful stem cell therapies to replace aged reservoirs of stem cells in our bodies with younger stem cells. Our aging stem cells gradually malfunction in more and more ways. We'd feel and function at a much higher level if we had younger stem cells that could repair lots of aged tissues all over the body.
The full Plos Biology article is available online. About 3000 genes undergo changes in their levels of expression as a result of aging.
Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.
I am very curious to know which genes or regulatory regions in chromosomes accumulate the most damage with age. If the number of key damaged areas is not too great then gene therapies could some day go in and repair those locations in the genome which accumulate damage.
(PHILADELPHIA) – Researchers at the Abramson Family Cancer Research Institute of the University of Pennsylvania have found that deleting a gene important in embryo development leads to premature aging and loss of stem cell reservoirs in adult mice. This gene, ATR, is essential for the body’s response to damaged DNA, and mutations in proteins in the DNA damage response underlie certain types of cancer and other disorders in humans. This work appears in the inaugural issue of Cell Stem Cell.
Signs of aging come fast if an organism can't do tissue repair.
“The reason these mice age prematurely is that we’re exhausting their ability to renew tissues,” says Eric J. Brown, PhD, Assistant Professor of Cancer Biology. “These findings may be helpful to the aging and oncology fields since premature aging syndromes and many cancers involve the loss of DNA repair genes.”
When the researchers deleted ATR in the tissues of adult mice, they noticed that the mice showed signs of premature aging, such as hair graying, hair loss, and osteoporosis, within three to four months.
To be able to renew itself, most tissues have a reservoir of specific adult stem cells. These stem cells don’t divide as frequently as other cell types since they need to maintain the integrity of their DNA, and multiple divisions lead to natural breaks in DNA. But when these stem cells are needed, their progeny can rapidly divide and are able to replenish the tissue with new cells.
As we age our stem cells age right along with the rest of us. Aged stem cells gradually slow down and lose their ability to create replacement cells to repair damage caused by aging. As the repair systems slow down more damage accumulates and we get older.
This study supports the notion that replacement of aged stem cells with youthful stem cells will help slow and even reverse the process of aging. The development of the ability to create the various adult stem cell types is a crucial step in the development of full body rejuvenation therapies. Once we can create such cells on demand then their injection into our blood streams and into specific stem cell reservoirs will give our bodies the resources needed to repair worn out and failing body parts.
As we age a key enzyme in our muscle declines and exercise does less to raise its level.
The researchers found that so-called AMP-activated protein kinase (AMPK) slows down in the skeletal muscle of 2-year-old rats relative to 3-month-old rats. A chief regulator of whole-body energy balance, AMPK in skeletal muscle stimulates the oxidation of fatty acids and the production, or biogenesis, of power-producing mitochondria that burn fat and fuel cells,according to the researchers.
The new findings might help to explain "what happens as we age," said Gerald I. Shulman, a Howard Hughes Medical Institute investigator at Yale University School of Medicine.
Why does AMPK decline as we age? Is the decline an adaptation because the muscle's mitochondria become too damaged?
In response to exercise and other stimuli older rats produced far less AMPK.
In the current study, the researchers set out to determine whether the declining mitochondrial function and increased intracellular fat content seen with aging could be traced back to deficiencies of AMPK. They compared AMPK activity in young and old rats following three "perturbations" that normally stimulate the enzyme and, in turn, mitochondria production. The treatments included acute exposure to an AMPK-stimulating chemical, chronic exposure through feeding of another chemical that induces AMPK by mimicking an energy shortage, and exercise.
In every case, older rats showed a decline in AMPK activity compared to younger animals. Young rats infused with a stimulatory chemical showed an increase in muscular AMPK activity not seen in old rats, they found. Similarly, the muscle of exercise-trained young rats showed more than a doubling in AMPK activity. In older rats, that AMPK hike with exercise was "severely blunted." The muscles of young rats fed the AMPK-stimulating chemical also showed an increase in AMPK and a 38% increase in mitochondrial density, they reported. In contrast, older animals' AMPK activity and mitochondrial numbers held steady.
As we get older exercise becomes less effective. Plus, a low level of AMPK might put us at greater risk of type 2 insulin insensitive diabetes.
Would a drug or gene therapy that stimulates AMPK production increase muscle strength and decrease fat? Would it come at some cost? Does the body slow down AMPK production because the muscle cells become too aged to do as much? Or would higher AMPK increase cancer risk?
PITTSBURGH, Dec. 20 – The accumulation of genetic damage in our cells is a major contributor to how we age, according to a study being published today in the journal Nature by an international group of researchers. The study found that mice completely lacking a critical gene for repairing damaged DNA grow old rapidly and have physical, genetic and hormonal profiles very similar to mice that grow old naturally. Furthermore, the premature aging symptoms of the mice led to the discovery of a new type of human progeria, a rare inherited disease in which affected individuals age rapidly and die prematurely.
"These progeroid mice, even though they do not live very long, have remarkably similar characteristics to normal old mice, from their physical symptoms, to their metabolic and hormonal changes and pathology, right down to the level of similar changes in gene expression," said corresponding author Jan Hoeijmakers, Ph.D., head of the department of genetics at the Erasmus Medical Center in Rotterdam, Netherlands. "This provides strong evidence that failure to repair DNA damage promotes aging— a finding that was not entirely unexpected since DNA damage was already known to cause cancer. However, it shows how important it is to repair damage that is constantly inflicted upon our genes, even through the simple act of breathing."
The study found that a key similarity between the progeria-like, or progeroid, mice and naturally old mice is the suppression of genes that control metabolic pathways promoting growth, including those controlled by growth hormone. How growth hormone pathways are suppressed is not known, but this response appears to have evolved to protect against stress caused by DNA damage or the wear-and-tear of normal living. The authors speculate that this stress response allows each of us to live as long and as healthy a life as possible despite the accumulation of genetic damage as we age.
Can we design humans to live longer? Or will we have to constantly repair accumulating damage? How to make the DNA in our cells less prone to accumulation of damage? Will the development of massive computer simulations for computer aided biological engineering allow us to find much better designs for enzymes that protect and repair DNA?
The scientists were set off on the road to make this discovery by their investigations into the causes of a boy's genetic disease.
A German physician had contacted the center about a 15-year old Afghan boy who was highly sensitive to the sun and had other debilitating symptoms including weight loss, muscle wasting, hearing loss, visual impairment, anemia, hypertension and kidney failure.
The boy turned out to have a defect in the DNA repair mechanism called nucleotide excision repair (NER). The scientists were able to trace down the mutation to a particular gene:
When the investigators obtained cells from the boy and tested them for NER activity, they found almost none. Further analysis of the boy’s DNA revealed a mutation in a gene known as XPF, which codes for part of a key enzyme required for the removal of DNA damage. The XPF portion of the enzyme harbors the DNA-cutting activity; whereas a second portion, known as ERCC1, is essential for the enzyme to bind to the damaged DNA. Mutations in either XPF or ERCC1 lead to reduced activity of this key DNA repair enzyme.
"We were completely surprised by the finding that the patient had a mutation in XPF, because mutations in this gene typically cause xeroderma pigmentosum, which is a disease characterized primarily by skin and other cancers rather than accelerated aging," said Dr. Hoeijmakers. "This patient, therefore, has a unique disease, which we named XPF-ERCC1, or XFE-progeroid syndrome."
DNA manipulation technologies have become powerful enough to allow creation of lab mice which have any mutation of interest. So these scientists do what many scientists do when faced with the need to better understand a human genetic variation: They created lab mice that contain the same genetic defect.
To understand why this XPF mutation caused accelerated aging, the investigators compared the expression pattern of all of the genes (approximately 30,000) in the liver of 15-day-old mice that had been generated in the laboratory to harbor a defect in their XPF-ERCC1 enzyme and that had symptoms of rapidly accelerated aging to the genes expressed by normal mice of the same age. This comparison revealed a profound suppression of genes in several important metabolic pathways in the progeroid mice. Most notably, the progeroid mice had a profoundly suppressed somatotroph (growth hormone) axis—a key pathway involved in the promotion of growth and development—compared to normal mice.
Damaged aging bodies probably produce less growth hormone as a way to reduce cancer risk. Aging cells with damaged genomes are at risk of becoming cancerous. Growth hormone exposure would make the cells divide. While a cell is dividing it is at increased risk of further DNA damage. Accumulation of DNA damage eventually causes some cells to mutate in their mechanisms for controlling cell growth. Then they start dividing continuously and you get cancer. Better to turn down the growth hormone and reduce the rate of DNA mutation accumulation than get cancer.
The investigators also found low levels of growth hormones in the progeroid mice and ruled out the possibility that this suppression was due to problems with their hypothalamus or pituitary glands, which regulate growth hormone secretion. Furthermore, they demonstrated that if normal adult mice were exposed to a drug that causes DNA damage, such as a cancer chemotherapy agent, the growth hormone axis was similarly suppressed. In other words, DNA damage somehow triggered hormonal changes that halted growth, while also boosting maintenance and repair.
Turns out these mutant mice get the same pattern of gene expression that normal old mice get. So the more rapid rate of accumulation of DNA damage causes mice to age in the same way as normal mice do but at a faster rate.
Because growth hormone levels go down as we get older, contributing to loss of muscle mass and bone density, the investigators systematically compared the gene expression pattern of their progeroid mice to normal old mice to look for other similarities. What they found was a striking similarity pattern between the progeroid and normal-aged mice in several key pathways.
Indeed, for genes that influence the growth hormone pathway, there was a greater than 95 percent correlation in changes in gene expression between the DNA repair-deficient mice and old mice. And, remarkably, there was a near 90 percent correlation between all other pathways affected in the progeroid mice and the older mice.
These results strongly suggest that most of normal aging is driven by accumulation of damage in DNA.
"Because there were such high correlations between these pathways in progeroid and normal older mice, we are quite confident that DNA damage plays a significant role in promoting the aging process. The bottom line is that avoiding or reducing DNA damage caused by sources such as sunlight and cigarette smoke, as well as by our own metabolism, also could delay aging," explained Dr. Niedernhofer.
We need gene therapies that will repair DNA damage. But if DNA damage involves most of a genome then gene therapy might not be practical. Current gene therapy techniques involve adding just a gene or two. Putting in much larger amounts of DNA is a much harder task. How to get completely new copies of entire genomes into hundreds of billions of cells throughout the body?
For neurons in the brain we have got to find ways to do extensive repair or replacement of chromosomes. We can't replace all our neurons without losing our identities. This result provides additional evidence that brain rejuvenation is our toughest rejuvenation challenge.
Update: In the last 5 years the two reports that have done the most to make full body rejuvenation look harder to me are this report above and another report that showed the blood of young mice improves the regenerative ability of the muscles of old mice. In both cases the upshot is that the scale of the changes needed to do rejuvenation came out looking bigger.
In the case of the young mouse blood, old mice, and muscle regeneration the result indicates that perhaps many cells all over the body excrete compounds into the blood that dampen down stem cells. Even if the compounds that cause this effect come from a few places and are easily blockable the fact that old bodies make stem cell suppressor compounds suggests that old bodies really need to make stem cell suppressor compounds in order to reduce the risk of cancer.
This latest report similarly points in the direction of more extensive changes needed to do rejuvenation. This report is worse news than the mouse blood report because development of ability to deliver full genome gene therapy hundreds of millions of cells strikes me as an incredibly difficult problem to solve. We will probably need some pretty sophisticated nanotechnology to solve it. I hope the nanotech optimists are right about how fast nanotech will advance. To do extensive genome repair we'll probably need nanotechnology.
Telomerase is an enzyme that rebuilds tips of chromosomes. The tips or ends of chromosomes get shorter each time a cell divides. As humans age our chromosome tips get shorter and once they get too short our cells can not divide well. Chronic stess not coincidentally shortens telomeres and also accelerates the aging of our bodies. So why don't our bodies just make enough telomerase enzyme to rebuild our chromosome tips? Evolutionary biologists theorize that selective pressures reduced telomerase expression to reduce cancer risk.
The link between telomerase and aging makes telomerase research an interest to biologists who study aging and cancer. Vera Gorbonova decided to compare the telomerase expression in 15 rodent species from around the globe and found telomerase expression is inversely correlated with body mass.
A key enzyme that cuts short our cellular lifespan in an effort to thwart cancer has now been linked to body mass.
Until now, scientists believed that our relatively long lifespans controlled the expression of telomerase—an enzyme that can lengthen the lives of cells, but can also increase the rate of cancer.
Vera Gorbunova, assistant professor of biology at the University of Rochester, conducted a first-of-its-kind study to discover why some animals express telomerase while others, like humans, don't. The findings are reported in today's issue of Aging Cell.
"Mice express telomerase in all their cells, which helps them heal dramatically fast," says Gorbunova. "Skin lesions heal much faster in mice, and after surgery a mouse's recovery time is far shorter than a human's. It would be nice to have that healing power, but the flip side of it is runaway cell reproduction—cancer."
The activation of telomerase could help rejuvenate bodies. But telomerase activation would probably come with higher risk of cancer. We need cures for cancer not only to avoid death from cancer but also to make it easier to use stem cells and other cell types to create replacement parts. Without those replacement parts we'll die from worn out organs and work out capillaries and other parts failures even if we can avoid cancer.
Are rodent species as close to each other on the evolutionary tree as this scientist assumes? How far back did the first branching of existing rodent species occur? Anyone know?
For over a year, Gorbunova collected deceased rodents from around the world and had them shipped to her lab in chilled containers. She analyzed their tissues to determine if the telomerase was fully active in them, as it was in mice, or suppressed, as it is in humans. Rodents are close to each other on the evolutionary tree and so if there were a pattern to the telomerase expression, she should be able to spot it there.
To her surprise, she found no correlation between telomerase and longevity. The great monkey wrench in that theory was the common gray squirrel, which lives an amazing two decades, yet also expresses telomerase in great quantity. Evolution clearly didn't see long life in a squirrel to be an increased risk for cancer.
I am guessing she was expecting to find an inverse correlation between telomerase expression and longevity. Shorter lived species ought to be able to allow greater repair by turning up telomerase since shorter lived species will die from other things before cancer.
But that line of thinking does not make sense anyway since we know short lived mice die from cancer. Their cells deterioriate and they lose control of them more quickly. Do their cells mutate more rapidly than human cells? I dimly recall that mice or rats have DNA polymerase enzymes that make errors at higher rates than human DNA polymerase.
Bigger bodies mean more cells which mean more risk of a cell mutating into cancers. So it is not surprising to me that bigger body rodents have less telomerase.
Body mass, however, showed a clear correlation across the 15 species. The capybara, nearly the size of a grown human, was not expressing telomerase, suggesting evolution was willing to forgo the benefits in order to reign in cancer.
The results cannot be directly related to humans, but Gorbunova set up the study to produce very strong across-the-board indicators. It's clear that evolution has found that the length of time an organism is alive has little effect on how likely some of its cells might mutate into cancer. Instead, simply having more cells in your body does raise the specter of cancer—and does so enough that the benefits of telomerase expression, such as fast healing, weren't worth the cancer risk.
One reason why the results do not directly relate to humans: We may have evolved better mechanisms for controlling cancer. Or maybe the rodents evolved better mechanisms to control cancer. But I would also expect rodents to differ between species in the quality of their mechanisms for doing cell replication and in their immune mechanisms for stopping cancer.
Larger animals have even larger numbers of cells and therefore, all else equal, even greater chances of developing cancer. Every additional cell is an additional risk for cancer. So the bigger an organism gets the greater the need to develop additional methods to control cancer.
Gorbunova points out that these findings raise another, perhaps far more important question: What, then, does this mean for animals that are far larger than humans? If a 160-pound human must give up telomerase to thwart cancer, then what does a 250,000-pound whale have to do to keep its risk of cancer at bay?
"It may be that whales have a cancer suppressant that we've never considered," says Gorbunova. "I'd like to find out what kind of telomerase expression they have, and find out what else they use to combat cancer."
We might eventually find genetic mechanisms for cancer prevention in other species that we could adapt to humans. Genes transferred from other species into human stems cells could serve to make youthful replacement organs less prone to become cancerous.
Here is the abstract and link to the paper.
Veins get stiffer as we age just as arteries do.
As if creaking joints and hardening of the arteries weren't bad enough, a research team from the University of Delaware and the Christiana Care Health System in Newark has now confirmed that even our veins stiffen as we age.
“When you are young, your veins are nice and elastic--like rubber bands,” William Farquhar, a cardiovascular physiologist in UD's College of Health Sciences, said. “But as you grow older, we've found that your veins become more like lead pipes.”
70% of your blood is in your veins but veins have been less studied than arteries. Well, veins age too and become less able to stretch to increase blood volume.
To determine if there are age-related differences in how our veins work, the research team recruited 24 people for their study--12 healthy young adults between the ages of 18 and 30, and 12 healthy older adults between 60 and 70 years old. Each individual underwent medical screening at Christiana Hospital, which included a lipid profile, blood pressure monitoring, electrocardiogram and several other tests to ensure overall good health.
Then each participant was involved in a series of research trials at UD's Human Performance Lab on the Newark campus. While each subject lay resting on a gurney, various gauges, connected to computers, were placed on their arms and legs. An arterial cuff was attached to an upper arm to monitor blood pressure, and venous cuffs were placed around the upper thigh and upper arm to measure the blood flow to the limbs.
As the cuffs were inflated over an eight-minute period, and then slowly deflated to let blood escape from the limbs, the blood volume was measured, recorded, and graphed. The consistently lower blood volume under pressure pointed to the less springy veins of the older participants.
So what causes vein stiffening with age? Increased thickness is one possibility. Another possibility is either less nitric acid to signal them to dilate or fewer or impaired receptors for the nitric acid dilation signal. Still another possibility is scar tissue.
Yet another possibility is chemical crosslinks called advanced glycation end-products (AGEs). The AGEs (also known as advanced glycosylation end-products) are obvious targets for drug development and a company called Alteon has been developing AGE breakers ALT-711 and alagebrium , drugs aimed at breaking AGE bonds in order to make aged tissues more flexible again.
Osteoarthritis, the degenerative inflammatory bone disease, may be a sign of faster "biological ageing," suggests research published ahead of print in the Annals of the Rheumatic Diseases.
The authors base their findings on a study of almost 1100 people, aged between 30 and 79. Most of them were female twins.
X-rays of both hands were taken of all participants to check for signs of osteoarthritis and a blood sample was taken to assess "biological ageing" in white cell DNA.
Biological ageing is likely to be reflected by the gradual shortening of telomeres, the length of DNA which caps the tips of chromosomes. A host of factors make them shorten over time, including insufficient repair of the damage caused by oxygen free radicals (oxidative stress).
Oxygen free radicals are the unstable molecules produced as a by-product of normal bodily processes, as well as external factors, such as tobacco, alcohol, and sunlight.
Osteoarthritis is the most common form of arthritis, with the hands being one of the sites most often affected. Its frequency rises dramatically with age, but it is still not known exactly what causes it.
Unsurprisingly, the findings showed that white cell telomere lengths were associated with chronological age. The older a person was, the shorter they were.
But among the 160 people with hand osteoarthritis, the telomere length was significantly shorter than among those without the disease, even after taking account of influential factors, such as obesity, age, sex, and smoking.
All those with hand osteoarthritis were over 50, and the amount of telomere shortening was equivalent to that accrued over 11 years in healthy people (178 base pairs).
Telomere length was also significantly associated with the severity of osteoarthritis. The more severe the disease, the shorter was the telomere length.
The authors suggest that both the ageing process and osteoarthritis share biological factors in common, including oxidative stress and low level chronic inflammation.
We need stem cell therapies to replace the aged stem cells around joints with younger stem cells. Most of us are fated to suffer increasing amounts of pain as we grow older unless cell therapies and gene therapies are developed soon enough to save us from painful joints, painful muscles, painful tendons, and pains in other parts of the body as well.
My advice: Tell your elected officials you want them to change policies and spending priorities in order to accelerate the rate of advance biomedical science and biotechnology.
Also see my previous posts: Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, and Telomeres Wear Down Quicker In Men Than Women.
Why do we age? Why don't our stem cells continue to divide to produce cells needed to repair and maintain the body? Three research groups at Harvard, University of North Carolina at Chapel Hill, and at University of Michican have found very strong evidence that as cells age they make more of a protein that slows down cells in order to reduce the risk of cancer.
ANN ARBOR, Mich.—The natural consequences of growing old include slower wound-healing and a brain that makes fewer new neurons because old tissues have less regenerative capacity. What has not been clear is why. A trio of papers published on-line Sept. 6 in the journal Nature shows that old stem cells don’t simply wear out, they actively shut themselves down, probably as a defense against becoming cancerous from genetic defects that accumulate with age.
"The good news is that we can get older before we get cancer," said Sean Morrison, director of the Center for Stem Cell Biology at the University of Michigan, and lead author on one of the three papers. "The bad news is that our tissues can’t repair themselves as well."
Though science has long known about the reduced regenerative capacity in aging tissues, the actual mechanisms are only now coming to light. What Morrison and his colleagues at Harvard University and the University of North Carolina have found is that a gene called Ink4a actively interferes with the ability of stem cells to divide in several different types of tissue, including the brain, the pancreas, and the blood-forming system of the bone marrow.
This important discovery came as a result of the development of a mouse with a gene knockout for Ink4a.
Though mice with Ink4a deleted had more regenerative capacity in tissues like the brain and the pancreas as they aged, they started dying of a wide variety of cancers at one year of age. So it can’t really be said that losing the gene helped them live longer.
"If you had a drug that could inhibit Ink4a function, you’d potentially have a therapy against degenerative diseases," Morrison said. "But you’d have to watch patients carefully for cancers. By the same token, drugs that mimic Ink4a function could be used to fight cancer." Ink4a was known to be a tumor suppressor gene that becomes more highly expressed with age, eventually triggering the cell to shut down replication. Sharpless was investigating cancer genes when he developed a mouse without Ink4a six years ago, while working at Harvard, but he also became intrigued by its 10- to 100-fold increase in expression with age.
I find these results thoroughly unsurprising. Biogerontologists have speculated that natural selection has selected for a trade-off where cells in older bodies become less able to divide in order to reduce the risk of cancer. The reduced cancer risk comes at the expensive of gradually losing the ability to do repairs. These results show a mechanism for how this works.
The researchers found that reducing the accumulation of p16INK4a in haematopoietic stem cells (blood stem cells) reduces cell death as well as defects in the ability of the cells to repopulate.
"There are two things about this that are important," Scadden said. "It shows that specific properties of aging stem cells directly contribute to the reduced healing that occurs with aging; and it indicates that one might be able to modify a single gene product and improve the function of aging stem cells and repair of aging tissue - and that is very encouraging. This may mean that there are opportunities to target this gene product with medication and potentially decrease the impact of aging.
"However," Scadden noted, "p16INK4a is also known to suppress tumor formation, so a judicious balance must be struck between reduced p16INK4a when needed for repair and sufficient p16INK4a to prevent emergence of malignant stem cells."
One obstacle to the use of stem cells as rejuvenation therapies is that the stem cells could become cancerous.
The UNC study focused on p16INK4a effects on the function of pancreatic islet cells. Islet cells are responsible for insulin production and secretion. Because p16INK4a stops cancer cells from dividing and demonstrates increased expression with age, the scientists suspected the gene played a similar role in aging. The researchers developed strains of mice that were either deficient in p16INK4a (the gene was deleted, or 'knocked out") or genetically altered to have an excess of the protein to a degree seen in aging.
According to Sharpless, islet proliferation persisted in p16INK4a -deficient animals as they aged, "almost as if they were younger animals." In mice with an excess of p16INK4a, "islet cells aged prematurely; they stopped dividing early."
"This suggests that if we could attenuate p16INK4a expression in some way in humans, it could lead to enhanced islet re-growth in adults and a possible new treatment for diabetes," Sharpless said.
Similar results were found in the other studies, which focused on brain stem cells and blood stem cells.
Diabetics experience accelerated aging. So use of a drug to temporarily suppress the INK4a gene that allowed pancreatic islet cells to repopulate would probably good trade-off on risks and benefits.
Sharpless cautions that any promise of a potential new aging treatment based on p16INK4a should include two important caveats. "First, even though old mice lacking p16INK4a show enhanced stem cell function, they do not live longer. This is because p16INK4a is an important cancer-suppressor gene, and mice lacking p16INK4a develop more cancers than old, normal mice," he said.
"Secondly, in all three studies, p16INK4a loss was associated with an improvement in some but not all of the consequences of aging. There are clearly things in addition to p16INK4a that contribute to aging. We don't yet know what they are."
However, the gene may prove immediately useful as a biomarker for studies of aging, Sharpless said. "If you were going to calorically restrict yourself or take green tea or resveratrol every day for years in an effort to prevent aging, wouldn't you like some evidence that these not entirely benign things were having a beneficial effect? Now we have a biomarker that can directly test the effects of such things," he said.
One really big question: Is the INK4a gene upregulated in older cells due to factors floating around in entire old bodies? Or is the gene upregulated by changes that happen in each cell? If the answer is the former possibility then even introduction of youthful stem cells into an old body will not help the old body rejuvenate very much. If compounds in circulation in old bodies can cause injected youthful stem cells to slow down and do less repair work then that makes rejuvenation much harder. I'm pessimistic on that score and my pessimism predates this latest report. See my previous post Young Mice Blood Turns On Regenerative Ability Of Old Mice Muscle.
Once we have highly effective and low general toxicity cures for cancer (i.e. cancer cures that only damage cancer cells) then drugs that turn down the activity of INK4a could be developed and used to safely make stem cells do more repair work. We need cures for cancer in any case. But cancer cures will also make possible more aggressive and risky uses of stem cell therapies.
Even without great cancer cures drugs that block INK4a would still be useful for people who are at very high risk of death from heart disease. Someone who has a great risk of death from heart disease probably would reduce their total risk of death even if they took an INK4a suppressor that increased their risk of cancer.
We need stem cells that do not have any mutations that increase the risk of cancer. We also need to prevent those stem cells from being suppressed by the INK4a gene. We also need gene therapies that will repair cells in the body so that their accumulated damage will not cause them or other cells to make INK4a.
Stem cell therapies are not the only method possible for replacing aged and damaged cells. Stem cells will also be used to grow replacement organs outside the human body for transplant. Those transplant organs will replace much larger chunks of aged cells. But replacement organs are not practical for all parts of the body - especially not for the central and peripheral nervous systems.
Update: Some types of neural stem cells slow down even without exposure to p16INK4a.
Morrison and his colleagues also found evidence that the gene does not play the same role in other neural tissues. “There are different kinds of stem cells in different regions of the brain, and some of those stem cells are more sensitive to factors like p16INK4a than others,” said Morrison. p16INK4a deficiency did not prevent the atrophy of the cortex that normally occurs with aging, they found. Nor did the deficiency prevent loss of function in another brain region, the hippocampus, that is also a center for neurogenesis in adults. The researchers also analyzed peripheral nerve cells in the gut and found that p16INK4a did not prevent loss of stem cell function there. “There are probably other factors that are important for aging of the hippocampus and the peripheral nervous system,” Morrison noted.
Nevertheless, he said, the discovery of the central role of p16INK4a is highly significant. “I think if you asked before these studies whether you could delete a single gene and rescue stem cell function in multiple tissues, and neurogenesis in an old brain, many people would have said that aging is such a complex phenomenon that you would not get a significant effect,” he said.
Morrison theorized that p16INK4a is a suppressor of stem cell function that evolved as part of the regulatory machinery that also includes proto-oncogenes that encourage cell proliferation. “We are all evolutionarily selected to, on the one hand, maintain regenerative capacity of our tissues through adult life so that we can repair our cells and survive injuries — while on the other hand, limit proliferation in our tissues with age, so cells don't divide out of control, causing cancers,” he said. “And the way that we achieve that balance is by having proto-oncogenes that promote proliferation come into balance with tumor suppressor genes that inhibit proliferation. This work shows one way that this balance changes with age.
What causes these other stem cells to slow down with age?
Stem cells that slow down due to internal damage or due to genetic clocks internal to each stem cell do not pose much of a problem for the development of rejuvenation therapies. Once scientists develop the ability to create replacement stem cells of each desired type then existing stem cell reservoirs in the body can be reseeded with younger and more vigorous stem cells
More systemic body-wide signals that tell cells throughout the body to slow down strike me as much more problematic for the development of rejuvenating stem cell therapies. I see two strategies for dealing with these signals. First, develop such great cancer treatments that it becomes very low risk to neutralize the hormones or other compounds that travel through the bloodstream to tell cells throughout the body to slow with age. A second approach would be to genetically program replacement stem cells to be less sensitive to the body-wide stem cell suppressor signals. The genetic programming of youthful stem cells could be done in a way that allowed those cells to ignore suppressor signals for a few decades. Basically give them a genetic clock that allowed them to divide even though the body has stem cell suppressor chemicals circulating in it that are the result of aging.
Men live fewer years on average than women do. Telomeres - cap structures on the ends of chromosomes - shorten with age and their shortening may be one cause of aging. A new study finds that telomeres wear down in the cells of aging men more rapidly than in the cells of aging women.
This new study published in the journal “Cytogenetic and Genome Research” shows significantly shorter telomeres and higher erosion rates in men than in women, which likely causes a shorter life expectancy of male cells and tissues.
Human telomeres form the terminal structures of human chromosomes and play a pivotal role in the maintenance of genomic integrity and function. During aging, telomeres gradually shorten, eventually leading to cellular senescence. Therefore, in humans, short telomeres are considered to be a sign of advanced age.
In this study, the authors investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes by T/C-FISH (telomere/centromere-fluorescence in situ hybridization), which allows precise measurement of individual telomeres.
In all chromosome arms there was a linear correlation between telomere length and donor age. Generally, the men had shorter telomeres and higher attrition rates than the women.
Even if we could lengthen our telomeres doing that might not increase life expectancy. Why? Wearing down of telomeres protects against cancer by reducing the number of times that cells can divided. Lift that limit and our risk of cancer would probably rise.
The development of effective and easy treatments to cure cancer would make telomere lengthening a much more attractive goal.