You collect about 10 mutations per blood stem cell per year. The accumulation of these mutations leads to a rising incidence of blood cancers (leukemias) as we age. We need youthful replacement stem cells that have very few harmful mutations
AML is a blood cancer that develops when too many immature blood cells crowd out the healthy cells. In recent years, Washington University researchers at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine have sequenced the genomes of 200 patients with AML to try to understand the mutations at the root of the disease.
Without fail, each patient's leukemia cells held hundreds of mutations, posing a conundrum for scientists, who have long believed that all the mutations in a cancer cell are likely to be important for the disease to progress.
"But we knew all of these mutations couldn't be important," says co-first author Daniel Link, MD, professor of medicine. "It didn't make any sense to us that so many mutations were present in all the cells in the tumor."
To investigate the origin of these mutations, the researchers isolated blood stem cells from healthy people of different ages. The youngest were newborns, and the oldest was in his 70s.
Every person has about 10,000 blood stem cells in their bone marrow, and the researchers found that each stem cell acquires about 10 mutations over the course of a year. By age 50, a person has accumulated nearly 500 mutations in every blood stem cell.
Future stem cell therapies will likely involve first filtering thru many individual cells from around the body to find cells that have no harmful accumulated mutations. Individual cells will be grown into several cells so a cell can be taken and sequenced without loosing a good original cell. The best cell discovered this way will be used to grow cell lines in vitro that will be manipulated for eventual return to the body in large numbers.
If we can replace aged stem cells in the bone marrow and other locations with far less mutated cells then our risk of cancer will decline substantially and the youthful stem cells will divide to produce adult cells that replace lost cells in various organs.
A pair of studies find a connection between stress and cellular aging as measured by lengths of telomeres. Chromosomes have telomere caps which are special sequences of DNA which get shorter as cells divide. Short telomeres interfere cell division and therefore make the body less able to do repairs. First, women who felt most threatened by the prospect of stressful tasks have shorter telomeres.
The ability to anticipate future events allows us to plan and exert control over our lives, but it may also contribute to stress-related increased risk for the diseases of aging, according to a study by UCSF researchers.
In a study of 50 women, about half of them caring for relatives with dementia, the psychologists found that those most threatened by the anticipation of stressful tasks in the laboratory and through public speaking and solving math problems, looked older at the cellular level. The researchers assessed cellular age by measuring telomeres, which are the protective caps on the ends of chromosomes. Short telomeres index older cellular age and are associated with increased risk for a host of chronic diseases of aging, including cancer, heart disease and stroke.
My advice: Live lower stress lives.
Scientists of a new study published this week in Biological Psychiatry sought to bring all this prior work together by studying the relationships between telomere length, stress, and depression.
They did so by measuring telomere length in patients with major depressive disorder and in healthy individuals. They also measured stress, both biologically, by measuring cortisol levels, and subjectively, through a questionnaire.
They found that telomere length was shorter in the depressed patients, which confirmed prior findings. Importantly, they also discovered that shorter telomere length was associated with a low cortisol state in both the depressed and healthy groups.
First author Dr. Mikael Wikgren further explained, "Our findings suggest that stress plays an important role in depression, as telomere length was especially shortened in patients exhibiting an overly sensitive HPA axis. This HPA axis response is something which has been linked to chronic stress and with poor ability to cope with stress."
My advice: conduct your life in ways that reduce the risk you'll find yourself in stressful situations. Also Always Look On The Bright Side of Life.
As your cells divide the telomere cap regions on the ends of chromosomes get shorter. Some studies have found short telomeres to be associated with higher disease risk and lower life expectancy. A Danish study finds more evidence that shorter telomeres are correlated with increased risk of early death.
In an ongoing study of almost 20,000 Danes, a team of researchers from the University of Copenhagen have isolated each individual’s DNA to analyse their specific telomere length – a measurement of cellular aging.
"The risk of heart attack or early death is present whether your telomeres are shortened due to lifestyle or due to high age," says Clinical Professor of Genetic Epidemiology Borge Nordestgaard from the Faculty of Health and Medical Sciences at the University of Copenhagen. Professor Nordestgaard is also a chief physician at Copenhagen University Hospital, where he and colleagues conduct large scale studies of groups of tens of thousands of Danes over several decades.
When telomeres get too short cell division (and therefore tissue repair) becomes hampered and even stops. So short telomeres are bad news.
If shorter telomeres really do boost heart attack risk this suggests that cell therapies which introduce cells with longer telomeres will increase life expectancy.
The recent “Copenhagen General Population Study” involved almost 20,000 people, some of which were followed during almost 19 years, and the conclusion was clear: If the telomere length was short, the risk of heart attack and early death was increased by 50 and 25 per cent, respectively.
Getting your telomeres tested would probably provide more disease risk insights than getting your DNA tested. Telomere length provides big insight into heart disease risk.
The study also revealed that one in four Danes has telomeres with such short length that not only will they statistically die before their time, but their risk of heart attack is also increased by almost 50 per cent.
This suggests that continuous replacement of dying cardiovascular system cells is essential to keep your heart and vascular system in good repair.
We need biotech that can take cells from our bodies, identify the healthiest and least damaged cells, restore telomere length, and then transform those cells into the various cell types a human body uses. With sufficient biotech we could restore and maintain our repair systems in a state of very high function. We could add decades to our lives just from youthful cell therapies delivered to many stem cell reservoirs in our bodies.
In a recent study led by Uppsala University, the researchers compared the DNA of identical (monozygotic) twins of different age. They could show that structural modifications of the DNA, where large or small DNA segments change direction, are duplicated or completely lost are more common in older people. The results may in part explain why the immune system is impaired with age.
During a person's life, continuous alterations in the cells' DNA occur. The alterations can be changes to the individual building blocks of the DNA but more common are rearrangements where large DNA segments change place or direction, or are duplicated or completely lost. In the present study the scientists examined normal blood cells from identical (monozygotic) twins in different age groups and looked for large or smaller DNA rearrangements.
In white blood cells of people over the age of 60 some large chunks of chromosomes are missing. Probably not coincidentally, immune function declines with age.
The results showed that large rearrangements were only present in the group older than 60 years. The most common rearrangement was that a DNA region, for instance a part of a chromosome, had been lost in some of the blood cells. Certain, almost identical, rearrangements were found in several individuals and some of these could be correlated with a known blood disease in which the bone marrow's capacity to produce new blood cells is disturbed. Rearrangements were also found in the younger age group. The changes were smaller and less complex but the researchers could also in this case show that the number of rearrangements correlated with age.
– We were surprised to find that as many as 3.5 percent of healthy individuals older than 60 years carry such large genetic alterations. We believe that what we see today is only the tip of the iceberg and that this type of acquired genetic variation might be much more common, says Jan Dumanski, professor at the Department of Immunology, Genetics and Pathology and one of the authors of the paper.
Imagine getting your white blood cells replaced as you age with youthful cells grown up from the least damaged cells in your body. Get a youthful immune system to replace your aging cells. The benefits would be many fold. Your risk of death from pneumonia and flu would go down of course. But also, the immune system kills cancer cells and as it ages it becomes less able to do so. Therefore a rejuvenated immune system would lower your risk of cancer. It might even be possible to enhance your immune system to make immune cells far more effective against cancer.
Replacement of aging immune cells with youthful and undamaged immune cells might also slow brain aging as immune T cells probably play a role in formation of new nerve cells.
In the present study, the scientists showed that the same immune cells may also be key players in the body's maintenance of the normal healthy brain. Their findings led them to suspect that the primary role of the immune system's T cells (which recognize brain proteins) is to enable the "neurogenic" brain regions (such as the hippocampus) to form new nerve cells, thus maintaining the individual's capacity for learning and memory.
We need cell therapies that replace aging cells with much more youthful cells. The immune system seems like a great place to start because its cells already circulate routinely through the blood stream and immune cells serve a wide range of beneficial functions.
Every time most cells divide their telomere chromosome caps get shorter. When the telomere caps get very short cellular division is inhibited. Cells that can't divide can not repair damaged tissue. It is not a coincidence that cells around damaged arthritic joints have short telomeres.
Telomeres, the very ends of chromosomes, become shorter as we age. When a cell divides it first duplicates its DNA and, because the DNA replication machinery fails to get all the way to the end, with each successive cell division a little bit more is missed. New research published in BioMed Central's open access journal Arthritis Research & Therapy shows that cells from osteoarthritic knees have abnormally shortened telomeres and that the percentage of cells with ultra short telomeres increases the closer to the damaged region within the joint.
While the shortening of telomeres is an unavoidable side effect of getting older, telomeres can also shorten as a result of sudden cell damage, including oxidative damage. Abnormally short telomeres have been found in some types of cancer, possibly because of the rapid cell division the cells are forced to undergo.
The question: are the short telomeres a result of osteoarthritis? Or are the short telomeres a cause of osteoarthritis? Does the inflammation associated with osteoarthritis accelerate cell division and thereby cause short telomeres? Or do joints wear down and become osteoarthritic once few cells remain that can do repairs on them?
A Danish team developed a better assay to measure telomere length. Better assays speed up scientific discovery.
There has been some evidence from preliminary work done on cultured cells that the average telomere length is also reduced in osteoarthritis (OA). A team of researchers from Denmark used newly developed technology (Universal single telomere length assay) to look in detail at the telomeres of cells taken from the knees of people who had undergone joint replacement surgery. Their results showed that average telomere length was, as expected, shortened in OA, but that also 'ultra short' telomeres, thought to be due to oxidative stress, were even more strongly associated with OA.
Maria Harbo who led this research explained, "We see both a reduced mean telomere length and an increase in the number of cells with ultra short telomeres associated with increased severity of OA, proximity to the most damaged section of the joint, and with senescence. Senescence can be most simply explained as biological aging and senescent cartilage within joints is unable to repair itself properly."
Cartilage damage and telomere shortening are both contributing to the development of osteoarthritis.
She continued, "The telomere story shows us that there are, in theory, two processes going on in OA. Age-related shortening of telomeres, which leads to the inability of cells to continue dividing and so to cell senescence, and ultra short telomeres, probably caused by compression stress during use, which lead to senescence and failure of the joint to repair itself. We believe the second situation to be the most important in OA. The damaged cartilage could add to the mechanical stress within the joint and so cause a feedback cycle driving the progression of the disease."
Lots of researchers investigate a large assortment of diseases of old age. But many of these diseases have a common cause: loss of ability of the body to do repairs. So while the diseases manifest in different ways with different symptoms they could be reversed with a common strategy: restore the body's ability to do repairs on itself. Cell therapies to deliver youthful cells are a key part of a larger strategy to reverse the aging process and repair aged tissues.
Mitochondria are sub-cellular organelles that break down sugar to make energy for the cell. Our mitochondrial DNA accumulate mutations and mitochondria become less functional as a result. Possibly other mechanisms are at working causing mitochondrial aging as well. A new report finds mitochondrial damage accumulation in stem cells has an especially large impact on overall aging.
Aging-related tissue degeneration can be caused by mitochondrial dysfunction in tissue stem cells. The research group of Professor Anu Suomalainen Wartiovaara in Helsinki University, with their collaborators in Max Planck Institute for Biology of Aging, Karolinska Institutet and University of Wisconsin reported on the 3rd January in Cell Metabolism their results on mechanisms of aging-associated degeneration.
Stem cells are called the spare parts for tissues, as they maintain and repair tissues during life. They are multipotent and can produce a variety of different cell types, from blood cells to neurons and skin cells. Mitochondria are the cellular engine: they transform the energy of nutrients to a form that cells can use, and in this process they burn most of the inhaled oxygen. If this nutrient 'burning' is inefficient, the engine will produce exhaust fumes, oxygen radicals, which damage cellular structures, including the genome. Antioxidants target to scavenge these radicals.
Already in 2004 and 2005 a research model was created in Sweden and USA, which accumulated a heavy load of mitochondrial genome defects. This led to symptoms of premature aging: thin skin, graying of hair, baldness, osteoporosis and anemia.
In the current publication, scientist Kati Ahlqvist in Professor Suomalainen Wartiovaara's group showed that these symptoms were partially explained by stem cell dysfunction. The number of stem cells did not reduce, but their function was modified: the progeny cells in blood and the nervous system were dysfunctional. The researchers also found out that these defects could be partially prevented by early antioxidant treatment.
Stem cells are needed to create replacements for damaged cells that die off or cease to do their jobs. Damaged stem cells are unable to perform their function. So less repair gets done as our stem cells accumulate damage and become dysfunctional with age. Biotechnology that would enable us to replace our old stem cells with younger ones would go far to slow and partially reverse aging.
Another research team found that in mice bred to age rapidly stem cell injections slowed aging and enabled the mice to live longer.
PITTSBURGH, Jan. 3 – Mice bred to age too quickly seemed to have sipped from the fountain of youth after scientists at the University of Pittsburgh School of Medicine injected them with stem cell-like progenitor cells derived from the muscle of young, healthy animals. Instead of becoming infirm and dying early as untreated mice did, animals that got the stem/progenitor cells improved their health and lived two to three times longer than expected, according to findings published in the Jan. 3 edition of Nature Communications.
Previous research has revealed stem cell dysfunction, such as poor replication and differentiation, in a variety of tissues in old age, but it's not been clear whether that loss of function contributed to the aging process or was a result of it, explained senior investigators Johnny Huard, Ph.D., and Laura Niedernhofer, M.D., Ph.D. Dr. Huard is professor in the Departments of Orthopaedic Surgery and of Microbiology and Molecular Genetics, Pitt School of Medicine, and director of the Stem Cell Research Center at Pitt and Children's Hospital of PIttsburgh of UPMC. Dr. Niedernhofer is associate professor in Pitt's Department of Microbiology and Molecular Genetics and the University of Pittsburgh Cancer Institute (UPCI).
"Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals," Dr. Niedernhofer said. "That tells us that stem cell dysfunction is a cause of the changes we see with aging."
Stem cells from young healthy mice enabled progeria mice (i.e. mice selected for to age more rapidly) to live longer.
Their team examined a stem/progenitor cell population derived from the muscle of progeria mice and found that compared to those from normal rodents, the cells were fewer in number, did not replicate as often, didn't differentiate as readily into specialized cells and were impaired in their ability to regenerate damaged muscle. The same defects were discovered in the stem/progenitor cells isolated from very old mice.
"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health."
The symptoms which old mice suffer from serve as a reminder of why we need rejuvenation therapies. Do you want to hunch over, tremble, or move slowly and awkwardly? I think not.
As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice that got a shot of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren't detected in those tissues.
Once rejuvenating stem cell therapies become available I expect people will start using them while still at fairly young ages. Starting in one's 20s doesn't seem too soon.
Calorie restriction is the only reliable way across a wide range of species to increase life expectancy. So the mechanism by which a low calorie diet extends life is a question which many researchers are pursuing. Since very few of us are willing to live in a state of perpetual hunger we need a drug that would give us the benefit of calorie restriction without the gaunt look and hunger pangs. So a report from a German group on an enzyme in a yeast model that appears to be key to life extension for calorie-restricted yeast merits some attention. The researchers are able to show that turning up the enzyme Srx1 protects an enyzme called Prx1 and the Prx1 is key to preventing aging damage. The result is more Prx1 activity, less damage, and longer life - at least in yeast.
By consuming fewer calories, ageing can be slowed down and the development of age-related diseases such as cancer and type 2 diabetes can be delayed. The earlier calorie intake is reduced, the greater the effect. Researchers at the University of Gothenburg have now identified one of the enzymes that hold the key to the ageing process.
"We are able to show that caloric restriction slows down ageing by preventing an enzyme, peroxiredoxin, from being inactivated. This enzyme is also extremely important in counteracting damage to our genetic material," says Mikael Molin of the Department of Cell and Molecular Biology.
This makes sense from a theoretical perspective. Turning up repair enzymes will reduce the rate at which permanent debilitating (and eventually fatal) damage accumulates. Whether more activity of these particular enzymes would extend life in humans remains to be seen. But it seems very likely that if not these enzymes then some other repair enzymes could extend our lives if we could find safe ways to turn them up to higher levels in our cells.
Prx1 breaks down hydrogen peroxide, a toxic by-product of normal human metabolism.
They are able to show that active peroxiredoxin 1, Prx1, an enzyme that breaks down harmful hydrogen peroxide in the cells, is required for caloric restriction to work effectively.
More Srx1 by itself extends yeast cell life without calorie restriction.
The results, which have been published in the scientific journal Molecular Cell, show that Prx1 is damaged during ageing and loses its activity. Caloric restriction counteracts this by increasing the production of another enzyme, Srx1, which repairs Prx1. Interestingly, the study also shows that ageing can be delayed without caloric restriction by only increasing the quantity of Srx1 in the cell. Repair of the peroxiredoxin Prx1 consequently emerges as a key process in ageing.
A drug that mimics the effects of calorie restriction will only slow down the rate of aging and probably not by a large amount. But slowed aging could give some of us enough time to live until rejuvenation therapies become available.
Retroransposons, located areas of the genome that have not been thought to have any functional purpose, get transcribed (read from DNA into RNA) in aging stem cells. The resulting RNA fragments mess up the aging stem cells and make them less able to divide and do repair to the body. Some Buck Institute and Georgia Tech researchers have demonstrated accumulated DNA damage with age allows the retrotransposons to interfere with stem cell function.
"We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional 'genomic junk'," said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.
Adult stem cells are not held back by shortening telomeres.
The team began by hypothesizing that DNA damage in the genome of adult stem cells would look very different from age-related damage occurring in regular body cells. They thought so because body cells are known to experience a shortening of the caps found at the ends of chromosomes, known as telomeres. But adult stem cells are known to maintain their telomeres. Much of the damage in aging is widely thought to be a result of losing telomeres. So there must be different mechanisms at play that are key to explaining how aging occurs in these adult stem cells, they thought.
The researchers looked at DNA damage at cells that had divided many times.
Researchers used adult stem cells from humans and combined experimental techniques with computational approaches to study the changes in the genome associated with aging. They compared freshly isolated human adult stem cells from young individuals, which can self-renew, to cells from the same individuals that were subjected to prolonged passaging in culture. This accelerated model of adult stem cell aging exhausts the regenerative capacity of the adult stem cells. Researchers looked at the changes in genomic sites that accumulate DNA damage in both groups.
They suppressed the toxic transcripts from retrotransposons and got cells more able to grow. But can this ever work in situ, i.e. in the body? I suspect the damaged cells just need to be replaced.
"We found the majority of DNA damage and associated chromatin changes that occurred with adult stem cell aging were due to parts of the genome known as retrotransposons," said King Jordan, associate professor in the School of Biology at Georgia Tech.
"Retroransposons were previously thought to be non-functional and were even labeled as 'junk DNA', but accumulating evidence indicates these elements play an important role in genome regulation," he added.
While the young adult stem cells were able to suppress transcriptional activity of these genomic elements and deal with the damage to the DNA, older adult stem cells were not able to scavenge this transcription. New discovery suggests that this event is deleterious for the regenerative ability of stem cells and triggers a process known as cellular senescence.
"By suppressing the accumulation of toxic transcripts from retrotransposons, we were able to reverse the process of human adult stem cell aging in culture," said Lunyak.
"Furthermore, by rewinding the cellular clock in this way, we were not only able to rejuvenate 'aged' human stem cells, but to our surprise we were able to reset them to an earlier developmental stage, by up-regulating the "pluripotency factors" – the proteins that are critically involved in the self-renewal of undifferentiated embryonic stem cells." she said.
So this, in a nutshell, is a major reason we grow old.
When the body fights oxidative damage, it calls up a reservist enzyme that protects cells – but only if those cells are relatively young, a study has found.
Biologists at USC discovered major declines in the availability of an enzyme, known as the Lon protease, as human cells grow older.
A protease is an enzyme that breaks down peptides (pieces of protein). So this enzyme does not neutralize free radicals. It breaks down proteins damaged by chemicals that rampage thru the cell doing damage. Without enough Lon (and other proteases as well) damaged pieces will accumulate in a cell. This has a number of undesirable consequences such as taking up space that would get used by functional proteins. Also, the damaged proteins will in some cases do wrong things such as generate reactive species that do even more damage. Aging is a vicious cycle where damage causes even more damage.
Would a drug be capable of boosting Lon activity? Is that even the right response to the problem found by these researchers?
The finding may help explain why humans lose energy with age and could point medicine toward new diets or pharmaceuticals to slow the aging process.
The researchers showed that when oxidative agents attack the power centers of young cells, the cells respond by calling up reinforcements of the enzyme, which breaks up and removes damaged proteins.
As the cells age, they lose the ability to mobilize large numbers of Lon, the researchers reported in The Journals of Gerontology.
A cell that does not have enough Lon protease has likely accumulated a lot of damage. The low Lon protease might even be the result of damage to mitochondria where the cell loses the ability to generate enough energy. It would not surprise me if the cell basically turns off optional systems like Lon when energy levels drop too lo. So just trying to boost Lon might not work.
If boosting Lon is either not practical or useful then what? I see two options: Fix the root cause of low Lon. If the root cause is damaged mitochondrial DNA then send in gene therapy to fix the mitochondria. Another option: Try to kill cells that do not make enough Lon. Then neighboring cells or stem cells could divide to replace them. That's an approach that would need selective control so that you don't die due to an organ suddenly failing due to excessive cell loss. Also, cell therapies would be needed to replace cells in organs that have limited repair capability (e.g. the heart).
There is a reason exercise becomes more difficult with age. A report in the August Cell Metabolism, a Cell Press publication, ties the weakness of aging to leaky calcium channels inside muscle cells. But there is some good news: the researchers say a drug already in Phase II clinical trials for the treatment of heart failure might plug those leaks.
A drug isn't the ideal solution. Some day a gene therapy that fixes the cells might be able to address a root cause. Though if the root cause is too complex cell therapies might be needed. It will be interesting to see how much of aging will be repairable with gene therapy alone.
The same leaking is seen with heart failure and Duchenne muscular dystrophy.
Earlier studies by the research team led by Andrew Marks of Columbia University showed the same leaks underlie the weakness and fatigue that come with heart failure and Duchenne muscular dystrophy.
This illustrates how therapies aimed at treating diseases will end up turning into more general anti-aging rejuvenation treatments. Future effective treatments that address root causes of muscle diseases will also end up getting used to rejuvenate muscle.
"It's interesting, normal people essentially acquire a form of muscular dystrophy with age," Marks said. "The basis for muscle weakness is the same." Extreme exercise like that done by marathon runners also springs the same sort of leaks, he added, but in that case damaged muscles return to normal after a few days of rest.
So will this drug work to reduce general muscle weakness with age?
Loss of a subunit called calstabin1 causes a calcium release channel to malfunction.
The leaks occur in a calcium release channel called ryanodine receptor 1 (RyR1) that is required for muscles to contract. Under conditions of stress, those channels are chemically modified and lose a stabilizing subunit known as calstabin1.
"Calstabin1 is like the spring on a screen door," Marks explained. "It keeps the door from flopping open in the breeze."
As is the case with many other mechanisms of aging failure begets more failure in a vicious cycle of aging and destruction of tissue:
Calcium inside of muscle cells is usually kept contained. When it is allowed to leak out into the cell that calcium itself is toxic, turning on an enzyme that chews up muscle cells. Once the leak starts, it's a vicious cycle. The calcium leak raises levels of damaging reactive oxygen species, which oxidize RyR1 and worsen the leak.
The Marks lab has been working on calcium channel stabilization for years. Best wishes for their continued progress. The sooner they succeed the more of us can avoid becoming weak with age.
Each time a cell divides its chromosome caps (called telomeres) get shorter. When telomeres get really short they interfere with the health of cells and cell division becomes more difficult. Telomere length is an indicator (albeit not perfect) of cell age and cell health. Therefore mechanisms by which telomere length impact cell health and cell death are as important topic of aging research. So it is interesting that NIH researchers have discovered a mechanism by which telomere shortening boosts production of the toxic protein progerin in cells.
National Institutes of Health researchers have identified a new pathway that sets the clock for programmed aging in normal cells. The study provides insights about the interaction between a toxic protein called progerin and telomeres, which cap the ends of chromosomes like aglets, the plastic tips that bind the ends of shoelaces.
The study by researchers from the National Human Genome Research Institute (NHGRI) appears in the June 13, 2011 early online edition of the Journal of Clinical Investigation.
Telomeres wear away during cell division. When they degrade sufficiently, the cell stops dividing and dies. The researchers have found that short or dysfunctional telomeres activate production of progerin, which is associated with age-related cell damage. As the telomeres shorten, the cell produces more progerin.
Progerin is a mutated version of a normal cellular protein called lamin A, which is encoded by the normal LMNA gene. Lamin A helps to maintain the normal structure of a cell's nucleus, the cellular repository of genetic information.
This finding ties the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS) which typically kills children by their early teens (see pictures of progeria children). The same progerin protein that causes cellular damage in progeria syndrome also causes the same sorts of damage as we grow older and our telomeres shorten.
You might think, why not rejuvenate by lengthening telomeres? The problem (see that link) is that telomere shortening is probably a defense mechanism against cancer. So lengthening telomeres (assuming we had a treatment that would do this) might not lower the risk of all-cause mortality. However, throw in some great cures for cancer (the sooner the better) and telomere lengthening will suddenly become a very appealing idea. Another possibility: If we could bioengineer our immune systems to very aggressively police against cancers we could reduce the cancer risk from making our telomeres long again. Immune system rejuvenation along with tweaks to make the immune system more aggressive against cancers could so reduce cancer risk that telomere lengthening would carry far less risk.
Cell therapies using rejuvenated stem cells with long telomeres (carefully checked to assure no cancer-causing mutations) will some day deliver some of the benefits of telomere lengthening. While cell therapies won't replace all the aged cells in bodies they at least will provide youthful cells that will do lots of tissue repair.Similarly, advances in tissue engineering to enable growth of replacement organs from youthful stem cells will allow us swap out organs that have lots of aged cells with short telomeres.
For a sense of how important telomeres are in the aging process see my previous posts Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, Telomere Genes Linked To Longer Life, and Telomere Test For Longevity Estimate.
PHILADELPHIA – Given the amount of angst over male pattern balding, surprisingly little is known about its cause at the cellular level. In a new study, published in the Journal of Clinical Investigation, a team led by George Cotsarelis, MD, chair of the Department of Dermatology at the University of Pennsylvania School of Medicine, has found that stem cells play an unexpected role in explaining what happens in bald scalp.
The stem cells available for conversion into progenitor cells appear numerous enough. They just need a signal to tell them to do their duty and suddenly receding hairlines would reverse course and bald spots would spout long strands.
Using cell samples from men undergoing hair transplants, the team compared follicles from bald scalp and non-bald scalp, and found that bald areas had the same number of stem cells as normal scalp in the same person. However, they did find that another, more mature cell type called a progenitor cell was markedly depleted in the follicles of bald scalp.
The researchers surmised that balding may arise from a problem with stem-cell activation rather than the numbers of stem cells in follicles. In male pattern balding, hair follicles actually shrink; they don’t disappear. The hairs are essentially microscopic on the bald part of the scalp compared to other spots
Do the stem cells collect too many genetic mutations or other damage? Or do other cells around them fail to send chemical messages to tell them to differentiate into progenitor cells?
I expect skin and hair rejuvenation therapies to come faster than rejuvenation therapies for the rest of the body. The skin is so accessible. Plus, people want youthful appearances and will pay dearly for them. One could make a fortune with a treatment that restores hair follicle progenitor cell count. The financial incentives are there.
Even skinnier old people with low muscle mass are at greater risk of type 2 (insulin resistant) diabetes. The risks do not just come from fat.
Sarcopenia — low skeletal muscle mass and strength — is often found in obese people and older adults; it has been hypothesized that sarcopenia puts individuals at risk for developing Type 2 diabetes.
To gauge the effect of sarcopenia on insulin resistance (the root cause of Type 2 diabetes) and blood glucose levels in both obese and non-obese people, UCLA researchers performed a cross-sectional analysis of data on 14,528 people from the National Health and Nutrition Examination Survey III.
They found that sarcopenia was associated with insulin resistance in both obese and non-obese individuals. It was also associated with high blood-sugar levels in obese people but not in thin people. These associations were stronger in people under age 60, in whom sarcopenia was associated with high levels of blood sugar in both obese and thin people, and with diabetes in obese individuals.
Dieting to be thin is on its own not enough to stave off diabetes. It is also important to be fit and, in particular, to have good muscle mass and strength.
I think arrows of causation on this one might be complex. Does the muscle loss directly contribute to the type II diabetes? Or do problems with the vascular system cause the muscle loss and the diabetes as well? Or does the vascular system first become unresponsive to insulin and does this then reduce food supplies to muscles, leading to sarcopenia? See my recent posts Aging Blood Vessels Cause Muscle Loss and Insulin Resisant Arteries Accelerate Atherosclerosis. The problem with teasing out the mechanisms of causation is that failing subsystems get into a vicious cycle of causing each other to fail even worse.
You can read the full paper for free at Plos One.
Sarcopenia was associated with insulin resistance in non-obese (HOMA IR ratio 1.39, 95% confidence interval (CI) 1.26 to 1.52) and obese individuals (HOMA-IR ratio 1.16, 95% CI 1.12 to 1.18). Sarcopenia was associated with dysglycemia in obese individuals (HbA1C ratio 1.021, 95% CI 1.011 to 1.043) but not in non-obese individuals. Associations were stronger in those under 60 years of age. We acknowledge that the cross-sectional study design limits our ability to draw causal inferences.
What I'd like to know: Does resistance weight training reverse the development of insulin resistant diabetes? Could weight training combined with dietary change reverse the disease development and restore muscle mass in old people?
Earlier studies showed that in the context of systemic insulin resistance, blood vessels become resistant, too. Doctors also knew that insulin resistance and the high insulin levels to which it leads are independent risk factors for vascular disease. But it wasn't clear if arteries become diseased because they can't respond to insulin or because they get exposed to too much of it.
Now comes evidence in favor of the former explanation. Rask-Madsen along with George King and their colleagues find that mice prone to atherosclerosis fare much worse when the linings of their arteries can't respond to insulin. The animals' insulin-resistant arteries develop plaques that are twice the size of those on normal arteries.
Insulin-resistant blood vessels don't open up as well, and levels of a protein known as VCAM-1 go up in them, too.
VCAM-1 belongs to a family of adhesion molecules, Rask-Madsen explained. "It sits on the endothelium and binds white blood cells." Those cells can enter the artery wall, where they start taking up cholesterol, and an early plaque is born.
"The results provide definitive evidence that loss of insulin signaling in the endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis," the researchers conclude.
Take a glance at the risk factors for type II insulin-resistant diabetes and consider steps you can take to reduce your risks. The risk factors are very similar to the risk factors for heart disease and stroke.
Also seem my recent related post on how aging blood vessels lose the ability to dilate in response to increased insulin and how that probably causes elderly muscle loss.
GALVESTON, Texas — Why do people become physically weaker as they age? And is there any way to slow, stop, or even reverse this process, breaking the link between increasing age and frailty?
In a paper published online this Wednesday in the Journal of Clinical Endocrinology & Metabolism, University of Texas Medical Branch at Galveston researchers present evidence that answers to both those questions can be found in the way the network of blood vessels that threads through muscles responds to the hormone insulin.
Normally, these tiny tubes are closed, but when a young person eats a meal and insulin is released into the bloodstream, they open wide to allow nutrients to reach muscle cells. In elderly people, however, insulin has no such "vasodilating" effect.
The researchers administered insulin to young people with and without a drug that blocks vasodilation. When administered with a drug that blocks vasodilation then a boost in muscle protein synthesis was blocked. This suggests that muscle wasting with old age is due to increasing rigidity of blood vessels.
We obviously need rejuvenation therapies that will make our blood vessels supple again. Youthful blood vessel stem cells are an obvious candidate therapy. But we also need therapies that will clean out accumulated plaque and other therapies that can reverse protein cross-linkages that reduce flexibility. I also wonder whether receptors for insulin binding decline with age.
Bottom line: Aging of subsystems of the body cause other subsystems to age as well. The ability to rejuvenate key subsystems (e.g. the cardiovascular system) will improve the performance of many other subsystems.
If you're an aging baby boomer hoping for a buffer physique, there's hope. A team of American scientists from Texas and Michigan have made a significant discovery about the cause of age-related muscle atrophy that could lead to new drugs to halt this natural process. This research, available online the FASEB Journal (http://www.fasebj.org), shows that free radicals, such as reactive oxygen species, damage mitochondria in muscle cells, leading to cell death and muscle atrophy. Now that scientists understand the cause of age-related muscle loss, they can begin to develop new drugs to halt the process.
Just because free radical damage to mitochondria accelerate age-related muscle loss that does not prove that accumulated damage to mitochondria is the major reason for muscle loss as we age. It might be the major cause. But this study does not prove it.
Regardless of what causes muscle atrophy there's a decent chance stem cell therapies that generate new muscle cells could reverse it. Though it is possible that existing damaged mitochondria spew out toxic compounds that would mess up new cells created from stem cells.
Mice lacking an enzyme that breaks down superoxide suffered faster muscle loss.
"Age-related muscle atrophy in skeletal muscle is inevitable. However, we know it can be slowed down or delayed," said Holly Van Remmen, Ph.D., co-author of the study, from the Sam and Ann Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center at San Antonio. "Our goal is to increase our understanding of the basic mechanisms underlying sarcopenia to gain insight that will help us to discover therapeutic interventions to slow or limit this process."
To make this discovery, Van Remmen and colleagues used mice that were genetically manipulated to prevent them from having a protective antioxidant (CuZnSOD). As a result of not being able to produce this antioxidant, the mice had very high levels of free radicals (reactive oxygen species) and lost muscle mass and function at a much faster rate than normal mice. Additionally, the muscles of the genetically modified mice were much smaller and weaker than those of normal mice. Scientists believe that these findings mimic effects of the normal aging process in humans, but at an accelerated rate.
Danish scientists say appearance alone can predict survival, after they studied 387 pairs of twins.
The researchers asked nurses, trainee teachers and peers to guess the age of the twins from mug shots.
Those rated younger-looking tended to outlive their older-looking sibling, the British Medical Journal reports.
The twins were in their 70s and older. The younger looking ones had longer telomere caps on their chromosomes.
In the study, the people who looked younger had longer telomeres.
The telomere link to life expectancy isn't surprising. Also see my posts Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, Telomeres Shorten Quicker If You Have Less Vitamin D, and Sedentary Lifestyles Age Chromosome Telomeres Faster.
The tips of chromosomes are known as telomeres and they shrink in size every time a cell divides. Eventually the telomeres become short and interfere with cellular replication. This interference is probably an anti-cancer defense mechanism. At the same time, the shrinking of telomeres probably contributes to aging by reducing the ability of the body to make replacement cells to repair the body as we age. Well, old people with genetic variants that cause longer telomeres have a greater chance of living to age 100.
November 11, 2009 — (BRONX, NY) — A team led by researchers at Albert Einstein College of Medicine of Yeshiva University has found a clear link between living to 100 and inheriting a hyperactive version of an enzyme that rebuilds telomeres — the tip ends of chromosomes. The findings appear in the latest issue of the Proceedings of the National Academy of Sciences.
This is a surprising result because longer telomeres in old age might increase the risk of cancer.
If higher activity in telomere enzymes delays onset of cardiovascular diseases then this suggests that lack of ability to make replacement cells contributes to the development of cardiovascular disease.
More specifically, the researchers found that participants who have lived to a very old age have inherited mutant genes that make their telomerase-making system extra active and able to maintain telomere length more effectively. For the most part, these people were spared age-related diseases such as cardiovascular disease and diabetes, which cause most deaths among elderly people.
These results suggest to me that the ability to create safe youthful stem cells for implantation in our bodies might slow the aging process. I want lots of replacement cells with few harmful mutations and long telomeres.
We do not just lose the ability to make hair pigment as we get older. Oh no, it is worse than that. Old hair cells pump out hydrogen peroxide (a toxic compound!) which turns our hair white.(thanks Lou Pagnucco for the heads-up)
Wash away your gray? Maybe. A team of European scientists have finally solved a mystery that has perplexed humans throughout the ages: why we turn gray. Despite the notion that gray hair is a sign of wisdom, these researchers show in a research report published online in The FASEB Journal (http://www.fasebj.org) that wisdom has nothing to do with it. Going gray is caused by a massive build up of hydrogen peroxide due to wear and tear of our hair follicles. The peroxide winds up blocking the normal synthesis of melanin, our hair's natural pigment.
This reinforces a belief I've long held: some of our cosmetic changes as we age aren't just cosmetic. The causes of the age-related changes in appearances exact a larger toll on the body. Hydrogen peroxide is toxic. We don't just go gray. Our heads get bathed in the constant release of a peroxide. When you see gray hairs in the mirror think "poison".
"Not only blondes change their hair color with hydrogen peroxide," said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. "All of our hair cells make a tiny bit of hydrogen peroxide, but as we get older, this little bit becomes a lot. We bleach our hair pigment from within, and our hair turns gray and then white. This research, however, is an important first step to get at the root of the problem, so to speak."
My guess is that skin aging similarly causes the skin cells to release compounds that make us less well in the rest of our body. If we could rejuvenate our skin cells we'd probably feel better as a result.
Our hair follicle cells do not make enough of the catalase enzyme which breaks down hydrogen peroxide. Would a gene therapy help or do we need cell therapy that replaces the aged cells?
The researchers made this discovery by examining cell cultures of human hair follicles. They found that the build up of hydrogen peroxide was caused by a reduction of an enzyme that breaks up hydrogen peroxide into water and oxygen (catalase). They also discovered that hair follicles could not repair the damage caused by the hydrogen peroxide because of low levels of enzymes that normally serve this function (MSR A and B). Further complicating matters, the high levels of hydrogen peroxide and low levels of MSR A and B, disrupt the formation of an enzyme (tyrosinase) that leads to the production of melanin in hair follicles. Melanin is the pigment responsible for hair color, skin color, and eye color. The researchers speculate that a similar breakdown in the skin could be the root cause of vitiligo.
"As any blue-haired lady will attest, sometimes hair dyes don't quite work as anticipated," Weissmann added. "This study is a prime example of how basic research in biology can benefit us in ways never imagined."
So your cells get too old and they start spewing toxins. That makes them age even more rapidly and things go from bad to worse in a vicious cycle. What's the answer? We need therapies to rejuvenate our bodies. We start with youthful healthiness. But things start falling apart. Everything else is the slow slide into disease.
New animal research in the February 18 issue of The Journal of Neuroscience may indicate how certain diseases make people feel so tired and listless. Although the brain is usually isolated from the immune system, the study suggests that certain behavioral changes suffered by those with chronic inflammatory diseases are caused by the infiltration of immune cells into the brain. The findings suggest possible new treatment avenues to improve patients' quality of life.
Chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, psoriasis, and liver disease cause "sickness behaviors," including fatigue, malaise, and loss of social interest. However, it has been unclear how inflammation in other organs in the body can impact the brain and behavior.
The researchers found that in mice with inflamed livers, white blood cells called monocytes infiltrated the brain. These findings support previous research demonstrating the presence of immune cells in the brain following organ inflammation, challenging the long-held belief that the blood-brain barrier prevents immune cells from accessing the brain.
The researchers identified chemicals that encouraged immune system monocytes to enter the brain.
"Using an experimental model of liver inflammation, our group has demonstrated for the first time the existence of a novel communication pathway between the inflamed liver and the brain," said the study's senior author Mark Swain, MD, Professor of Medicine at the University of Calgary.
Swain and his colleagues found that liver inflammation triggered brain cells called microglia to produce CCL2, a chemical that attracts monocytes. When the researchers blocked CCL2 signaling, monocytes did not enter the brain despite ongoing inflammation in the liver.
Liver inflammation also stimulated cells in the blood to make an immune chemical (TNFα). When the researchers blocked the signaling of this immune chemical, microglia produced less CCL2, and monocytes stayed out of the brain.
This is usable information because there are lots of ways to decrease the level of inflammation in your body. You can eat tart cherries, pistachios, grapes, vegetables, and omega 3 fatty acids from fish to cut down in your body's level of inflammation. Exercise helps too. Feeling fatigued? You might need a better diet and exercise.
Some important types of cells (e.g. neurons, muscle cells) do not divide. Cells that divide dilute junk that accumulates inside of them and the newly divided cells can manufacture new internal structures (e.g. proteins in membranes). The non-dividing (aka post-mitotic) cells do not do this dilution and do not create as much internal structure. Some researchers at the Salk Institute find that key proteins in nuclear membranes (which enclose and protect our DNA) do not get replaced as we age. These components of our membranes deteriorate with age and make the nuclei of cells basically spring leaks. Not good.
As parts of us age, even the membrane bound nuclei , which house the genetic instructions for life that are "written" in our DNA, begin to show considerable wear and tear, suggests a new report in the January 23rd issue of the journal Cell, a Cell Press publication. The nuclear pore complexes that normally act as gatekeepers--selectively importing and exporting the molecular ingredients for life to and from the nucleus--begin to break down and spring leaks.
That's because some of the 30 or so nucleoporin proteins that make up those complexes can't be replaced once cells stop dividing, they found.
We need to develop the means to create replacements and somehow tear down old nucleoporin proteins. That will not be easy to do.
" These proteins are unusually stable," said Martin Hetzer of the Salk Institute for Biological Studies. "Most proteins turnover within minutes or hours. These last the entire life span of the cell," a period that can in some cases be decades. In fact, he said, many cells in the body do not actively divide most of the time, and that lack of cell division is particularly dramatic for cells such as muscle and neurons.
Earlier studies had shown that some components of the nuclear pore complexes are very dynamic while others hang around throughout the cell cycle, getting replaced only when cells split into two daughter cells, Hetzer explained. His team wondered what that meant for cells that had stopped dividing.
As long time readers know, I see the brain as the most difficult part of the body to rejuvenate. Some parts of the body will get rejuvenated by replacement. Got an old and failing liver or kidneys? Grow new parts using future advances in tissue engineering and transplant in the new parts. Or find a way to grow new organs inside of our bodies. But neurons with leaking nuclear membranes are especially problematic because the neurons must be repaired rather than replaced.
They now report that the scaffold nucleoporins are extremely stable and do not exchange once they are incorporated into the nuclear membrane, persisting for the entire life span of a differentiated cell. In those cells, the nuclear pore complexes deteriorate with time, eventually losing nucleoporins that are critical for maintaining the pore diffusion barrier. Strikingly, they found that nuclei of old rat neurons containing deteriorated nuclear pore complexes become increasingly permeable.
The proteins in the nuclear membranes that serve as pores also serve as structure to maintain the membrane's three dimensional structure. To replace these proteins is akin to replacing structural beams in a building without letting the building collapse. This is far harder to do at microscopic levels and in hundreds of millions of cells.
Cells are usually very efficient at getting rid of old or damaged proteins and replacing them with new copies, Hetzer said, but it seems they have no way to replace the most stable components of the nuclear pore complexes. He suspects that's because the pores are not only essential for molecular transport, but they are also structural components of the double lipid layer that is the nuclear membrane. If those gated holes are lost, the membrane collapses, he said.
" How do you replace a bridge while transport is happening?" he asked. "It's not possible."
I disagree with the "It's not possible" claim. But development of techniques for doing this will be very difficult and I fear this problem won't be solved for decades.
As we age the levels of cyclooxygenase 2 (COX-2) declines in stem cells. Researchers at U Rochester found that the decline in COX-2 causes a reduction of conversion of stem cells into cartilage and this slows or prevents bone repair with age.
"The skeleton loses the ability to repair itself as we age," said Regis J. O'Keefe, M.D., Ph.D., chairman of the Department of Orthopaedics at the University of Rochester Medical Center and corresponding author of the article. "Our results position the COX-2 pathway as one of several under exploration with the common goal of accelerating healing in aging humans, and with the potential to come together in future combination therapies."
Turning Back the Clock
In the current study, healing rates were compared between a group of young mice (7-9 weeks old) and a group of old mice (52-56 weeks of age), with healing evaluated by imaging and gene expression studies. Specifically, the current study found that the older mice experienced delayed fracture healing, decreased bone formation and decreased resupply of blood vessels to the healing site in aging mice. Expression of the gene that codes for production of the COX-2 was reduced by 75 percent in fractures between aged mice and young mice during the early healing phase five days after a fracture. COX-2 expression in young mice peaked at the exact time that stem cells were changing into cartilage within the fracture callus of young mice, and was reduced during that period in older mice.
In addition, experiments confirmed that COX-2 is expressed primarily in early stem cell precursors of cartilage that also express collagen, type II, alpha 1 (col2a1), the gene that codes for production of a key part of type II collagen in mice and humans, the fibrous, structural protein that lends strength to bone. Researchers observed in aged mice a dramatic decrease as well in the expression of other genes known to contribute to bone formation as well (e.g. osteocalcin and type X collagen). Altogether the results suggest that in aging animals gene expression is altered early in fracture repair with consequences for the entire healing cascade.
The researchers demonstrated that a drug which boosts prostaglandin E2 (PGE2) production improves bone healing ability.
Researchers found further proof that COX-2 is responsible for loss of bone healing ability with age when they were able to reverse the process with a drug known to encourage the COX-2 signaling effect. COX-2 catalyzes the conversion of a fatty acid to prostaglandin E2 (PGE2), a hormone with many functions in the animal body depending on the type of cell they interact with, from blood vessel dilation to embryo implantation in the womb to bone healing. PGE2 is known to have it effect on cells by reacting with one of four receptor proteins (EP1–EP4) on the surface of cells, including the surfaces of bone marrow stem cells, cartilage cells and bone-producing cells (osteoblasts). Human cells send and receive signals that switch on life processes through workhorse proteins called receptors that enable messages to penetrate cells.
You might think that a drug which acts like COX-2 to cause more prostaglandin E2 (PGE2) production and therefore more bone healing is the ticket. But every time we hear about a drug that can reverse some metabolic change that comes with aging we have to ask why the body changed with age in the first place. The decline of COX-2 with age down-regulates stem cells to inhibit stem cell activity. Why? Just an accident of decay? Or was this selected for because older stem cells are at risk of becoming cancerous when they divide?
I hope that drugs which up-regulate stem cells for repair do not boost our risk of cancer. Alternatively, once cancer becomes easily curable we'll be able to take more risks by stimulating cell growth because any resulting cancer will eventually become easy to snuff out. We need cures for cancer that have only mild side effects both because we want to avoid our existing risk of death from cancer and also so we can turn up cell activity in aged cells without running a greater risk of death from cancer.
What I would be curious to know: Would stem cells from young mice stuck into old mice express youthful levels of COX-2 or lower older levels of COX-2? To put it another way: does the environment which the stem cell finds itself in send signals to the stem cell that suppress COX-2? Or does the cell internally change with age in ways that reduce COX-2 expression? The latter possibility is in some ways a better answer. If we can just replace stem cells to get better repair then future stem cell therapies will be easier to develop. If the whole body is suppressing repair then rejuvenation becomes a much taller order.
"In the end, this information can change the way we do business," said MaryFran Sowers, professor in the U-M School of Public Health Department of Epidemiology. "The information provides a roadmap as to how fast women are progressing through the different elements of their reproductive life."
A research team headed by Sowers examined the naturally occurring changes in three different biomarkers over the reproductive life of more than 600 women: follicle-stimulating hormone (FSH), anti-Mullerian hormone (AMH) and inhibin B.
Researchers found that the biomarker AMH declined to a very low or non-measurable level five years prior to the final menstrual period. This decline pinpoints a critical juncture in which a woman probably has so few follicles (eggs) that her fertility becomes increasingly questionable, Sowers said. They found that the changes in AMH and inhibin B concentrations were predictive of the time to menopause.
The research team also measured and reported the rates of change in FSH and used the information to identify different reproductive stages. Based on a woman's age and the level of FSH in the blood, researchers were able to describe four different stages that occur for women from their late reproductive period to the time of their final menstrual period.
It would be a lot more helpful if the predictions could be done for longer periods of time before infertility. This would allow better planning and ladies could decide when to settle for Mr. Close Enough.
Too much fat causes lower eyelids to sag with age. This suggests mini-liposuction will work to reverse and prevent it.
Many theories have sought to explain what causes the baggy lower eyelids that come with aging, but UCLA researchers have now found that fat expansion in the eye socket is the primary culprit.
As a result, researchers say, fat excision should be a component of treatment for patients seeking to address this common complaint.
The study, published in the September issue of the peer-reviewed Journal of Plastic and Reconstructive Surgery, is the first to examine the anatomy of multiple subjects to determine what happens to the lower eyelid with age. It is also the first to measure what happens to the face with age using high-resolution magnetic resonance imaging (MRI).
"A common treatment performed in the past and present is surgical excision of fat to treat a 'herniation of fat' — meaning that the amount of fat in the eye socket does not change but the cover that holds the fat in place, the orbital septum, is weakened or broken and fat slips out," said lead author Dr. Sean Darcy, a research associate in the division of plastic and reconstructive surgery at the David Geffen School of Medicine at UCLA and a plastic surgery resident at the University of California, Irvine. "This orbital septum weakening or herniation-of-fat theory is what most plastic surgeons have been taught.
"However, our study showed there is actually an increase in fat with age, and it is more likely that the fat increase causes the baggy eyelids rather than a weakened ligament," Darcy said. "There have been no studies to show that the orbital septum weakens."
The study looked at MRIs of 40 subjects (17 males and 23 females) between the ages of 12 and 80. The findings showed that the lower eyelid tissue increased with age and that the largest contributor to this size increase was fat increase.
It is surprising to me that this explanation was only figured out in the year 2008.
One of the hopes for rejuvenation therapies is to develop biotechnologies that can induce senescent (old and barely functioning) cells to commit suicide in order to make room for healthier cells to divide and take their place. But senescent cells serve useful functions.
Although post-reproductive life in humans is often associated with decline and a loss of powers, an analogous state in certain cells -- called senescence -- is proving to be one of ironic potency. Scientists at Cold Spring Harbor Laboratory (CSHL) today reported that a particular class of senescent liver cells orchestrates a sequence of events in living mice that can limit fibrosis, a natural response of the liver to acute damage.
The surprising finding follows on the heels of experiments conducted by the same CSHL team last year linking senescence in liver cells with the organ's ability to fight off liver cancer, also called hepatocellular carcinoma, or HCC.
The new findings are the first to establish a specific role for cellular senescence in a non-cancer pathology, and, the CSHL team notes, suggests a new therapeutic approach that could help human patients with precursors of serious liver diseases such as cirrhosis, which is the 12th most common cause of death in the United States.
My fear on rejuvenation therapies is that it might be necessary to orchestrate many forms of repair at once in order to keep cells and metabolism in balance. If destroying senescent cells will increase the incidence of other forms of disease and malfunction then we will at least need to weigh the relative risks of treatment versus non-treatment.
" Fibrosis is a disease of many organs—lungs, kidneys, pancreas, prostate, skin," said Valery Krizhanovsky of Cold Spring Harbor Laboratory. "It's possible this mechanism in the liver is relevant to fibrotic situations in other tissues."
The state of cell-cycle arrest known as senescence was first described decades ago, but the phenomenon was thought to occur only in cultured cells in the laboratory, Krizhanovsky explained. More recent studies found that cellular senescence helps protect against the formation of tumors and aids in the response to certain anticancer agents.
Interestingly, the researchers said, senescent cells had also been observed in some aged or damaged tissues, including the cirrhotic livers of human patients. However, the functional contribution of cellular senescence to diseases other than cancer hadn't been examined.
Of course, just as better cancer treatments could eliminate concern that cancer could come as a complication of rejuvenation therapy a better treatment for fibrosis could eliminate the need for senescent cells to protect against fibrosis.
Update: Note that the need to leave senescent cells in place goes way down once we can replace whole organs. No need for senescent cells to suppress nearby cancer cells if all the cells in an organ are youthful and relatively undamaged. Grow new organs from a well tested stem cell line and then when, say, a new youthful liver replaces an old liver we get rid of the senescent cells and the precancerous cells at the same time.
A couple of days ago I argued immune system rejuvenation is one of the top rejuvenations I'd like to get. Well, in some recent comments Aubrey de Grey describes how part of immune system rejuvenation could be done by killing off senescent CD8 T cells.
Another area of SENS that is completely separate from cancer is the elimination of cells that won’t die. Of course cancer is a problem of having too many cells because the cells are dividing like crazy. They are also dying like crazy, but they are dividing even more crazily. That’s what cancer is. There are other problems that are caused by cells that are actually not dividing, but they are not dying either, and they are accumulating slowly as a result. They get in the way and cause various problems just by being there.
Probably the most serious example of this is the immune system. In the immune system we have a wide range of different types of white blood cells that have different functions in protecting us from infections. They have a large number of different things to do. There is one particular type of white blood cell called a cytotoxic T lymphocyte—CD8 is the name of the protein that these cells express on the surface—that is the main problem in respect to this accumulation of cells that I mentioned.
Here is what happens: Some viruses that we get are what are called “persistent,” which means that we get this infection and the immune system brings it under control, there are no symptoms, but the immune system does not succeed in completely eliminating the virus from the body. The virus hangs out, latently, in one or two places. There is a particular family of viruses called the herpes viruses, which are particularly bad at this. Within the family of herpes viruses, there is one virus called cytomegalovirus, which used to be considered completely harmless and uninteresting from a medical point of view.
Cytomegalovirus, clinically, does not present any obvious symptoms except in people who have got advanced AIDS or other really severe problems with their immune system. It seems to be the number one reason why you have these CD8 cells accumulating in old age in most people. Most people are infected with CMV from an early age. The way it seems to work is that these CD8 cells, which are specific to CMV and are involved in controlling it, divide. They essentially get rid of a lot of the virus but not all of it, and every time that the virus tries to have another go, it gets beaten back, but it gets beaten back by another round of division of the same family of cells.
What seems to happen is a sort of somewhat variant form of what is called replicative senescence in virto—the concept that so many of you heard about from Len Hayflick fifty years ago, whereby cells end up, due to telomere shortening, getting into a state where they cannot divide anymore. Now, in the immune system, there is a lot of cell division that goes on, and for that reason, telomerase is turned on when it is needed. But, probably as a secondary anti-cancer strategy, cells in the immune system—especially CD8 cells—do not like to do that indefinitely. They get into a state where the sort of stimulus that would normally make them proliferate and turn on telomerase, only makes them proliferate and not to turn on telomerase very much. It leads to an interesting state where they will not divide at all. It will neither divide nor turn on telomerase.
The ability to kill cancer cells attracts a lot more attention. But the ability to kill senescent cells is badly needed as well. If we could kill off old CD8 cells that would make more room for immune cells that can still attack and kill pathogens. But even better, a younger immune system would do a better job of killing cancer cells. So kill older copies of one kind of cell in order to allow a younger copies to kill cancer cells. We need this capability just as we need the capability to kill cancer cells directly.
Telomeres, which are caps at the ends of chromosomes are known to get shorter as we age. Shorter telomeres might increase mortality risk. Also, lack of vitamin D and chronic stress both seem to make telomeres shorter. So telomere length really seems to matter. With all that in mind: Exposure to a pathogen causes telomeres to shrink more rapidly.
We experimentally tested whether repeated exposure to an infectious agent, Salmonella enterica, causes telomere attrition in wild-derived house mice (Mus musculus musculus). We repeatedly infected mice with a genetically diverse cocktail of five different S. enterica strains over seven months, and compared changes in telomere length with sham-infected sibling controls. We measured changes in telomere length of white blood cells (WBC) after five infections using a real-time PCR method. Our results show that repeated Salmonella infections cause telomere attrition in WBCs, and particularly for males, which appeared less disease resistant than females. Interestingly, we also found that individuals having long WBC telomeres at early age were relatively disease resistant during later life. Finally, we found evidence that more rapid telomere attrition increases mortality risk, although this trend was not significant.
I have a sore throat as I write this post. Therefore my immune system is getting a little more aged and my white blood cell telomeres are getting shortened. Bummer dudes. Fortunately I only very rarely get sick. But if you live a lifestyle that causes you to get colds and flus every year then think about what steps you can take to cut your frequency of sickness. Every bout with some germ is making you another day older and closer to death.
What we really need: technologies for stem cell manipulation to produce youthful replacement immune system stem cells. That will do more than just reduce deaths of old people from influenza, pneumonia, and other pathogens which kill the elderly. Stronger rejuvenated immune systems will reduce death from cancer and maybe reduce the incidence of auto-immune disorders.
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 more 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.
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.
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.
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.
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.
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.
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.
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.