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Fight Aging! Newsletter, October 13th 2014

FIGHT AGING! NEWSLETTER
October 13th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENTS

  • BioWatch News on Rejuvenation Biotechnology 2014
  • A Mechanism for Calorie Restriction to Reduce Both DNA Damage and Cellular Senescence
  • Growth Hormone and Growth Hormone Receptor Required for Life Extension Due to Methionine Restriction
  • A Demonstration of Reduced Life Span via Mitochondrial Mutations, but is it Relevant?
  • Towards the Indefinite Postponement of Menopause
  • Latest Headlines from Fight Aging!
    • A Look at Various Approaches to Prosthetic Vision
    • Blocking Blood Vessel Inflammation to Diminish Atherosclerosis
    • Female Survival Advantage Diminishes with Age
    • A Look at the Current State of Drug Treatments for Amyloidosis
    • Enhanced Catalase in the Mitochondria Improves Muscle Function in Aging
    • HIF-1 and AMPK in Regulation of Mitochondrial Generation of Reactive Oxygen Species
    • Linking Blood Vessel Degeneration with Age-Related Failure of Amyloid-β Clearance
    • Transplanted Dopamine Neurons Can Last a Long Time
    • NAD Mechanisms Necessary for Calorie Restriction Benefits
    • Considering Cellular Senescence in the Development of Type 2 Diabetes in Aging

BIOWATCH NEWS ON REJUVENATION BIOTECHNOLOGY 2014
https://www.fightaging.org/archives/2014/10/biowatch-news-on-rejuvenation-biotechnology-2014.php

BioWatch News is a market analysis venture focused on biotechnology, especially medical research and development. This is a fairly common business model: find a niche and help to explain it to investors. People with a lot of money at stake in the market will pay a proportionally greater price for good articles and analysis. Biotechnology is a field that is changing so fast and for which the course of the near future is so very unpredictable that there is considerable demand for vision, knowledge, and explanation on the part of those who know more about what is going on than your average fund manager.

Interestingly, investors - even large-scale investors - are the small fry among those people concerned about uncertainty in the future of medical development. The pension, medical insurance, and life insurance industries are far bigger and will destroy themselves if they bet the wrong way on whether or not radical life extension will happen in the decades ahead. The existing trends, if extended, predict only mild life extension, the addition of less than a year of adult life with each passing decade. These trends are based on the medicine of the past, however, and more importantly on an approach to aging and age-related disease that is both inefficient and changing. Up until this decade researchers made little to no effort to tackle the causes of aging directly, while going forward they will be doing exactly that, in numerous different ways. The trend in adult life expectancy will break upwards, a great discontinuity as lifespans suddenly leap due to the implementation of treatments to reverse the few forms of cellular and molecular damage that causes various aspects of degenerative aging.

When will this happen? That depends on how much funding is devoted to SENS-like repair strategies for aging, and how soon that funding arrives. Timelines and amounts are highly uncertain, as repair of the root causes of aging is still a disruptive new approach in its early growth phase. Small choices on the part of funding sources at this stage make a large difference to the future course of development. This sort of uncertainty gives financial managers heartburn, but even those who have never heard of SENS can see the currently riotous degree of debate and change in aging research. It is a field in the slow roil of scientific revolution. That in turn creates reports from professional actuaries that add ever greater uncertainty to future predictions of life expectancy, the all-important numbers upon which the strategy of financial giants turns. Times are changing.

As I'm sure you recall, the SENS Research Foundation recently hosted the Rejuvenation Biotechnology 2014 conference. This was one part of what will be a years-long strategy to build the necessary bridges with industry to ensure a smooth hand-off from laboratory to developer for future repair treatments aimed at the causes of aging. While we'd all like to think that a way to revert atherosclerosis or cut age-related loss of blood vessel and skin elasticity by half would wake the dead and cause funding to fall from the sky like golden rain, in reality it requires considerable organization to transition even an obvious, amazingly effective prototype treatment into a development program for clinical translation. Thus building bridges and making connections is a very necessary part of the future of rejuvenation research.

The BioWatch crew put out a special issue of their magazine for Rejuvenation Biotechnology 2014, in which there are interviews with Jerri Barrett and Aubrey de Grey of the SENS Research Foundation, Adina Mangubat of Spiral Genetics, and noted researcher George Church. There is also a great deal of commentary on where things are going and what needs to be done. You can download the PDF version at the SENS Research Foundation website. This is a 40-page magazine from industry watchers devoted to the concept of founding a rejuvenation biotechnology industry; you should read the whole thing:

BioWatch Complementary SENS Edition (PDF)

In holding RB2014, we hope to create an environment where we might foster cross-fertilization between disease researchers. Why? Because all of these diseases share at least one common causal factor: aging. What we are seeing is that sometimes a treatment designed for one disease of aging will also have a positive effect on another disease of aging. For example, much of the work that has been done in cancer has been adapted and is also being used in the treatment of Alzheimer's disease. This is exciting, and we see it as an opportunity to create an industry that is focused on the development of these treatments.

What makes this conference unique is that it is not just a scientific conference; we're also bringing in economists, regulatory experts, and venture capitalists. Rejuvenation biotechnology is not just business as usual in the biotech arena. These emerging new treatments mean that a lot of how we do business needs to adapt and change as well.

When Aubrey de Grey founded SENS Research Foundation, he had a vision to address the different kinds of cellular damage and how that cellular damage leads to the diseases of aging. Because of this vision, SRF is currently funding research for 18 different projects - three of them here at our headquarters in Mtn. View, and many others at different locations around the world.

Within the walls of SRF, we frequently talk about the fact that nothing can be accomplished in a vacuum. Using the example of Alzheimer's disease, a research team in one part of the world may be focused on one type of damage and making great strides; but unfortunately, without addressing the other two types of damage, they alone will not cure the disease. Let's say, however, that in another part of the world there are two other teams who are addressing the two other types of damage; If you break down silos and create an environment where these three teams can work together, there is a greater possibility of eradicating the disease.

Traditionally, SENS Research Foundation conferences have tended to be very academic and research focused; but we are recognizing that if we are actually going to create forward momentum in facilitating these changes, and bringing actual cures to the public, or to the patient world; then we have to take a step back and look at the much larger picture.

The war on the diseases of the aging is not a third world problem; nor is it confined to one particular country, or one particular race, or one particular gender. The war on the diseases of aging is global; affecting every continent, culture, society, and economy on earth today. Tackling this problem will require a paradigm shift in the usual pharmaceutical method of operation when it comes to bringing therapies to market. We must be willing to break down our silos and learn to collaborate with one another, taking advantage of the wisdom of the global collective of ingenuity, so that true invention and breakthrough can be achieved.

To this end, we give the SENS Rejuvenation Biotechnology Conference (RB2014) a great big around the world and back again, thumbs up. SENS Research Foundation has already stepped out in front to lead the way in breaking down research silos; they have locations all over the world working together, sharing research, collaborating together for true CURES to the diseases of aging. RB2014 is the first conference of its kind to offer further breaking down of silos between other researchers, and breaking down silos between regulatory personnel, investors, other professionals in the industry and even the public. The entire conference has been meticulously planned in the hopes of setting the stage for all of these people to work together and to have a real input into the formation of this emerging market.

A MECHANISM FOR CALORIE RESTRICTION TO REDUCE BOTH DNA DAMAGE AND CELLULAR SENESCENCE
https://www.fightaging.org/archives/2014/10/a-mechanism-for-calorie-restriction-to-reduce-both-dna-damage-and-cellular-senescence.php

The practice of calorie restriction, consuming fewer calories while still obtaining optimal levels of dietary micronutrients, has been demonstrated to greatly improve measures of health in humans and slow the progress of near every measure of degenerative aging in numerous species in the laboratory. It extends life by up to 40% or so in mice and similarly in other short-lived species, but the effects on life span in comparatively long-lived primates appears to be more limited. Yet the health benefits and alterations to the operation of metabolism are very similar in mice and primates, providing a puzzle that will keep researchers occupied for some years to come, I expect.

Calorie restriction has been shown to slow the accumulation of DNA damage measured in aging, and evidence suggests that this is due to changes in the very complex array of DNA repair mechanisms hard at work in our cells. Calorie restriction also slows the pace at which senescent cells gather in tissues, and short-term calorie restriction can even modestly reduce the numbers of those cells present in older tissues. Senescent cells are those that have removed themselves from the cell cycle in reaction to damage or signals in the tissue environment associated with risk of damage, such that causes by excess heat and toxins. Some forms of DNA damage such as double-strand breaks can trigger cellular senescence; this process is considered to be an evolutionary adaptation to suppress the risk of cancer arising from just such damaged cells. However there are also harmful consequences, as senescent cells degrade surrounding tissues, spurring their neighbors to also become senescent. The growing presence of these cells directly contributes to many of the degenerative conditions of aging.

The research linked below uncovers a link between low nutrient environments in tissues, such as those created by calorie restriction, and more proficient DNA repair. It is no doubt far from the only contributing mechanism to the benefits of calorie restriction for DNA repair. The response to calorie restriction is enormously complex, touching on near every major area of research into metabolism, and as yet no complete model exists for even the better studied parts of the process:

A Diet for the Cell: Keeping the DNA Fit with Fewer Calories

Cells harbour genetic material in the form of DNA, which contains all the information required for the cell to function. Every time a cell divides this information has to be precisely copied so that the newly made cell receives a perfect replica in order that it, too, can function properly. The inheritance of damaged DNA, however, must be inhibited. In order to recognise altered DNA and prevent it from getting passed on to daughter cells, cells have developed surveillance mechanisms, or checkpoints. Checkpoints stop cells from dividing; thereby allowing more time for the cell to repair damaged genetic material. In some cases, however, the DNA cannot be efficiently repaired even though the checkpoints have been activated. If DNA damage persists for a very long time the cells may eventually turn the checkpoints off without waiting for the DNA to get repaired. This process, referred to as adaptation, may initially seem advantageous to the cell because it can finally grow again. "However, for the whole organism, adaptation is often dangerous, as the unrepaired DNA may lead to diseases such as cancer."

Molecular biologists have found a way to prevent cells from turning off the checkpoint and therefore increase the time available for repair, while at the same time preventing damaged DNA from getting passed to newly made cells. The researchers discovered that the amount of nutrients in the cellular environment is a major factor influencing this process. When cells with DNA damage are exposed to low levels of nutrients, they do not adapt and instead remain fully arrested with an active checkpoint. The same effect was observed when cells with DNA damage were treated with the drug "rapamycin", which inhibits metabolic signalling and therefore mimics nutrient starvation. "The cells that are in low nutrient conditions end up being much more viable, likely because they have waited for the damaged DNA to be repaired before starting to divide again. We believe that high nutrients are pushing cells to grow and proliferate even when the cells should not, e.g. with damaged DNA. Low nutrient conditions likely ensure that cells will only 'risk' dividing when the DNA has been completely repaired."

High Nutrient Levels and TORC1 Activity Reduce Cell Viability following Prolonged Telomere Dysfunction and Cell Cycle Arrest

Cells challenged with DNA damage activate checkpoints to arrest the cell cycle and allow time for repair. Successful repair coupled to subsequent checkpoint inactivation is referred to as recovery. When DNA damage cannot be repaired, a choice between permanent arrest and cycling in the presence of damage (checkpoint adaptation) must be made. While permanent arrest jeopardizes future lineages, continued proliferation is associated with the risk of genome instability.

We demonstrate that nutritional signaling through target of rapamycin complex 1 (TORC1) influences the outcome of this decision. Rapamycin-mediated TORC1 inhibition prevents checkpoint adaptation via both Cdc5 inactivation and autophagy induction. Preventing adaptation results in increased cell viability and hence proliferative potential. In accordance, the ability of rapamycin to increase longevity is dependent upon the DNA damage checkpoint. The crosstalk between TORC1 and the DNA damage checkpoint may have important implications in terms of therapeutic alternatives for diseases associated with genome instability.

GROWTH HORMONE AND GROWTH HORMONE RECEPTOR REQUIRED FOR LIFE EXTENSION DUE TO METHIONINE RESTRICTION
https://www.fightaging.org/archives/2014/10/growth-hormone-and-growth-hormone-receptor-required-for-life-extension-due-to-methionine-restriction.php

Methionine is one of the essential amino acids for mammals, a molecule necessary for synthesis of proteins but which our biochemistry cannot manufacture from scratch. Thus we have to obtain methionine from our diets, and without it we will die. But eating less than we might choose to has the opposite effect: the evidence to date strongly suggests that a large fraction of the beneficial effects on health and longevity produced by calorie restriction actually stem from methionine restriction: eat less food overall and you eat less methionine, since comparatively few foodstuffs have low methionine content. The operation of metabolism reacts to methionine levels with increased cellular housekeeping and other activities seen in low-calorie diets, and rodent studies broadly similar outcomes for methionine restriction and calorie restriction in rodents.

That said, methionine restriction is nowhere near as well studied as calorie restriction, though inroads are being made. It is also a great deal more difficult to organize as a lifestyle in comparison to calorie restriction, intermittent fasting, and the like, as the data on methionine levels is comparatively poor and there are few options when it comes to assembling meal plans. Most dietary staples are rich in methionine. If you want to obtain the benefits of an optimal metabolism, the old fashioned way is still best supported by evidence: regular moderate exercise and calorie restriction.

Beyond less food and less methionine there are many ways to manipulate the operation of metabolism in order to modestly slow aging and extend life in laboratory animals such as mice and flies. The most effective at present involve gene therapy to disable growth hormone or its receptor: the longest lived growth hormone receptor knockout (GHRKO) mice are dwarfs with life spans as much as 60-70% longer than their unmodified peers. Unfortunately that isn't likely to translate into extension of human life spans. The small population of mutants with Laron Syndrome have a similarly impacted growth hormone metabolism, and while it is possible that they are more resistant to some common age-related diseases, they don't live markedly longer than the rest of us.

There has been some interest in mixing and matching various means of slowing aging as a way to better identify which of them are just different ways of altering the same root mechanisms. It is probably the case that while there exist dozens of genetic alterations that extend life in laboratory animals, only a few underlying important changes in metabolism actually determine variations in longevity. Cells are machine shops in which everything connects to everything else: evolution produces promiscuous reuse of parts, and any given protein usually has multiple roles to play in quite diverse processes. It is impossible to change anything in isolation in the biochemistry of the cell.

Hence here is an open access paper in which researchers try methionine restriction for long-lived growth hormone mutant mice, and find that the mutants don't benefit from it at all. This strongly implies that whatever is turned on by methionine restriction is already turned on in the growth hormone mutants, and thus these are just different windows onto the same room. Growth hormone disruption is just another way to trigger something that looks like the calorie restriction response. That in turn reinforces the present consensus that both calorie restriction and disruption of growth hormone metabolism are not going to perform miracles for human longevity: we have too many examples in which that is not the case. The evolutionary explanation for calorie restriction is that it is an adaptation to seasonal famine, and thus short-lived animals evolve a much more plastic life span in response to that circumstance. A season is a large fraction of a mouse life span, but not so for humans.

Growth hormone signaling is necessary for lifespan extension by dietary methionine

Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high-plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, for example, in the Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, and thus, GH mutant mice and respective wild-type littermates were fed 0.16%, 0.43%, or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild-type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance did not respond to altered levels of methionine in terms of lifespan, body weight, or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes, thus strongly linking growth and lifespan to amino acid availability.

Ames dwarf and GHRKO mice lived a similar length of time as their wild-type controls when fed the 0.16% MET. Importantly, this finding reflects both a lack of response to low MET by the GH signaling-deficient mice and a significant extension of lifespan by their respective wild-type mice. On higher levels of MET, both the GHRKO and Ames mice outlived (median) their wild-type counterparts by 7-8 and 11-12 months, respectively. Maximal longevity did not differ between GHRKO or Ames mice, regardless of diet.

Here, we show that active GH signaling is necessary for mice to respond to changes in dietary methionine in terms of lifespan, body weight, and food consumption. The survival curves of mice with normal or excess plasma GH levels appeared similar. In contrast, the lifespans of Ames dwarf and GHRKO mice indicate that without GH signaling, the system is unable to detect or sense changes in dietary methionine. Thus, the underlying genotype effects that result in a lack of GH signaling are not apparent when animals consume low MET diets. In cases of either GH or MET deficiency, metabolic reprogramming occurs possibly shifting resources away from growth toward more protective mechanisms, resulting in lifespan extension.

A DEMONSTRATION OF REDUCED LIFE SPAN VIA MITOCHONDRIAL MUTATIONS, BUT IS IT RELEVANT?
https://www.fightaging.org/archives/2014/10/a-demonstration-of-reduced-life-span-via-mitochondrial-mutations-but-is-it-relevant.php

Mitochondria are bacteria-like organelles within cells responsible for, among other things, generating the adenosine triphosphate (ATP) molecules used as a chemical energy stores to power cellular activities. This process produces a varying flux of reactive oxygen species (ROS), molecules that can cause significant damage to molecular machinery when present in large numbers. Large and complex molecules participating in vital cellular processes are fragile things in the face of a horde of small reactive molecules trying to form bonds and bend their partners out of shape. Many aspects of cellular metabolism react to raised levels of ROS, especially those playing a part in housekeeping activities such the prompt removal of damaged proteins and repair of DNA. This dance is a regular part of life: it happens every time you exercise, for example, and is an important part of the way in which exercise produces health benefits. ROS flux in this case is a signal resulting in reactions at the cellular level that lead to improved tissue function at the higher level.

Mitochondria have their own DNA, a legacy of their evolutionary past as symbotic bacteria. It is stuck right next door to the intricate structures that generate both ATP and potentially harmful reactive molecules. Damage to mitochondrial DNA occurs on an ongoing basis, possibly due to the flux of ROS they themselves generate, and possibly during the many, many times mitochondria divide to make up their numbers in a cell. Some of this DNA damage is inconsequential and essentially random: it doesn't spread among mitochondria, and it doesn't appear to cause any great harm. There are mouse lineages artificially weighed down with point mutations in mitochondrial DNA, for example, that seem to suffer no ill effects as a result. However some forms of more drastic mutation, such as deletions, can remove one or more necessary genes from mitochondrial DNA, causing that mitochondrion to fall into a dysfunctional state that can spread. This particular type of dysfunction leads to preferential survival for the malfunctioning mitochondria and they quickly take over the cell, causing it to malfunction also. This is one of the causes of degenerative aging.

Mitochondria within a cell are far from being a static population of structures: mitochondria replicate by division like bacteria, and there are processes watching mitochondria for damage or dysfunction, culling the herd of faulty organelles. Mitochondria are also quite capable of swapping proteins and parts between themselves, or even fusing together. All of this complicates any attempt to watch the progress of damage to mitochondrial DNA in cells: it is evidently rapid, as researchers never find cells in mid-transition between some mitochondria exhibiting harmful DNA damage and all mitochondria in a cell exhibiting that damage.

The way to address this contribution to the aging process is through some form of repair. The Strategies for Engineered Negligible Senescence (SENS) approach is to work around the damage by placing copies of mitochondrial DNA in the cell nucleus. Mitochondrial DNA mutation is only a problem if mitochondria must rely on their DNA to produce needed protein machinery: if there is another source, then the damage is irrelevant. There are numerous other possible approaches, however: repair the DNA directly and periodically, introduce whole new mitochondria into tissues, and so forth. All too few researchers are working on this, however. While it is generally agreed that mitochondria are very important in the aging process, the mainstream position is to work on gathering more data rather than work to fix the damage - though to my eyes this is one of many areas in which it is probably more cost effective to enact a repair therapy and see what happens.

In this research the opposite approach is taken: create damage to mitochondrial DNA and watch the results in mice. This sort of thing is very rarely as educational as we would like it to be, however. It is too easy to break biology in ways that shorten life, and the breaking changes have no necessary connection to aging or ways to lengthen life even when they take place in related areas of molecular biology. Mitochondrial dysfunction of a variety of forms that don't occur in aging cause disease and shorter life spans, and so the details matter greatly, here as everywhere else. Not all mitochondrial DNA mutations are equal, and an experiment of this nature is one where it takes a real specialist in the field to comment on its relevance to aging:

Mom's Mitochondria Affect Pup Longevity

The new study shows that mitochondrial DNA mutations in the mother's eggs can shorten her pups' lives by approximately one third. The mice that inherited mutant mitochondrial DNA showed an average lifespan of 100 weeks compared with 141 weeks for control mice. What is not yet known is how mitochondrial DNA mutations shorten lifespan. Dysfunctional mitochondria could impair cellular metabolism and lead to a variety of problems, such as the accumulation of damaging reactive oxygen species, reduced vitality of stem cells, and reduced DNA repair, leading to the accumulation of damage to the genome in the nucleus. "Aging is a complex process and involves so many different facets, so maybe it's a little bit of everything that together keeps on beating down the organism a little at a time."

Maternally transmitted mitochondrial DNA mutations can reduce lifespan

The accumulation of mitochondrial DNA (mtDNA) mutations resulting in mitochondrial dysfunction has been heavily implicated in the aging process as well as various age-related disorders and diseases. Replication of the mitochondrial genome continues in mitotic and meiotic cells, as well as in non-dividing cells, with an ~10-fold higher mutation rate than nuclear DNA. Thus, mutations can occur in the maternal germline and be transmitted to offspring. Despite the presence of protective mechanisms that eliminate deleterious mtDNA mutations, evidence indicates inheritability of low levels of heteroplasmy in humans; however, the influence of such mutations on health and lifespan has been largely unclear.

To determine the extent to which inherited mtDNA mutations may contribute to the rate of aging, we designed a series of mouse mutants and previously demonstrated that germline mtDNA mutations can induce and augment aging phenotypes. We also unexpectedly found that a combination of inherited and somatic mtDNA mutations cause stochastic brain malformations. These results suggest that starting life with healthy mitochondria might be important for the maintenance of health during aging. This suggests that the rate of aging may be set early in life before reproduction ends. We now present evidence to demonstrate that the presence of low levels of germline-transmitted mtDNA mutations during development can have life-long consequences not only by causing premature aging phenotypes, but also by shortening lifespan.

Our previous and present findings allow us to conclude that inherited mtDNA mutations alone or in combination with somatic mtDNA mutations, augments the rate of aging and shortens lifespan. These results also provide additional evidence for the hypothesis that certain determinants of aging are present prior to conception and during development. It would be interesting to understand if the rate of aging, determined early during life, can be altered.

That all individuals start life with an initial damage load is supported by the reliability theory of aging, a model of system failure over time in which an organism is considered as a collection of redundant breakable components. This turns out to be a fairly robust and useful way of thinking about the aging of biological organisms at a high level. It has nothing to say about mechanisms, but it does help to steer thinking as to what the plausible mechanisms of aging might be.

TOWARDS THE INDEFINITE POSTPONEMENT OF MENOPAUSE
https://www.fightaging.org/archives/2014/10/towards-the-indefinite-postponement-of-menopause.php

The future elimination of menopause through medical advances to treat aging has been in the news of late. Menopause is an undesirable thing that happens during aging, and the ultimate objective of rejuvenation research projects is to indefinitely postpone all of the undesirable things that happen during aging. Degenerative aging is a combination of primary damage, spiraling secondary forms of damage, and the evolved reactions of still-functioning systems to that damage. The best way forward to deal with all of this is that of the SENS research programs, among other lines of research: repair the damage. Don't try to compensate for damage, or alter the operation of biology to work better when damaged, as that is an expensive and futile undertaking. It is very hard to try to maintain a system on verge of failure due to damage. Instead work to remove the cause of the problems, giving our biology the chance to repair and restore itself. Our tissues can perform that task very proficiently when not operating in a damaged environment.

The media, and possibly the public, often seem to be far more taken with the possibilities of rejuvenation that don't matter than with those that do. Things like regrowth of lost hair, for example. This seems like a trivial thing. Aging cripples us and kills us: it takes away to ability to walk, to think, to live without constant pain. Yet the trivial, the hair and the wrinkles, captures all of the attention. This is just one of many ways in which it might be argued that we are not a particularly rational species. From where I stand, menopause is not all that much better as a focus for attention: it is far from the worst thing that will happen to any given aging woman.

Nonetheless, a recent interview in which Aubrey de Grey of the SENS Research Foundation mentioned in passing the prospect of the elimination of menopause was widely noted. That comment - out of all the things said - became the focus of dozens of press articles. Why don't people get this worked up about actually fatal age-related conditions like heart disease and dementia? Nonetheless, it should be the case that a woman of the future who has regular access to a comprehensive suite of repair therapies built after the SENS model, reverting the damage to cells and tissues that causes aging, will not suffer menopause. She will have tissues and systems that are the same as those of a young woman no matter her current chronological age. That is the goal, and no more menopause is a side-effect of keeping her healthy.

Over at the SENS Research Foundation you'll find a good science-heavy article on the end of menopause to counterbalance the near-complete absence of scientific details that is the status quo for the popular press. The excerpts below are just small excerpts - you should read the whole thing:

Rejuvenation Biotechnology: Toward the Indefinite Postponement of Menopause

SENS Research Foundation works to catalyze the development of rejuvenation biotechnology: a new class of medicines that will keep us young and healthy and forestall the disease and debility that currently accompany a long life, by targeting the root causes of age-related ill health. Menopause shares much in common with major age-related health problems, inasmuch as they all result from the accumulation of cellular and molecular damage in our tissues over time. Because this damage takes our tissues' microscopic functional units offline, aging damage gradually degrades each tissue's capacity to carry out its normal function with time. When enough of this damage accumulates in a particular tissue, specific diseases and disorders of aging characteristic of that tissue emerges, whether it's in the brain (Alzheimer's and Parkinson's disease), or the heart and circulatory system (atherosclerosis and heart failure), or the machinery controlling cellular growth (cancer) - or the ovaries (menopause). The corollary of this is that by removing and repairing this damage, rejuvenation biotechnology will restore the proper structure of the cellular machinery that keeps our tissues functioning, restoring their ability to keep us alive and with the good health that most of us enjoy at earlier ages.

So maintaining a woman's fertility and postponing or eliminating menopausal symptoms comes down to a mixture of repairing and replacing damaged cells (notably egg cells) and tissues (follicles) whose age-related degradation leads to menopause in the first place, bringing the whole system back to its youthful, functional norm. Today, researchers are pursuing several "damage-repair" approaches to realize this goal, and that's what we'll discuss in this article.

Cell Therapy

You're probably familiar with the promise of stem cells and other cell therapies to treat a variety of diseases and disorders involving cell loss, particularly diseases of aging. Cell therapy is an straightforward way to counteract the loss of viable egg cells with age, particularly in restoring a woman's fertility. To give a woman a new supply of eggs that matches her original genetics will require that those new egg cells begin with her own cells. Scientists are now mastering a couple of ways whereby a person's ordinary, mature cells can have their developmental clocks reset.

Tissue Engineering

This approach is similar to cell therapy, but focuses on the larger-scale goal of replacing an entire organ or tissue instead of replacing specific, critical cell types. In an exciting study, Stanford scientists have reported the ability to generate new follicles from ovarian tissue from women with primary ovarian insufficiency, in which a woman's ovaries stop producing new eggs before the age of 40 and she enters early menopause.

Awakening "Oogonial Stem Cells"

But maybe we don't need to actually give women new ovarian tissue to revive ovarian function. Since the 1950s, it's been the dogma that women are born with a fixed supply of early-stage egg cells that are produced during embryonic development. But this widely-accepted view has been strongly challenged in the last decade, [offering] the potential that "oogonial stem cells" (OSC) may lie dormant in aging women, waiting to be revitalized with the right cocktail of cells or signaling factors.

Cell Encapsulation

The rejuvenation biotechnologies we've explored so far involve replacing egg cells, or whole follicles, or even whole ovaries with new tissue, which would restore both fertility and normal, youthful hormone production. But the disruption of the hormonal system that drives the symptoms of menopause is only indirectly related to the actual release of egg cells. The two cell populations involved in the production and release of release sex hormones [are] part of the follicle itself, and their release is not directly tied to ovulation. If these cells could be replaced and maintained in the ovaries, they could potentially carry on producing sex hormones and maintain the normal system of feedback between the ovaries, those hormones, and the regulatory centers in the brain, even with no egg cell replacement.

Women Age as Whole People

But of course, a woman is more than a womb, and her aging is more than the aging of her reproductive system. Aging affects every organ, every tissue, every cell. And while specific diseases and disorders arise most recognizably when the burden of cellular and molecular damage to some particular tissue crosses a "threshold of pathology," no organ ages in isolation. We age as whole people, with stiffening arteries damaging our kidneys and brains, failing eyesight impairing our intellectual work, and a rising burden of tissue damage across the entire body forcing all of our cells operate in a haze of oxidative stress and inflammation. In the end, women will be truly free of menopause when and only when we are all free of the entire degenerative aging process: when a comprehensive panel of rejuvenation biotechnologies is developed to remove, repair, replace, or render harmless the full range of the damage of aging, and all of our tissues are made new.

LATEST HEADLINES FROM FIGHT AGING!

A LOOK AT VARIOUS APPROACHES TO PROSTHETIC VISION
Monday, October 6, 2014
https://www.fightaging.org/archives/2014/10/a-look-at-various-approaches-to-prosthetic-vision.php

Artificial vision for the blind lies ahead, and this research and development proceeds in competition with regeneration medicine approaches that aim to reverse degeneration and damage in the eye. Some of the most advanced prototype devices presently in use take the approach of linking a camera to an electrode grid embedded in the retina, building a moving picture of glowing dots. But this isn't the only way forward:

Blindness is still one of the most debilitating sensory impairments, affecting close to 40 million people worldwide. Many of these patients can be efficiently treated with surgery or medication, but some pathologies cannot be corrected with existing treatments. In particular, when light-receiving photoreceptor cells degenerate, as is the case in retinitis pigmentosa, or when the optic nerve is damaged as a result of glaucoma or head trauma, no surgery or medicine can restore the lost vision. In such cases, a visual prosthesis may be the only option. Similar to cochlear implants, which stimulate auditory nerve fibers downstream of damaged sensory hair cells to restore hearing, visual prostheses aim to provide patients with visual information by stimulating neurons in the retina, in the optic nerve, or in the brain's visual areas.

In a healthy retina, photoreceptor cells - the rods and cones - convert light into electrical and chemical signals that propagate through the network of retinal neurons down to the ganglion cells, whose axons form the optic nerve and transmit the visual signal to the brain. Prosthetic devices work at different levels downstream from the initial reception and biochemical conversion of incoming light photons by the pigments of photoreceptor rods and cones at the back of the retina. Implants can stimulate the bipolar cells directly downstream of the photoreceptors, for example, or the ganglion cells that form the optic nerve. Alternatively, for pathologies such as glaucoma or head trauma that compromise the optic nerve's ability to link the retina to the visual centers of the brain, prostheses have been designed to stimulate the visual system at the level of the brain itself.

While brain prostheses have yet to be tested in people, clinical results with retinal prostheses are demonstrating that the implants can enable blind patients to locate and recognize objects, orient themselves in an unfamiliar environment, and even perform some reading tasks.

BLOCKING BLOOD VESSEL INFLAMMATION TO DIMINISH ATHEROSCLEROSIS
Monday, October 6, 2014
https://www.fightaging.org/archives/2014/10/blocking-blood-vessel-inflammation-to-diminish-atherosclerosis.php

Researchers have a found a way to selectively interfere with inflammatory processes in blood vessel walls so as to slow the onset of atherosclerosis:

Normally, the lining of blood vessels, or endothelium [ignores] the many cells and other factors rushing by in the bloodstream. But in response to inflammatory signals, as well as other stimuli, endothelial cells change suddenly and dramatically - sending out beacons to attract inflammatory cells, changing their surface so those cells can stick to and enter tissues, and initiating a complex cascade of responses essential to fighting infection and dealing with injury. Unfortunately, these same endothelial responses also promote atherosclerosis, the build-up of plaque in arteries that cause heart attacks, strokes, and other inflammatory diseases.

A [new study] is the first to demonstrate that BET bromodomain-containing proteins help execute inflammation in the endothelium while inhibition of BET bromodomain can significantly decrease atherosclerosis in vivo. "BET bromodomain-containing proteins have been studied in cancer for some time, where they are in therapeutic trials, but now we have mechanistic evidence for how BETs and their inhibition can impact endothelial inflammation and atherosclerosis."

In preclinical models, the researchers found that activating NF-kB, a canonical mediator of inflammation, rapidly redistributed the BET protein known as BRD4 to chromosomal sites where super enhancers driving expression of nearby inflammatory genes are located. Bromodomains are amino acid regions that bind to specifically modified sites on histones, the proteins around which DNA is coiled. By binding to these amino acid regions, BET bromodomain inhibitors block the assembly of protein complexes that drive expression of certain genes. In these studies, inhibiting BET bromodomains turned off an inflammatory program in human endothelial cells, decreased white blood cells adhering to endothelial cells, and decreased atherosclerosis in mice.

FEMALE SURVIVAL ADVANTAGE DIMINISHES WITH AGE
Tuesday, October 7, 2014
https://www.fightaging.org/archives/2014/10/female-survival-advantage-diminishes-with-age.php

Women live longer than men, and while there is no shortage of theories as to why this is the case, the research community has yet to convincingly demonstrate which of them are correct. Adding an additional twist that will need to be explained, these researchers suggest that the size of the mortality rate advantage enjoyed by women diminishes considerably in late old age:

Although increased survival longevity among females is observed throughout much of adult life, supporting evidence among the oldest old is lacking. [Here, we] examine the hypothesis that gender differences in longevity [and] survival diminish with advancing age. The Jerusalem Longitudinal Study follows a representative cohort born 1920-21, comprehensively assessed at ages 70, 78, 85, and 90. Mortality data were collected from 1990-2013. Kaplan-Meier survival curves and Mortality Hazards Ratios were determined, adjusting for gender, marital status, education, loneliness, self-rated health, physical activity, functional status, neoplasm, diabetes mellitus, hypertension, ischemic heart disease.

Survival between ages 70-78 was 77.3%, 78-85 was 68.9%, 85-90 years was 71.1%, and 90-93 years was 80.5%. With advancing age, the survival advantage among females vs. men declined: at ages 70-78 (85.6% vs. 71%), 78-85 (74% vs. 63%), 85-90 (74% vs. 67.5%), and 90-93 (80% vs. 81%). Compared to females, the male mortality adjusted hazard ratio from ages 70-78 was 2.93; ages 78-85 was 2.1; ages 85-90 was 1.6; and ages 90-93 was 1.1. Our findings confirm the hypothesis that the increased longevity observed among females at age 70 gradually diminishes with advancing age, and disappears beyond age 90.

A LOOK AT THE CURRENT STATE OF DRUG TREATMENTS FOR AMYLOIDOSIS
Tuesday, October 7, 2014
https://www.fightaging.org/archives/2014/10/a-look-at-the-current-state-of-drug-treatments-for-amyloidosis.php

Amyloids are formed from handful of types of misfolded proteins that interact to form insoluble deposits in tissues. The presence of amyloid grows with aging, and eventually causes the serious, fatal disruption of tissue function found in the family of amyloidosis conditions. The best approach to dealing with amyloid is to simply remove it, such as by using immune therapies of the sort currently in early stage trials for Alzheimer's disease. These are treatments that aim to use the immune system to break down harmful amyloid aggregates, and success should lead to a general technology platform that can be turned against any form of amyloid.

There is a way to go towards this goal, however, and in the meanwhile the present state of drug-based therapies for various forms of fatal amyloidosis is better than nothing but leaves a lot to be desired. As is still the case for many forms of cancer, the mainstream focus is on improving survival on a scale of adding additional months or a few years to remaining life, and reuse of existing drugs is always the first thing to be tried rather than the development of entirely new technologies:

The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent-based therapy. We report here treatment with lenalidomide-dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%).

On an intention-to-treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2-year OS and progression-free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months.

Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits.

ENHANCED CATALASE IN THE MITOCHONDRIA IMPROVES MUSCLE FUNCTION IN AGING
Wednesday, October 8, 2014
https://www.fightaging.org/archives/2014/10/enhanced-catalase-in-the-mitochondria-improves-muscle-function-in-aging.php

Mitochondria are the cell's power plants, swarming in bacteria-like herds to create chemical energy stores. They bear their own DNA, distinct from that in the cell nucleus. This mitochondrial DNA can become damaged in aging and some forms of this damage create harmful, malfunctioning mitochondria that overtake their cell and cause it to export damaging reactive compounds into surrounding tissues. One possible cause of this mitochondrial DNA damage is the fact that generating chemical energy stores results in the creation of reactive oxygen species (ROS) as a byproduct. This flux of ROS influences cellular activities in many ways, such as by spurring greater or lesser levels of housekeeping activity, and by causing damage directly through reactions with important molecular machinery.

In past years researchers have demonstrated benefits resulting from the delivery of targeted antioxidant compounds to the mitochondria, with the assumption that they produce benefits by soaking up more of the ROS before they can cause harm. One approach here is to use genetic engineering to increase levels of the natural antioxidant catalase: some studies have shown extension of life in mice via this method, while others have not. The delivery of artificial mitochondrially targeted antioxidants as drugs has been studied more closely, in comparison, and the results there are generally more consistent, showing small effects on life span and enough of a benefit to health for some conditions to make it worth building treatments.

Age-related muscle weakness has major adverse consequences on quality of life, increasing the risk of falls, fractures, and movement impairments. Albeit an increased oxidative state has been shown to contribute to age-dependent reduction in skeletal muscle function, little is known about the mechanisms connecting oxidation and muscle weakness. We show here that genetically enhancing mitochondrial antioxidant activity causes improved skeletal muscle function and voluntary exercise in aged mice.

Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca2+ transients, decreased intracellular Ca2+ leak and increased sarcoplasmic reticulum (SR) Ca2+ load compared with age-matched wild type (WT) littermates.

Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca2+ leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.

HIF-1 AND AMPK IN REGULATION OF MITOCHONDRIAL GENERATION OF REACTIVE OXYGEN SPECIES
Wednesday, October 8, 2014
https://www.fightaging.org/archives/2014/10/hif-1-and-ampk-in-regulation-of-mitochondrial-generation-of-reactive-oxygen-species.php

Many of the varied genes and proteins that can be manipulated to extend longevity in lower animals are associated with mitochondrial function, and specifically the pace at which mitochondria generate reactive oxygen species (ROS) in the course of performing the task of generating adenosine_triphosphate, a chemical energy store used to power cellular processes. Cells react to the levels of ROS produced by their mitochondria, such as by dialing up their housekeeping and repair efforts when ROS output increases during exercise. More extended periods of increased cellular housekeeping lead to extended longevity for all the obvious reasons, as damaged molecular machinery and metabolic wastes are given less time to cause further damage.

Thus it isn't too surprising given current knowledge to find links between genes and proteins involved in cellular housekeeping and the behavior of mitochondria, and further between those involved in nutrient sensing and immune system regulation. Researchers interested in the intersection of metabolism and aging are exploring a network of interacting machines and feedback loops, in which every change causes reactions and adaptations elsewhere in the grand collection of machinery we call a cell:

Reactive oxygen species (ROS) have long been thought to cause aging and considered to be toxic byproducts generated during mitochondrial respiration. Surprisingly, recent studies show that modestly increased ROS levels lengthen lifespan, at least in the roundworm Caenorhabditis elegans. It was unclear how the levels of potentially toxic ROS are regulated and how ROS promote longevity. Here we demonstrate that ROS activate two proteins, AMP-activated kinase (AMPK) and hypoxia-inducible factor 1 (HIF-1), to promote longevity by increasing immunity.

Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMPK. We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, balancing ROS at optimal levels appears to be crucial for organismal health and longevity. AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.

LINKING BLOOD VESSEL DEGENERATION WITH AGE-RELATED FAILURE OF AMYLOID-β CLEARANCE
Thursday, October 9, 2014
https://www.fightaging.org/archives/2014/10/linking-blood-vessel-degeneration-with-age-related-failure-of-amyloid-β-clearance.php

Amyloid-β is one of the forms of misfolded protein that accumulate in tissues with age, precipitating to form solid clumps and fibrils. This one forms in the brain and is associated with Alzheimer's disease. Amyloid levels are fairly dynamic, and their growth with age appears to be a slow failure of clearance mechanisms rather than a gradual accumulation. One of those discussed here in the past is the choroid plexus, a filtration system for cerebrospinal fluid. Here, however, is consideration of another failing mechanism, one that is more tightly bound to the degeneration of blood vessel tissues.

This is of interest because Alzheimer's risk is strongly correlated to blood vessel health. Further, the process of age-related degeneration in blood vessels is one for which the links to forms of cellular and molecular damage that cause aging are fairly well understood at this time: cross-links formed by metabolic waste degrade blood vessel elasticity, for example. Ways to effectively remove those cross-links, such as those envisaged as the end result of work underway at the SENS Research Foundation, should be broadly beneficial to brain health as well as other tissues.

In Alzheimer's disease, amyloid-β (Aβ) accumulates as insoluble plaques in the brain and deposits in blood vessel walls as cerebral amyloid angiopathy (CAA). The severity of CAA correlates with the degree of cognitive decline in dementia. The distribution of Aβ in the walls of capillaries and arteries in CAA suggests that Aβ is deposited in the perivascular pathways by which interstitial fluid drains from the brain. Soluble Aβ from the extracellular spaces of gray matter enters the basement membranes of capillaries and drains along the arterial basement membranes that surround smooth muscle cells toward the leptomeningeal arteries. The motive force for perivascular drainage is derived from arterial pulsations combined with the valve effect of proteins present in the arterial basement membranes.

Factors that affect cerebrovascular health, such as age and APOE genotype, alter both the structure of the blood vessels and the expression of the basement membrane proteins such that the efficiency of perivascular drainage of Aβ is reduced. As increasing amounts of Aβ become entrapped within the drainage pathways, it causes damage to the underlying vasculature, further reducing the functionality of the vessel and creating a feedforward mechanism by which increasing amounts of Aβ accumulate as CAA. Finally, diffusion of soluble Aβ and interstitial fluid through brain tissue is blocked by insoluble Aβ in the extracellular spaces, levels of soluble Aβ and other metabolites in brain parenchyma rise and dementia ensues.

The failure of perivascular clearance of Aβ may be a major factor in the accumulation of Aβ in CAA and may have significant implications for the design of therapeutics for the treatment of Alzheimer's disease.

TRANSPLANTED DOPAMINE NEURONS CAN LAST A LONG TIME
Thursday, October 9, 2014
https://www.fightaging.org/archives/2014/10/transplanted-dopamine-neurons-can-last-a-long-time.php

Many cell transplants have been shown to produce no long-lasting cells in the recipient. In stem cell treatments, for example, it is frequently the case that the stem cells have a short-term effect on the signaling environment that boosts regeneration by changing the behavior of native cell populations, but the transplanted cells do not take up residence and are gone within a few days to a few weeks. The research noted here lies at the opposite end of the spectrum, however, and confirms that dopamine-generating neurons transplanted to replace those lost to the mechanisms of Parkinson's disease last for a very long time indeed:

To determine the long-term health and function of transplanted dopamine neurons in Parkinson's disease (PD) patients, the expression of dopamine transporters (DATs) and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation.

The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients' own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15-18 years in patients.

NAD MECHANISMS NECESSARY FOR CALORIE RESTRICTION BENEFITS
Friday, October 10, 2014
https://www.fightaging.org/archives/2014/10/nad-mechanisms-necessary-for-calorie-restriction-benefits.php

Nicotinamide adenine dinucleotide cycles between two forms, NAD+ and NADH, in the course of participating in important cellular processes such as the mitochondrial respiration whose dysfunction is implicated as a cause of aging. Earlier this year researchers showed that NAD levels decline with age and restoring them can improve measures of health in old mice. Here the same research group notes that NAD mechanisms are required for most of the health and longevity benefits produced by the practice of calorie restriction, and their data suggests that this has a lot to do with changing the operation of mitochondria. Alterations to mitochondrial function show up time and again in considerations of aging and longevity, and are a factor in most of the known ways to slow aging in laboratory animals:

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol.

DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption.

We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

CONSIDERING CELLULAR SENESCENCE IN THE DEVELOPMENT OF TYPE 2 DIABETES IN AGING
Friday, October 10, 2014
https://www.fightaging.org/archives/2014/10/considering-cellular-senescence-in-the-development-of-type-2-diabetes-in-aging.php

To be clear, type 2 diabetes is a self-inflicted harm for the majority of sufferers, caused by too much food and too much fat tissue carried over the years. It is a condition that can be turned back even in comparatively late stages by nothing more than weight loss and a much reduced diet. Nonetheless it is a prevalent condition and a great deal of research effort is focused on finding more sophisticated methods of treatment.

Here researchers consider the role of cellular senescence in the loss of active pancreatic beta cells involved in the condition: to what degree is type 2 diabetes age-related because of the trend towards increasing weight gain and lack of exercise versus the rising numbers of senescent cells in older tissues? Cells become senescent, removing themselves from the cell cycle, in response to damage or tissue conditions and a signaling environment that implies damage lies ahead. Senescent cells accumulate with age and are a meaningful contribution to the aging process, playing a role in the pathology of many age-related conditions. Given the trials showing that lifestyle choices can reverse type 2 diabetes, however, I am skeptical that cellular senescence is an important factor in most of the cases seen these days:

The incidence of type 2 diabetes significantly increases with age. The relevance of this association is dramatically magnified by the concomitant global aging of the population, but the underlying mechanisms remain to be fully elucidated. Here, some recent advances in this field are reviewed at the level of both the pathophysiology of glucose homeostasis and the cellular senescence of pancreatic islets. Overall, recent results highlight the crucial role of beta-cell dysfunction in the age-related impairment of pancreatic endocrine function.

Alterations of glucose homeostasis increase with age and represent leading causes of morbidity and mortality, mainly linked to both the complications associated with type 2 diabetes and the increased risk for several other age-related diseases. The classical pathophysiological factors responsible for this age-related failure of glucose homeostasis (insulin resistance and decreased secretory capability of beta cells) are quite well characterized, but new mechanisms have recently been revealed. Central to this new development is the key concept that loss or dysfunction of pancreatic beta cells plays a crucial role in the pathogenesis of type 2 diabetes. Since the predominant mechanism of beta-cell generation seems to be self-renewal, the senescence-associated cell cycle dysregulation and the consequent proliferative arrest assume a particular relevance.

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