Fight Aging! Newsletter, April 6th 2015

April 6th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, 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.

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  • Living Longer and Aging More Slowly
  • Increased FGF21 May Spur Greater Liver Regeneration
  • Control ALT, Delete Cancer: Coverage of the SENS Research Foundation OncoSENS Project
  • Reverting the Consequences of Biology Deliberately Made Dysfunctional Rarely Tells Us Anything About Aging
  • Peter Thiel on Longevity Research and the Defeat of Aging
  • Latest Headlines from Fight Aging!
    • Considering Alzheimer's Disease as a Type 3 Diabetes
    • Fitness Versus Mortality after Cancer Diagnosis
    • Investigating Hibernation and Longevity in Lemurs
    • More on Molecular Tweezers to Treat Amyloid Accumulation
    • Life Extension via Calorie Restriction Requires FOXO3
    • Silencing FL2 Accelerates Wound Healing
    • Why Do Most People Evade Cancer?
    • Organovo and Bioprinted Kidney Tissues
    • Stem Cells Preferentially Discard Old Mitochondria During the Process of Cell Divison
    • More Deaths, But Lower Mortality Rates


The old are not as physically aged as they used to be. Today's old people are in better shape than their predecessors, with access to better medicine and having been exposed to a lesser burden of infectious disease and other causes of cell and tissue damage over the course of a lifetime. Given the pace of progress in medical science these improvements can be seen even over the course of the past few decades. Many of today's researchers look at this and see compression of morbidity, a popular viewpoint in which it is believed that healthy life span can be extended considerably without extending overall life span. This doesn't make a great deal of sense from the viewpoint of aging as a consequence of accumulated biological damage, however. In the damage perspective the risk of death and level of dysfunction and frailty are determined by the present levels of various forms of damage. Reducing the pace at which the damage load increases extends both overall life span and time spent in decline; you can't have one without the other. Making an immediate reduction in damage, such as through some form of rejuvenation treatment, will extend healthy life span and postpone the future decline, but absent further treatments that decline would look exactly the same when it does arrive.

The only way in which you might see something that looks like compression of morbidity is if the pace of accumulation for most forms of damage are slowed, but not for one or more late-onset types of damage that produce reliably fatal consequences. This may or may not be what has happened over the past fifty years or so; there is a lot of room for argument given the present state of data. One intriguing line of thought relates to senile systemic amyloidosis, which seems to be the cause of death for most supercentenarians. It isn't much seen in less aged individuals, and there is comparatively little known of its progression in old age.

Still, the old are getting younger. Not fast enough yet, but step by step as a side-effect of improvements across the board in health, wealth, and medical science. The goal for the future is to step away from this incidental improvement in favor of strategies that deliberately target the causes of aging for treatment and repair. The coming age of medicine will prove to be far more effective in extending healthy life: there is a great deal of difference between trying and not trying to achieve a given goal.

Aging Today Better Than It's Ever Been, With Fewer Diseases And Stronger Treatment

Looking at two stages of the Berlin Aging Study, the first carried out between 1990 and 1993 and the second between 2013 and 2014, the team made some large-scale assessments of how old-age vitality has changed, along with some speculations as to why. Overall, despite growing obesity concerns and a stagnant international smoking rate, people seem to be aging more gracefully. Past the advances that have kept people in better physical shape, cognitive tests showed 75-year-olds today were an average of 19.6 years "younger" relative to 75-year-olds in the early 1990s. That is, people tested at 75 today performed as well as a 55-year-old would have two decades ago. "This is, by any means, a huge effect."

Old age is getting younger

On average, today's 75-year-olds are cognitively much fitter than the 75-year-olds of 20 years ago. At the same time, the current generation of 75-year-olds also reports higher levels of well-being and greater life satisfaction. "The gains in cognitive functioning and well-being that we have measured here in Berlin are considerable and of great significance for life quality in old age." The researchers relate the gains to sociocultural factors such as education. In their opinion, the increase in well-being is also due to better physical fitness and higher levels of independence in old age. "However, we expect that these positive historical trends are attenuated at the end of life." During the final stage of life, the increase in good years of life is likely to give way to a rapid and marked drop in both cognition and well-being.

Secular Changes in Late-life Cognition and Well-being: Towards a Long Bright Future with a Short Brisk Ending? (PDF)

We compared data obtained 20 years apart in the Berlin Aging Study (BASE, in 1990-93) and the Berlin Aging Study II (BASE-II, in 2013-14). Relative to the earlier-born BASE cohort, the later-born BASE-II cohort showed better cognitive performance and reported higher well-being, presumably due to culture-based advances in the course of the past century. Our results suggest that historical trends favoring later-born cohorts in cognitive performance carry into old age, constitute strong effects at age 75 years, and generalize to multiple key indicators of perceived quality of life. The cognitive performance of BASE-II participants was on average 19.61 years "younger" relative to the BASE cohort.


Fibroblast growth factor 21 (FGF21) has been the focus of some interest in the research community in recent years. Raised levels of FGF21 have been shown to notably increase mean life span in mice, most likely primarily by interfering in mechanisms related to growth hormone. After more than a decade of earnest research into the mechanisms of aging and longevity in mammals, the longest lived mice are still those in which growth hormone or its receptor are disrupted, a comparatively early discovery in the field. There are numerous ways to influence these biochemical pathways, and altering levels of FGF21 is one of them.

Some researchers classify manipulation of FGF21 as a calorie restriction mimetic treatment given that mice engineered to have more FGF21 show some of the same changes as produced by the practice of calorie restriction. In the other direction, calorie restriction increases circulating FGF21 levels. Restricting only dietary methionine intake also seems to increase FGF21 levels at the same time as it extends healthy life spans in mice. However, other studies have shown that FGF21 isn't required for the production of these benefits. It is probably best to think of any area of metabolism as a machine with many interconnected levers and dials. You can achieve similar results by changing different settings, but not all of the options or the machinery are required for any given outcome, and it is far from straightforward to determine what is actually happening under the hood.

Here researchers find another interesting role for FGF21, picking up on differences in the efficiency of liver regeneration when comparing mice and humans. The first results are a little indirect, but further research should confirm whether or not the observed outcome will hold up in a medically useful context.

FGF21 boosts regenerative ability in mice carrying human PPARα protein

Researchers have illuminated an important distinction between mice and humans: how human livers heal. The difference centers on a protein called PPARα, which activates liver regeneration. Normally, mouse PPARα is far more active and efficient than the human form, allowing mice to quickly regenerate damaged livers. However, the research shows that protein fibroblast growth factor 21 (FGF21) can boost the regenerative effects of human PPARα. The findings suggest that the molecule could offer significant therapeutic benefits for patients who have had a liver transplant or suffer from liver disease. "We found that FGF21 is a good rescuing molecule that facilitates liver regeneration and perhaps tissue repair. Our data suggests that FGF21 could help with liver regeneration, either after removal or after damage caused by alcohol or a virus."

Even after having two-thirds of their livers removed, normal mice regained their original liver mass within seven to 10 days. By contrast, mice with human PPARα never fully regenerated, even after three months. However, by increasing FGF21, the team boosted human PPARα's ability to regenerate and heal mouse livers. While mouse PPARα has regenerative advantages over the human version, there is also a downside, as this ability can lead to cancer. Human PPARα does not cause cancer; however, as noted, it cannot match the mouse protein's regenerative capacity. This trade-off provides a number of advantages on the human side. For example, several popular drugs target PPARα to treat high cholesterol and triglycerides. Still, in the right context, a more active human PPARα could be a great boon for patients with liver conditions. Using FGF21 to boost this regenerative capacity is an important step in that direction.

Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis

The current study demonstrated that PPARα-humanized mice (hPPARαPAC) mice exhibit reduced hepatocyte proliferative capability during liver regeneration in comparison with WT mice. The presented data showed that human PPARα-mediated signaling that controls liver regeneration was less effective than that of mouse PPARα. Thus, in response to liver regeneration, hPPARα is not as effective as mouse PPARα in regulating lipid metabolism as well as hepatocyte proliferation. Metabolism, which is mainly controlled by the liver, is about 7 times faster in mice than humans. Liver regeneration, which can be completed within 7-10 days in mice, takes about 60-90 days to complete in humans. Thus, it seems that the metabolic rate and proliferative capability are correlated, and that the species difference of PPARα may account for such difference.

Because overexpression of FGF21 could restore the normal progression of liver regeneration in hPPARαPAC mice, FGF21 appears to not only repair injury, but also compensate for the reduced ability of human PPARα to hasten liver regeneration. These findings suggest that FGF21 infusion would be of therapeutic value to improve the outcome of liver transplantation and liver disease in humans.


It is always pleasant to see scientific media outlets treat the work of the SENS Research Foundation with the respect it deserves. The Foundation staff are engaged in a modest range of research projects, usually in collaboration with major laboratories in the US and Europe, all of which relate to the defeat of degenerative aging. How to achieve that goal? By repairing the cellular and molecular damage that causes aging, and by cutting off major avenues of dysfunction at the simplest possible point of commonality in the underlying biochemistry. In most cases that point of commonality is the damage: for example you might think of the accumulation of metabolic waste products such as amyloid between cells and lipofusin inside cells. Those waste products can in principle be cleared, removing their effects. For cancer, however, there is a different story.

Cancer is the result of nuclear DNA damage. This damage accumulates in a stochastic fashion across a lifetime, and the more of it you have the greater your odds on any given day of a cell running amok and successfully evading the immune system to generate a tumor. Of course it doesn't help that the immune system is itself also increasingly damaged and subject to dysfunction with advancing age, but cancer is fundamentally an age-related condition because of growth in DNA damage over time. Repairing this damage isn't a near term feasible project. Researchers can fairly clearly envisage and model the sort of molecular nanorobotics that would be needed, but their creation is somewhere several cycles ahead in the march of progress.

So what to do in the meanwhile? The challenge of cancer lies in the fact that it is a broad category covering many, many forms of dysfunctional cellular mechanisms. A treatment built using even the best of today's drug discovery approaches may only work on one of the thousands of classified forms of cancer, and an individual tumor of that type may very well rapidly evolve its way out of being vulnerable in any given treated patient. There is, however, one point of commonality shared by all cancerous cells. They must all continually lengthen their telomeres; if deprived of all means to do so, they will cease to replicate in short order upon reaching the Hayflick limit. Each cell division shortens telomeres and cells with very short telomeres will self-destruct or become senescent. All cancers abuse telomerase or the comparatively poorly understood alternative lengthening of telomeres (ALT) mechanisms in order to continue to exist. Here, then, is the root to strike at, the field from which the ultimate cure for cancer may emerge.

While a number of research groups are hard at work on safely disrupting telomerase activity as a cancer treatment, the SENS Research Foundation is largely focused on the building the tools needed to do the same for ALT:

Control ALT, Delete Cancer

Cellular immortality is a hallmark of cancers that distinguishes them from normal tissue. Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called the telomeres, gets shorter. When the telomeres shorten too much, an alarm signal is generated, and the cell permanently stops dividing and enters senescence or undergoes apoptosis. Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Cancer cells, on the other hand, can become immortalized by activating a telomere maintenance mechanism (TMM) that counteracts telomere shortening by synthesizing new telomeric DNA from either an RNA template using the enzyme telomerase or a DNA template using a mechanism called alternative lengthening of telomeres (ALT).

Because the presence of a TMM is an almost universal characteristic of cancer cells, and experimentally repressing these mechanisms results in cancer cell senescence or death, TMMs may be useful targets in treating cancer. Indeed, several therapies targeting the well-described telomerase-based pathway are in the advanced stages of clinical development. There are currently no ALT-targeted therapeutics, however, largely because this process is less well understood.

In contrast to telomerase-driven telomere lengthening, which does occur in the stem cells of healthy tissues and organs, ALT activity is not found in normal human postnatal tissues - a fact that would allow for more-effective dosing with minimal side effects. And based on the conservative estimate that 10 percent of cancers employ an ALT strategy to achieve cellular immortality, there are about 1.4 million new cases and 820,000 deaths globally due to ALT cancers every year. These include some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers. Clearly, targeting ALT is a very attractive strategy in the development of novel cancer therapies.

The development of ALT-targeted therapies is quite challenging, however. Unlike the telomerase pathway, the ALT mechanism has no known specific enzyme activity, and all the enzymes identified to date that play a role in ALT are also essential to normal cellular pathways. The presence of ALT activity has often been inferred from detecting telomere-related phenotypes, such as long and heterogeneous telomere length distributions or ALT-associated promyelocytic leukemia nuclear bodies (APB), which indicate the abnormal presence of telomeres inside a complex formed from otherwise ubiquitous nuclear proteins. These markers are not entirely satisfactory, as they can sometimes yield inaccurate results and are not practical for high-throughput applications or clinical laboratories.

A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle. C-circles are an unusual type of circular DNAs that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The development of the C-circle assay as well as improvements to the APB assay could, in the near future, make it feasible to perform robust high-throughput screenings to search for modulators of the ALT pathway, which will greatly speed the pace of discovery in this field. Further research will no doubt lead to a more complete mechanistic understanding of this phenomenon and to the first ALT-specific therapies against cancer. Controlling ALT could very well help delete the burden of cancer from society.


The goal of aging research should, in a perfect world, be to repair the causes of age-related degeneration, frailty, and disease. Forms of damage to cells and tissue accumulate as a side-effect of the normal operation of metabolism, and that leads to a chain of consequences that is eventually fatal. Think of rust or wear on toothed gears and the consequences of that; aging is much the same thing, only far more complex because we are very complex, self-repairing machines. The best therapies for aging will be those that revert damage and rescue us from the consequences of that damage.

Researchers often work with animals whose biochemistry has been deliberately altered to malfunction. Accelerated aging through DNA repair deficiency, for example. This is done because animal studies are enormously expensive, but if there is a way to compress the time needed to evaluate specific aspects of biology, then that will be done. In the future this will be replaced with simulation and engineered tissue rather than whole animals, but for now there are many lineages of mice and other species engineered to age more rapidly. Except that they are not in fact aging more rapidly: their biology is broken in a fundamental way that happens to produce more of certain types of cellular and tissue damage. That in the end produces consequences that somewhat resemble aging, but it isn't the same. Think of the difference between progeria and normal aging in humans: at the high level there are apparent similarities, but at the level of cells and tissues it is very different.

Researchers interested in aging have engineered lineages of mice in which metabolism is broken in some fundamental way, and then gone on to restore some of the harm done via a prospective treatment. At the high level you might think that this looks very similar to the description of the best path towards the treatment of aging: there is damage, and that damage is restored or worked around. Yet it is a very different situation. It is very rarely the case that researchers can make any useful claim related to normal aging based on rescue of a pathologically dysfunctional metabolism through treatment. Such studies are a starting point only, a comparatively low cost way to carry out a preliminary proof of concept for the mechanisms involved, or to investigate specific biochemical processes by creating a situation in which they function in a different way. It is a way to make sure that the actual mechanics of the potential therapy are in fact doing what they are supposed to be doing. Then research can move on to tests in normal animals.

This is exactly what happened for senescent cell clearance as a treatment for aging over the past few years: the initial proof of concept was carried out in an accelerated aging mouse lineage, and while this was one of the rare cases where being excited about the outcome (a slowing of dysfunction) was actually merited, it was still the case that only a demonstration in normal mice would seal the deal. That happened this year, and the fact that it was a mere four years between the two research reports is noteworthy: that is rapid indeed in the world of life science research.

Given all of this, when reading about the research quoted below bear in mind that this is really only a demonstration to show that the relevant mechanism probably work as expected in mammals. It says little about whether or not the treatment will prove to be in any way useful in normal animals rather than those with an artificial accelerated aging condition produced by genetic damage of DNA repair mechanisms. It is interesting to speculate given the details regarding increased resilience in the face of certain types of DNA damage, but until it is tried in healthy, normal animals that will remain speculation.

Team succeeds in doubling life span of mice suffering from premature aging (PDF)

Mice with low levels of the ATR protein, essential for the repair of damaged DNA, age faster than normal. Researchers have established a method to rescue the premature aging in these mice, doubling their life span. The strategy: to introduce a mutation capable of increasing the body's capacity to produce nucleotides - the building blocks of DNA - available in the cells. Together with the original mutation in ATR that caused the premature aging, the animals contained multiple copies of Rrm2, the key gene for the synthesis of nucleotides. The results showed how the accelerated aging was significantly alleviated in these mice, namely increasing their survival from an average of 24 weeks to 50 weeks.

The genome of every living being contains certain fragile areas. These are defined due to their tendency to break spontaneously, and they have been shown to be involved in human diseases, including cancer. The studies described in this research paper showed that those mice with additional copies of Rrm2 suffered less DNA breaks in these fragile areas, this being the first mammal described to present a genome which is less fragile than that of a normal mouse.

Whether these results are relevant with respect to normal - rather than premature - aging remains to be discovered. Whatever the case, the authors point out that standard medical practice includes prescribing folic acid (or vitamin B12) supplements to the elderly to delay or lessen the degenerative symptoms associated with advanced age. Bearing in mind that folic acid is, among other things, a precursor molecule in the synthesis of nucleotides, these results might indicate that a scarcity of nucleotides could contribute towards the aging process in humans. "The question we are asking ourselves now is whether an increase in the capacity to produce nucleotides could also lengthen life expectancy in normal animals without premature aging."

Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2TG) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.


It has always been the case that the cause of serious rejuvenation research needs more well-regarded individuals to stand up and talk in public about the road ahead, the prospects for success, and the righteousness of the goal. Just lay out the situation as it is, no need for salesmanship: it is simply the need for this to be a topic not left on the edge of polite society. Aging is by far the greatest cause of suffering and death in the world, and we should all be doing more than we are to help bring an end to all of that pain, disease, and loss. For that to happen, the vast majority of people who never think about aging and rarely think about medical research need to give the topic at least as much thought and approval as presently goes towards the cancer research community.

We find ourselves in a peculiar time. Technological barriers to the successful treatment of aging are next to non-existent; progress is falling out of the woodwork even at low levels of funding and interest; this is an age of revolutionary gains in the tools of biotechnology, and that drives the pace of medicine while the cost of meaningful research plummets. This isn't a space race situation in which the brute force of vast expenditure was used to wrest a chunk of the 21st century into the 20th and land men on the moon. If following the SENS program aimed at repair of the causes of aging, the cost of implementing the first prototype, working rejuvenation treatments in old mice would by current estimates be only 1-2% of the Apollo Program budget. There was vast popular approval for the space race to match the vast expense. The path to human rejuvenation is in exactly the opposite situation: there is very little support for the goal of treating aging as medical condition, but the costs of doing so successfully are so small that given even a minority of the public in favor those funds would be raised.

This is why advocacy is so very important. This is why people with large soapboxes can help greatly simply by talking on the topic. Investor and philanthropist Peter Thiel has been supporting scientific programs such as SENS and related areas in biotechnology for a decade now, but I notice that he is more vocal and direct in public about this cause now that other organizations such as Google Ventures are making large investments. This is all good; we need a sea change in the level of public support for rejuvenation research, and their understanding of the prospects for the future. Aging is far from set in stone, and a range of the biotechnologies needed to treat aging and bring it under medical control are on the verge of breaking out into commercial development, or just a few years away from that point. All it takes to turn the stream into a rapids is a little more rain.

Peter Thiel's quest to find the key to eternal life

WP: Why aging?

Thiel: I've always had this really strong sense that death was a terrible, terrible thing. I think that's somewhat unusual. Most people end up compartmentalizing, and they are in some weird mode of denial and acceptance about death, but they both have the result of making you very passive. I prefer to fight it. Almost every major disease is linked to aging. One in a thousand get cancer after age 30. Nixon declared war on cancer in 1971, and there has been frustratingly slow progress. One-third of people age 85 and older have Alzheimer's or dementia, and we're not even motivated to start a war on Alzheimer's. At the end of the day, we need to do more.

WP: All your philanthropic projects are founded on the idea that there's something wrong with the way the current system works. What are the challenges you see in biomedical research?

Thiel: I worry the FDA is too restrictive. Pharmaceutical companies are way too bureaucratic. A tiny fraction of a fraction of a fraction of NIH [National Institutes of Health] spending goes to genuine anti-aging research. The whole thing gets treated like a lottery ticket. Part of the problem is that aging research doesn't always lend itself to being a great for-profit business, but it's a very important area for a philanthropic investment. NIH grant-making decisions end up being consensus-oriented, focused on doing things that a peer review committee thinks makes sense. So you end up with a very conservative bias in terms of what gets done. [On the other hand,] the original DARPA [Defense Advanced Research Projects Agency] was phenomenally successful. You had a guy running it, and he just gave out the money. It was more focused on substance and less on the grant-writing process. That's the direction we should go. I worry that right now, we have people who are very nimble in the art of writing grants who have squeezed out the more creative.

WP: You're currently funding Cynthia Kenyon, Aubrey de Grey and a number of other researchers on anti-aging. What was it about these individuals and their work that got your attention?

Thiel: They think far outside the conventional wisdom and are far more optimistic about what can be done. I think that's important to motivate the research.

WP: How long is long enough? Is there an optimal human life span?

Thiel: I believe if we could enable people to live forever, we should do that. I think this is absolute. There are many people who stop trying because they think they don't have enough time. Because they are 85. But that 85-year-old could have gotten four PhDs from 65 to 85, but he didn't do it because he didn't think he had enough time. If it's natural for your teeth to start falling out, then you shouldn't get cavities replaced? In the 19th century, people made the argument that it was natural for childbirth to be painful for women and therefore you shouldn't have pain medication. I think the nature argument tends to go very wrong. . . . I think it is against human nature not to fight death.

WP: Assuming the breakthrough in eternal life doesn't come in our lifetime, what do you hope to have achieved through your philanthropy before you die? What would you like to be remembered for?

Thiel: I think if we made some real progress on the aging thing, I think that would be an incredible legacy to have. I have been fortunate with my business successes, so I would like to encourage, coordinate and help finance the many great scientists and entrepreneurs that will help bring about the technological future. It's sort of not important for me to get credit for the specific discoveries, but if I can act as a supporter, mentor and financier, I think that feels like the right thing.


Monday, March 30, 2015

A number of researchers have pointed out similarities between some of the risk factors and mechanisms of type 2 diabetes and Alzheimer's disease, a few even going so far as to suggest that Alzheimer's should be classified as type 3 diabetes:

Type 2 diabetes mellitus (T2DM) is currently extremely common due to the prevalence of obesity, as well as the aging of the population. Prevention and treatment strategies for the classical macrovascular and microvascular complications of diabetes mellitus have significantly improved. Therefore, people are living longer with diabetes mellitus, which might lead to the emergence of new complications. Dementia is one example of these emerging new complications. Compared with the general population, the increased risk of dementia is 50%-150% in people with T2DM.

Over the past three decades, numerous epidemiological studies have shown a clear association between T2DM and an increased risk of developing AD. In addition, T2DM-related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, may also be risk factors for AD. The exact mechanisms with clinical relevance are unclear. Several mechanisms have been proposed, including insulin resistance and deficiency, impaired insulin receptor and impaired insulin growth factor (IGF) signaling, glucose toxicity, problems due to advanced glycation end products and their receptors, cerebrovascular injury, vascular inflammation, and others.

In this review, we discuss insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-β protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as "type 3 diabetes". Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. Although the results of these trials seem to be contradictory, this approach is also full of promise.

Monday, March 30, 2015

A greater level of fitness in mid-life is shown in many large studies to correlate with improved health and greater life expectancy. The data from this study shows that increased fitness correlates with lower mortality from cardiovascular disease and some cancers in those patients with a cancer diagnosis in their medical history:

Cardiorespiratory fitness (CRF) as assessed by formalized incremental exercise testing is an independent predictor of numerous chronic diseases, but its association with incident cancer or survival following a diagnosis of cancer has received little attention. The study included 13 949 community-dwelling men who had a baseline fitness examination. All men completed a comprehensive medical examination, a cardiovascular risk factor assessment, and incremental treadmill exercise test to evaluate CRF. We used age- and sex-specific distribution of treadmill duration from the overall Cooper Center Longitudinal Study population to define fitness groups as those with low (lowest 20%), moderate (middle 40%), and high (upper 40%) CRF groups. Cardiorespiratory fitness levels were assessed between 1971 and 2009, and incident lung, prostate, and colorectal cancer using Medicare claims data from 1999 to 2009; the analysis was conducted in 2014.

Compared with men with low CRF, the adjusted hazard ratios (HRs) for incident lung, colorectal, and prostate cancers among men with high CRF were 0.45, 0.56, and 1.22, respectively. Among those diagnosed as having cancer at Medicare age, high CRF in midlife was associated with an adjusted 32% risk reduction in all cancer-related deaths and a 68% reduction in cardiovascular disease mortality following a cancer diagnosis compared with men with low CRF in midlife. There is an inverse association between midlife CRF and incident lung and colorectal cancer but not prostate cancer. High midlife CRF is associated with lower risk of cause-specific mortality in those diagnosed as having cancer at Medicare age.

Tuesday, March 31, 2015

There has been some interest in deeper investigations of metabolism and aging in mammals via the study of hibernating species. For any stable altered state of metabolism, such as the calorie restriction response or hibernation, a greater understanding of the mechanisms involved may shed light on a range of issues. In the case of hibernation there is a long way to go yet, however. Research is still in the early stages, and comparatively few scientists study hibernation with this perspective:

The conventional wisdom in longevity research is that smaller species live shorter lives than larger ones. For example, humans and whales can live to be over 100; yet the average lab mouse doesn't live beyond its third birthday. The researchers found an exception to this pattern in a group of hamster-sized lemurs with a physiological quirk - they are able to put their bodies in standby mode.

Researchers combed through more than 50 years of medical records on hundreds of dwarf lemurs and three other lemur species for clues to their exceptional longevity. How long the animals live and how fast they age correlates with the amount of time they spend in a state of suspended animation known as torpor, the data show. Hibernating lemurs live up to ten years longer than their non-hibernating cousins. Dwarf lemurs were the most extreme examples in their study, spending up to half the year in deep hibernation in the wild. Dwarf lemurs go into a semi-hibernation state for three months or less in captivity, but even that seems to confer added longevity.

Hibernating dwarf lemurs can reduce their heart rate from 200 to eight beats per minute. Breathing slows, and the animals' internal thermostat shuts down. Instead of maintaining a steady body temperature, they warm up and cool down with the outside air. For most primates such vital statistics would be life-threatening, but for lemurs, they're a way to conserve energy during times of year when food and water are in short supply. Hibernating lemurs not only live longer, they also stay healthier. While non-hibernators are able to reproduce for roughly six years after they reach maturity, hibernators continue to have kids for up to 14 years after maturity, the researchers found. Although all species they examined suffered from cataracts and other age-related eye diseases as they got older, the hibernators managed to stave off symptoms until much later in life.

Tuesday, March 31, 2015

Amyloids are misfolded proteins that gather to form solid aggregates in tissues. Their presence grows with age and some types of amyloid are known to contribute to the pathology of specific age-related conditions: amyloid-β in Alzheimer's disease and misfolded transthyretin in senile systemic amyloidosis for example. Any potential rejuvenation toolkit must include a reliable technology platform for clearance of the various forms of amyloid. Of late researchers have been working on the use of what they call molecular tweezers for this purpose, and seem to be making meaningful progress:

An international team of more than 18 research groups has demonstrated that the compounds they developed can safely prevent harmful protein aggregation in preliminary tests using animals. The findings raise hope that a new class of drugs may be on the horizon for the more than 30 diseases and conditions that involve protein aggregation, including diabetes, cancer, spinal cord injury, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). Proteins are necessary for almost every cellular process. However, when cell machinery doesn't clear out old proteins, they can clump, or aggregate, into toxic plaques that lead to disease.

The researchers call the compounds that they developed molecular tweezers because of the way they wrap around the lysine amino acid chains that make up most proteins. The compounds are unique in their ability to attack only aggregated proteins, leaving healthy proteins alone. To develop a new drug, researchers typically screen large libraries of compounds to find ones that affect a protein involved in a disease. This team used a fundamentally different approach to develop the molecular tweezers. "We looked at the molecular and atomic interactions of proteins to understand what leads to their abnormal clumping. Then, we developed a tailored solution. So unlike many other drugs, we understand how and why our drug works."

The team is in the process of testing multiple versions of the tweezers, each with a slightly different molecular makeup. For CLR01, one of the most promising versions, the researchers have demonstrated therapeutic benefits in two rodent models of Alzheimer's disease, two fish and one mouse model of Parkinson's disease, a fish model of spinal cord injury and a mouse model of familial amyloidotic polyneuropathy, a rare disease in which protein aggregation affects the nervous system, heart and kidneys. "Our data suggest that CLR01, or a derivative thereof, may become a drug for a number of diseases that involve protein aggregation. We also found a high safety window for CLR01." In one of the safety tests, mice receiving a daily CLR01 dose 250 times higher than the therapeutic dose for one month showed no behavioral or physiological signs of distress or damage. In fact, blood cholesterol in the mice dropped by 40 percent, a possible positive side effect of CLR01.

Wednesday, April 1, 2015

The forkhead box (FOX) family of proteins includes members such as FOXO3 that seem to be important in longevity and regeneration in a variety of very different species. Here researchers show that FOXO3 is required for the additional longevity created by the practice of calorie restriction:

Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). This study examined the role of Foxo3 in lifespan extension and cancer suppression in DR mice. Wild-type (WT) and Foxo3-knockout heterozygous (+/-) and homozygous (-/-) mice were subjected to a 30% DR regimen initiated at 12 weeks of age. Control mice were fed ad libitum (AL) throughout the study. The food intake by Foxo3+/- and Foxo3-/- mice was similar to those by WT mice under the AL condition, and thus, the daily allotments for each DR group were almost the same during the lifespan study. The average body weights of WT, Foxo3+/-, and Foxo3-/- mice were also similar under AL and DR conditions.

In contrast to WT mice, DR did not significantly extend the lifespan of Foxo3+/- or Foxo3-/- mice. However, DR reduced the prevalence of tumors at death in WT, Foxo3+/-, and Foxo3-/- mice. These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3+/- mice contrast with those in Foxo1+/- mice reported previously by our laboratory and suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3.

Wednesday, April 1, 2015

A reliable means to safely accelerate natural healing would be a generally useful technology for all stages of life, but it is the elderly who suffer the most due to slower and more dysfunctional healing of even minor injuries:

An experimental therapy cut in half the time it takes to heal wounds compared to no treatment at all. Researchers discovered that an enzyme called fidgetin-like 2 (FL2) puts the brakes on skin cells as they migrate towards wounds to heal them. They reasoned that the healing cells could reach their destination faster if their levels of FL2 could be reduced. So they developed a drug that inactivates the gene that makes FL2 and then put the drug in tiny gel capsules called nanoparticles and applied the nanoparticles to wounds on mice. The treated wounds healed much faster than untreated wounds. "We envision that our nanoparticle therapy could be used to speed the healing of all sorts of wounds, including everyday cuts and burns, surgical incisions, and chronic skin ulcers, which are a particular problem in the elderly and people with diabetes."

The wound-healing therapy uses molecules of silencing RNA (siRNAs) specific for FL2. The siRNAs act to silence genes. They do so by binding to a gene's messenger RNA (mRNA), preventing the mRNA from being translated into proteins (in this case, the enzyme FL2). However, siRNAs on their own won't be effectively taken up by cells, particularly inside a living organism. They will be quickly degraded unless they are put into some kind of delivery vehicle, and so the researchers collaborated with another group who had developed nanoparticles that protect molecules such as siRNA from being degraded as they ferry the molecules to their intended targets. The nanoparticles with their siRNA cargoes were then tested by topically applying them to mice with either skin excisions or burns. In both cases, the wounds closed more than twice as fast as in untreated controls. "Not only did the cells move into the wounds faster, but they knew what to do when they got there. We saw normal, well-orchestrated regeneration of tissue, including hair follicles and the skin's supportive collagen network."

Thursday, April 2, 2015

Cancer as a threatening medical condition occurs in a third of all people. Given that tiny, non-threatening cancers exist in all people by old age, why not the other two thirds? The glib answer is that they are killed by something else before a threatening cancer arises. Cancer risk is seen as a continual game of odds, the chance of cancer rising throughout most of life as DNA damage accumulates. The third are the unlucky ones. There is probably more to it than that at the detailed level of cellular biochemistry, however:

Approximately one in three people is struck by neoplastic disease in his or her lifetime. But, the other side of that coin is that two out of three people remain unaffected. Even the majority of heavy smokers, who bombard their lungs with carcinogens and tumor promoters over many years, remain cancer free. Naturally, the suffering of cancer patients and their families has inspired researchers to study the cellular changes unique to cancer and the genetics of cancer susceptibility. The genetics of cancer resistance, as a topic in its own right, has remained largely unexplored.

Pathologists have shown that virtually all men age 60 or older have microscopic prostate cancer when examined at autopsy. Most of these microtumors never develop into cancer, however. It is also known that disseminated cancer cells are present throughout the body in most cancer patients, but only a small minority of these cells develop into secondary tumors. The rest are kept under control by the body. Indeed, metazoan evolution has led to many adaptations that protect species across the animal kingdom from outlaw cells. Immune surveillance plays a major role in the defense against virus-associated tumors, where the virally encoded transforming proteins provide readily recognizable foreign targets. But nonviral tumors, which are composed of aberrant host cells, do not provide such targets, and the immune response is suppressed by defenses against autoimmune reactions. Rather, we now know that the main safeguards against cancer are not immunological at all.

Several cancer-resistance mechanisms appear to have evolved to maintain cellular or genomic integrity. For example, normal stroma, the connective material that supports the cells of a tissue, appears to inhibit cancer growth. Other resistance mechanisms include DNA repair, suppression of oncogene activation, tumor-suppressor genes, epigenetic stabilization of chromatin structure, and apoptosis. These mechanisms are well-studied, and each provides a potential road map for prevention and treatment.

Thursday, April 2, 2015

Here is a popular science article on the topic of bioprinting complex tissues, which at this stage is largely used to provide small living tissue structures for research and development. These represent a great improvement in cost and efficiency when compared with the other options of cell culture and animal studies. Nonetheless, this is but a stepping stone on the path to the greater goal of tissue engineered organs assembled to order via 3-D printing technologies:

Just like you would hope, something very cool was revealed at the 2015 Experimental Biology conference in Boston: the biomedical company Organovo showed off its technique for 3D printing human kidney tissue. Organovo has been working on printing functional human tissue since being incorporated in 2007, and first printed a cellular blood vessel in 2010. Since January 2014, it has offered bioprinted liver tissue for companies to use in drug trials and disease modeling, and it looks as though its bioprinted human kidney tissue will be used for the same tasks, starting sometime in the latter half of 2016. "The product that we intend to build from these initial results can be an excellent expansion for our core customers in toxicology, who regularly express to us an interest in having better solutions for the assessment of human kidney toxicity."

So far Organovo's 3D-printed liver tissue is used for preclinical drug trials because the tissue responds like a real life human liver would for 42 days. That's much longer than the single layers of cells previously used in tests, which wilt in a few days. There are mixed views on how far off printing functional organs for transplant is. Growing tissue is one thing, but growing an organ and integrating it into a living body is another. "Everybody's dream is the 3D-printed organ. Are we ever going to get there?" asked Gabor Forgacs, whose research forms the basis of Organovo's method. Forgacs argued that there was no reason functional organs couldn't be made eventually, but that printing replacement organs on demand was still decades away.

Friday, April 3, 2015

Mitochondrial damage is considered to be an important contribution to degenerative aging. Here researchers find stem cells performing a preferential assignment of cellular components during cell division, giving one of the daughter cells more of the components likely to be damaged - such as older mitochondria. This differential assignment of damage during replication has been seen in bacteria as well; it is clearly a very ancient aspect of cellular biology.

While interesting, there may or may not be any near term practical application for the treatment of aging resulting from a better understanding of how cells are determining which mitochondria to assign to which daughter cell. A more direct path such as mitochondrial repair or replacement may be a more efficient towards medical intervention in the aging process given the present state of technology and knowledge:

During division, stem cells distinguish between old and young mitochondria and allocate them disproportionately between daughter cells. As a result, the daughter cell destined to remain a stem cell receives predominantly young mitochondria, while the cell meant to differentiate into another cell type carries with it a higher compliment of the aged organelles. This asymmetric apportioning of cellular contents may represent a mechanism through which stem cells prevent the accumulation of damage in their lineage over time.

Among the hallmarks of stem cells is so-called asymmetric cell division. Unlike their ordinary cellular counterparts, which divide symmetrically to create two cells with identical fates, stem cell division can produce one daughter cell that will remain a stem cell and another bound for further differentiation into another cell type. Scientists have observed that non-mammalian organisms are able to apportion damaged components asymmetrically during cell division, but it was unclear whether mammalian stem cells could behave similarly.

To track the destinations of subcellular components during cell division, the researchers tagged the components - including lysosomes, mitochondria, Golgi apparatus, ribosomes, and chromatin - with a fluorescent protein that glows when hit by a pulse of ultraviolet light. By tracing the movements of the glowing organelles, the researchers were able to demonstrate that while normal epithelial cells distributed all of the tagged components symmetrically to daughter cells, stem cells localized their older mitochondria distinctly and passed on the lion's share of them to the daughter cells headed for differentiation. The researchers ultimately found that the number of older mitochondria in those cells was roughly six times that in daughter cells whose fate was to remain as stem cells.

Further, they discovered that chemically disrupting the cells' inherent mitochondrial quality-control mechanisms prevented asymmetric apportioning of young and old mitochondria and caused the loss of stem-like characteristics. Taken together, these results indicate that this disproportionate allocation of aged mitochondria during stem cell division is essential for maintaining stemness in the next generation. "While we do not know how stem cells recognize the age of their mitochondria, forced symmetric apportioning of aged mitochondria resulted in loss of stemness in all of the daughter cells. This suggests that the age-selective apportioning of old and potentially damaged organelles may be a way to fight stem cell exhaustion and aging."

Friday, April 3, 2015

Mortality rates continue to fall for common age-related diseases, especially cardiovascular conditions. Yet the overall death toll increases because the population is larger and on average older. Gaining medical control over degenerative aging only grows more important with the passing of time: there are so very many lives to be saved.

As the global population pushes past 7 billion and more people reach old age, the number of deaths from cardiovascular diseases is on the rise. Cardiovascular diseases, the leading cause of premature death in the world, include heart attacks, strokes, and other circulatory diseases. At the same time, efforts to prevent and treat cardiovascular diseases appear to be working as the rise in deaths is slower than the overall growth of the population. Globally, the number of deaths due to cardiovascular diseases increased by 41% between 1990 and 2013, climbing from 12.3 million deaths to 17.3 million deaths. Over the same period, death rates within specific age groups dropped by 39%, according to an analysis of data from 188 countries. Death rates from cardiovascular diseases were steady or fell in every region of the world except western sub-Saharan Africa.

South Asia, which includes India, experienced the largest jump in total deaths due to cardiovascular diseases, with 1.8 million more deaths in 2013 than in 1990 - an increase of 97%. In line with global trends, the increase in deaths from cardiovascular disease in India is driven by population growth and aging without the decrease in age-specific death rates found in many other countries. This pattern is reversed to some extent in the Middle East and North Africa, which includes countries such as Saudi Arabia, Lebanon, and Jordan. In these regions, population growth and aging have been offset by a significant decline in age-specific death rates from cardiovascular disease, which has kept the increase in deaths to just under 50%. East Asia experienced a similar rise of almost 50%, 1.2 million additional deaths, because declines in the risk of cardiovascular diseases offset the effect of a rapidly aging population. Taken together as a region, the United States and Canada were among a small number of places with no detectable change in the number of deaths from cardiovascular diseases, because aging and population growth balanced out declines in age-specific death rates. The same was true in southern Latin America, including Argentina and Chile, as well as Australia and New Zealand.

Researchers found that population aging contributed to an estimated 55% increase in cardiovascular disease deaths globally, and population growth contributed to a 25% increase. These demographic factors are not the only drivers behind the trend of increasing deaths and falling death rates. Changes in the epidemiology of cardiovascular diseases is another factor. Ischemic heart disease is both the leading cause of death worldwide and accounts for almost half of the increase in the number of cardiovascular deaths, despite a 34% decrease in age-specific death rates. Researchers also examined whether wealthier countries fared better than lower-income countries when it comes to cardiovascular deaths and found there was not a strong correlation between income per capita and lower age-specific death rates. The dramatic improvement in the death rates seen in some regions was attributed to prevention and treatment of cardiovascular diseases, in part by reducing risk factors including smoking.


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