Fight Aging! Newsletter, March 30th 2015

March 30th 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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  • DNA Methylation and Natural Variation in Human Longevity
  • More Signs that Calico Will Fund Broad Mainstream Drug Discovery and Genetic Research
  • Excess Fat is Bad, Intentional Loss of that Fat is Good
  • Genes Become Increasingly Important in Extreme Old Age
  • A Tour of Pharmaceuticals that Extend Life in Nematodes
  • Latest Headlines from Fight Aging!
    • Theorizing that the Brain is Destroyed by the Pulse
    • Ceria Nanoparticles Enhance Autophagy
    • Another Study to Argue that Tau is Primary and Amyloid Secondary in Alzheimer's Disease
    • The "Aging Kills" Initiative
    • Who Funds Basic Aging Research in the US?
    • Education Correlates With Longevity
    • Further Investigations of Neuropeptide Y and the Hypothalamus in Calorie Restriction
    • A New Era of Aging Research
    • Leucine Supplementation as a Sarcopenia Treatment
    • Myostatin Insufficiency Produces 15% Life Extension in Mice


DNA methylation is an epigenetic alteration in which genes are decorated with methyl groups. It is one of a range of epigenetic processes that establish a feedback loop linking the pace at which specific proteins are built from genetic blueprints, the activities of those proteins once built, and environmental circumstances in tissues such as nutrient availability, temperature, damage, and disease. All of the switches and dials for molecular machinery inside cells are essentially built on top of the circulating levels of specific proteins, and these are altered via epigenetics: protein levels are in constant flux, as are countless epigenetic modifications to DNA.

In recent years researchers have demonstrated that specific patterns of DNA methylation within this broader tapestry correlate very well with age. Researchers can use these patterns in a tissue sample to identify an individual's age with an accuracy of five years or so. We all age due to the same underlying processes, some of us faster than others largely due to unfortunate lifestyle choices such as lack of exercise, excess weight, and smoking. Small differences in stochastic damage to cells and tissues snowball over the years into comparatively large differences in outcomes: the roots of variability in the mean time to failure in a very complex system. Given that the same forms of damage accumulate in all of us as a side effect of the same metabolic processes, it shouldn't be surprising to find that researchers can pull out patterns in the controlling mechanisms of metabolism - epigenetic alterations - that are tightly coupled to age. These are reactions to the environmental state of being damaged.

Studies that investigate DNA methylation from other perspectives should pick up the same signs of the same underlying processes, and same broad similarities between individuals. This is the case even when looking for signs of differences between old individuals, in search of a better explanation of the genetic contribution to extreme longevity in humans. So far genetic studies have turned up very few associations between genetic variants - meaning actual differences in the structure of specific genes - and longevity. Those that are found in one study rarely show up in others. This suggests that if variants are important in determining survival in extreme old age, then there must be a very large number of such variants with individually small effects, and the patterns of genetic differences must vary widely between regional populations. A very complex picture with little hope of complete understanding or any sort of resulting application in medicine in the near future, in other words. Is this in fact the case, however? These researchers suggest that epigenetic changes are instead where we should look, and that the picture isn't as complex as feared:

A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

Human longevity is believed to be an integrating result of genetic and environmental factors. Although previous studies have shown that genetic variation may explain 20-30% contribution to human longevity, much remains to be known for its underlying genetic mechanism. In the past decade, a number of genes were discovered, in which some specifically genetic alterations may confer advantage in extending the organisms' lifespan, suggesting the existence of longevity genes. These findings however could not fully explain the significantly reduced incidence of age-related diseases in centenarians and their offspring, as it requires a broad effect of longevity genes, including conferring beneficial effects in extending life span as well as suppressing deleterious influence from the disease-associated genes. Alternatively, it is possible that the low prevalence of the age-related diseases in the long-lived people is attributed to a much lower frequency of risk alleles. Unfortunately, the latter notion fails to find support from a recent study in which the long-lived people were shown to carry similar frequencies of risk alleles as did in the young controls. This observation seems to echo with the suggestion that the longevity-related variants may compress the morbidity of long-lived people as these variants were significantly enriched in disease-related genes.

Hitherto, the obtained genetic evidence, based virtually on mutation screening, find no support for the hypothesis that lack of disease-related mutations contributes to healthy aging. However, taking into account the heterogeneity in longevity, in which multiple ways could be adopted to achieve longevity, and the crucial role of epigenetic modification in gene regulation, we hypothesize that suppressing the disease-related genes in the longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. A reduction of genome-wide DNA methylation level and locus-specific hyper-methylation has been observed with aging, whereas changes in DNA methylation were reported to be associated with the occurrences of age-related diseases, such as cardiovascular disease, diabetes and cancer.

To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.

I'd want to see a much larger study before taking this result at face value, but to find consistencies across populations in this sort of data shouldn't be too surprising given the points made above about the fact that we all age in the same way. Patterns of similarity should be there to be found in many different ways.


Google is pouring a large amount of money into aging research via the Calico Labs initiative. Their declared aim is to produce treatments that impact the whole of age-related degeneration, and their open support of that goal is certainly going to make it easier for other initiatives to raise funding in the future - it adds that much more legitimacy to the space in the eyes of investors and philanthropists who have so far stayed away. That is the good part. However it has become increasingly clear that the Calico Labs approach, telegraphed pretty early on, is to broadly fund the central mainstream of research and development relating to aging, which at this time is the standard process of drug discovery and investigations of the genetics of longevity. In this they might be considered a second iteration of the Ellison Medical Foundation, a funding addendum to the present efforts of the NIA and pharmaceutical companies, but really introducing no fundamentally new and better strategy. So expect past performance to predict the next decade or so here.

The Ellison Medical Foundation achieved essentially nothing of great note over the course of its existence, a period when the same could be said of most NIA projects, because the mainstream approach to aging does not consist of strategies likely to produce any significant gains in healthy human life span. I've talked about why this is the case at length over the years, but in essence it boils down to the same reasons as to why I support the SENS programs for rejuvenation biotechnology development. The preponderance of evidence strongly suggests that aging is caused by an accumulation of damage to cells and tissues. The best approach, which is the SENS approach, is to repair that damage periodically but otherwise not tinker with the operation of our metabolism: it is complicated and we understand very little of it in comparison to our understanding of the damage that is linked to aging. This is not the mainstream approach, however. In the mainstream of aging research, where researchers are interested in treating aging at all that is, the focus is on finding ways to alter the operation of our metabolism so as to slow down damage accumulation.

It doesn't require a vast and detailed understanding of biology to grasp that slowing damage is a worse strategy than repairing damage in any system, complex or not. It cannot restore youthful function and is of limited utility to old people. Further, safely altering metabolism to achieve specific goals is much harder than repairing known and clearly demarcated forms of cellular damage. This is illustrated by the fact that a clear set of plans for damage repair exist with many different options for implementation, but at this time - and after decades of work and billions of dollars invested - researchers still don't have a clear understanding of how calorie restriction works or can be reproduced, and that is the simplest and most reliable altered state of metabolism known to extend life and improve health. Even if the calorie restriction response could be recreated with a drug, the outcome would be far less health and life gained than for even a partial implementation of repair treatments.

Here are some recent news reports on the Calico initiative that reinforce the point on the broad fundamental research strategy they are choosing to take, acting in essence as a supplemental fund for existing programs and approaches to drug development, with a heavy emphasis on genetics:

Broad Institute and Calico announce an extensive collaboration focused on the biology of aging and therapeutic approaches to diseases of aging

The Broad Institute of MIT and Harvard has entered into a partnership with Calico around the biology and genetics of aging and early-stage drug discovery. The partnership will support several efforts at the Broad to advance the understanding of age-related diseases and to propel the translation of these findings into new therapeutics. "This alliance is a key part of Calico's strategy to bring the best cutting-edge science to bear on problems of aging. The Broad Institute is one of the nation's preeminent research organizations whose outstanding research has repeatedly revealed fundamental mechanisms of the biology and genetics of disease," said Art Levinson, Chief Executive Officer of Calico.

Calico, QB3 Launch Longevity R&D Partnership

Google-back Calico said Tuesday it will partner with the University of California institute QB3 to study longevity and age-related diseases, as well as create and foster an interdisciplinary community of scientists in those fields. The four-year partnership is designed to generate discoveries that will translate into greater understanding of the biology of aging and potential therapies for age-related diseases. The partnership plans to identify, fund and support QB3 research projects focused on aging, using committed funding from Calico - which focuses on aging research and therapeutics. "We are all aging, and we will all benefit from the discoveries made in this program and the therapies that will result," QB3 director Regis Kelly said in a statement. "We are grateful to Calico for recognizing the deep expertise at the University of California that attracts so many scientists of exceptional ability."

For those of us who do support the SENS repair approach, the lesson to take home and remember is that we will see mainstream funding of SENS-related research and development when that work becomes mainstream. Not before. It is already the case for cancer and stem cell science, where there are strands of SENS-like work taking place in many laboratories, but for the other forms of tissue repair there must be demonstrations of effectiveness. We can learn from the growing interest in senescent cell clearance: that only emerged in earnest after the 2011 demonstration of improved health in accelerated aging mice. This year we are seeing the fruits of that interest in the form of new demonstrations of effectiveness in normal mice and the first company founded to commercialize an approach to clear senescent cells. More researchers, more results, more programs underway.

However frustrating it might be, funding follows success. This is why it is so important that we continue to raise funds for early stage SENS research in order to create the technology demonstrations that can pull in that attention and funding. We are, after all, winning at this game step by step. Five years ago senescent cell clearance was something that no research groups looked at in earnest, and now we have mice that are healthier as a result of treatments that remove senescent cells. Ten years from now there will be clinical trials underway in humans. Meanwhile there are four or five other important forms of damage repair that must make the same leap, and that is only going to happen with the support of you, I, and other philanthropists.


One of the things that turns up in large sets of data on weight and mortality - by which I really mean amount of fat tissue and mortality - is that both maintaining excess fat tissue and later the loss of that fat tissue are associated with increased mortality. This is because visceral fat tissue causes chronic inflammation and other forms of metabolic dysregulation. The more of it you have, the worse off you are over the long term: it is actively causing harm that accumulates to significantly raise the risk of all of the common age-related disease. Later in life, the progression and treatment of many of these age-related conditions, such as cancer, are accompanied by involuntary weight loss. There are many reasons for this ranging from simple loss of appetite to disease mechanisms that impact the normal operation of metabolism in pathological ways. If you pick out a group of people who are sharply losing weight, especially older people, the mortality rate for that group will tend to be higher than for those who maintain their weight. This is because the losing group contains a larger number of individuals who are suffering the later stages of age-related disease.

This does not mean, as some have said in the past, that it is good to be overweight. You can't lump this data together and make that claim. Involuntary weight loss is so very joined at the hip to high mortality risk that it distorts the picture, and most of the good data sources for large numbers of people make no distinction as to how or why weight changes occur. Any number of people in the world want to be told that is is fine to be overweight and nothing bad is going to happen as a result: there is always a market for comforting lies. Even a moderate level of excess fat tissue has a significant impact on the future risk of incurring all of the common age-related diseases, however. If you want the best odds of living a healthy life for as long as possible, then don't allow yourself to become fat. It is a choice, and one that you can avoid or reverse with sufficient exercise of willpower.

Unlike involuntary weight loss, deliberately setting out to lose your excess fat tissue is a good thing and produces benefits. You are cutting out a source of damage to your health, and that makes a difference over the long-term to your mortality risk. That shows up in epidemiological data, as demonstrated here.

Intentional Weight Loss and All-Cause Mortality: A Meta-Analysis of Randomized Clinical Trials

Advanced age and obesity are risk factors for disability, morbidity, and mortality. Weight loss interventions in overweight and obese older adults positively affect several strong risk factors for mortality. Yet, many observational studies in middle-aged and older adults report an association between weight loss and increased mortality. Difficulty reconciling these contradictory findings (the so-called "obesity paradox"), coupled with the strong negative prognostic implication of rapid involuntary weight loss with advanced age, has led to a reluctance to recommend weight loss in older adults. Attempts to refine observational analyses to avoid confounding (i.e. distinguishing between intentional and unintentional weight loss, and restricting populations to those without co-morbid conditions or non-smokers) typically reveal no increase, and perhaps some decrease, in mortality risk with intentional weight loss.

Although results from a randomized controlled trial (RCT) of weight loss would theoretically resolve these issues, such a trial would require a large sample size over a long duration to detect clinically meaningful differences in mortality. In light of the high prevalence of obesity, its negative impact on health and quality of life, and the discrepancy between the proven risk factor improvements of short-term intentional weight loss and the inverse association of weight loss with increased all-cause mortality frequently seen in observational studies, we conducted a meta-analysis to estimate the effect of interventions which included intentional weight loss on all-cause mortality in overweight and obese adults. We hypothesized that intentional weight loss would be associated with reduced all-cause mortality. Further, as weight loss in older persons is a cause of clinical concern that may lead health care providers to recommend against weight loss for obese, older adults, we sought to examine the effects in a subset of trials with a mean baseline age of at least 55 years.

Trials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30-46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk. There was no evidence for heterogeneity of effect.


The lesson to take away from the last fifteen years of study of the genetics of longevity is that genetic variation in humans is simply not all that important throughout most of life. Aging is caused by damage, and certainly during the period of life in which damage levels in cells and tissues are still comparatively low, all the way into early old age, the vast majority of genetic variants identified in our species have little to no effect on survival. Given that the best possible path forward to treat aging is to build treatments to periodically repair damage levels so as to keep them low, this tells me that the study of the genetics of longevity variance is not very important from a practical point of view, meaning from the standpoint of building new medical technologies to extend healthy life. It is the study of how extremely damaged biology works, and how normally unimportant genetic variants can suddenly become much more relevant to survival in frail individuals suffering advanced stages of the degeneration of aging. That is an interesting area of study, as is true of all biochemistry, but not a good focus if we want to see extended healthy life, more time spent alive with little accumulated damage.

When it comes to aging, damage, and repair, to a first approximation we are all the same. Treatments for repair of aging will be mass-manufactured once developed, exactly the same therapy for every individual: it will be the polar opposite of the often envisaged future of personalized medicine. The genetics of variations in the longevity of physically old people will become a historical curiosity, like the genetics of smallpox survival. Outside of narrow specialties in history and biochemistry we don't care as to how genetic variations influence smallpox survival, and rightly so. The research community found the means to eliminate the condition for everyone and the world moved on. This is an age in which genetics is the newest tool in the toolbox, the technologies suddenly cheap and capable, and it is being applied to everything. Hence the existence of ventures like Human Longevity, Inc. Genetic studies of aging won't provide a straightforward path to much greater healthy longevity, however, because - as noted - genetic variants are only important to the course of aging and disease in the old and the frail. Meaningful treatments for aging will be those that prevent people from ever being old and frail, or rescue them from that state, by repairing the damage that causes aging.

None of this is preventing considerable growth in the study of the genetics of longevity and aging in humans, of course. It is very much a part of the research mainstream. As more data accumulates, the present picture of genes and aging is refined to show that the increase in the relevance of genetic variants to survival in a damaged state just keeps on growing the further into extreme old age you go. The more damaged you are, the more your particular genetic quirks matter.

BU/BMC study finds the role of genes is greater with living to older ages

Genes appear to play a stronger role in longevity in people living to extreme older ages. The study found that for people who live to 90 years old, the chance of their siblings also reaching age 90 is relatively small - about 1.7 times greater than for the average person born around the same time. But for people who survive to age 95, the chance of a sibling living to the same age is 3.5 times greater - and for those who live to 100, the chance of a sibling reaching the same age grows to about nine times greater. At 105 years old, the chance that a sibling will attain the same age is 35 times greater than for people born around the same time - although the authors note that such extreme longevity among siblings is very rare. "These much higher relative chances of survival likely reflect different and more potent genetic contributions to the rarity of survival being studied, and strongly suggest that survival to age 90 and survival to age 105 are dramatically different phenotypes or conditions, with very different underlying genetic influences."

The study analyzed survival data of the families of 1,500 participants in the New England Centenarian Study, the largest study of centenarians and their family members in the world. Among those families, the research team looked at more than 1,900 sibling relationships that contained at least one person reaching the age of 90. The findings advance the idea that genes play "a stronger and stronger role in living to these more and more extreme ages," and that the combinations of longevity-enabling genes that help people survive to 95 years are likely different from those that help people reach the age of 105, who are about 1,000 times rarer in the population. For a long time, based upon twins' studies in the 1980s and early '90s, scholars have maintained that 20 to 30 percent of longevity or even life span is due to differences in genes, and that the remainder is due to differences in environment, health-related behaviors or chance events. But the oldest twins in those studies only got to their mid- to late-80's. Findings from this and other studies of much older (and rarer) individuals show that genetic makeup explains an increasingly greater portion of the variation in how old people live to be, especially for ages rarer than 100 years."


Most threads of aging research start in studies of very short-lived species, most commonly the nematode worm C. elegans. These animals are cheap to maintain over the course of a study, live for only a few weeks, and are probably better understood at the cellular and genetic level than any other species. A mature and continually improving infrastructure of automation and provision exists to serve scientists running nematode studies. Despite the vast gulf between humans and nematodes many of the fundamental cellular mechanisms of metabolism are similar. Both degenerative aging and the basic structure of animal cells arrived early on in the evolution of multicellular life. Thus most of the better known phenomena of aging, such as the slowing of aging induced by calorie restriction, are preserved across near all species, whether nematodes or mammals. Researchers have learned a great deal about the fundamentals of aging by studying nematodes, and it makes good sense to pursue uncertain ideas with an unknown likelihood of success in a low-cost environment before moving to much more expensive mammalian studies.

Over the past twenty years researchers have developed scores of ways to slow aging and extend life in nematodes, some of which have translated to some degree into mice. There are outright genetic alterations and drugs that tweak some of the same levers of metabolism: genes produce protein that serve as machinery and signals, and a drug can be tailored to produce a similar effect to that of a genetic alteration upon the circulating levels of a specific protein. In many cases the goal isn't to find ways to extend life but rather to gain insight into portions of metabolism that would otherwise remain opaque, and it happens that slowing aging can be very useful for that purpose. Nematodes may be perhaps the most cataloged and understood form of life on the planet, but it remains that case that the present model of the operation of metabolism is woefully incomplete. There is a long way to go yet towards the grail of a complete, enormously complicated catalog of every last detail of the metabolism of a complete individual and how it changes over the course of aging.

Fortunately we don't need that catalog in order to build effective means to treat degenerative aging. Researchers just need the list of fundamental differences, forms of damage, that distinguish old tissues from young tissues. That list is much less complicated and essentially complete today. All that needs to be done is build therapies that can repair the damage: still a huge project, but well within the budget of the medical research community, something that might be completed in a decade or two were researchers to start in earnest today. If we want to safely slow down aging by altering the operation of metabolism, however, then the research community really would need to establish much more of the vast and incomplete catalog of metabolic processes. No-one has the knowledge today to produce a good plan for recreating even calorie restriction, the most studied altered state of metabolic operation. No-one has the knowledge to even estimate how long it would take to produce such a plan, or what it would look like. Scientists are a long, long way away from being able to safely alter metabolism to slow aging in a deliberate and planned way.

What researchers do have is a panoply of drugs that happen to alter some of the same mechanisms involved in the calorie restriction response, or produce other related changes in the biochemistry of nematode worms. All have side-effects, and none are resulting in exactly the same changes as are produced actual calorie restriction. When you mine the natural world for compounds that happen to do more good than harm, you take what you get. Again, you should probably look upon all this work as an investigation of metabolism that helps to build the grand catalog, not efforts aimed at producing treatments to extend life. Life extension is not a primary goal for most researchers in the field.

Pharmacological classes that extend lifespan of Caenorhabditis elegans

As a consequence of the seminal discoveries demonstrating that lifespan can be modulated by genes, it became clear that lifespan might also be extended using chemicals. This concept has certainly been demonstrated, and today many compounds have been identified that extend lifespan in model organisms such as worms, flies and even mice. Among all of these model organisms, Caenorhabditis elegans stands out because of the large variety of compounds known to extend lifespan. It is now possible to group these compounds into pharmacological classes, and use these groupings as starting points to search for additional lifespan extending compounds. For many of these compounds, mammalian pharmacology is known, and for some the actual targets have been experimentally identified.

There are two fundamentally different approaches to identify compounds that have a desired biological effect. These two approaches are often referred to as forward and reverse pharmacology, analogous to forward and reverse genetics. Forward pharmacology approaches, also called phenotypic screens, screen for compounds that elicit a desired phenotype, like the extension of lifespan. While forward pharmacology is intuitively appealing, as it searches for the desired effect, it has a number of drawbacks. The first is that screens must generally be conducted in vivo. In vivo screens are more complex, generally longer, and have higher costs associated than in vitro screens. Even if these disadvantages are overcome, elucidating the mechanisms by which a hit-compound achieves the desired effect is difficult. Elucidating drug mechanisms generally requires the identification of the drug target, which even today represents a major challenge (i.e., the binding target of the compound).

Reverse pharmacology circumvents the problem of target identification by screening for compounds that bind to, or inhibit, the function of a specific protein target. Reverse pharmacology screens are largely done in vitro, and offer the ability to screen very large chemical libraries (+500,000). Targets are validated based on prior knowledge, such as genetic studies in model organisms or gene association studies in humans affected by the disease. However, target validation, or choosing the protein target against which to develop a drug, also poses considerable difficulties. As the process of aging is not easily replicated in vitro, most lifespan extending compounds have been identified by simply testing whether or not a given compound extends lifespan in a model organism (forward pharmacology). Thus far, most compounds that have been tested for their ability to extend lifespan had prior known pharmacology. Initially, these compounds were developed to inhibit a specific target, independent of their effect on aging. Only later were they tested for their ability to extend lifespan in C. elegans or other organisms. Thus, at its current state, the pharmacology of aging is a hybrid of forward and reverse pharmacology.


Because of Harman's theory of oxidative stress, antioxidants were some of the first compounds to be tested for their ability to extend lifespan. Indeed, antioxidants that extend C. elegans lifespan have been identified. These findings initially lent support to the idea that oxidative stress causes aging. However, later experiments guided by the theory of hormesis have challenged this view of aging. While lifespan extending antioxidants were found based on candidate approaches, unbiased screens testing many pharmacological classes for their ability to extend C. elegans lifespan did not result in any lifespan extending antioxidants. This observation suggests that, as a pharmacological class, antioxidants may not be a particularly strong candidate for identification of lifespan extending compounds.


The first ever intervention found to verifiably extend lifespan was dietary restriction. Thus, dietary restriction immediately linked the process of aging to metabolism. In recent years, metabolites have received increased interest, due in part to technical advances in metabolomics and the identification of metabolic enzymes important in the determination of lifespan. Today, multiple metabolites are known that play a role in the determination of adult lifespan.

Kinase Inhibitors

The first cloned gene found to be important for lifespan determination was the class-I phosphatidylinositol 3-kinase age-1. In addition to age-1, numerous mutations in various kinases have been found to extend C. elegans lifespan, including the receptor tyrosine kinase daf-2, akt-1, TOR, and S6 kinase, to name a few. Mutations in kinases like age-1 and the insulin/IGF receptor daf-2 cause some of the most dramatic effects on lifespan. As mutations in kinases are also frequently found in cancers and other diseases many kinase inhibitors were found to extend C. elegans lifespan with the most promising being rapamycin. However, thus far none of the tested kinase inhibitors has been able to reproduce the spectacular longevity seen in age-1 or daf-2 mutants.

Nuclear Hormone Receptors

Nuclear hormone receptors are an important class of regulatory proteins that activate or repress gene expression patterns in response to cellular signals. The fact that these signals generally consist of small molecules, like steroid hormones, makes nuclear hormone receptors important drug targets. One problem with studying nuclear hormone receptors using C. elegans is its vastly expanded repertoire of 284 nuclear hormone receptors, compared to 49 in mammals making it difficult to translate C.elegans findings to mammals.

G Protein Coupled Receptor Ligands

Compounds affecting GPCR are among the most important pharmacological classes for drug discovery. In medium scale screens for compounds with known pharmacology that extend lifespan, 50% of all hit compounds targeted GPCRs. It appears that GPCRs exist that must be active during development in order to affect lifespan when blocked in adults, probably because their function is to modulate lifespan in response to environmental change.

Natural Compounds

What makes a natural compound approach attractive is that plant extracts are generally regarded as safe, and are often used as food supplements. However, natural compounds are hard to synthesize and modify, and thus target identification is particularly difficult for natural compounds. The ongoing dispute on the mechanism of action of resveratrol certainly gives testimony on such difficulties.


Monday, March 23, 2015

It is uncontroversial that the age-related deterioration of the vascular system leads to damage to the brain, causing cognitive decline and then dementia. Progressive stiffening due to cross-links and calcification and inflammation-driven remodeling of blood vessel walls reduces structural integrity at the same time as it causes hypertension, raised blood pressure that puts more stress on those same blood vessel walls. This paper presents a novel way of looking at this contribution to the aging process:

The brain and its blood vessels are very different tissues. The nerve and glial cells of the brain (its processing machinery) develop from the ectoderm of the embryo; the brain's blood vessels (its system of oxygen supply and metabolite removal) develop from mesoderm, growing from the heart to surround and then penetrate the developing brain. By birth, vessels have branched through every millimeter of brain tissue, and they become involved in most, if not all, diseases or injuries of the brain.

Age-related dementia has seemed, to Alois Alzheimer and to most observers since, to be a degeneration of the brain, of its nerve cells. This review brings together two bodies of evidence, from which we propose that the dementia is primarily vascular, caused by the destructive effective of the pulse on cerebral blood vessels, with the loss of neurons occurring secondarily to vascular breakdown. We argue, further, that dementia is age-related because the pulse becomes more intense and more destructive with age.

The idea is uncongenial and counterintuitive. It is uncongenial because it does not appear to offer a simple path to therapy, counter-intuitive because we are used to thinking of the brain as a dependent ward of the heart, not as a victim of its beat. The idea may be correct, however counter-intuitive, for its explanatory power is considerable. It links the puse to hemorrhage, and to the neuropathology and arteriosclerosis that Alzheimer described; it explains the link from age to dementia, in the stiffening of the walls of the great arteries, and the effect of that stiffening on blood pressure. Here we review the evidence that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death.

There are, in fact, comparatively straightforward paths to therapies that can mitigate this contribution to the aging process, though at present their development is given far too little attention and support by the research community. Firstly prevent and reverse loss of elasticity in blood vessels, such as by breaking down persistent cross-links, and secondly target the mechanisms of atherosclerosis responsible for remodeling blood vessel walls to suppress inflammation and clear plaques. Target the root causes and natural repair mechanisms should do much to clean up the rest of the issue.

Monday, March 23, 2015

Autophagy is one of the cellular housekeeping processes responsible for promptly clearing out damaged proteins and cell components before they cause more harm. Autophagic activity declines with age, in part due to a build up of resilient metabolic waste in lysosomes, the organelles responsible for breaking down materials and structures for recycling. The SENS strategy for this contribution to degenerative aging is to aim to remove that waste in order to restore function. Globally increased autophagy is also a factor in many genetic and other alterations shown to slow aging and increase healthy life span in laboratory animals. Thus some researchers are investigating ways to boost this form of cellular housekeeping, and there have been some interesting demonstrations over the years, such as restoration of youthful liver function in old mice. Here one research group finds that nanoparticles can spur greater autophagy:

Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome-autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material.

We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system.

This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome-autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material.

Tuesday, March 24, 2015

The struggle to show meaningful progress in treatment of Alzheimer's disease via clearance of amyloid has fueled significant investment into alternative hypotheses regarding the disease process. The biochemistry of Alzheimer's - and the brain in general - is so very complex that at this point it is a challenge to say whether the issue is that it is intrinsically hard to produce a useful clearance therapy via the present approaches, or whether amyloid is the wrong target for best effect. A leading alternative candidate is a different form of metabolic waste, neurofibrillary tangles made of an altered form of the tau protein. Here is one of a number of studies that point the finger at tau rather than amyloid accumulation as the primary source of pathology:

By examining more than 3,600 postmortem brains, researchers have found that the progression of dysfunctional tau protein drives the cognitive decline and memory loss seen in Alzheimer's disease. Amyloid, the other toxic protein that characterizes Alzheimer's, builds up as dementia progresses, but is not the primary culprit, they say. The findings suggest that halting toxic tau should be a new focus for Alzheimer's treatment. "The majority of the Alzheimer's research field has really focused on amyloid over the last 25 years. Initially, patients who were discovered to have mutations or changes in the amyloid gene were found to have severe Alzheimer's pathology - particularly in increased levels of amyloid. Brain scans performed over the last decade revealed that amyloid accumulated as people progressed, so most Alzheimer's models were based on amyloid toxicity. In this way, the Alzheimer's field became myopic."

Researchers were able to simultaneously look at the evolution of amyloid and tau using neuropathologic measures. "Studying brains at different stages of Alzheimer's gives us a perspective of the cognitive impact of a wide range of both amyloid and tau severity, and we were very fortunate to have the resource of the Mayo brain bank, in which thousands of people donated their postmortem brains, that have allowed us to understand the changes in tau and amyloid that occur over time.

"Tau can be compared to railroad ties that stabilize a train track that brain cells use to transport food, messages and other vital cargo throughout neurons. In Alzheimer's, changes in the tau protein cause the tracks to become unstable in neurons of the hippocampus, the center of memory. The abnormal tau builds up in neurons, which eventually leads to the death of these neurons. Evidence suggests that abnormal tau then spreads from cell to cell, disseminating pathological tau in the brain's cortex. The cortex is the outer part of the brain that is involved in higher levels of thinking, planning, behavior and attention - mirroring later behavioral changes in Alzheimer's patients."

"Amyloid, on the other hand, starts accumulating in the outer parts of the cortex and then spreads down to the hippocampus and eventually to other areas. Our study shows that the accumulation of amyloid has a strong relationship with a decline in cognition. When you account for the severity of tau pathology, however, the relationship between amyloid and cognition disappears - which indicates tau is the driver of Alzheimer's. Our findings highlight the need to focus on tau for therapeutics, but it also still indicates that the current method of amyloid brain scanning offers valid insights into tracking Alzheimer's. Although tau wins the 'bad guy' award from our study's findings, it is also true that amyloid brain scanning can be used to ensure patients enrolling for clinical trials meet an amyloid threshold consistent with Alzheimer's - in lieu of a marker for tau."

Tuesday, March 24, 2015

A number of the efforts undertaken by the ever industrious Alex Zhavoronkov of InSilico Medicine involve reaching out into new communities to educate and raise awareness on the need for longevity science and the prospects for developing the means to treat aging. He was presenting at a computing hardware conference recently, for example, talking about the path to greater healthy life spans to people who have probably never given the subject much thought. In advocacy experimentation is always necessary: success is obvious in hindsight, but you never really know where you are going to find significant new support for the cause. This, for example, is presently an effort to make inroads into the electronic music and information technology communities:

Aging is humanity's greatest challenge killing more people every year than any war in human history. It is the central cause of many diseases like cancer, cardiovascular diseases, Alzheimer's, Parkinsons, and many others. And since we could not do anything about aging for millions of years, we take it as given and accept our fate. With the advances in biomedical sciences and information technology this no longer needs to be the case. We understand aging better than ever before and many promising interventions are being discovered in labs around the world every year. We already demonstrated that stopping aging will lead to unprecedented economic growth and prosperity and will not cause overpopulation and if we don't cure aging soon, we will find ourselves in a state of economic decline and possibly even collapse of the modern civilization as we know it.

Trillions of dollars are being wasted every year on patching the breaches in our economic systems and on marginally extending patients' lives on the deathbed instead of looking for interventions that will prevent diseases and return our bodies to healthy state. What is more appalling is that most people don't want to cure aging. They got comfortable with the concept and don't want to give themselves hope and set the bar too high. This is wrong and we need to change this! We need to tell the world that it is sick and help people realize that aging is a disease.

Many people in information technology and other fields can make a major impact in aging. Nowadays most of biology is data, which needs to be analyzed, structured, interpreted and used to develop working interventions to slow down pathologic changes. We need to motivate thousands or even millions of programmers, hackers, rebels to get into aging research and start a massive campaign to defeat death. This is a worthy cause to unite the world against the common problem.

Wednesday, March 25, 2015

Here is an interesting post from the Buck Institute on sources of funding for fundamental research into aging, with tables listing the various contributing organizations. While looking through the list, it is worth bearing in mind that for really early stage, high risk, novel research the largest sources are unavailable. NIA grants, for example, only become a possibility once you've actually made the initial breakthrough and have early proof that you have achieved something new. This is a systematic issue in medical research, and it is why philanthropic donations are essential for progress. Few really important novel attempts to advance the state of the art are directly funded at the outset by large institutional sources like the NIA or large pharmaceutical companies, though there is certainly a lot of creative bookkeeping that takes place in larger laboratories in order to split off the necessary funds for early stage, prospective work. Without that very early stage work there would be no progress, but most funding sources - public and private - act as though the prototypes they are willing to fund come into existence from nothing, as if by magic.

Where does the money to fund basic aging research come from? After all, scientists need to be paid, purchase supplies for their research, and somehow find the money to attend conferences to talk about their results. In the US at least (the funding situation is different in the UK), money comes primarily in the form of grants from the federal government, which both pay the salaries of researchers and provide them with money for their experiments.

The National Institute of Health (NIH, a federal agency) is huge and awesome. The main mechanism by which money it distributes money is through "R" grants. These are large multi-year grants awarded to principal investigators (usually professors) at research institutions who go through a competitive process to apply for them. About 90% of non-profit aging research project funding comes from the NIH, and most of that is in the form of "R" grants. NIH funding has shrunk in real terms by 11% since 2003. Thankfully the NIA, the wing of the NIH, is one of the few institutes who have seen extra budgetary support in recent years.

Apart from the NIH, there are several private foundations that support aging research and specific diseases of aging. Budgets are from the latest available information, and frankly I was surprised by how small this chunk is. Don't get me wrong, each of these foundations are great and their funds support promising scientific projects and programs. But all together, they're less than 10% of the annual R-grant budget (note that a different situation exists in the UK, where the giant Wellcome Trust funds about hundreds of millions in biomedical research). A lot of private giving to aging research is not structured as annual grant programs, though. For example, at the Buck we receive generous one-time donations from local businesses, individuals, and some of the aging foundations listed below to support our facilities.

There are also a bunch of institutes and research departments dedicated to basic aging research. A lot of universities and medical schools have some department with "aging" or "gerontology" or "geriatrics" in their name. Each of these typically distributes intramural funds. Want their money? Get a job there.

But if we move outside academic research to money spent on commercialized research applications by private companies, the pie changes quite a bit. In aggregate, drug companies outspend the NIH on R&D every year by over $20 billion. The precise portion of this going towards "aging research" is hard to measure. While most aging research at drug companies is not focused on aging itself, diseases of aging such as diabetes, heart disease, and cancer are intense areas of study. Recent years have seen the founding of private companies dedicated specifically to aging research. It is hard to guess at annual budgets for these new players, but they're pretty huge. Calico's hundreds of millions in committed funds, for example, is over half the amount the NIA spends on R grants in a year.

Wednesday, March 25, 2015

It is known that greater educational achievement is associated with greater longevity, and this is one facet of a web of related correlations between various measures of intelligence, wealth, and health. To my eyes this probably all boils down to influences on the degree to which people look after the health basics over a lifetime: exercise, weight, and smoking are the most important factors under individual control. Maintaining a good, healthy lifestyle in this sense certainly doesn't require wealth, but it happens that wealthy communities and networks do better than their less wealthy counterparts. People tend to adopt the culture that surrounds them.

Educational attainment may be an important determinant of life expectancy. However, few studies have prospectively evaluated the relationship between educational attainment and life expectancy using adjustments for other social, behavioral, and biological factors. The data for this study comes from the Reasons for Geographic and Racial Differences in Stroke study that enrolled 30,239 black and white adults (≥45 years) between 2003 and 2007. Demographic and cardiovascular risk information was collected and participants were followed for health outcomes. Educational attainment was categorized as less than high school education, high school graduate, some college, or college graduate. Proportional hazards analysis was used to characterize survival by level of education.

Educational attainment and follow-up data were available on 29,657 (98%) of the participants. Over 6.3 years of follow-up, 3673 participants died. There was a monotonically increasing risk of death with lower levels of educational attainment. The same monotonic relationship held with adjustments for age, race, sex, cardiovascular risk factors, and health behaviors. The unadjusted hazard ratio for those without a high school education in comparison with college graduates was 2.89. Although adjustment for income, health behaviors, and cardiovascular risk factors attenuated the relationship, the same consistent pattern was observed after adjustment. The relationship between educational attainment and longevity was similar for black and white participants. The monotonic relationship between educational attainment and longevity was observed for all age groups, except for those aged 85 years or more.

Thus educational attainment is a significant predictor of longevity. Other factors including age, race, income, health behaviors, and cardiovascular risk factors only partially explain the relationship.

Thursday, March 26, 2015

A number of lines of research suggest that the benefits of calorie restriction for health and longevity largely derive from increased cellular housekeeping processes such as autophagy. For example, the calorie restriction response requires neuropeptide Y (NPY), and here researchers explore the linkage of NPY with autophagy. They suggest that the role of autophagy in calorie restriction is indirect, and that it is a lynchpin part of the process only because a portion of the brain involved in the global control of metabolism responds to the level of autophagic activity:

One thing that has been clear for a while now is that autophagy is at the center of the aging process. Low levels of autophagy (cells with impaired "housekeeping") are linked to aging and age-related neurodegenerative disorders. This is easily explained as autophagy clears the cells "debris" keeping them in good working order. That the process is so important in the brain is no surprise either, because neurons are less able to replenish themselves after cell damage or death. But about a year ago a remarkable new discovery was made: the hypothalamus, which is a brain area that regulates energy and metabolism, was identified as a control center for whole-body aging.

Calorie restriction increased autophagy in the hypothalamus but also boosted levels of the molecule NPY, and mice without NPY do not respond to calorie restriction. Furthermore NPY, like autophagy, diminishes with age. All this, together with the new identified role of the hypothalamus suggested that this brain area and NPY were the key to the rejuvenating effects of calorie restriction. The researchers started by taking neurons from the hypothalamus of mice and put them growing in a medium that mimicked a low caloric diet, to then measure their autophagy. Like expected, their autophagy levels in this calorie restriction-like medium were much higher than normal. But if NPY was blocked, the medium had no consequences on the neurons. So calorie restriction's effect on hypothalamic autophagy appeared to depend on NPY.

To test this, next the researchers tested mice genetically modified to produce higher than normal quantities of NYP in their hypothalamus, and found higher levels of autophagy supporting their theory that autophagy was controlled by NPY. In conclusion, calorie restriction seems to work by increasing the levels of NPY in the hypothalamus, which in turn trigger an increase in autophagy in these neurons, "rejuvenating" them and delaying aging signs by restoring their ability to control whole-body aging.

Thursday, March 26, 2015

Using the recent development of killifish as a model organism as a starting point, this popular science article looks at some of the more recent high profile developments in the study of aging. It largely takes the longevity dividend party line of talking about extending healthy life span without extending overall life span, however. This is probably an impossible goal, and not even a desirable goal in comparison to extending both measures, but one that is politically easier to sell for various reasons. So there is no discussion of approaches leading to rejuvenation and the prospects for radical life extension here. This gap in the conversation is a persistent remnant of the recent past in which researchers were very reluctant to talk about or attempt to work on any form of intervention in aging:

Aging is inherently interesting, because we're all doing it. Like it or not, our bodies are slowly winding down as time passes. But what actually happens in our tissues and cells? It's clear that we are subject to a plethora of depressing outcomes, including sagging tissues (hello, wrinkles), reduced cognitive capacity (where did I put my car keys?) and a slowing metabolism that (tragically) favors belly padding over muscle building. Inside our cells, the situation looks even more dire. DNA mutations begin to accumulate, our cells' energy factories begin to wind down, and proteins policing gene expression appear to "forget" how to place the chemical tags on DNA that serve as runway lights for the appropriate production of proteins. The protein production, transportation and degradation network that cells depend on to deliver these molecular workhorses to all parts of the cell at exactly the right times also falls into disarray. Proteins are degraded too soon, or begin to clump together in awkward bundles that interfere with cellular processes. These events have obvious, previously inescapable, outcomes.

"As we age, time becomes compressed and we tend to develop many chronic diseases or health problems simultaneously. Many elderly people are dealing with a constellation of health conditions. We'd like to imagine ways to stretch out the healthy period of our lives, so it comprises more of the totality. This is something we call 'health span,' and it would be tremendously advantageous to stretch out that portion of our lives."

Nationwide, both public and private efforts have been launched to better understand and prolong our golden years. Associated with the growth in funding is an expansion in laboratory research that suggests the possibility of intervening in the aging process and extending the human health span. "It may one day be possible to avoid chronic diseases, living into old age free from dementia, diabetes and heart disease. Our tissues will still age, but we may be able to delay or prevent the onset of the decline in function that comes with passing years. We have high hopes that our research strategy will help move collaborative efforts to the next level. What has come out of our work is a keen understanding that the factors driving aging are highly intertwined and that in order to extend health span we need an integrated approach to health and disease with the understanding that biological systems change with age."

Friday, March 27, 2015

The systematic loss of muscle mass and strength with age is given the name sarcopenia. One of the potential contributing causes involves progressive dysfunction in processing of the amino acid leucine, and this might in theory be partially offset by leucine supplementation in the diet. This meta-analysis of past studies indicates that as a treatment it modestly improves muscle mass but not strength:

The primary objective of the present systematic review and meta-analysis was to synthesize the available literature relating to leucine supplementation in the elderly with respect to its effects on anthropometrical parameters and muscle strength. The secondary aim was to perform a selective subgroup analysis when possible differentiating between healthy and sarcopenic subjects.

A literature search was performed with restrictions to randomized controlled trials or studies. Parameters taken into account were body weight, body mass index, lean body mass, fat mass, percentage of body fat, hand grip strength, and knee extension strength. For each outcome measure of interest, a meta-analysis was performed in order to determine the pooled effect of the intervention in terms of weighted mean differences between the post-intervention (or differences in means) values of the leucine and the respective control groups.

A total of 16 studies enrolling 999 subjects met the inclusion criteria. Compared with control groups, leucine supplementation significantly increased gain in body weight [mean differences 1.02 kg], lean body mass [mean differences 0.99 kg], and body mass index [mean differences 0.33 kg/m2], when compared to the respective control groups. With respect to body weight and lean body mass, leucine supplementation turned out to be more effective in the subgroup of study participants with manifested sarcopenia. All other parameters under investigation were not affected by leucine supplementation in a fashion significantly different from controls.

It is concluded that leucine supplementation was found to exert beneficial effects on body weight, body mass index, and lean body mass in older persons in those subjects already prone to sarcopenia, but not muscle strength. However, due to the heterogeneity between the trials included in this systematic review, further studies adopting a homogenous design with respect to participant characteristics duration as well as the kind and amount of daily supplement in use are required.

Friday, March 27, 2015

Targeting myostatin and related biochemistry is well demonstrated to increase muscle mass and strength in mammals such as laboratory mice. There are even rare natural mutants, including a few cows and humans, who lack normal myostatin and are as a result exceptionally strong in comparison to their peers. Here researchers show that loss of myostatin mutations in mice produce extended life spans, but too much suppression of myostatin may remove that benefit due to the cardiac issues that can accompany an overly large heart:

The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN+/− and MSTN−/− mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN+/+ and MSTN−/− mice, MSTN+/− mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity.

The mechanism behind the increased longevity of MSTN+/− mice is not known, but inhibition of myostatin can reduce systemic inflammatory proteins and body fat. Given the increase in relative heart mass, the contribution of aging-associated cardiomegaly to mortality and that inhibition of myostatin can increase heart mass, it is possible that positive effects of increased skeletal muscle mass on the longevity of MSTN−/− mice was offset by cardiac pathologies. Most genetic models of enhanced longevity in mice have identified an inverse relationship between body mass and longevity, which has lead to the observation that 'big mice die young'. However, the results from the current study support the epidemiological observations in humans that when it comes to skeletal muscle mass and longevity, bigger may be better.


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