Fight Aging! Newsletter, May 11th 2015

May 11th 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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  • Considering Angiotensin II and Aging
  • A Review of DNA Methylation as a Tool For Measuring Age
  • A Small Selection of Recent Calorie Restriction Research
  • Many People Hope for Longevity, But All Too Few Work to Make the Hope a Reality
  • There are Many Theories of Aging
  • Latest Headlines from Fight Aging!
    • A Trial of Stem Cell Treatment for Macular Degeneration
    • Is Calcification of Tissue a Primary Form of Damage in Aging?
    • A Role for the Epicardium in Heart Regeneration
    • Cellular Senescence as a Contributing Cause of Glaucoma
    • Much of Aging Research Has Little Relevance to Radical Life Extension
    • The Genetic Roots of Longevity are Complex
    • A Review of Adenylyl Cyclase Type 5 Inhibition and Longevity
    • A Method of Pharmacological Modulation of Mitophagy
    • Exercise and Muscle Mitochondria in Aging
    • Protein Aggregation as a Protective Mechanism


When reading about research into any particular gene or protein and its influence on aging it is important to keep in mind that our biochemistry is a network of connections. Nothing happens in isolation, and any change in the amount of a particular protein or interference in its activities will cause a cascade of consequences though its interactions with other proteins. Thus there are probably comparatively few important mechanisms involved in determining natural variations in longevity but many distinct ways to manipulate those mechanisms.

Decades of research focused on treating cardiovascular disease and hypertension have resulted in a range of drugs that interfere with the activities of angiotensin II and the broader renin-angiotensin system it is a part of. These biological systems have a fairly direct role in determining blood pressure, and hence have long been a target for efforts to slow down the onset of hypertension. Thanks to the easy availability of drugs targeting the renin-angiotensin system, a fair amount of research has taken place into the effects of these interventions on aging in mice. Disrupting an angiotensin II receptor increases mouse life span, for example, as does a reduction in levels of ACE, the angiotensin I-converting enzyme responsible for transforming angiotensin I into angiotensin II. These interventions may work to extend life by reducing blood pressure, and may have other important effects involving enhanced mitochondrial function.

Definitive answers as to how specific approaches to alter the operation of metabolism actually work under the hood so as to extend life span are slow in arriving, however. Cellular biochemistry is enormously complex, so much so that it is par for the course for a decade or more to come and go without too much progress being made in understanding how a particular mechanism influences longevity. This is the case for angiotensin II and the systems it participates in. Below are linked a few recent papers on the topic; they don't add a great deal over similar papers published ten years ago, beyond reinforcing the point that high blood pressure is a potent source of tissue damage in old age, and being more openly enthusiastic about building treatments for aging:

The Intrarenal Renin-Angiotensin System in Hypertension

The renin-angiotensin system (RAS) is a well-studied hormonal cascade controlling fluid and electrolyte balance and blood pressure through systemic actions. The classical RAS includes renin, an enzyme catalyzing the conversion of angiotensinogen to angiotensin (Ang) I, followed by angiotensin-converting enzyme (ACE) cleavage of Ang I to II, and activation of AT1 receptors, which are responsible for all RAS biologic actions.

Recent discoveries have transformed the RAS into a far more complex system with several new pathways. Instead of a simple circulating RAS, several independently functioning tissue RASs exist, the most important of which is the intrarenal RAS. Several physiological characteristics of the intrarenal RAS differ from those of the circulating RAS, autoamplifying the activity of the intrarenal RAS and leading to hypertension.

Angiotensin II Blockage: How its Molecular Targets May Signal to Mitochondria and Slow Aging

Caloric restriction (CR), rapamycin-mediated mTOR inhibition and renin angiotensin system blockade (RAS-bl) increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated to their physiological benefits. mTOR-inhibition and enhanced sirtuin and Klotho signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference.

Here we review how mTOR-inhibition extends lifespan, Klotho functions as an aging-suppressor, sirtuins mediate longevity, Vitamin-D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR, upregulates Klotho, sirtuin and VitaminD-receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, klotho and sirtuin expression and Vitamin-D signaling, paralleling CR actions in age retardation.

Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.

Pleiotropic Effects of Angiotensin II Receptor Signaling in Cardiovascular Homeostasis and Aging

Most of the pathophysiological actions of angiotensin II (Ang II) are mediated through the Ang II type 1 (AT1) receptor, a member of the seven-transmembrane G protein-coupled receptor family. Essentially, AT1 receptor signaling is beneficial for organismal survival and procreation, because it is crucial for normal organ development, and blood pressure and electrolyte homeostasis. On the other hand, AT1 receptor signaling has detrimental effects, such as promoting various aging-related diseases that include cardiovascular diseases, diabetes, chronic kidney disease, dementia, osteoporosis, and cancer. Pharmacological or genetic blockade of AT1 receptor signaling in rodents has been shown to prevent the progression of aging-related phenotypes and promote longevity. In this way, AT1 receptor signaling exerts antagonistic and pleiotropic effects according to the ages and pathophysiological conditions.


DNA methylation, the decoration of DNA with methyl groups, is one of the mechanisms involved in epigenetic control over production of proteins from their blueprint genes. A cell is a factory packed with levers, dials, and feedback loops, most of which involve the amounts of specific proteins present in the cell and its surrounding environment. Cell behavior changes from moment to moment in reaction to circumstances, and epigenetic alterations such as DNA methylation regulate these changes by altering rates of protein production.

Over the past five or six years a number of researchers have made inroads in the use of patterns of DNA methylation as a measure of either biological age or chronological age. If we consider aging to be caused by an accumulation of damage to cells and tissue structures, then we should expect certain characteristic patterns of epigenetic alterations to emerge in response. Everyone ages due to the actions of the same underlying processes, and while most DNA methylation appears to be highly individual, patterns nonetheless emerge.

All of this is of interest to the aging research community because there is a great need for accurate ways to measure biological age. Testing proposed treatments that might slow or reverse aging takes far too long at the present time, requiring animal studies that last for years and cost millions to gain even a vague idea as to how effective any given treatment might be. If there was an agreed upon way to reliably measure the systematic reaction to higher levels of damage in an aged individual, then new therapies could be rapidly filtered for those that actually make a difference. To my eyes that should mean therapies that repair the forms of damage known to cause aging. I see a good marker for biological age as something that could bring an end to much of the debate over causes of aging, which causes are more important, and which strategy for the development of treatments should be pursued. A great deal of the present diversity of opinion and theory would evaporate in the face of better data.

On this topic, here is a very readable open access review paper that covers the recent history of work on DNA methylation as a measure of aging. As it makes clear, finding DNA methylation patterns that look promising is only the start of the process of producing an acceptable standard of measurement for aging:

DNA methylation and healthy human aging

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor.

DNA methylation changes that are associated with age can be considered part of two related phenomena, epigenetic drift and the epigenetic clock. We have defined epigenetic drift as the global tendency toward median DNA methylation caused by stochastic and environmental individual-specific changes over the lifetime. The epigenetic clock, on the other hand, refers to specific sites in the genome that have been shown to undergo age-related change across individuals and, in some cases, across tissues.

A number of aspects of age-related DNA methylation remain, which should be further scrutinized. First, it is expected that certain life periods, such as early childhood, puberty, and advanced age, result in accelerated epigenetic changes. Most studies of DNA methylation and age have examined changes within specific periods of life - the first few years of life or adulthood to old age, for example. Moving forward, it will be important to determine what periods during the lifespan are the most changeable, which highlights the need for more rigorous studies. Moreover, work on the effects of environmental stimuli on the rates of epigenetic aging would contribute insight into how or why specific environmental exposures result in increased mortality. It could be hypothesized that people who are exposed to factors that affect mortality show advanced epigenetic compared to chronological age, although these effects may be tissue specific.

Several recent cross-sectional studies have published epigenetic clocks. Comparison of these sites across longitudinal studies, while controlling for confounders in DNA methylation such as tissue type, cellular composition, ethnicity, and environment, is necessary to confirm a consistent, reliable, and independent signature of DNA methylation and aging. This type of age predictor could be of use in a number of areas. In health, epigenetic age could be used to target or assess interventions or treatments. However, the health-related potential of epigenetic age still waits on an assessment of concordance between epigenetic and chronological age across a large population with longitudinal tracking of health during the aging process. This field has immense potential to inform human populations and will undoubtedly continue to develop in the near future.


Calorie restriction with optimal nutrition is the practice of eating fewer calories, cutting perhaps a third of those in a normal healthy diet, while still obtaining optimal amounts of essential micronutrients. Calorie restriction reliably extends healthy and maximum life spans by up to 40% in short-lived mammals such as mice and rats. It slows aging and extends life in near all species for which rigorous life span studies have been carried out, in fact. The calorie restriction response seems almost universal in the animal kingdom, with many of the identified mechanisms similar or the same in widely separated species. This is a phenomenon that probably originates a long way back in evolutionary time, in other words. When it comes to longer-lived species such as primates, including we humans, the only truly comprehensive and rigorous data presently to hand covers short-term reactions to calorie restriction, however. It takes a long time to run a life span study for humans or even for our neighboring primates: two calorie restriction studies in rhesus macaques have been running for decades now, and there is some debate over whether the study design has led to data that is too flawed to be useful.

The bottom line question: does calorie restriction extend life in humans? The present consensus in the scientific community is that the answer is probably yes, but not by anywhere near the same degree as in short-lived mammals. From an evolutionary perspective, the calorie restriction response arises because it improves survival in the face of seasonal famine. A season is a large portion of a mouse life span, but not so much time for a human, and thus only the mouse evolves a dramatic plasticity of aging and longevity in response to circumstances. Nonetheless, the cataloged health benefits of calorie restriction in humans are impressive and very similar to those observed in mice. There is no presently available medical technology that can grant the same degree of benefits to a basically healthy individual, when looking at important measures such as blood pressure, resistance to common age-related diseases, and so forth. It is true that you can't reliably live to age 90 and beyond in good health via any lifestyle choice, calorie restriction included, but in the present era of rapid progress in medicine, every extra year that you can win for yourself counts. The line in the sand to separate those who die too soon to benefit from near future rejuvenation technologies and those who just make it will be narrow indeed.

So give a little thought to trying calorie restriction. What do you have to lose? Here are a couple of items pulled from the stack, pointers to recent research into calorie restriction and the health benefits it produces. These are all fairly typical of the field, meaning a narrow investigation of one small aspect of biochemistry, and a confirmation that calorie restriction improves matters by slowing or delaying age-related changes:

SAGE Review: New insights into calorie restriction and its effects on sarcopenia and aging

Researchers reported that calorie restriction in rats has an age-dependent protective effect on age-related muscle loss by improving skeletal muscle metabolism in rats. The authors fed young (4 month) and middle-aged (16 month) rats one of two diets - either a normal diet, ad libitum (AL), or a restricted diet, 40% calorie restriction (CR), for a total of 14 weeks. They found that normalized muscle weight (muscle weight divided by body weight) was lower in normal, AL-fed, middle-aged rats compared to young rats. However, when the two age groups were fed the CR diet, skeletal muscle in middle-aged rats was protected from expected age-related degeneration and muscle mass was comparable to levels of young rats fed the AL diet. Interestingly, CR had a negative effect on normalized muscle weight in young mice and caused a decrease in muscle mass.

It seems that CR has an age-dependent beneficial effect on skeletal muscle mass in rats and can reprogram skeletal muscle metabolism to function at levels that resemble those of young rats fed a normal diet. A more applicable question arising from this study is whether CR can counteract muscle degeneration in middle-aged or elderly humans. This study suggests that middle-aged humans could potentially benefit from a CR diet with respect to preventing muscle loss. Conducting a similar experiment in humans will be a much larger endeavor, however, scientists can use what we learn from these rat studies and other model organisms to better understand metabolic pathways that go awry with aging. Ultimately, understanding the mechanisms behind the beneficial effects of CR and how they influence muscle loss during aging will open the doors for the development of therapies to prevent or treat aging-related diseases.

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR.

We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.

Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain

Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging.


Longevity science, work on the foundations of rejuvenation therapies to extend healthy life, isn't a special snowflake in any way. It isn't magically separate, distinct, and remote from other areas of medicine. It has exactly the same goals, which are to prevent suffering and death. It builds upon the same modern understanding of cellular biochemistry. Also, just like near all medical research, it is ignored by most people most of the time, despite the fact that everyone's future health is absolutely dependent on advances in medical science.

Medicine is pivotal, and yet you might not think so given the tiny fraction of a fraction of overall expenditures that we devote to the task of improving medical technologies, of building new and better treatments. Every improvement in the technologies of health that we rely upon here and now was constructed with scraps and leftovers of funding, accomplished in spite of a vast and bland indifference on the part of the public at large. Vast sums are devoted to decorations and frivolity in place of building better medicine. It is unfortunately human nature to fixate upon circuses, politics, and distractions, on things that matter very little in comparison to the life and death work of finding cures for fatal medical conditions.

Fatal medical conditions such as degenerative aging, for example. The one that everyone suffers from, and which will kill more than nine-tenths of everyone you know, after decades of increasing pain and disability, should you be fortunate enough to live in one of the wealthier parts of the world. Going by the way most people act, this isn't a big deal. Even the most horrible situations will be accepted, even defended, if they happen to be the long-standing present status quo, and aging is perhaps the best example of this phenomenon. If you didn't have it, would you volunteer for it? The years of decline and pain, the corrosion of the mind, the eventual drawn out death? That would be crazy. Yet you don't have to wander far today to find people praising aging and eventual death as a wonderful and proper set of circumstances.

Kicking our societies out of the present status quo and into a better one is left to the rebels, the iconoclasts, and other varieties of unreasonable visionary. This has been underway in earnest for decades now in the matter of bringing aging under medical control, and change is coming. The ranks of those willing to speak out and act are growing, both within and outside the life science community. There are still all too many people who see at least a little of the possibilities for the future but do nothing but hope in private, however. Hope on its own achieves nothing: the future you desire won't just happen by itself. The future is what we choose to build, and those who act are those who build it.

Futurist: I will reap benefits of radical life extension

The idea of people [routinely] living deep into their 70s is relatively new, dating back, according to World Bank statistics, to only the 1960s in the U.S. In developing parts of the world, that long of a life is still a dream. But today, enterprising scientists and brash thinkers are considering a life far longer, pondering a future where people in all parts of the globe regularly live deep into their 100s. Research institutes (such as the Buck Institute for Research on Aging in California), charitable foundations (like the SENS Research Institute and Glenn Foundation for Medical Research) as well as companies (like Google) are all pouring money into work to understand, counteract and delay aging.

This idea, immortality, has been around seemingly forever. What's different about it today, this quest?

What makes discussions about radical life extension, I think, different today is that it's transcended the spiritual realm, it's transcended the supernatural. It was something that didn't really have any basis in science or technology, it was more of a longing, a desire to live forever whether it be in this world or in some alternate world. The big difference now of course is that we're starting to have a sense of the technologies, the science, that could make this happen.

But isn't that something that every generation believes - that they're closer than ever to solving aging? Can you convince a cynic that there's something real here?

I think there is a big difference between what we're accomplishing today as opposed to what was done a hundred or two hundred years ago. We are actually, over the last hundred years - actually, specifically, even maybe the last 50 - we're starting to develop medical technologies that are genuinely prolonging life. Whether it be such things as antibiotics and vaccines, and even things like surgery and now artificial organs and so on -most recently of course the advent of stem cells and regenerative medicine. These are on an order of scale far different than what we've seen in the past. We have seen the first developments of bona fide life-extension technologies.

It seems like most of the people seeking to fight aging, they're tech guys, not doctors. It's not like they're a minority of doctors, they're a completely different community.

There are many reasons the medical community would wish to shy away from this conversation. One, this is still very fringe. It's not something accepted in the medical community that you could actually cure aging. Aging is not even looked at as a disease, for example. This is the paradigm shift that's currently happening - yes, we are looking at it as a disease that can be defeated. That's the shift that is going to have to be made within the medical community.

Right now, each and every specialist, whether they are looking at neurological disorders or looking at cardiovascular problems, or diabetes or what have you, they're very focused on that particular area and they don't necessarily see the big picture of it all. Yet the irony of it is that every one of these specialists is contributing to what will be a therapy that will be used to prolong life. This would be a suite of therapies that would tackle every facet of aging, and as we know, we're learning on a regular basis that aging is a multifaceted process that affects so many different parts of our bodies.

Eventually I think that once we get over the inhibition or the taboo of talking about radical life extension, and the idea that we can live forever, I think we'll see the medical community and individuals in medicine start to talk a bit more openly and frankly about the possibilities. It'll start to become ridiculous not to do so.

Take the haves and the have-nots: As these technologies come out, who will have access to them and who won't? You have to assume those with money will probably have access to them.

As we've seen time and time again, the first generation or two of any technological development, whether it be a gadget that you can get at your technological store, whether it be medical advances, is pretty much reserved for those who have the money to pay for it. So I think that it's good that we're talking about it now. It surely shouldn't be something that will preclude these technologies from being developed.

The mentality that if a few people can't have it, nobody should be able to have it, is really a facile argument and really should be shoved away as quickly as possible. The larger issue is how quickly can we make these technologies available to as wide a group of people as is possible, that's absolutely fundamental to this discussion.

Be someone who acts, that's my advice. Find a way to help, and then do so, whether that is raising funds for SENS rejuvenation research, or persuading a friend to see aging in a different light, or writing for the public at large. The more of us there are, the shorter the span of time between now and the first therapies that will control, halt, and reverse the consequences of aging.


In aging research, just as in any field of science where much is left to discover and catalog, and where the pace of discovery is slow in comparison to the size of the territory left to map, you will find a promiscuous proliferation of theories and hypotheses. A well constructed theory of aging can last for decades waiting to be disproved, all the while spawning variants and competitors. Hypotheses come and go almost like fashions when the time taken to gather sufficient evidence to swing the pendulum one way or another can extend for a sizable fraction of a researcher's career. This is something to bear in mind when reading any discussion of theories of aging: you are looking at a snapshot of science in development, the final answer still unsettled, all too many details yet to be filled in robustly and defensibly.

The present consensus position on aging is that it is caused by an accumulation of damage. There are probably a score of good theories discussing exactly what damage is involved, and how important various different types of damage might be. There are another score of outdated, or dubious, or too narrowly focused, or myopic theories on aging as damage beyond that circle. On the small scale there are a hundred debates over cellular and tissue damage with relation to aging, all of which are waiting on better data for one side to declare a definitive victory. That will happen for some of these issues over the next decade, with the damage caused by cellular senescence being one of the next in line, I'd imagine.

At the large scale, the big debate is between the majority position of aging as damage accumulation versus the minority position of aging as an evolved program that causes damage. This division emerges from work on evolutionary theories of aging, which are as much focused on trying to explain the origin and history of aging as on the precise mechanisms involved. Nonetheless this seems to me more important to the near future of efforts to treat aging as a medical condition than divisions within the aging-as-damage community. This is because the recommended strategy for treating aging that emerges from the programmed aging view is very different, and probably ineffective if aging is indeed damage accumulation.

In the programmed aging framework the best approach to rejuvenation is to identify changes in metabolism characteristic of old age and try to revert them to youthful configurations, such as through pharmacological interventions to change the levels of circulating proteins. In that view, changing the operation of metabolism to a more youthful track should cause damage accumulation to cease and existing damage to be repaired to at least some degree. From the perspective of aging as damage accumulation, altered levels of circulating proteins are a reaction to damage, however, and thus aiming to alter them is putting the cart before the horse - it is targeting consequences rather than causes, and should thus be largely ineffective in comparison to direct efforts to repair the damage.

Ironically much of the research community adheres to the view of aging as damage, but for historical and regulatory reasons these scientists follow research strategies that are more suited to the programmed aging playbook. If you survey the laboratories involved in aging research you are far more likely to find researchers developing drugs to alter protein levels than you are to find researchers trying to repair the recognized forms of cellular and tissue damage. This must change, I believe, if we are to see meaningful progress in our lifetimes.

Theories of Aging: An Ever-Evolving Field

Senescence has been the focus of research for many centuries. Despite significant progress in extending average human life expectancy, the process of aging remains largely elusive and, unfortunately, inevitable. In this review, we attempted to summarize the current theories of aging and the approaches to understanding it. A number of theories, which fall into two main categories, have been proposed in an attempt to explain the process of aging. The first category is comprised of concepts holding that aging is programmed and those positing that aging is caused by the accumulation of damage. Conversely, the latter category of theories suggests various sources and targets of the damage. They are not necessarily mutually exclusive. Rather, aging could vary across different species, and programmed senescence can accelerate the buildup of damage or decrease the capacity for repair.

Most obviously, the average lifespan within a given species is genetically programmed in one way or the other. Nevertheless, the current theories of aging differ in viewing aging as a consequence or a side effect of genetic pathways. According to the well-known disposable soma theory, aging is a trade-off in the allocation of limited energy resources between maintenance and restoration of tissue homeostasis and other traits needed for survival. This trade-off is demonstrated when comparing the mean lifespan of related animal species with different predation risks. When the risk is high, delayed senescence has no added benefit relative to, for example, rapid reproduction.

Nearly all current theories of aging have in common the fact that the fundamental cause of aging is the accumulation of molecular damage brought about mainly by reactive oxygen species, but the role of amyloid protein, glycation end-products, and lipofuscin is acknowledged as well. The current theories differ in the extent to which the buildup of waste is encoded in the genome and whether it is programmed death or this accumulation that is deemed to bear the costs of evolutionary benefits. In addition to damage itself, the rate of accumulation is also of concern, which results from overall metabolic activity. The most significant changes in the longevity of model organisms prove to be mutations in metabolic pathways.


Monday, May 4, 2015

Researchers here report on another trial of embryonic stem cells, with a focus on demonstrating safety and absence of side-effects. The study size of four individuals, each given the treatment in one eye only, is too small to take the positive results as a sign that the treatment is effective enough to take to the clinic. The outcome is encouraging nonetheless:

Since their discovery and isolation in 1998, human embryonic stem cells (hESCs) have been considered a potentially valuable tool for generating replacement cells for therapeutic purposes. However, despite success in numerous animal models, fears over tumorigenicity and immunogenicity, coupled with ethical concerns, and inefficiencies in differentiation methods have all contributed to delays in carrying out human clinical trials. Only one group has reported the results of the safety and possible biological activity of embryonic stem cell progeny in individuals with any disease, but these investigators only enrolled patients who were mostly Caucasian. Here, we confirmed the potential safety and efficacy of hESC-derived cells in Asian patients.

Loss of the retinal pigment epithelium (RPE) is an important part of the disease process in several retinal disorders, including age-related macular degeneration (AMD) and Stargardt macular dystrophy (SMD). Animal studies have shown that hESC-derived RPE cell transplantation can rescue photoreceptors, resulting in the improvement of visual functions in RPE-oriented retinal degeneration models. Clinical trials of hESC-derived RPE cell transplantation have begun recently in the United States and Europe. Herein, we report on four Asian patients with macular degeneration (two with AMD and two with SMD) who underwent subretinal transplantation of hESC-derived RPE and were followed for 1 year to assess safety and tolerability.

In the two dry-AMD patients, visual acuity in the treated eyes improved by one letter (stable at counting fingers at 4 ft) and nine letters (a two-line improvement from 20/320 to 20/200) at 52 weeks, respectively. In contrast, the fellow (untreated) eyes decreased by 6 and 20 letters, respectively, during the same time period. In the two SMD patients, visual acuity improved in the treated eyes by 12 letters (counting fingers at 2 ft to 20/640) and 19 letters (a four-line improvement from 20/640 to 20/250), respectively, compared with nine letters of improvement in the fellow eyes at 52 weeks compared to baseline. The visual acuity improvement noted in the fellow eyes of SMD patients may be due to poorer baseline visual acuity than in the fellow eyes of the dry AMD patients. A 15-letter improvement (a doubling of the visual angle) is generally accepted as a clinically significant change.

Monday, May 4, 2015

The SENS model of aging, and the resulting research programs aimed at producing rejuvenation treatments, are predicated on identifying the forms of cellular and tissue damage that are the initial, primary cause of aging. This means damage that occurs directly as a result of the normal operation of healthy metabolism, and excludes damage that occurs as a secondary consequence of other forms of damage. There is arguably a far greater variety of secondary damage than primary damage, which is only to be expected given the complexity of living organisms. Simple damage in a complex system produces complex results. This is why SENS can be viewed as a shortcut to meaningful results in treating aging: it is focused on a narrow, fairly well understood, and simpler region of our biology. The hope is that in repairing the primary forms of damage, most of the secondary forms of damage will then be repaired by our own maintenance mechanisms.

You don't have to dive too far into the research literature to find grey areas and unknowns, however. There are a number of forms of damage that could be either primary or secondary harms, and finding out which is the case still lies somewhere in the future. If funding for SENS research was far greater than it is now, then it would make sense to open repair programs for all of the ambiguous forms of damage: err on the side of caution and fix everything. Since funding is still minimal, however, the most cost-effective path is to work on fixing the definitive forms of primary damage and then see how that affects other forms of damage and change that occur in aging.

Q: A lot of tissues, including notably the arteries, develop calcium deposits with age. Isn't this also an important kind of aging damage? Don't you need to develop a new rejuvenation biotechnology to remove it from our tissues?

A: To answer the question, we first need to disaggregate (no pun intended) the general category of "calcification." There are quite a few tissues that calcify to some degree in most or all aging people, and the reasons why this occurs and the nature of the structural disruption it causes are quite distinct depending on the tissue. In fact, even looking at just the arteries, there are several different kinds of "arterial calcification," including calcification connected with atherosclerotic plaque and calcification of the fibrils of elastin protein that loan the arteries their elasticity.

It's unlikely that all of these are true aging damage, but it's quite plausible that at least some of them are. The key question is whether each of these calcified deposits are really an intrinsically more or less irreversible change, or if like many other things that go wrong in aging they're sufficiently dependent on other, primary age-related changes that they would revert to the healthy norm if the original insult were resolved. In the former case, we would indeed need to develop rejuvenation biotechnologies to remove them. But it seems likely that some forms of age-related tissue calcification occur and are sustained by the effects of other forms of aging damage or the body's responses to them - things like oxidative stress caused by accumulation of cells that have been taken over by mutant mitochondria, or the inflammatory secretions of senescent cells. If calcification is driven and perpetuated by the effects of other, primary kinds of aging damage, then all we will really have to do is remove or repair the original aging damage, and the downstream calcification will resolve itself "for free" (or the body's natural repair and maintenance machinery will do it for us).

The more well-understood form of arterial calcification, for instance, is pretty clearly a secondary effect of local atherosclerotic lesions, and driven by inflammation. Once we clear the oxidized cholesterol products from atherosclerotic foam cells and allow them to egress, the body's wound-healing response will cease to play its perverse role in perpetuating and complicating the lesion but will instead begin resolving and repairing the damage wrought in the artery wall. Under those conditions, the calcium deposits may well simply dissolve, or resolve as local cells are no longer being pushed (as they often are in atherosclerotic lesions) into adopting behaviors that closer resemble those of bone-forming cells.

Ultimately, barring strong evidence coming in one way or the other, the best policy is to remain agnostic about such cases, and focus precious research investments on those therapies that target the clearly-identified, recalcitrant cellular and molecular damage of aging. Like many types of secondary damage, other forms of tissue calcification may similarly become a non-issue once we've taken care of the core damage driving degenerative aging. If this turns out to be the case, calcification-specific rejuvenation biotechnologies will not be necessary.

Tuesday, May 5, 2015

For some years now researchers have been investigating the biochemistry of species such as salamanders and zebrafish that are capable of regrowing limbs and internal organs. It is as yet unknown how hard it will be to improve human regenerative capacity using what is learned from this research, but definitive answers may emerge over the next decade:

While the human heart can't heal itself, the zebrafish heart can easily replace cells lost by damage or disease. Now, researchers have discovered properties of a mysterious outer layer of the heart known as the epicardium that could help explain the fish's remarkable ability to regrow cardiac tissue. After an injury, the cells in the zebrafish epicardium dive into action - generating new cells to cover the wound, secreting chemicals that prompt muscle cells to grow and divide, and supporting the production of blood vessels to carry oxygen to new tissues.

Researchers found that when this critical layer of the heart is damaged, the whole repair process is delayed as the epicardium undergoes a round of self-healing before tending to the rest of the heart. "The best way to understand how an organ regenerates is to deconstruct it. So for the heart, the muscle usually gets all the attention because it seems to do all the work. But we also need to look at the other components and study how they respond to injury. Clearly, there is something special about the epicardium in zebrafish that makes it possible for them to regenerate so easily. The epicardium is underappreciated, but we think it is important because similar tissues wrap up most of our organs and line our organ cavities. Some people think of it as a stem cell because it can make more of its own, and can contribute all different cell types and factors when there is an injury. The truth is we know surprisingly little about this single layer of cells or how it works. It is a mystery."

The new research showed that the process requires signaling through a protein called sonic hedgehog, and demonstrated that adding this molecule to the surface of the heart can drive the epicardial response to injury. Researchers also found that the epicardium produces a molecule called neuregulin1 that makes heart muscle cells divide in response to injury. When they artificially boosted levels of neuregulin1, even without injury, the heart started building more and more muscle cells. The finding further underscores the role of this tissue in heart health. The researchers now plan to perform larger screens for molecules that could enhance heart repair in zebrafish, and perhaps one day provide a new treatment for humans with heart conditions.

Tuesday, May 5, 2015

With advancing age an ever greater number of cells in the body linger in a senescent state in which replication is halted rather than destroying themselves after reaching the Hayflick limit. This can be a reaction to cellular damage or potentially damaging tissue environments, and at least initially helps to lower the incidence of cancer by preventing cells that are potentially at risk from continuing to replicate. Unfortunately senescent cells secrete a range of proteins that degrade surrounding tissue and encourage nearby cells to also become senescent. Given large enough numbers of senescent cells this activity leads to meaningful loss of function in important organs and contributes to the development of age-related disease.

In recent years researchers have demonstrated benefits to health and healthy life span resulting from selective clearance of senescent cells in mice, and removing senescent cells is one of the targets of the SENS rejuvenation research program. Here scientists link cellular senescence to mechanisms known to contribute to glaucoma, a form of blindness caused by raised fluid pressure inside the eye and resulting nerve damage:

The most common form of glaucoma, primary open angle glaucoma, is an aging associated disease often characterized by elevated intraocular pressure induced by increased outflow resistance of the aqueous humor. The human trabecular meshwork (HTM), a complex three-dimensional structure comprised of cells, interwoven collagen beams and perforated sheets, is believed to provide the majority of outflow resistance in both normal and glaucomatous eyes. HTM cells, depending on the region of the HTM, either form sheets covering extracellular matrix (ECM) structures or are scattered throughout the ECM. What changes in the HTM resulting in increased resistance is poorly understood, but our recent study showed the HTM is ~20 fold stiffer in glaucoma, suggesting a prominent role of HTM mechanobiology. This tissue-scale stiffening is likely a result of biophysical changes to both the ECM and constituent cells, as structural changes to both the cytoskeleton and ECM have long been associated with glaucoma.

Building upon these findings, further research has led to a growing body of evidence that these biophysical changes are not epiphenomena, but upstream of factors important in the progression of the disease. A prime candidate for this process is cellular senescence, the irreversible arrest of cellular proliferation. Senescence is thought to contribute to many of the physiological changes associated with aging as well as aging associated disease. In this study, primary HTM cells were serially passaged until senescence and atomic force microscopy (AFM) was used to measure the intrinsic mechanical properties of senescent cells compared to normally proliferating controls. We found that stiffness was significantly increased in high passage HTM cells. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases.

Wednesday, May 6, 2015

This report from a recent symposium is a good reminder that the majority of work in the aging research community has little or no relevance to the goal of extending healthy human longevity by a large amount. There are very few research programs that offer the possibility of adding decades of healthy life to the present human life span if followed through to completion, and the SENS projects are so far the only coherent, well-organized example of those. The average research organization is conducting work much more in line with the projects noted below:

What have we learned about aging during the past few decades and where is that knowledge taking us as society continues to skew older? To answer those questions, the USC Davis School of Gerontology hosted "What's Hot in Aging Research at USC," the sixth annual interdisciplinary symposium at the Ethel Percy Andrus Gerontology Center. Faculty members shared their current research, offering insight as to how it would impact older adults, their families and communities in the future.

The morning session opened with a discussion of the biological mechanisms behind aging, life span and aging-related disease. Valter Longo, Edna M. Jones Professor and USC Longevity Institute director, emphasized the importance of understanding the basic mechanisms of aging, not just hunting for specific remedies for aging-related diseases such as diabetes and cancer. As the population as a whole grows older, many of humanity's most important health challenges will be rooted in the aging process, and researchers will need to "go after the aging process itself, not just Band-Aid solutions," he said.

University Professor Caleb Finch and Professor Christian Pike described their research into inflammatory responses in the brain and Alzheimer's disease. Finch has been exploring the possible links between pollution-induced inflammation and the disease, while Pike has probed the connections between obesity and increased expression of inflammatory factors that heighten Alzheimer's risks. Assistant Professor Sean Curran discussed his work on the interaction of diet and genetics, outlining the possible translational path his studies would take from C. elegans to humans, highlighting the possibilities for personalized nutritional insight ushered in by the genomics revolution. "Every person in every environment is different. If you have a variation in specific genes, how is that predictive of what diet will give you maximum success?"

Addressing several myths about longevity, Assistant Professor Jennifer Ailshire said that although the portion of the population reaching age 100 is still tiny, more people are reaching the milestone than ever. Demographics show that some who become centenarians can reach old age in relatively good health and don't simply spend more years in poor health than others.

Wednesday, May 6, 2015

Studies searching for genetic differences capable of explaining natural variations in human longevity, such as the existence of long-lived families, have turned up little in the way of consistent results. Associations in one study rarely replicate in other study populations, even in the same geographic regions. This most likely means that genetic contributions to longevity are numerous, individually tiny, and have a complicated set of relationships with one another. There is no easy road to enhanced longevity here:

Longevity is an extremely complex phenotype that is determined by environment, life style and genetics. Genome wide association studies (GWAS) have been a powerful tool to identify the genetic origin of other complex outcome with a similar heritability. Here we discuss the findings all GWAS of longevity conducted to date. Various cut-off to define longevity have been used varying from 85+, 90+ and 100+ years and the impact of these difference are addressed. The only consistent association emerging from GWAS to data is the APOE gene that has been already identified as a candidate gene. Although (GWAS) have identified biologically plausible genes and pathways, no new loci for longevity have been conclusively proven.

A reason for not finding any replicated associations for longevity could be the complexity of the phenotype, although heterogeneity also underlies many other traits for which GWAS has been successful. One may argue that rare variants explain the high heritability of longevity and the segregation of the trait in families. Yet, whole genome analyses of GWAS data still suggest that over 80% of the heritability is explained by common variants. Although findings of GWAS to date have been disappointing, there is ample opportunity to improve the statistical power of studies to find common variants with small effects. In the near future, joining of the published studies and new ones emerging may surface new loci.

Thursday, May 7, 2015

Inhibiting adenylyl cyclase type 5 (AC5) has been demonstrated to extend life in mice. This open access review paper covers what is known of the mechanisms involved:

Adenylyl cyclase (AC) is a ubiquitous enzyme which regulates all organs and catalyzes the conversion of ATP to cAMP. There are nine major mammalian AC isoforms; types 5 and 6 are the major isoforms in the heart. Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against obesity, the cardiomyopathy induced by aging, diabetes, and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection.

Inhibition of AC5 naturally becomes an important mechanism for clinical translation. There have been recent clinical studies supporting our findings in the AC5 KO model. The clinical genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the ADCY5 gene associated with increased type 2 diabetes risk, which is the inverse of AC5 inhibition and therefore consistent with our findings. However, it is difficult to isolate the specific action of one gene in human genome studies, as we have done by disrupting the AC5 gene in mice. Unfortunately disrupting the AC5 gene in patients is not feasible and therefore it becomes necessary to identify a pharmacological inhibitor of AC5. One example of a pharmacological compound that replicates many of the features of AC5 inhibition is an FDA approved antiviral drug, Vidarabine, which protects against the development of cardiomyopathy in mice. However, this drug is not purely an AC5 inhibitor and has the disadvantage that it cannot be administered orally. Accordingly, further work is required to develop a nontoxic AC5 inhibitor that is soluble and can be given to patients orally.

Thursday, May 7, 2015

Mitochondria are biological power plants, swarming and multiplying in their hundreds like bacteria inside every cell. They contain a little DNA, separate from that in the cell nucleus, and some forms of damage to that DNA result in cells taken over by malfunctioning mitochondria. These faulty cells increase in number over a lifetime, exporting damaged molecules far and wide in the body, and contributing to numerous aspects of degenerative aging.

Quality control mechanisms watch over mitochondria and destroy those that become damaged, a process known as mitophagy. Clearly these mechanisms are not perfect and important forms of damage slip through the net. While it is thought that increased cellular housekeeping activity, including mitophagy, is a key contributing mechanism in most of the known methods of slowing aging in mice and other species, it is unclear as to whether this can provide protection against forms of damage to mitochondia that evade mitophagy under normal circumstances. Will they still evade a more active level of mitophagy that is just a greater repetition of the same processes? In part this uncertainty is due to the lack of any methodology to spur the operation of mitophagy in isolation, so as to see what happens without the complication of numerous other changes taking place at the same time. These researchers claim development of such a means:

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent.

We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.

Friday, May 8, 2015

Regular moderate exercise extends healthy life span and slows many of the declines associated with aging. This is at least in part due to mitochondrial processes:

Inactivity accelerates muscle catabolism, mitochondrial dysfunction, and oxidative stress accumulation and reduces aerobic capacity . These problems can lead to a "vicious circle" of muscle loss, injury, and inefficient repair, causing elderly people to become increasingly sedentary over time. Thus, it is imperative to implement preventive and therapeutic strategies to boost muscle mass and regeneration in the elderly and hence maintain and improve both their health and independence and prevent the occurrence of the frailty condition.

Current evidence certainly indicates that a regular exercise program reduces and/or prevents a number of functional declines associated with aging. Since, besides genetic, environmental, and nutritional factors, the lack of physical activity plays a major role in the pathophysiology of frailty, regular exercise has also the potential to reduce the incidence of this problematic expression of population aging. Older adults can adapt and respond to both endurance and strength training. Aerobic/endurance exercise helps to maintain and improve cardiovascular and respiratory function, whereas strength/resistance-exercise programs have been found to be helpful in improving muscle strength, power development, and function.

In this review we describe the pleiotropic effect of physical activity on multiple targets that have a role in preventing the decline of mitochondrial "quality," which is implicated in the aging process of skeletal muscle. Recent evidences consistently show that the "quality" of skeletal muscle mitochondria declines during aging. Indeed, in this condition we can observe (i) mitochondrial DNA mutations; (ii) specific epigenetic drift; (iii) decreased expression of mitochondrial proteins; (iv) reduced enzyme activity of cellular respiration; (v) reduced total mitochondrial content; (vi) increased morphological changes; (vii) a decrease in mitochondrial turnover. All of these factors probably contribute to age-associated sarcopenia, and a growing body of evidence suggests that most of these skeletal muscle age-related changes can be prevented and or attenuated by physical activity. In short, physical activity should be prescribed for older adults. It not only improves physical function, helping the elderly to maintain independence, but also enhances overall health and increases longevity.

Friday, May 8, 2015

One of the distinguishing features of old tissues is the presence of solid protein aggregrates. In some cases these are clearly linked to the pathology of specific diseases, such as Alzheimer's or forms of amyloidosis. For others no clear association with age-related dysfunction has yet been found. It seems prudent to develop means to remove these aggregates regardless, and this is one of the pillars of the SENS approach to rejuvenation treatments. In this paper, researchers propose that not all aggregates are equal, and some are the result of protective mechanisms that sequester an excess of proteins created through age-related dysfunction, rather than being a form of damage in and of themselves:

Researchers used the tiny nematode worm Caenorhabditis elegans as a model organism to analyse the changes that occur in the proteome (the entirety of all proteins) during a lifespan. "The study is the most extensive of its kind in a whole organism quantifying more than 5,000 different proteins at multiple time points during aging." The researchers were able to show that the proteome undergoes extensive changes as the worms age. About one third of the quantified proteins significantly change in abundance. The normal relation between different proteins, which is critical for proper cell function, is lost. This shift overwhelms the machinery of protein quality control and impairs the functionality of the proteins. This is reflected in the widespread aggregation of surplus proteins ultimately contributing to the death of the animals.

Based on these findings, the researchers also analysed how genetically changed worms with a substantially longer or shorter lifespan manage these changes. "We found that proteome imbalance sets in earlier and is increased in short-lived worms. In contrast, long-lived worms coped much better and their proteome composition deviated less dramatically from that of young animals." Surprisingly, the long-lived worms increasingly deposited surplus and harmful proteins in insoluble aggregates, thus relieving pressure on the soluble, functional proteome. However, in contrast to the aggregates found in short-lived animals, these deposits were enriched with helper proteins - the so-called molecular chaperones - which apparently prevented the toxic effects normally exerted by aggregates.

"These findings demonstrate that the cells specifically accumulate chaperone-rich protein aggregates as a safety mechanism. Therefore, the aggregates seem to be an important part of healthy aging." Indeed, it is known that insoluble protein aggregates also accumulate in the brains of healthy elderly people. So far, researchers assumed that neurodegeneration and dementia appear to be mainly caused by aberrant protein species accumulating in aggregates. This assumption may now be tested again: "Clearly, aggregates are not always harmful. Finding ways to concentrate harmful proteins in insoluble deposits might be a useful strategy to avoid or postpone neurodegenerative diseases as we age."


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