Fight Aging! Newsletter, September 12th 2016

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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  • An /r/futurology AMA with Aubrey de Grey and Matthew O'Connor on MitoSENS Research Progress, Monday September 12th, 11AM PST
  • Entering the Final Days of the SENS Universal Cancer Treatment Fundraiser
  • Considering Age Reversal Therapeutics
  • Mitotech and Clinical Progress for Mitochondrially Targeted Antioxidants
  • A Cellular Cause for Calcification of Blood Vessels
  • Yet More Genetic Mapping of Degenerative Aging
  • Latest Headlines from Fight Aging!
    • Quantifying the Assertion that Some Older People are in Better Shape than Others
    • Altering the Balance of Bone Deposition and Absorption to Treat Osteoporosis
    • First Published Paper for the SENS Research Foundation Mitochondria Team
    • A Review of Aging and Cognitive Decline
    • The Cryoprize Initiative
    • A Profile of Research into FGF21 in Aging and Thymic Function
    • Evidence for Serotonin Signaling to be Important in Calorie Restriction
    • Fatty Acid Metabolism and Age-Related Heart Failure
    • Reduced Age-Related Increase in Blood Pressure via Modulation of Vasoconstriction
    • Less Growth Hormone in Long-Lived Families

An /r/futurology AMA with Aubrey de Grey and Matthew O'Connor on MitoSENS Research Progress, Monday September 12th, 11AM PST

Over at Reddit, the /r/futurology community are hosting an AMA event with Aubrey de Grey and Matthew O'Connor of the SENS Research Foundation on Monday September 12th, starting at 11AM PST. They will be answering your questions about the MitoSENS research program and the recent progress in allotopic expression of mitochondrial genes, a way to prevent mitochondrial DNA damage from contributing to the aging process. The AMA is open in advance, so by all means visit and add any questions you might have about recent events and the future of this part of the SENS program.

Entering the Final Days of the SENS Universal Cancer Treatment Fundraiser

The last few days have arrived for this year's SENS Research Foundation crowdfunding campaign, focused on important groundwork to establish a universal therapy for all types of cancer. There is still a few thousand left in the matching fund, so donations are still being matched. Cancer is just as much a part of aging that must be ended, brought completely under control, as all of the other line items in the SENS rejuvenation research portfolio, and this year is the first time that the SENS Research Foundation has run a fundraiser for this program.

Hopefully there is no need to remind the audience here that the SENS Research Foundation, and important ally the Methuselah Foundation, have in recent years achieved great progress in the field of rejuvenation research on the basis of our donations and our support. Some of the high points you'll find mentioned here and there at Fight Aging!: support and ongoing expansion of the mitochondrial repair technologies now under development at Gensight; seed funding Oisin Biotechnologies for senescent cell clearance; unblocking efforts to clear glucosepane cross-links that stiffen tissues; running the lauded Rejuvenation Biotechnology conferences; and many more. If only all charities produced as great an impact with as few resources - and if only we were further along in the bootstrapping of an industry focused on the development of rejuvenation therapies. But we are where we are, and it remains wholly our opportunity as grassroots activists to light the way for others, to point out the research programs most likely to produce great gains in human health and longevity, and to attract a larger community of supporters to help out. They will be drawn by the fact we are a growing crowd, and that we have declared our support and expectation of good results from these programs: from senescent cell destruction, from mitochondrial repair, from glucosepane cross-link clearance, and from the others of the SENS program.

These SENS rejuvenation biotechnologies are unified by the theme of picking out specific areas of research that have been or are presently largely ignored, but that are also essential to the production of enormously beneficial outcomes in medicine, great leaps ahead rather than the incremental plodding that is the more usual state of medical progress. We live in an era of enormously rapid progress in biotechnology, and our medicine should reflect that fact - but in all too much of the research community there is a decided lack of ambition, and a culture that prefers to inch forward by increments. The entire point of the SENS vision, and the activities of the SENS Research Foundation and its allies, is to demonstrate that timidity and incrementalism can be bypassed to the benefit of all. There are large gains in health out there to be had, if the right strategy is chosen for research and development.

When it comes to the matter of aging that strategy is to focus on repairing the fundamental biomolecular damage of aging, the well-cataloged changes that distinguish old tissues from young tissues, and which have no other cause beyond the normal operation of healthy metabolism. These are forms of biological wear and tear, if you like, the accumulation of waste products and tiny breakages that spiral out into dysfunction and organ failure. For cancer research, meanwhile, the situation is more akin to an economic revolution, or disruptive advance in technology. Because all cancers must lengthen their telomeres, and because telomere lengthening is governed by a small number of processes, there is the opportunity to change the focus of cancer research from an endless procession of expensive new therapies, each targeting a tiny number of the hundreds of subtypes of cancer, to one single therapy that can effectively suppress all cancers. That is a huge difference, and turns the complete medical control of cancer from a distant future prospect into something that might be achieved from start to finish in a few decades.

The SENS Research Foundation's contribution to this project, the work that we as philanthropists choose to fund, is to run an assay with new tools against the standard drug library to find candidates to suppress alternative lengthening of telomeres (ALT). This should lead to a better understanding of how to build very effective therapies for ALT cancers, and in the best scenario will produce the starting point for a first wave of general therapies that can be applied to these cancers within a few years from discovery, based on repurposing known drugs. Other research groups are working on suppressing telomere lengthening by blocking telomerase, but it is becoming increasingly clear that telomerase cancers are quite capable of switching to become ALT cancers if provoked. The effectiveness of this road towards a universal cancer treatment depends on the blockade of both ALT and telomerase, but next to no-one has been working on ALT. This is where the SENS Research Foundation scientists, supported by you and I, can do their part to make this new approach to cancer a reality, by picking up this neglected but vital line of research and making the same success of it as they have in other areas.

How to make this happen? All we have to do is donate, mention this to our friends, say something to the world about how important it is that the whole of cancer research be transformed in this way. It is a golden opportunity to do something here and now to help build the type of future that we want to see.

Considering Age Reversal Therapeutics

Age Reversal Therapeutics is an initiative launched by quite the varied set of people: leaders from the "anti-aging" marketplace's Life Extension Foundation, a SENS Research Foundation researcher, a selection of biotech industry veterans, a practitioner of anti-aging medicine, and a reputable genetics researcher quite well known in our community. Strange bedfellows indeed - a meeting of many houses of the broader community interested in aging, houses that typically don't have much to do with one another, and indeed in some cases don't think much of one another. The basic plan here is to raise money from investors and then put it into some of the most promising of recent research and development initiatives in the treatment of aging. It is intended to be one of those hybrids that is something like a company and something like an investment fund. You can read their plans in some detail in their large PDF prospectus; scroll all the way down past the legal and fiscal matters to page 124 for the discussion of what exactly they intend to fund and the overall goals of the venture.

It is my belief that over the long term the currently terrible "anti-aging" marketplace will see the useless pills, creams, supplements, and potions replaced by rejuvenation technologies that actually work - as those technologies emerge from the scientific community, that is. The "anti-aging" marketplace always was, to a very large degree, a pipeline established by earnest believers in the end goal of extending healthy life spans, but who were unfortunate enough to have found that calling well in advance of the existence of any way to meaningfully alter the course of aging. Having the heart in the right place doesn't excuse what came next, of course, in which any old junk was thrust into the market in order to make money from the credulous, and thanks to the megaphone of marketing the whole concept of intervening in the aging process became synonymous in many eyes with rampant fraud over the course of the last few decades of the last century. This history does explain why some of the notable companies in the space, such as the supplement seller Life Extension Foundation, do in fact devote funding to legitimate research that you and I might approve of: stem cell trials, SENS programs, cryopreservation technology, targeted cancer therapies, and the like.

Age Reversal Therapeutics represents one of a number of possible next steps beyond those activities, now that the environment and awareness of aging as a therapeutic target has advanced to the point at which the rejuvenation therapy of senescent cell clearance is under development in startups, Calico Labs and Human Longevity have raised large sums, and other efforts make it clear that there is money out there for meaningful commercial work on the problem of aging. The question is how to take this new enthusiasm among for-profit investors and turn it into the research funding still needed to push new rejuvenation therapies to the point of commercial viability. Years of work and millions in fundraising yet remain to be accomplished to reach that point in most cases. The SENS Research Foundation has launched Project|21 as one possible answer to this question. Age Reversal Therapeutics is another possible answer. There are other groups out there taking the more traditional paths of establishing venture funds or starting their own companies. Old habits die hard, sad to say, and most investors are not yet willing to abandon profit as the primary marker of success, when the only real measure of success is future health and longevity. What use is financial profit to those crippled by age, who cannot buy the only thing they really want?

I think the next ten to twenty years of transition in the "anti-aging" marketplace from junk and outright lies to therapies that work is going to be messy for any poorly educated consumer. For people like me it will be increasingly hard to draw good lines between good and bad initiatives. We are absolutely going to see clinics marketed as anti-aging salons selling fully functional senescent cell clearance treatments in a package with entirely useless apple stem cell facial scrubs, and making little effort to educate their customers as to where the benefit comes from. We will eventually see clinics selling packages wherein, unlike the obvious example above, I cannot make a good judgement call as to which components are worth the candle. The glass half full view is that this will be much better than the present situation. An "anti-aging" marketplace in which only 10% of the products actually work is still 10% better than what we have today. So to the degree that the Age Reversal Therapeutics principals find new sources of significant investment from the Life Extension Foundation sphere of influence, then go on to fund projects that I agree with, and note that rejuvenation of the thymus is on their list, for example, and further manage to push the results into clinics for medical tourism and trials for validation, then I'm all in favor of the mess that lies ahead. It will certainly beat the present mess, featuring as it does a complete lack of ways to effectively treat aging as a medical condition.

But I encourage you to explore the Age Reversal Therapeutics website and form your own opinions. Certainly there is always the lingering suspicion that a venture led by the Life Extension Foundation and other "anti-aging" marketplace principals will go on to fund projects that I would characterize as useless at best and objectionable at worst. We shall see. I choose to be cautiously optimistic, and believe that, if the funding can be found, this has the potential to become something that looks a lot like the Life Extension Foundation's research funding program shorn of the Life Extension Foundation itself.

Mitotech and Clinical Progress for Mitochondrially Targeted Antioxidants

The path from laboratory to clinic is a lengthy one. It helps to keep an eye on specific projects across the years to better calibrate one's expectations for new lines of research. Today's example of the mitochondrially targeted antioxidant molecule SkQ1, a form of plastiquinone, has been under development for quite the long time, starting with Russian lab work that first attracted my notice ten years ago - and of course had been going on for quite some time prior to that, stuck on the wrong side of the language barrier to catch the best opportunities for investment and interest. Following years of animal studies of various sorts, SkQ1 is presently being brought to the clinic by the European company Mitotech. They are in the midst of a human trial for dry eye syndrome and have recently obtained a patent in the US:

Mitotech S.A. is granted a patent in anti-aging

Mitotech S.A., a Luxembourg based clinical stage biotechnology company focused on age-related disorders, announced that it received a U.S. patent covering deceleration of aging in living organisms by its lead compound SkQ1. "The main aspect of the mechanism of action of our lead compound is protecting mitochondria from oxidative stress, which is a confirmed key factor in cell aging. That's one of the reasons SkQ1 proved to be effective in a wide spectrum of models of age-related disorders. This particular patent, however, may pave the way for Mitotech to pursue aging as a standalone indication. Of course, that would be a major undertaking in terms of the volume of clinical development and regulatory work, but we think it's an attractive opportunity and the field is wide open for a break-through technology."

One of the more intriguing outcomes of targeted mitochondrial antioxidant research is that it has shown promise as a treatment for a number of quite different eye conditions, such as cataracts, glaucoma, and dry eye syndrome. That is the path that was eventually chosen for initial commercial development. Dry eye syndrome is not to be dismissed lightly; ask anyone unfortunate enough to have suffered it. It is quite prevalent in old age and produces an negative impact on quality of life far larger than one might imagine would result from the tiny systems failures that cause the condition. That said, the reason that this community is interested in mitochondrially targeted antioxidants is because of the possibility that they can slow one of the forms of damage that contributes to degenerative aging, within which dry eye syndrome is but the tiniest mote.

As for any discussion of mitochondrially targeted antioxidants such as plastiquinones, SS-31, and MitoQ, it is worth taking a moment to point out that they are very different from the common or garden antioxidants that you can buy in the store. It is generally accepted in the research community that taking general antioxidant supplements is modestly harmful over the long term. In animal studies it tends to reduce life span by a modest amount. One of the mechanisms by which this might occur is that antioxidants will intercept and suppress the excess reactive oxygen species generated during exercise. That excess is a signal, and spurs a range of activities that result in everything from additional cellular maintenance to muscle repair and growth. This is something to bear in mind. Mitochondrially targeted antioxidants, on the other hand, localize to the mitochondria in cells. They primarily soak up reactive molecules there, not generally throughout tissues. This produces a range of effects because mitochondria are of great importance to cellular metabolism, and also of great importance in the aging process.

There are a couple of things going on for mitochondria in aging. The one that is the subject of more research is a downstream result of the many forms of molecular damage in aging, in which mitochondrial operation in cells declines in general, and tissues suffer as a result. This is a very complex and still poorly understood situation governed by epigenetics and scores of related, interdependent reactions to the low-level damage of aging, and which varies widely between tissue types and individuals. The less well researched issue is that mitochondria suffer damage to their DNA, separate from that of the cell nucleus. If genes essential to normal mitochondrial operation are deleted or damaged as a result, then the mutant mitochondria can either replicate more rapidly or become more resistant to quality control than their undamaged peers - it isn't clear which is the case at this point. Regardless, such mutants quickly take over cells and run rampant, turning these host cells into damaging exporters of reactive molecules that can cause all sort of harm in tissues both near and far. How does this DNA damage come about? It might be breakage during replication, but the consensus candidate has long been the generation of reactive oxygen species that happens inside mitochondria, right next door to their vulnerable DNA. Experiments with increased levels of natural mitochondrial antioxidants such as catalase provide supporting evidence for this proposition. Delivering artificial mitochondrially targeted antioxidants is thought to reduce the pace of mutational damage, and thus modestly improve healthy life span in this way.

Given the complexity of mitochondrial biochemistry, and its influential role on metabolism as a whole, I should say that almost everything I've said above has been disputed by one or more research groups at some point in time. The consensus is of varied resilience and always under attack. When it comes to the effects of mitochondrially targeted antioxidants on various medical conditions, their relevance may be as much damping down some of the oxidative signaling produced by mitochondria in inflamed tissues, or protecting mitochondria from an influx of oxidative molecules arriving from elsewhere, as anything else. This seems to help slow progression of a number of diseases with inflammatory components, as inflammation and oxidative stress go hand in hand. For all the focus on aging in the materials on SkQ1, the more rigorous life span studies of SkQ1 show only modest extension of life in short-lived animals, such as the recent demonstration of 10% life extension in flies. This is really not large enough to make it something that I'd consider worth chasing as an intervention in aging; short-lived species have very plastic life spans, and a 10% gain in flies is small in comparison to, say, the outcomes for calorie restriction. Get out there and exercise more and eat less, and you'll probably be doing more for your long-term health. If, however, as seems to be the case, these targeted antioxidants can have a significant positive impact on the later stages of a fair number of different age-related diseases that involve raised levels of oxidative stress and inflammation, well, then that was still research and development time well spent, even if it wasn't the outcome hoped for.

A Cellular Cause for Calcification of Blood Vessels

The publicity materials and paper linked below discuss the identification of a cell type and related mechanisms responsible for calcification of blood vessels. The focus is on the environment of kidney disease, and thus on kidney tissue, but we might hope that this has a broader relevance to the age-related calcification that occurs in all blood vessels over the years. The more that is known of blood vessel calcification, the better the odds that something might be done about it soon enough to matter for you and I. The deposition of calcium in blood vessel walls is considered to be an important contribution to the loss of elasticity in these tissues. The stiffening of blood vessels with age drives the development of hypertension, an increase in blood pressure. Hypertension and stiffening cause detrimental remodeling of heart tissue that leads towards heart failure, as well as ever greater breakage of tiny blood vessels, such as in the brain, where the resulting tissue damage produces cognitive decline. Most forms of age-related cardiovascular dysfunction are exacerbated by hypertension: the higher the blood pressure, the worse the long-term prognosis.

While calcification in blood vessels is universally agreed to be a bad thing for the reasons given above, it is one of the many age-related changes for which there is no robustly defended line that can be drawn, leading through clearly demarcated steps, starting from an increase in fundamental forms of cell and tissue damage, the wear and tear caused by the normal operation of our biology, and ending with an increase in calcification. There is, however, a fair amount of evidence that can be used to argue over whether or not calcification is itself a fundamental form of damage, whether or not it is secondary to other forms of damage and change, and the nature of the processes that cause it. For example, calcification may be made worse by the presence of metabolic waste, of a type that the SENS Research Foundation has worked on clearing. It is also argued to be made worse by inflammation and by destruction of elastin, the basis for tissue elasticity. Sedentary individuals exhibit more calcification, as do those who report more time spent sitting.

The best path to deal with calcification depends on whether or not it is a fundamental form of damage. If it is a downstream effect of the classes of molecular damage outlined in the SENS vision for rejuvenation therapies, then the fix for calcification, as for near all aspects of aging, is to build those therapies, capable of repairing the root cause molecular damage. If calcification has a cellular cause, in that specific types of cells are changing their behavior in increasing numbers to deposit calcium where they should not be depositing calcium, then that scenario makes it much more likely that this is a secondary or later effect of other molecular damage. This unwanted change in cell behavior has been seen by other researchers in recent years, in heart tissue, for example. Separately, various therapeutic approaches based on removing the calcium deposits have been suggested by research groups over the years. It is likely that these approaches would be needed in addition to damage repair for people who have already grown old; simply repairing other forms of damage may not lead to the removal of excess calcium that has already accumulated. On this front it has been suggested to make use of osteoclasts, the cells responsible for dismantling bone, or, more conventionally, some form of chelation.

Scientists find culprit responsible for calcified blood vessels in kidney disease

Scientists have implicated a type of stem cell in the calcification of blood vessels that is common in patients with chronic kidney disease. The research will guide future studies into ways to block minerals from building up inside blood vessels and exacerbating atherosclerosis, the hardening of the arteries. "In the past, this calcification process was viewed as passive - just mineral deposits that stick to the walls of vessels, like minerals sticking to the walls of water pipes. More recently, we've learned that calcification is an active process directed by cells. But there has been a lot of controversy over which cells are responsible and where they come from."

The cells implicated in clogging up blood vessels with mineral deposits live in the outer layer of arteries and are called Gli1 positive stem cells. They have the potential to become different types of connective tissues, including smooth muscle, fat and bone. In healthy conditions, Gli1 cells play an important role in healing damaged blood vessels by becoming new smooth muscle cells, which give arteries their ability to contract. But with chronic kidney disease, these cells likely receive confusing signals and instead become a type of bone-building cell called an osteoblast, which is responsible for depositing calcium. "We expect to find osteoblasts in bone, not blood vessels. During kidney failure, blood pressure is high and toxins build up in the blood, promoting inflammation. These cells may be trying to perform their healing role in responding to injury signals, but the toxic, inflammatory environment somehow misguides them into the wrong cell type. We found Gli1 cells in the the calcified aortas of patients in exactly the same place we see these cells in mice. This is evidence that the mice are an accurate model of the disease in people."

Further supporting the argument that Gli1 cells are driving the calcification process, the researchers showed that removing these cells from adult mice prevented the formation of calcium in their blood vessels. "A drug that works against these cells could be a new therapeutic way to treat vascular calcification, a major killer of patients with kidney disease. But we have to be careful because we believe these cells also play a role in healing injured smooth muscle in blood vessels, which we don't want to interfere with."

Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease

Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during atherosclerosis and arteriosclerosis in ApoE-/- mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.

Yet More Genetic Mapping of Degenerative Aging

Today I'll point out a two open access papers on the mapping of genetics, epigenetics, aging, and age-related disease. There is a lot of this sort of work taking place these days: it is ever easier to raise funding for any sort of work on genetics, and this is the beginning of the age of practical gene therapy. Intervening in the aging process to slow or reverse aging, as opposed to trying to patch over the late stage consequences of specific age-related diseases without actually touching the processes of aging itself, remains a comparatively small initiative within the aging research community. Most funded work on aging goes towards cataloging and mapping, a part of the great life science initiative to produce a comprehensive atlas of living biology from top to bottom: how our cells and tissues work, and how every function of every biological system changes over time, understood all the way down to the roles of individual molecular interactions. This is an enormous project, staggering in scope, with the present vast databases of molecular biochemistry just a sketch of the outline of the whole when held up against the bigger picture. Barring revolutionary advances in automation and computation this project will be nowhere near complete even several decades from now.

To the extent that factions within the scientific community prioritize complete understanding of aging above interventions in aging based on what we do already know, they have decided that no significant progress on lengthening life will be made in our lifetimes. If this view dominates, the future will be much the same as the recent past, in that the steady upward slope of small gains in adult life expectancy will continue, with the bulk of these benefits arising from incidental side-effects of the standard medical approach to late-stage aging and age-related disease. The patches will get better, but a patched and damaged system still fails; the patch can only delay the inevitable. The most important debate in medical research today is between those who prioritize full understanding and slow progress towards slowing aging versus those who want to take the current catalog of known differences between old and young tissue and fix them in advance of full understanding. That will cost a lot less and achieve answers on the relevance of this damage to aging and rejuvenation far more rapidly than any other methodology.

Unfortunately, gathering greater support and adoption of work on biological repair and rejuvenation is still an uphill battle, despite successes in the making such as senescent cell clearance, an approach gathering more attention these days. The majority of research into aging looks a lot more like the open access papers linked here, which is to say it is interesting, largely focused on genetics, generates a lot of data, and is of little practical use in the near term. Altering gene expression levels in the hopes of improving the situation for older people is somewhat like adjusting the fuel balance of a rusted and worn engine in the hopes that it will run a little longer. It misses the point, the direct and most useful thing that could be done to improve matters. The grand map of molecular biochemistry is absolutely something that should be constructed, and will be of great use to the next generation of biotechnologies - but to focus on that entirely is to sacrifice countless lives, when the research and development community could also be building the first generation of therapies that will help bring an end to degeneration aging.

Discover the network mechanisms underlying the connections between aging and age-related diseases

Although our knowledge of aging has greatly expanded in the past decades, it remains elusive why and how aging contributes to the development of age-related diseases (ARDs). In particular, a global mechanistic understanding of the connections between aging and ARDs is yet to be established. We rely on a network modelling named "GeroNet" to study the connections between aging and more than a hundred diseases. By evaluating topological connections between aging genes and disease genes in over three thousand subnetworks corresponding to various biological processes, we show that aging has stronger connections with ARD genes compared to non-ARD genes in subnetworks corresponding to "response to decreased oxygen levels", "insulin signalling pathway", "cell cycle", etc.

Based on subnetwork connectivity, we can correctly "predict" if a disease is age-related and prioritize the biological processes that are involved in connecting to multiple ARDs. Using Alzheimer's disease (AD) as an example, GeroNet identifies meaningful genes that may play key roles in connecting aging and ARDs. The top modules identified by GeroNet in AD significantly overlap with modules identified from a large scale AD brain gene expression experiment, supporting that GeroNet indeed reveals the underlying biological processes involved in the disease.

Systematic analysis of the gerontome reveals links between aging and age-related diseases (full text is PDF only)

In model organisms, over 2,000 genes have been shown to modulate aging, the collection of which we call the "gerontome". Although some individual aging-related genes have been the subject of intense scrutiny, their analysis as a whole has been limited. In particular, the genetic interaction of aging and age-related pathologies remains a subject of debate. In this work, we perform a systematic analysis of the gerontome across species, including human aging-related genes. First, by classifying aging-related genes as pro- or anti-longevity, we define distinct pathways and genes that modulate aging in different ways. Our subsequent comparison of aging-related genes with age-related disease (ARD) genes reveals species-specific effects with strong overlaps between aging and age-related diseases in mice, yet surprisingly few overlaps in lower model organisms.

We discover that genetic links between aging and age-related diseases are due to a small fraction of aging-related genes which also tend to have a high network connectivity. Other insights from our systematic analysis include assessing how using datasets with genes more or less studied than average may result in biases, showing that age-related disease genes have faster molecular evolution rates and predicting new aging-related drugs based on drug-gene interaction data. Overall, this is the largest systems-level analysis of the genetics of aging to date and the first to discriminate anti- and pro-longevity genes, revealing new insights on aging-related genes as a whole and their interactions with age-related diseases.

We first characterized functions and pathways overrepresented in pro- and anti-longevity genes. Major anti-longevity pathways and processes include insulin signaling, growth hormone signaling and mTOR signaling. Key pro-longevity pathways include p53, cell cycle and autophagy. Although such pathways and processes are known to be related to aging, it is interesting that they are classified as anti-and pro-longevity in our systematic analysis of the genetics of aging. Differentiation between anti-longevity and pro-longevity genes and processes can provide additional clues about aging-related processes and can help identify other genes with a similar effect on aging. In order to find relations between aging and ARD, we compared aging-related gene sets with ARD genes. Limitations of our study include the fact that possibly many genes associated with longevity and disease remain to be identified, and the causal genes in many genetic associations with disease are still unknown. In spite of these caveats, our results show an association between aging and ARDs at the genetic level, although this is surprisingly species-specific with a stronger overlap in mice than in invertebrates (flies and worms) and practically no overlap in yeast.

The overlap analyses of anti- and pro-longevity genes shows differences in musculoskeletal, nervous system and cardiovascular diseases. The identified overlaps suggest that the musculoskeletal and nervous systems are related to pro-longevity genes while anti-longevity genes seem more associated with cardiovascular diseases. Looking at ARD classes which overlap with human aging-related genes, a significant overlap is verified for all classes as expected, except for immune system diseases. The nutritional and metabolic diseases, the neoplasms, the cardiovascular diseases and the nervous system diseases have the most significant overlap with human aging-related genes. Eye diseases, respiratory tract diseases (which we considered a negative control) and immune system diseases had the least overlap, but it is important to mention that these are (together with musculoskeletal diseases) the age-related disease classes with fewer genes.

The main conclusion from this work is that aging and age-related diseases are related and share more genes than expected by chance. Human aging-related genes showed a considerable overlap with ARDs. These overlaps are driven by a small subset of aging-related genes which are associated with various age-related diseases and are hubs in networks. Besides, the extent of overlaps decreases with the increase of evolutionary distance, and yeast aging-related genes show practically no overlap with ARDs. Novel differences in overlapping age-related disease classes between anti- and pro-longevity genes were observed: Nervous system and musculoskeletal diseases seem more associated with pro-longevity, while cardiovascular diseases have a stronger association with anti-longevity genes. Moreover, network analyses suggest the existence of intermediate genes which promote the associations between aging and age-related disease genes.

Latest Headlines from Fight Aging!

Quantifying the Assertion that Some Older People are in Better Shape than Others

It is undeniably the case that some older people are in relatively good shape when compared to their peers, and even when compared to individuals a decade or two younger. Aging is a process of damage accumulation, and thus you don't get to have a longer life expectancy in later life without being in better shape. In earlier old age a majority of the difference is made by lifestyle choices, but the longer you live the more of the difference becomes genetic in nature, the degree to which your physiology can resist or accommodate various forms of damage. Over the last decade researchers have increasingly worked to quantify exactly how the older people with better health are different from those who suffer more and die younger. This is all interesting work, but actually of little relevance to the future of human longevity. When, in the years ahead, clinics can repair the damage that causes aging, no-one will ever get to the point at which genetic differences and the ability to soldier on while very damaged become significant. Learning how a damaged system can better operate is really nowhere near as important as learning how to repair the damage.

In a pilot study on some of the oldest people of the world, researchers discovered that the perfusion of organs and muscles of the centenarians was as efficient as that in people who were 30 years younger. Results of the CIAO (Cilento Intitiative on Aging Outcome) pilot study suggest that low blood levels of the peptide hormone adrenomedullin (bio-ADM) are an indicator for such a good microcirculation. Making longevity measurable has long been a scientific goal as it could open up the avenue to a systematic identification of factors contributing to an extended life span.

The team carried out comprehensive health and life style assessments of two study groups that live in the Cilento region, located in the province of Salerno in southern Italy: In the first were 29 so-called 'SuperAgers' (median age 92 years), while the second was made up of 52 younger relatives (median age 60 years, living in the same household) who are expected to live just as long because they have the same genetic background and have been exposed to the same environmental and lifestyle factors. Blood biomarker analyses measured levels of the heart-function biomarker MR-proANP, as well as a marker for kidney function (penKid) and bio-ADM. The last is a regulator of vasodilation and blood vessel integrity, which both affect blood pressure. The results were compared to those of a cohort of 194 healthy persons (median age 63.9 years), who were monitored over eight years in the earlier Malmö Preventive Project (MPP).

As expected, low values of MR-proANP and penKid among the subjects in the two younger control groups indicated no signs of heart or kidney dysfunction. In contrast, both biomarkers were elevated in the SuperAgers, possibly due to the process of organ aging. However, even though the older group had levels of the two biomarkers that were as high as those found in patients experiencing heart failure (HF) or acute kidney injury (AKI), they were in clinically good condition. Surprisingly, in the group of SuperAgers, the bio-ADM values - which are often pathologically elevated in HF or AKI patients - were as low as those in both reference groups. Very low concentrations of this biomarker indicate a well-functioning endothelial and microcirculatory system allowing good blood perfusion of organs and muscles. A good microcirculation is what makes marathon runners perform better at the same heart rate than the average man or woman on the street.

Altering the Balance of Bone Deposition and Absorption to Treat Osteoporosis

The proximate cause of osteoporosis is a growing imbalance between the activities of osteoclasts, responsible for removing bone, and osteoblasts, responsible for creating bone. As is true of most issues in aging today, there is no clear line to be drawn between the fundamental damage that is the root cause of aging and the final link in the chain, which is to say differing cell behavior in bone remodeling. A great deal remains to be mapped, for all that enough is understood of the root causes to work towards repairing them. Unfortunately the majority of the research community tends to focus on proximate causes, which here means constructing therapies capable of adjusting the balance of activities for osteoclasts and ostoblasts. There are a range of potential approaches, but these researchers have settled on manipulation of a regulatory protein that diminishes bone absorption and increases bone deposition. A number of groups are working on this initiative, and new progress was recently reported:

Osteoporosis particularly affects elderly women: the bone's structure weakens and the risk of suffering fractures rises. Patients are advised to have a healthy diet and perform physical exercises; when the risk of bone fractures is high, medicine preventing further bone loss is prescribed in addition. In the search for better treatments for this disease the protein Sclerostin, which plays an important role in bone metabolism, is of major interest. When its function is impeded, bone resorption diminishes and bone re-growth is stimulated. First clinical trials with a Sclerostin-inhibiting antibody showed promising results in that the bone mass of participants suffering from osteoporosis increased.

Currently, studies are continued at several locations. In a collaborative project novel Sclerostin-inhibiting antibodies were generated and analysed for their suitability as osteoporosis treatment option. Now, for the first time scientists crystallized an antibody effective against Sclerostin and analysed its mode of action in detail. "Our findings could have a positive impact on the design of new inhibitory antibodies targeting Sclerostin." In this project, ten promising antibodies were developed in the initial round. After testing in cell culture one showed the favoured activity to neutralize Sclerostin. An in-depth analysis of the binding epitopes was performed using peptide chemistry and NMR spectroscopy. From these methods the binding site of the antibody in Sclerostin could be deduced. "Until now, we could only determine the structure of the antibody alone."

First Published Paper for the SENS Research Foundation Mitochondria Team

For most of the past decade the SENS Research Foundation has helped to fund work by various groups on allotopic expression of mitochondrial genes, a way to both cure mitochondrial disease and, more importantly, prevent mitochondrial DNA damage from contributing to the aging process. Allotopic expression works by creating backup copies of important mitochondrial genes in the cell nucleus, altered such that the resulting proteins can make their way back to the mitochondria where they are needed. Some of that work gave rise to Gensight in France, where researchers are commercializing the ability to move one of these genes into the nucleus. Last year a crowdfunding initiative provided the funds for the SENS Research Foundation in-house scientific team to finalize demonstration of allotopic expression of two more genes. The open access paper resulting from that work was recently accepted for publication, and here it is:

Mitochondria carry out oxidative phosphorylation principally by using pyruvate, fatty acids and amino acids to generate adenosine triphosphate (ATP). In animals, mitochondria are the only cellular organelles that possess their own DNA, mitochondrial DNA (mtDNA), which in humans contains 37 genes including genes encoding mitochondrial tRNAs, mitochondrial rRNAs and 13 oxidative phosphorylation (OxPhos) complex proteins. Both pediatric and adult-onset diseases have been identified that are caused by point mutations or partial deletions in mtDNA. Mitochondrial diseases tend to be fairly complex, with patients often presenting with multiple symptoms, and/or suffering from symptoms that differ between patients with the same mtDNA mutation. Traditional approaches include palliative treatments such as surgery or drugs, but are of limited use for mitochondrial diseases because they fail to address the underlying defect in the mtDNA.

Gene therapy may have the potential to treat mitochondrial disease, but many challenges exist. Direct transfection of replacement genes into mitochondria is extremely challenging. As an alternative, allotopic expression (the translocation of genes from their normal location in the mitochondria to the nucleus, followed by expression in the cytoplasm and re-insertion into the correct location in the mitochondria) was proposed as a potential method of gene therapy for congenital mutations over 25 years ago. This technique introduces additional challenges as, in addition to transfection into the cell, the allotopically expressed gene product must also translocate to the mitochondria and integrate into the appropriate protein complex. Nature already uses such targeting methods with the vast majority of proteins that comprise the mitochondrial proteome that are encoded by the nuclear genome.

In the time since allotopic expression of mitochondrially-encoded proteins was first proposed, several groups have attempted the method with mixed results. ATP6 protein was shown to integrate into Complex V (CV) and partially rescue growth of ATP6 mutant cells. ATP6 expression was also able to partially rescue mutant CHO cells while exogenous ND4 expression has been claimed to rescue rodent models of Leber's hereditary optic neuropathy. Mutant MT-ND1 cells were complemented by allotopic expression of ND1 with dramatic changes in the bioenergetics state and tumorgenic potential of the mutant cells. On the other hand, allotopically expressed ND6 protein localized to the mitochondria but failed to import properly or complement the loss of ND6 function. Allotopically expressed CYB was found to be similarly difficult to import into the mitochondria.

In order to unequivocally demonstrate functional import of a codon-corrected mtDNA gene, we sought to work in a system that was completely null for a mitochondrially encoded protein. We chose a transmitochondrial cybrid cell line which was derived from a patient whose mtDNA contained a nonsense mutation in ATP8. We have further characterized the cells and found them to contain reduced levels of ATP6 protein. Here, we demonstrate stable protein expression and mitochondrial import of ATP6 and ATP8 in the mutant cells. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6.

A Review of Aging and Cognitive Decline

The brain is a machine like all of our organs, and aging gradually destroys its function. All of the various forms of outright dementia are caused by processes that take place in all of us: accumulation of metabolic wastes; failure of clearance and maintenance processes; dysfunction of the immune system and consequent neuroinflammation; diminished rate of creation and integration of new neurons; the countless tiny undetected strokes caused by structural failure of small blood vessels; and so on. As this damage accumulates, there is a steady decline in function. Much of this, however, consists of later consequences of fundamental damage. For example the ongoing destruction of brain tissue in small amounts due to tiny strokes is driven to a considerable degree by stiffening of blood vessels and consequent hypertension, which at root is caused by some combination of inflammation, cellular senescence, and calcification and cross-linking in the extracellular matrix of blood vessel walls. If those line items can be addressed, then the later consequences will be prevented, and the decline of cognitive abilities postponed.

Cognition is critical for functional independence as people age, including whether someone can live independently, manage finances, take medications correctly, and drive safely. In addition, intact cognition is vital for humans to communicate effectively, including processing and integrating sensory information and responding appropriately to others. Cognitive abilities often decline with age. It is important to understand what types of changes in cognition are expected as a part of normal aging and what type of changes might suggest the onset of a brain disease. It is imperative to understand the effects of age on cognition because of the rapidly increasing number of adults over the age of 65 and the increasing prevalence of age-associated neurodegenerative dementias. Because many more people are living longer, the number of people with age-associated neurodegenerative dementias also is increasing rapidly. The Alzheimer's Association estimates that 5.2 million people in the United States had a clinical diagnosis of Alzheimer disease (AD) in 2014, and the number of people with a diagnosis of AD is projected to increase to 13.8 million people in 2050, unless effective preventative or treatment strategies are developed. Thus, it is vital to understand how age impacts cognition and what preventative or treatment strategies might preserve cognition into advanced age. Any approaches that could decrease the negative effects of age on cognition or decrease the risk of developing a neurodegenerative dementia would have a tremendous impact on the quality of life of millions of older adults in the United States.

Cognitive abilities can be divided into several specific cognitive domains including attention, memory, executive cognitive function, language, and visuospatial abilities. Each of these domains has measurable declines with age. For each of these domains, a subject must first perceive the stimulus, process the information, and then respond. Both sensory perception and processing speed decline with age, thus impacting test performance in many cognitive domains. For example, auditory acuity begins to decline after age 30, and up to 70% of subjects age 80 have measurable hearing loss. Also, speech discrimination and sound localization decrease in advance age. In addition to these change in sensory perception, there is a clear decline in processing speed in advancing age with older adults performing these activities more slowly than younger adults. This slowing of processing speed causes worse test performance on many types of tasks that involve a timed response. The most noticeable changes in attention that occur with age are declines in performance on complex attentional tasks such as selective or divided attention. Selective attention is the ability to focus on specific information in an environment while at the same time ignoring irrelevant information. Divided attention is the ability to focus on multiple tasks simultaneously, such as walking an obstacle course and answering questions. Normal subject performance declines progressively with age on these more complex attentional tasks. However, simple attention tasks such as digit span are maintained in normal subjects up to age 80.

Executive cognitive function involves decision making, problem solving, planning and sequencing of responses, and multitasking. Each of these areas of executive cognitive function declines with advancing age. Executive cognitive function is particularly important for novel tasks for which a set of habitual responses is not necessarily the most appropriate response and depends critically on the prefrontal cortex. Performance on tests that are novel, complex, or timed steadily declines with advancing age, as does performance on tests that require inhibiting some responses but not others or involve distinguishing between relevant and irrelevant information. In addition, concept formation, abstraction, and mental flexibility decline with age, especially in subjects older than age 70. There are age-related declines in aspects of visuospatial processing and constructional praxis. Visual recognition of objects, shapes, gestures, and conventional signs remains stable into advanced age. However, visuoperceptual judgment and ability to perceive spatial orientation decline with age. A person's ability to copy a simple figure is not affected by age, but ability to copy a complex design declines with age. On standard IQ measures such as block design and object assembly, much of the declines with age are due to time, but when time is factored out, there are still declines in test performance with increasing age.

The Cryoprize Initiative

The Immortalist Society is one of the oldest of all cryonics groups, being originally founded back at the very start of the modern cryonics movement. The organization is presently seeking the funds to set up a research prize for technological progress in reversible organ cryopreservation. Research prizes are consistently shown to work pretty well when it comes to spurring investment and advancement in research and development, and for this particular technology it seems to be a good time for such an effort. You might look back at the Brain Preservation Prize competition that took place over the past few years to see how that worked to draw attention to the specific goals of the prize founders, and to improve the state of the art in cryopreservation. The intended goal for the Immortalist Society prize is plausible given the current state of work on cryopreservation techniques, a growing number of new entries into this research community, and the initial proof of principle demonstration of reversible cryopreservation of a rabbit kidney some years ago. Reversible cryopreservation for use in the organ transplant field is a gateway likely to lead to greater investment in cryonics technologies and greater acceptance of cryopreservation as a sensible end of life choice, given the lack of other options.

Currently there is a critically short window of time during which a donated organ remains viable, so distance and transport are major obstacles to treatment. Today an organ donor and a recipient must be matched immediately for any chance of a successful transplant. The challenges involved with matching a patient and a donor, relative to distances and timing, mean that thousands of potentially life-saving donor organs are unused every year. The Cryoprize is a grassroots initiative to solve these challenges and help these people get the life-saving treatment they need. Our goal is to encourage and reward the critical research needed to eliminate the current obstacles to successful organ transplants. Cryobiology, the science of preserving tissues and organs at ultra-low temperatures, can provide the solution. An organ successfully preserved by cryogenic means would remain viable indefinitely, eliminating the challenges of transport and distance. Permanent organ banks could be established, much the same as the blood banks hospitals rely on today.

The goal of the Cryoprize is to award a minimum of fifty thousand in prize money to any individual or group that is able to place one of several mammalian organs at cryogenic temperatures, transplant the organ into a mammalian animal for a period of at least nine months, and show, during that time period, proper clinical function of the organ. The organs in question are the heart, lung, kidney, liver and pancreas. The prize amount to be awarded has as an initial goal a minimum of 50,000, with the further goal that the prize grow to at least 1 million. The prize is sponsored by The Immortalist Society, a non-profit organization dedicated to longevity research and outreach. But we need your help to fund this initiative. Please donate today, in any amount, and help us save lives.

A Profile of Research into FGF21 in Aging and Thymic Function

This popular science article takes a look at one of the groups working on characterizing the role of FGF21 in aspects of aging. Genetic engineering to increase levels of FGF21 extends life in mice, and also improves the function of the thymus and thus the immune system, as the thymus is where some classes of immune cell mature after their creation in the bone marrow. FGF21 is also involved in the beneficial effects of calorie restriction on health and longevity, but there appear to be significant differences between mice and humans on this count - and there must be significant differences somewhere in the biochemistry of the calorie restriction response, as human life spans are nowhere near as plastic in response to circumstances and therapies as those of mice. Calorie restriction extends mouse life spans by as much as 40%, but certainly doesn't do that for people despite being very beneficial for health.

Most mice start showing signs of aging by 2 years old. These mice didn't. Instead they entered what should have been their twilight years with vigor, approaching their third birthday free of the disease and the decreased mobility expected in animals their age. In a laboratory setting, regular mice would have a life expectancy of around three years, but these mice lived much longer, almost four years. Their secret was a hormone called fibroblast growth factor-21 (FGF21) that has an extraordinary effect on the immune system. Beginning in 2007, researchers began studying the hormone and its effects on mice genetically engineered to produce more of it. In 2012, scientists published a study finding that the hormone increased the lifespan of mice by as much as 40 percent. Last January, it was shown that in addition to extending the life expectancy of mice, FGF21 protects against the loss of immune function that comes with age.

The research into FGF21 builds on previous studies showing that severely restricting food intake can extend the lifespan of several different animals. Increasing levels of FGF21, which is secreted by the liver during fasting and helps the body adapt to starvation, seems to provide the benefits of dieting without limiting food intake. FGF21 plays an important role in the thymus, a small organ located between the lungs that has an integral role in the immune system. When functioning properly, the thymus produces infection-fighting T cells, but as we age the thymus becomes fatty and stops producing T cells capable of fending off infection. As a result, the immune system is compromised, becoming more susceptible to both infection and certain forms of cancer. But increasing levels of FGF21 in the thymus fends off the organ's age-induced decline, allowing it to continue to produce T cells to battle infection.

The aging field in general has picked up over the last five to 10 years. "There's more people proposing work related to aging and definitely more funding. Normally you get a drug approved by the FDA to treat a disease. But this is different. You're not trying to slow the progression of disease. You're trying to slow the progression of aging, and aging is not a disease, so it's a different paradigm." The focus on this new paradigm comes from a growing realization in the scientific community that as we age, we become more susceptible to such a wide variety of diseases that developing effective treatments for aging itself might be something of a cure-all. "Aging is the biggest risk factor for chronic diseases. The association between aging and chronic disease is stronger than the association between smoking and lung cancer. So, if you understand what is happening during aging, how it is happening and what are the mechanisms, cellular and molecular, then we may be able to delay the onset of diseases like Alzheimer's, arthritis, diabetes, certain cancers, kidney disease, macular degeneration, you name it. All these diseases are all linked to aging. I think the question we are more interested in is not just longevity, but actually the health and lifespan. So that extension of lifespan is associated with reduction of morbidity, or a period of life where we are free of disability. That is the real goal. Nobody wants to live an additional 40 years in a bed."

Evidence for Serotonin Signaling to be Important in Calorie Restriction

Calorie restriction produces improved health and extended longevity in most species, with a much larger effect in short-lived species that tend to have very plastic life spans in response to circumstances. One of the many interesting results to emerge from calorie restriction research is that this effect on health and longevity can be manipulated by altering systems of perception, work that has largely been carried out in flies and nematodes. Calorie restriction effects can be reduced by exposing flies to the presence of more food without letting them eat it, for example, and tinkering with the sensory neurons responsible for identifying and characterizing food content can induce some of the effects of calorie restriction without reducing calorie intake. Researchers here link serotonin signaling with the mechanisms of food sensing, and show that disrupting it has a fairly sizable effect on fly life span under some dietary conditions:

Limiting the amount of protein eaten, while still eating enough to avoid starving, has an unexpected effect: it can slow down aging and extend the lifespan in many animals from flies to mice. Previous work suggests that how an animal perceives food can also influence how fast the animal ages. For example, both flies and worms actually have shorter lifespans if their food intake is reduced when they can still "smell" food in their environment. However, the sensory cues that trigger changes in lifespan and the molecular mechanisms behind these effects are largely unknown.

Researchers therefore asked whether fruit flies recognize protein in their food, and if so, whether such a recognition system would influence how the flies age. Flies that had been deprived of food for a brief period tended to eat more protein than other flies that had not been starved. The researchers then revealed that serotonin, a brain chemical that can alter the activity of nerve cells, plays a key role in how fruit flies decide to feed specifically on foods that contain protein. Further experiments revealed also that flies age faster when they are allowed to interact with protein in their diet independently from other nutrients, despite eating the same amount. Disrupting any of several components involved in serotonin signaling protected the flies from this effect and led to them living almost twice as long under these conditions.

Researchers propose that the components of the recognition system work together to determine the reward associated with consuming protein by enhancing how much an animal values the protein in its food. As such, it is this protein reward or value - rather than just eating protein itself - that influences how quickly the fly ages. Further work is now needed to understand how the brain mechanisms that allow animals to perceive and evaluate food act to control lifespan and aging.

Fatty Acid Metabolism and Age-Related Heart Failure

Researchers here propose that alterations in fatty acid metabolism in aged heart tissue make up one of the contributing factors to the age-related loss of function in the heart, a process that eventually leads to heart failure and death. As a mechanism this is is situated somewhere in the middle of the chain of cause and consequence that starts with molecular damage caused by the normal operation of metabolism, a sort of biological wear and tear, then passes through a complex series of reactions to that damage, some helpful and some harmful, and finally leads to functional failure in organs as the network of damage and consequences becomes too much.

Age-related cardiac dysfunction is a major factor in heart failure. The elderly accounts for at least 80% of patients with ischemic heart disease, 75% of patients with congestive heart failure, and 70% of patients with atrial fibrillation. Heart failure with either lower or preserved ejection fraction is common for hospitalized patients with cardiac abnormalities. Cardiac aging, which is evident in both humans and mice, plays an important role for both types of heart failure. Several components of cardiac function, including energetic homeostasis, adrenergic signaling, and mitochondrial dysfunction, can be compromised during aging. Balanced cardiac lipid metabolism is critical for normal function of the heart. Any deviation toward either increased or reduced fatty acid metabolism may be detrimental for cardiac function, primarily depending on the type of pathophysiological challenge. Aging-related cardiomyopathy has been associated with downregulation of peroxisome proliferator-activated receptor (PPAR)-α, which is a central regulator of cardiac fatty acid metabolism and cardiac lipid accumulation. Thus, impairment of fatty acid metabolism may at least partially account for the aggravation of cardiac function that occurs with aging.

The heart normally consumes a large amount of ATP in order to pump more than 7,000 liters of blood on a daily basis. For the production of ATP that is needed for this massive amount of work, the heart oxidizes fatty acids, glucose, lactate, ketone bodies, and amino acids as energy-providing substrates. Fatty acid oxidation (FAO) is a major component of the energy production process as it accounts for the generation of approximately 70% of cardiac ATP. FA utilization in healthy hearts is a complex process that includes several steps, including: FA uptake, transfer of fatty acids into the mitochondria, and oxidative phosphorylation for ATP production. The flawless transfer of fatty acids from cellular uptake to mitochondrial oxidation prevents accumulation of excess lipids. A study in humans showed that aging decreases myocardial FA utilization and FAO without any difference in myocardial glucose utilization. Several types of cardiac dysfunction are associated with impaired FAO, which frequently leads to lipid accumulation characterized as cardiac lipotoxicity.

Although cardiac toxic lipids have been associated with cardiac dysfunction, it has not been studied thoroughly whether they mediate aging-related cardiomyopathy, as well as what lipid-driven signaling mechanisms may be involved. Various studies have established a correlation between cardiac lipid accumulation and aging in humans and animal models. Several proteins of the energy production machinery that mediates processing of FAs and ATP production are regulated at the transcriptional level by PPARα. The importance of PPARα inhibition in accelerating cardiac aging was demonstrated in 20-month-old rats that were treated with the lipid lowering drug atorvastatin, which increases PPARα expression. The treatment with atorvastatin reduced cardiac hypertrophy, collagen deposition, oxidative stress, expression of inflammatory cytokines, and the aging marker β-galactosidase. Although reduced cardiac PPARα expression has been associated with aging-related cardiomyopathy, the underlying mechanisms that mediate the beneficial effect of PPARα have not been fully elucidated.

In summary, cardiac FAO is important for lipid metabolism homeostasis and normal cardiac function. Inhibition of FAO leads to increased cardiac lipid content, which is often accompanied by increased levels of toxic lipids. These lipids compromise cardiac function via β-adrenergic receptor desensitization, which is driven by activation of the protein kinase C signaling pathway. Aging-related cardiomyopathy is associated with reduced cardiac levels of PPARα, a master regulator of cardiac FAO, as well as with inhibition of β-adrenergic receptor signaling and mitochondrial dysfunction. These components of cardiac lipotoxicity that are also involved in cardiac aging indicate therapeutic targets that may alleviate age-related cardiomyopathy.

Reduced Age-Related Increase in Blood Pressure via Modulation of Vasoconstriction

The research linked here is an excellent example of the way in which most initiatives in medicine focus on compensatory adjustments to the disease state rather than on addressing root causes. The authors of this paper produce a beneficial reduction in age-related increase in blood pressure by altering the operation of vasoconstriction, an approach which does nothing at all to address the stiffening of blood vessel tissues that causes the high blood pressure of hypertension, and is therefore somewhat limited in the scope of improvements that it can produce. Even mild hypertension is so very damaging to health in old age that any approaches to safely reducing blood pressure should be celebrated, but nonetheless a research community that adopts a strategy of ignoring root causes is a research community that will continue to produce marginal therapies that can only modestly delay the inevitable results of aging. Only by repairing the root cause damage that results in age-related changes like arterial stiffening and hypertension can the length of healthy life be greatly extended, and age-related disease ended entirely.

Advancing age is a universal, potent, and currently un-modifiable risk factor for the development of hypertension and cardiovascular disease. Essential hypertension (high blood pressure (BP) without a secondary cause) is nearly an absolute consequence of aging in developed nations, affecting 60% of Americans over the age of 60 and 80% of the rapidly growing population over 80. Hypertension (HTN) is a substantial source of morbidity and mortality in the elderly, as high BP increases the risk of heart attack, stroke, vascular dementia, heart failure, kidney failure, and death. Despite this, only half of hypertensives over 50 years of age are controlled with current therapies.

The kidney is an established target of many antihypertensive therapies because it is a critical regulator of BP by modulating sodium and water balance. Perhaps less appreciated is the concept that in response to increases in blood volume from renal mechanisms and vasoconstrictor pathways that are enhanced with aging, smooth muscle cells (SMC) in the resistance vasculature constrict, thereby increasing peripheral vascular resistance and exacerbating hypertension. Thus, the vasculature is also an important contributor to the development of hypertension and to BP control. In humans and rodents, vascular aging is associated with enhanced vascular oxidative stress and increased responsiveness to the vasoconstrictor hormone angiotensin II (AngII) and these factors contribute to enhanced vasoconstriction with aging. However, the molecular mechanisms driving these vascular changes that contribute to hypertension with aging have not been elucidated.

Although the adrenal hormone aldosterone and its mineralocorticoid receptor (MR) are well known regulators of BP by promoting renal sodium reabsorption in the kidney, we previously demonstrated that MR is also expressed and functional in human vascular SMC. Moreover, we found that mice with MR specifically deleted from SMC in adulthood (SMC-MR-KO mice), are protected from the modest aging-associated rise in systolic BP that occurs in MR-intact mice, despite no change in renal function, sodium handling, or serum aldosterone levels. Rather, aged SMC-MR-KO mice had decreased vasoconstriction in response to increased intravascular pressure (termed myogenic tone) and were protected from AngII-induced vasoconstriction and vascular oxidative stress, important drivers of vascular dysfunction and hypertension with aging. Thus, the SMC-MR-KO mouse was used to explore mechanisms driving vasoconstriction with aging as these mechanisms may contribute to hypertension in elderly humans and could suggest new therapeutic strategies to improve BP control. We discovered that with aging, MR expression rises in resistance vessels along with a decline in microRNA (miR)-155 and increased expression of predicted miR-155 targets including the L-type calcium channel (LTCC) subunit Cav1.2 and the angiotensin type-1 receptor (AgtR1), genes that contribute to vasoconstriction and oxidative stress in aging mice. Restoration of miR-155 in aged vessels decreased target gene expression and vasoconstriction. Finally, in older humans, changes in miR-155 levels in response to MR antagonism correlated with improved BP response to therapy.

Overall, these data provide new insight into mechanisms driving vasoconstriction with aging that may contribute to the associated rise in BP. The data are consistent with the model in which enhanced SMC-MR expression and activity in aging resistance vessels suppresses vascular miR-155 transcription resulting in increased LTCC and AgtR1 expression. In this way, SMC-MR contributes to maintenance of myogenic tone and LTCC-induced constriction and primes the vasculature for enhanced AngII-induced oxidative stress and vasoconstriction, important components of the vascular aging phenotype that contributes to hypertension with aging. These results support the need for further studies in humans to determine if miR-155 could be a biomarker of MR activation in the setting of vascular aging with important implications for improving BP control in the rapidly aging population.

Less Growth Hormone in Long-Lived Families

That lower levels of growth hormone lead to greater longevity in short-lived mammals has been comprehensively established. The longest-lived genetically engineered mice are those in which the growth hormone activity has been suppressed in some way, such as via knockout of the growth hormone receptor. Short-lived species have far more plastic life spans than we do, however: the analogous population of humans with a growth hormone receptor mutation, those with Laron syndrome, certainly don't exhibit the same large increase in life span. So to what degree do natural variations in growth hormone activity impact human longevity? The open access paper here adds more data to the existing evidence:

Genetic disruption of the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway can delay aging and promote longevity in a wide variety of species. In mammalian species, growth hormone (GH) plays a pivotal role in the regulation of the IIS pathway and mutations affecting GH action have consistently been shown to alter lifespan. Increased longevity in mice can be induced by mutations that result in GH deficiency. However, little is known about how more subtle differences in GH/IGF-1 secretion would affect human longevity. Interestingly, female centenarians were found to be enriched for rare mutations causing slight IGF-1 resistance and resulting in a somewhat smaller stature. Likewise, we previously observed that a combination of polymorphisms in the GH/IIS pathway, linked to smaller stature in female octogenarians, was associated with better survival in old age. However, to the best of our knowledge, no study has assessed the association of human longevity with GH secretion.

GH secretion by somatotrophic cells in the anterior lobe of the pituitary gland is stimulated by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin, both produced by the hypothalamus. GH exerts its functions by binding to GH receptors located on tissue target cells. A key function of GH is to stimulate production of IGF-1 by the liver, which subsequently inhibits GH secretion via negative feedback. Circulating IGF-1 is mostly bound to binding proteins of which insulin-like growth factor binding protein 3 (IGFBP3) is the most abundant. The IGF-1/IGFBP3 molar ratio is considered an indicator of IGF-1 bioavailability. In humans, many other tissues besides the liver express GH receptors indicating that GH may exert effects independent from IGF-1. To identify determinants of human longevity, the Leiden Longevity Study (LLS) included offspring of long-lived families that are enriched for exceptional longevity and partners thereof, serving as a control group. Indeed, offspring were found to have less age-related diseases and reduced mortality compared with controls. Previously, no differences were observed between offspring and controls in circulating IGF-1 concentrations. However, the magnitude and control of GH secretion have not yet been studied in human familial longevity. Therefore, we aim in this study to compare GH secretion parameters and the strength of GH secretion control signals between offspring of long-lived families and age-matched controls.

The two main findings of this study are that GH secretion is lower and more tightly controlled in subjects enriched for familial longevity compared with age-matched controls. The observed association between reduced GH secretion and human familial longevity is in line with experimental studies in mice, which found that reduced GH action resulted in extended health and lifespans. Our results implicate the highly conserved GH/IGF-1 signaling pathway, which has been linked to delayed aging and longevity in numerous animal models, is also linked to human longevity. The observed differences in GH secretion between offspring and controls can probably not be explained by a faster clearance of GH from the blood, as the slow half-life was comparable between groups. We hypothesize that the offspring are therefore more efficient in regulating the magnitude and the timing of GH secretion. Our data strengthen the hypothesis that GH/IGF-1 signaling is a conserved mechanism implicated in mammalian longevity.


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