Fight Aging!

We stand at a very interesting juncture in the ongoing development of medicine, travel, and communication. The world is becoming a small place, in which geographically dispersed interest groups can find one another, talk, and organize. The cost of either a round trip by air to a different continent or a cruise that covers a dozen countries is considerably less than the cost of many of the new classes of stem cell therapy or gene therapy. These treatments have been or soon will be available via medical tourism. They are not available or are only just starting to become available in countries such as the US due to the incredible cost and time required to comply with US regulatory requirements in comparison to those elsewhere. Stem cell treatments were the important class of new treatment available via medical tourism over the past decade and in the decade to come will be joined by elective gene therapies, such as myostatin knockout for muscle growth. You'll recall that the analogous follistatin gene therapy was undertaken in an overseas clinic as a proof of concept by the CEO of startup BioViva not so long ago. In a year or two anyone with the money and the insider connections will be able to do the same, and five years from now a competitive international marketplace will offer this gene therapy at a comparatively low cost.

The next decade of therapies available via medical tourism will also include the first narrowly focused rejuvenation therapies. Those already technically possible include the senescent cell clearance approach of Oisin Biotechnologies and the transthyretin amyloid clearance trialed by Pentraxin and GlaxoSmithKline. I expect to see these joined by glucosepane cross-link clearance and perhaps allotopic expression of all mitochondrial genes in the years ahead. Senescent cell clearance is certainly very close, close enough, I think, to that we should be planning how we can help to place these therapies into clinics as soon as possible.

I put down a few thoughts on this topic earlier in the month, focused on how rejuvenation therapies might follow the trail blazed by the stem cell research and development community fifteen years ago, producing widespread and cost-effective availability of treatments - and data on patient outcomes - long before regulators in the US were willing to approve these therapies. Today I'll talk about a different approach to gaining access to therapies for early adopters, one that looks a lot like the organization of group buys or vacations. If you look at what BioViva organized for one person's gene therapy, it is fairly easy to imagine organizing it for a dozen people willing to put up $20,000 and fly to the very same clinic to undertake the very same treatment on the same day. Or get on a cruise and head out to international waters with a staffed clinic on board. The economics will scale as the number of people involved grows: if we can organize a conference in which hundred of people fly to a distant city, or if the "anti-aging" marketplace can organize their large conferences, can we not also organize a hundred people paying $10,000 for a myostatin gene therapy or for the Oisin Biotechnologies senescent cell clearance technology? At that scale, the potential revenue per event becomes large enough to make this worth trying for a startup company - it is comparable to the size of early fundraising rounds.

Of course you or I can't just call up a hundred people and get them on board for a five figure payment and a trip on a given date, for all that I'm very certain that a hundred people in our extended community are up for early access to gene therapy or senescent cell clearance. Gathering this crowd, both for the first time and for later organized medical tourism group buys, would require a small organization devoted to the purpose: web site, a phone line, outreach, marketing, staff to do the work implied by all of the above, and so forth. Fortunately there is no shortage of small organizations in our neck of the woods, and one might reasonably expect advocates to create another if none of the existing groups wanted to take this on. This sounds like a good fit for Lifespan.io or Longecity, for example, if they chose to head in that direction. The entrepreneurs at either BioViva or Oisin Biotechnologies should certainly consider playing their parts in such a plan if provided solid evidence that the market is there and people are willing to pay.

How do you prove a market? Well, the traditional method is that you register an organization, put up a website and phone line, and collect expressions of interest of one form or another: people willing to sign up, people willing to put down a refundable deposit, that sort of thing. If you have a few hundred people willing to do this, well: there you go. Companies have been launched with less proof. This is not to say that I think this will all be straightforward and smooth sailing. Ask anyone who organizes conferences for a living about the challenges inherent in putting a few hundred people in one distant building at one given time. Or ask a cruise line operator about the analogous portions of their business. That said, group buys, medical tourism, and group vacations such as cruises are all established practices. There are people who know how to run these things, and none of the potential problems are surprises in and of themselves. This seems to me a logical evolution of the present medical tourism industry. It doesn't exist today because the sort of treatments that people travel to undertake are highly individual. But given the advent of enhancement and rejuvenation therapies that everyone can benefit from, a whole different dynamic emerges.

So for the community at large, as we ask ourselves how we can best help the rapid development and clinical availability of rejuvenation therapies, I think that the approach I sketched here is worth thinking on. It is something that many of us could help bring about: few specialized skills are required for the mundane tasks of advocacy or assembling an organization to put together group buys. Many of us could help in meaningful ways, and a great many people are motivated to bring about the end result, including those who are presently working on the biotechnology side of the house.

Many groups are working to advance the state of the art in bioprinting, seeking to engineer simpler tissue structures using a printed scaffold and cells cultured from a patient tissue sample. This example is focused on dental reconstruction:

The team are using the latest 3D bioprinting to produce new, totally 'bespoke,' tissue engineered bone and gum that can be implanted into a patient's jawbone. The approach begins with a scan of the affected jaw, prior to the design of a replacement part using computer-assisted design. A specialised bioprinter, which is set at the correct physiological temperature (in order to avoid destroying cells and proteins) is then able to successfully fabricate the gum structures that have been lost to disease - bone, ligament and tooth cementum - in one single process. The cells, the extracellular matrix and other components that make up the bone and gum tissue are all included in the construct and can be manufactured to exactly fit the missing bone and gum for a particular individual.

In the case of people with missing teeth who have lost a lot of jawbone due to disease or trauma, they would usually have these replaced with dental implants. However, in many cases there is not enough bone for dental implant placement, and bone grafts are usually taken from another part of the body, usually their jaw, but occasionally it has to be obtained from their hip or skull. These procedures are often associated with significant pain, nerve damage and postoperative swelling, as well as extended time off work for the patient. In addition, this bone is limited in quantity. By using this sophisticated tissue engineering approach, researchers can instigate a much less invasive method of bone replacement. A big benefit for the patient is that the risks of complications using this method will be significantly lower because bone doesn't need to be removed from elsewhere in the body. The approach also bypasses the problem of limited supply when using the patient's own bone. Currently in pre-clinical trials, the aim is to trial the new technology in humans within the next one to two years.

Link: https://app.secure.griffith.edu.au/news/2016/03/30/griffith-uses-3d-tissue-engineering-to-revolutionise-dental-disease/

Bacteriophages, or simply phages, are viruses that infect bacteria. This article covers the lengthy process of turning a serendipitous discovery, that a particular phage can dissolve the amyloids and other aggregates involved in neurodegenerative conditions, into a drug candidate. It demonstrates well why medical development takes a long time, more than a decade so far in this case even prior to entering the regulatory process. Each step in the process can take years to work through, funding is ever a problem, and there are frequent delays and dead ends.

In 2004, researchers were running an experiment on a group of mice that had been genetically engineered to develop Alzheimer's disease plaques in their brains. They wanted to see if human-made antibodies delivered through the animals' nasal passages would penetrate the blood-brain barrier and dissolve the amyloid-beta plaques in their brains. Seeking a way to get more antibodies into the brain, she decided to attach them to M13 phages in the hope that the two acting in concert would better penetrate the blood-brain barrier. As a scientific control, one group received the plain phage M13. Because M13 cannot infect any organism except E. coli, it was expected that the control group of mice would get absolutely no benefit from the phage. But, surprisingly, the phage by itself proved highly effective at dissolving amyloid-beta plaques and in laboratory tests improved the cognition and sense of smell of the mice.

In 2007, with $150,000 in seed money, a new venture, NeuroPhage Pharmaceuticals, was born. After negotiating a license to explore M13's therapeutic properties, the founders reached out to investors willing to bet on M13's potential therapeutic powers. By January 2008, they had raised over $7 million and started hiring staff. Over the next two years, researchers then discovered something totally unexpected: that the humble M13 virus could also dissolve other amyloid aggregates - the tau tangles found in Alzheimer's and also the amyloid plaques associated with other diseases, including alpha-synuclein (Parkinson's), huntingtin (Huntington's disease), and superoxide dismutase (amyotrophic lateral sclerosis). This was demonstrated first in test tubes and then in a series of animal experiments. This phage's unique capacity to attack multiple targets attracted new investors in a second round of financing in 2010.

Their therapeutic product, a live virus, it turned out, was very difficult to manufacture. It was also not clear how sufficient quantities of viral particles could be delivered to human beings. In 2010, researchers were able to figure out that the phage's special abilities involved a set of proteins displayed on the tip of the virus, called GP3. The phage's normal mode of operation in nature was to deploy the tip proteins as molecular keys; the keys in effect enabled the parasite to "unlock" bacteria and inject its DNA. Sometime in 2011, the researchers became convinced that the phage was doing something similar when it bound to toxic amyloid aggregates.

Over the next two years, NeuroPhage's scientists engineered a new antibody (a so-called fusion protein because it is made up of genetic material from different sources) that displayed the critical GP3 protein on its surface so that, like the phage, it could dissolve amyloid plaques. By 2013, NeuroPhage's researchers had tested the new compound, which they called NPT088, in test tubes and in animals, including nonhuman primates. It performed spectacularly, simultaneously targeting multiple misfolded proteins such as amyloid beta, tau, and alpha-synuclein at various stages of amyloid assembly. According to Fisher, NPT088 didn't stick to normally folded individual proteins; it left normal alpha-synuclein alone. It stuck only to misfolded proteins, not just dissolving them directly, but also blocking their prion-like transmission from cell to cell.

There was a buzz of excitement in the air at NeuroPhage's offices in the summer of 2014. The 18 staff were hopeful that their new discovery, which they called the general amyloid interaction motif, or GAIM, platform, might change history. Will it work in humans? While NPT088, being made up of large molecules, is relatively poor at penetrating the blood-brain barrier, the medicine persists in the body for several weeks, and so the researchers estimates that over time enough gets into the brain to effectively take out plaques. The concept is that this antibody could be administered to patients once or twice a month by intravenous infusion for as long as necessary. NeuroPhage must now navigate the FDA's regulatory system and demonstrate that its product is safe and effective. So far, NPT088 has proved safe in nonhuman primates. But the big test will be the phase 1A trial expected to be under way this year. This first human study proposed is a single-dose trial to look for any adverse effects in healthy volunteers. If all goes well, NeuroPhage will launch a phase 1B study involving some 50 patients with Alzheimer's to demonstrate proof of the drug's activity.

Link: http://www.pbs.org/wgbh/nova/next/body/phage-alzheimers-cure/

Below you'll find links to a selection of recent papers and research publicity materials on exercise in the context of aging. Regular moderate exercise is a good plan, the standard issue thirty minutes to an hour a day on most days of the week that is put forward by the experts. Human statistical studies show strong correlations between moderate exercise, a lower incidence of age-related disease, and three to seven years of additional life expectancy. The corresponding animal studies show causation between exercise, health, and longevity, providing solid evidence for exercise to produce these benefits. Of course a piano could tomorrow fall upon even the most health conscious of us, but this is a game of weighting the odds in your favor, and not one of absolute outcomes.

Over the long term, regular exercise can do things for us that no medical technology can presently reproduce. This is a disappointing state of affairs, given that we are in the midst of a revolution in the capabilities of biotechnology, but the dominion of exercise will be slowly gnawed away in the years ahead, its benefits reproduced by medicine. As a first step, we might look at gene therapies and inhibitors to block myostatin for example, approaches that produce a gain in muscle tissue without the need to work for it. That will certainly be useful as a way to compensate for the progressive loss of muscle mass and strength that occurs in aging. Most of the benefits of exercise are more subtle and complex than this, however, involving poorly understood shifts in the operation of cellular metabolism. We might look back at the expensive and so far futile history of research aimed at calorie restriction mimetic drugs to see a preview of future efforts to produce exercise mimetic drugs. Safely adjusting metabolism into even well-known and well-cataloged states is a challenge.

In the long run, the important research in aging has little to do with exercise, however. You can't exercise your way to 100, or even 90 with any reliability. Three quarters of the population, including most of those with the best health, are dead before they see their 90s. Good health practices such as exercise just tend to make the decline somewhat less terrible. The only way to avoid the same trajectory of aging suffered by all of your ancestors is through the development of treatments that can repair the root causes of aging, many of which are actually modestly slowed by exercise: stem cell decline, mitochondrial damage, cellular senescence, metabolic waste products such as lipofusin, amyloids, and cross-links. The difference between modest slowing and actual repair is night and day. Sufficiently comprehensive repair creates rejuvenation, a life of health and vigor for as long as you desire, as the treatment can be repeated as needed. Just when these therapies will arrive is another game of odds: we can help to speed things up in many ways, but it happens when it happens. That we are not there yet is why exercise remains just as important as it ever was, and possibly more so now that it can weight the odds a little towards living long enough to benefit from the first rejuvenation treatments.

Exercise Keeps Muscles - And You - Young

The study compared world-class track and field athletes in their 80s with people of the same age who are living independently. There have been few such studies of aging and muscle weakening in masters athletes in this age group. The study found that athletes' legs were 25 per cent stronger on average and had about 14 per cent more total muscle mass. In addition, the athletes had nearly one-third more motor units in their leg muscles than non-athletes. More motor units, consisting of nerve and muscle fibres, mean more muscle mass and subsequently greater strength. With normal aging, the nervous system lose motor neurons, leading to a loss of motor units, reduced muscle mass, less strength, speed and power. That process speeds up substantially past age 60.

A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia

Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motor neuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.

Serum Klotho Levels in Trained Athletes

Klotho is an anti-aging protein that is predominantly secreted by the kidneys. The aim of the study was to measure and compare the circulating Klotho levels in the serum of trained athletes and in healthy, non-athlete controls. Thirty trained football players were enrolled and their serum Klotho levels were measured the morning after their last evening exercise training. The plasma free Klotho concentration was significantly higher in the athlete group compared to the non-athletes. Regular aerobic exercise could increase plasma Klotho levels, and this could be an explanation for exercise-related anti-aging effects.

An Acute Bout of Exercise Improves the Cognitive Performance of Older Adults

There is evidence that an acute bout of exercise confers cognitive benefits, but it is largely unknown what the optimal mode and duration of exercise is and how cognitive performance changes over time after exercise. We compared the cognitive performance of 31 older adults using the Stroop test before, immediately after, and at 30 and 60 minutes after a 10 and 30 minute aerobic or resistance exercise session. Heart rate and feelings of arousal were also measured before, during and after exercise. We found that independent of mode or duration of exercise, the participants improved in the Stroop Inhibition task immediately post-exercise. We did not find the exercise influenced the performance of the Stroop Color or Stroop Word Interference tasks. Our findings suggest that an acute bout of exercise can improve cognitive performance, and in particular the more complex executive functioning, of older adults.

Regular physical activity and vascular aging

Aging and low physical activity are associated with the development of diseases (hypertension, type 2 diabetes, dyslipidemia, obesity) marked by chronic low-grade inflammation. Cardiovascular disease is the most common cause of death worldwide, while exercising muscle tissue can increase the secretion of myokines that can reestablish a possible inflammatory process in virtue of the anti-inflammatory effect. The objective of this review is to focus on molecular mechanisms involved between different kinds of exercise and cellular oxidative stress, and the emerging therapeutic strategies which have the potential to promote benefits in vascular health.

Regular exercise increases shear stress, mitochondrial biogenesis, and upregulates mitochondrial antioxidant system, inducing anti-inflammatory actions, such as suppression of TNF-α which may offer protection against TNF-α-induced vascular impairment. Exercise training of various durations and intensities appears to prevent and restore the age-related impairment of endothelial function, likely through the restoration of nitric oxide availability, reduction in oxidative stress, and turnover of the apoptotic process in the endothelium, thus minimizing vascular inflammation and decreasing the formation of atherosclerotic plaques.

Exercise training as a drug to treat age associated frailty

Exercise causes an increase in the production of free radicals. As a result of a hormetic mechanism antioxidant enzymes are synthesized and the cells are protected against further oxidative stress. Thus, exercise can be considered as an antioxidant. Age-associated frailty is a major medical and social concern as it can easily lead to dependency. In this review we describe that oxidative stress is associated with frailty and the mechanism by which exercise prevents age-associated frailty. We propose that individually tailored multicomponent exercise programmes are one of the best ways to prevent and to treat age-associated frailty.

In the paper linked here, researchers catalog some of the harm done by age-related modifications to the collagen molecules of the extracellular matrix, with particular attention given to bone. The extracellular matrix is constructed by cells, and its intricate molecular structure, largely consisting of forms of collagen, determines the properties of that tissue: elasticity in skin, for example, or ability to bear load in bone. Chemical modifications to collagen molecules, especially cross-linking by advanced glycation end-products in which different molecules are chained together, disrupt the physical and structural properties of the matrix. This is one of the causes of age-related loss of elasticity in skin and blood vessels, for example, the second of which is ultimately fatal. In principle all of these causes can be reversed and addressed: chemical bonds can be broken, cross-links attacked and disassembled with designed drugs. This is still a work in progress, however, in need of greater support and funding.

During aging, changes occur in the collagen network that contribute to various pathological phenotypes in the skeletal, vascular, and pulmonary systems. The aim of this study was to investigate the consequences of age-related modifications on the mechanical stability and in vitro proteolytic degradation of type I collagen. Analyzing mouse tail and bovine bone collagen, we found that collagen at both fibril and fiber levels varies in rigidity and Young's modulus due to different physiological changes, which correlate with changes in cathepsin K (CatK)-mediated degradation.

A decreased susceptibility to CatK-mediated hydrolysis of fibrillar collagen was observed following mineralization and advanced glycation end product-associated modification. However, aging of bone increased CatK-mediated osteoclastic resorption by ∼27%, and negligible resorption was observed when osteoclasts were cultured on mineral-deficient bone. We observed significant differences in the excavations generated by osteoclasts and C-terminal telopeptide release during bone resorption under distinct conditions. Our data indicate that modification of collagen compromises its biomechanical integrity and affects CatK-mediated degradation both in bone and tissue, thus contributing to our understanding of extracellular matrix aging.

Link: http://dx.doi.org/10.1074/jbc.M115.644310

Researchers here put forward evidence for reduced levels of FK506-binding protein 12.6/1b (FKBP1b) to be a proximate cause of age-related dsyregulation in calcium (Ca2+) signaling in the brain, which is itself both associated with and a possible cause of cognitive decline. The researchers reversed this decline with gene therapy in old rats and observed resulting improvements in specific measures of cognitive function:

Brain Ca2+ regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca2+-dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca2+ channel activity and ryanodine receptor (RyR)-mediated Ca2+ release, but underlying molecular mechanisms are poorly understood. Previously, we found that expression of the gene encoding FKBP1b, a small immunophilin that stabilizes RyR-mediated Ca2+ release in cardiomyocytes, declines in hippocampus of aged rats and Alzheimer's disease subjects. Additionally, knockdown/disruption of hippocampal FKBP1b in young rats augments neuronal Ca2+ responses. Here, we test the hypothesis that declining FKBP1b underlies aging-related hippocampal Ca2+ dysregulation.

Using microinjection of adeno-associated viral vector bearing a transgene encoding FKBP1b into the hippocampus of aged male rats, we assessed the critical prediction that overexpressing FKBP1b should reverse Ca2+-mediated manifestations of brain aging. Immunohistochemistry and qRT-PCR confirmed hippocampal FKBP1b overexpression 4-6 weeks after injection. Compared to aged vector controls, aged rats overexpressing FKBP1b showed dramatic enhancement of spatial memory, which correlated with marked reduction of sAHP magnitude. Furthermore, simultaneous electrophysiological recording and Ca2+ imaging in hippocampal neurons revealed that the sAHP reduction was associated with a decrease in parallel RyR-mediated Ca2+ transients. Thus, hippocampal FKBP1b overexpression reversed key aspects of Ca2+ dysregulation and cognitive impairment in aging rats, supporting the novel hypothesis that declining FKBP1b is a molecular mechanism underlying aging-related Ca2+ dysregulation and unhealthy brain aging and pointing to FKBP1b as a potential therapeutic target.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518058/

Today I'll point out an open access theory of aging paper that I found intriguing, given that it represents a fairly different viewpoint on aging, seemingly assembled from portions of other mainstream views on theories of aging. Almost every faction within the aging research community would find parts to agree with, parts to reject, and parts that will make you think things through. If you have strong opinions on theories of aging, you'll probably get a lot out of it. The contents defy short summary, but the more important points seem to be the idea of aging as an absence of process, as a lack of maintenance systems, and a rejection of the idea that the fundamental mechanisms of aging are as universal as the present mainstream consider them to be.

I've made the point in the past that lack of progress towards effective treatments on the part of the dominant paradigm in a field of medicine tends to lead to a lot of alternative, competing theorizing. It is much cheaper and easier to produce hypotheses than to undertake research programs and trials. Aging research has been stuck in this state for quite some time now, and, since the molecular biology associated with the progression of aging is immensely complex and poorly understood, there is a lot of room for theories to flourish without the possibility of effective contradiction. Cellular metabolism is in and of itself immensely complex and incompletely understood, and the effects of aging at the detail level are a large superset of all aspects of cellular metabolism, extending out to include the ways in which this intricate group of systems changes over time. So, and in recent years especially, there has been a great mixing and seeding of ideas when it comes to the fundamental level of theory regarding aging, and little ability to cull the field with clear and direct evidence.

The vast complexity of our biology, and the equally vast cost in time and money required to map it or manipulate it, is what makes the SENS damage repair approach to rejuvenation treatments very attractive. For all that the progression of aging is yet to be mapped in detail at the cellular level, for the reasons given above, the research community does have a good understanding and a good, defensible list of the causes of aging. This knowledge is complete enough to design and build effective treatments to block, repair, or reverse those causes, and those plans and research programs exist. Taking this path is comparatively cheap, in comparison to trying to understand or manipulate the operation of cellular metabolism, and effectiveness can be proven by building and testing. It is an end-run around gaps in knowledge and the expense required to fill them, taking the engineering approach to the problem. In fact, I see this as the most cost-effective path forward to determining the relevance of various theories of aging, and to answering many questions on the role of specific mechanisms in cellular biology in aging.

Given that we have the potential to address aging, to intervene effectively and extend life, I think that more important as a goal than theorizing. There is more to learn and more to gain by taking action in the present state of aging research, by building the comparatively cheap first wave of rejuvenation biotechnologies such as senescent cell clearance treatments, and then evaluating their effects. I think the character of the field of aging research is going to change dramatically in the years ahead as a result of the advent of SENS-style rejuvenation therapies. Theorizing will decline in favor of discovery and evaluation, with directions for research following on from the most effective therapies and their impact on metabolism. For now, however, on with the theorizing, and note that the quotes below are only small sections of a long but very readable paper:

Principles of alternative gerontology

Damage itself does not mean aging. Senescence is observed only if the effects of these negative events have not been eliminated. One can conclude, therefore, that senescence takes place only if allowed by low effectiveness of life programs of a particular organism. In other words, senescence is a result of allowing for manifestation of unavoidable effects of various adverse forces. As shown below, the degree of that allowance is different in various clades. Considering that the same forces can disrupt various organismal functions in varying ways depending on a particular organism, no universal mechanism of aging can exist. For example, oxidative damage to cells of Saccharomyces cerevisiae does not include various destructive processes resulting from peroxidation of polyunsaturated fatty acids, as the latter are not produced by the species. On the other hand, accumulation of rDNA circles noted in yeast is not found in human cells where an open mitosis process is observed.

Aging is not a genuine trait. Aging evolved only as a side effect of the choice of a particular life strategy of a clade. As such, it corresponds perfectly to the term "spandrel" introduced by Gould and Lewontin. With that in mind, gerontologists would be amiss to look for any universal mechanisms of aging because they simply do not exist. As a rational consequence, in order to explain the mechanisms of human aging, it is necessary to use the closest possible relatives of human beings as model organisms of gerontology. Accepting the interpretation that the incidence and nature of aging processes are side effects of the chosen life strategies rather than genuine traits suggests the need to transform the methodological approach to the phenomenon.

The problem of aging of animals practically does not exist in natural populations. Animals in the wild rarely survive until the symptoms of senescence become visible. As a biological science, gerontology is now strongly supported not so much for transcendental reasons, but rather because the age structure of the developed societies will soon create economic and social problems. The most important goal for such studies is to diminish the costs of population aging. Geriatrics needs a scientific basis for improving medical practice. Consequently, the aim of gerontology is to prevent the most life-devastating symptoms of senescence. Therefore, the basic role of gerontology, at least in the short term, should be identifying mechanisms that slow down and minimise the effects of senescence. In other words, the role of gerontology is not to extend the maximum lifespan above the limit characteristic for the given species. However, rather disappointingly, this is precisely what experimental gerontologists have been doing: rather than looking for mutants of various organisms in which the symptoms of senescence appear later or are less detrimental, they have been mainly looking for mutants with increased lifespan.

In human beings the term "aging" means appearance of symptoms of senescence and increased probability of death at advancing age. However, after an analysis of various life forms, one can conclude that senescence and unavoidability of death in general are at least partly separable in mortal organisms, while numerous groups of simpler animals are biologically immortal. The phenomenon of senescence is observed in those species or life stages of organisms that cannot by principle remove the damage done by various adverse extrinsic and intrinsic forces. An analysis of differences in life programs among various taxonomic groups of animals as well as within a particular group allows for a generalisation that there are three main aging phenotypes.

The first encompasses representatives of the simplest animals like sponges, cnidarians, annelids, nemerteans or echinoderms that show biological immortality, that is, lack of intrinsic causes of death. These animals rarely manifest symptoms of senescence. The reason for their immortality is the ability to reproduce agametically (besides sexually), resulting from the enormous ability of cell replacement and regeneration. The second group is represented by the organisms which, while being mortal, show no visible symptoms of senescence. This phenotype is a consequence of the constant increase in body size after reaching sexual maturity. Because proportional growth requires constant availability of most of organismal-level developmental programs, such constant growth is accompanied by high cell replacement and regeneration ability. The best known representatives of that group are crustaceans and molluscs among invertebrates and fish and reptiles among vertebrates. Constant growth corresponds to the adolescence period of mammals or larval stages of insects as these animals do not show organismal-level senescence. Consequently, continuously growing animals are "young forever". The third and very diverse group is represented by insects and roundworms among invertebrates and mammals and birds among vertebrates. These animals show evident symptoms of senescence but differ in longevity. Their adult representatives live for a very short time. The presence of symptoms of senescence in these animals results from their primary life programs. Their sensecence is a consequence of the lack of, or very limited, cell replacement and regeneration mechanisms.

The practical conclusion that can be drawn from these considerations is that lack of universality of aging suggests a fundamental change in approach to gerontological problems. Instead of looking for mutants of simple and evolutionarily distant species with increased lifespans, gerontology should focus on finding factors alleviating the most life-disrupting effects of senescence.

This article notes evidence for age-related arterial stiffening to start in mid-life and be correlated with damage in the brain, due to structural failure of small blood vessels, even at that age. Arterial stiffness is argued to cause hypertension, increased blood pressure that only aggravates the tendency for blood vessel failure in the brain and elsewhere. Given the realization of therapies that can address the causes of arterial stiffening, such as clearance of cross-links in blood vessel walls, everyone over the age of 30 should be treated every few years. Some of those therapies are a few years away from prototypes given sufficient funding, but funding for rejuvenation research is ever an issue.

A large, multicenter study led for the first time has shown that people as young as their 40s have stiffening of the arteries that is associated with subtle structural damage to the brain that is implicated in cognitive decline and Alzheimer's disease later in life. The study found that, among young healthy adults, higher aortic "stiffness" was associated with reduced white matter volume and decreased integrity of the gray matter, and in ages much younger than previously described. "This study shows for the first time that increasing arterial stiffness is detrimental to the brain, and that increasing stiffness and brain injury begin in early middle life, before we commonly think of prevalent diseases such as atherosclerosis, coronary artery disease or stroke having an impact."

The study also noted that elevated arterial stiffness is the earliest manifestation of systolic hypertension. The large study involved approximately 1,900 diverse participants in the Framingham Heart Study, who underwent brain magnetic resonance imaging (MRI), as well as arterial tonometry. The tests measured the force of arterial blood flow, the carotid femoral pulse wave velocity or CFPWV - the reference standard for noninvasive measurement of aortic stiffness - and its association with subtle injury to the brain's white and gray matter. The research found that increased CFPWV was associated with greater injury to the brain. The reasons this is so are complex, and more study is needed. However, with age high blood pressure causes the arteries to stiffen, further increasing blood pressure as well as increasing calcium and collagen deposits, which promotes atrophy, inflammation and further stiffening, decreasing blood flow to vital organs including the brain and promoting brain atrophy. "Our results emphasize the need for primary and secondary prevention of vascular stiffness and remodeling as a way to protect brain health."

Link: http://www.ucdmc.ucdavis.edu/publish/news/newsroom/10911

There is little to disagree with in Ray Kurzweil's futurism when presented in this brief way, though here he glosses over the difference between medicine that reduces mortality in the young, the cause of most historical increases in life expectancy, and medicine that reduces mortality in the old, which is still a comparatively recent development. That aside, I think most of the disagreement tends to be over details and timelines. Our future is one of great longevity and transcendence of many present limits on the human condition, largely enabled by the merging of technology and biology at the nanoscale, and later by the wholesale replacement of biology with more robust entirely artificial systems. We will be able to replicate the processes of intelligence in machinery, and that capability will be applied in ways that not all of us will want to embrace. This vision doesn't seem terribly controversial in these very early stages of the process, in which there are many ongoing examples of work on rejuvenation therapies, bioartificial tissues, gene editing, and deciphering the physical basis of the brain.

Our immediate reaction to death is that it's a tragedy. And that's really the correct reaction. We have rationalized it, saying, oh, that tragic thing that's looming, that's actually a good thing. But now we can actually seriously talk about a scenario where we will be able to extend our longevity indefinitely.

This little computer is billions of times more powerful per dollar than the computer I used when I was an undergraduate. We will do that again in the next 25 years. And we will have computers the size of blood cells, little robotic devices that can go through our bloodstream, its capability thousands or millions-fold by connecting to the cloud. That's a 2030s scenario.

We have been expanding our life expectancy for thousands of years. It was 19 1,000 years ago, 37 in 1800. We're going to get to a point 10, 15 years from now where we're adding more time than is going by to our remaining life expectancy. People say, oh, I don't want to live past 90, but, you know, I talk to 90-year-olds, and they definitely want to live to 91 and to 100. People sometimes say that death gives meaning to life because it makes time short, but, actually, death is a great robber of meaning, of relationships, of knowledge.

We're going to be able to overcome disease and aging. Most of our thinking will be nonbiological. That will be backed up, so part of it gets wipes away, you can recreate it. And we will be able to extend our lives indefinitely. I would rather use that word than forever.

Link: http://www.pbs.org/newshour/bb/inventor-ray-kurzweil-sees-immortality-in-our-future/

In the paper I'll point out today, researchers propose a novel mechanism by which fat tissue produces inflammation, involving the effects of DNA fragments released from the debris of dying cells. The presence of extracellular DNA increases with age, and this phenomenon is attracting more attention in the research community. Is it a fundamental form of age-related damage, or can it be considered secondary to other forms of damage, such as those that tend to produce more dysfunctional, dying cells? That is an open question for now.

It is well known that the presence of excess visceral fat tissue, found packed around the abdominal organs, causes a significant increase in chronic inflammation, over and above the age-related inflammatory state produced by the progressive dysfunction of the immune system. Subcutaneous fat is more benign, but even a small amount of excess fat in exactly the wrong place can cause grave consequences. You might recall the evidence for type 2 diabetes to result from a tiny excess of fat in the pancreas - but in normal circumstances, a large amount of surrounding visceral fat is required to create the metabolic dysfunction that allows that tiny but critical amount of pancreatic fat to come into being.

Chronic inflammation is a serious concern when considering its effects of the span of years. It speeds and worsens the development of near all of the common fatal age-related conditions. The effect is large enough that surgical removal of visceral fat extends healthy life in rats, though not by as much as is seen in the calorie restricted rats who never put on that fat in the first place. This is mirrored in human studies showing statistical effects on life expectancy and disease risk in people who were overweight at any point in their lives. Consequences scale by the degree of excess fat, and the time is is carried. The generation of inflammation by fat tissue appears to be one of the more important drivers of the well-documented association in human populations between fat tissue and mortality.

How does visceral fat tissue generate inflammation? The paper here outlines one mechanism. Other researchers point to the false distress signals released by fat cells in overweight individuals that cause the immune system to constantly overreact. An older view is that fat cells become overburdened and die in an environment of overnutrition, and this is enough to draw in the immune system and make it overactive, spurring inflammation. There are numerous other explorations of the precise details of the links between overnutrition and immune system misbehavior. The bottom line is that there is unlikely to be just one mechanism or group of mechanisms responsible for the chronic inflammation resulting from fat tissue. Few things in biology are simple or run along just one track. Still, however many mechanisms there are, known or unknown, they can't significantly harm you if you don't get fat, and they can't harm you any more than they already have if you lose the excess visceral fat you are presently carrying around. Food for thought.

Adipocyte-Derived DNA Triggers Inflammation

Dying fat cells in obese mice release cell-free DNA, recruiting immune cells that can drive chronic inflammation and insulin resistance within adipose tissue. The observed accumulation of macrophages in murine fat tissue depended on the expression of Toll-like receptor 9 (TLR9). Obese mice missing TLR9 had fewer macrophages and were more insulin sensitive compared to their TLR9-expressing counterparts. The new work may partly explain how obesity can drive chronic inflammation.

Because prior observational studies have shown that fat cells degenerate in obese individuals, researchers investigated whether obese mice fed a high-fat diet had higher levels of cell-free DNA - shed from the dying fat cells - compared to non-obese mice fed a standard diet. The researchers found higher levels of both double- and single-stranded DNA (ssDNA) as well as increases in cell-free ssDNA that were proportional to increases in visceral fat and blood glucose levels in the obese mice compared to controls. Notably, the ssDNA accumulated in adipose tissue macrophages in obese mice, but not in lean mice.

The team focused on TLR9 because it is expressed in several types of immune cells, binds to exogenous DNA, and has been implicated in the development of several inflammation-associated diseases. Recent studies also revealed that TLR9 can recognize DNA fragments released from degenerated or damaged cells and organs. Consumption of a high-fat diet increased the expression of Tlr9 in visceral fat of the obese mice, particularly in the macrophages within the adipose tissue. Using cultured wild-type macrophages or those that did not express TLR9, the researchers demonstrated that TLR9 is activated by cell-free DNA from dying adipocytes and stimulates proinflammatory activity of the macrophages. Adding tumor necrosis factor α (TNF- α) - previously shown to stimulate degeneration of adipocytes - boosted the amount of cell-free DNA released from dying adipocytes.

In the obese mice, TLR9-driven inflammation contributed to decreased insulin sensitivity. TLR9 knockout mice fed the same high-fat diet had less adipose tissue inflammation and better insulin sensitivity. Adding back TLR9 specifically to the bone marrow cells of mice missing Tlr9 restored increased levels of inflammation and insulin resistance compared to control mice that received bone marrow cells that did not express TLR9. Obese mice given a TLR9 inhibitor showed fewer macrophages within their visceral fat tissue, reduced inflammation, and increased insulin sensitivity compared to their placebo-administered counterparts. Consistent with their mouse data, the researchers found that people with high levels of visceral fat also had elevated cell-free, ssDNA levels in their plasma compared to their more-lean counterparts. These cell-free, ssDNA levels correlated with markers of insulin resistance.

Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

Cell-free DNA (cfDNA) circulating in the blood has recently received much attention as a potential biomarker for monitoring both physiological and pathological conditions. Apoptosis and/or necrosis are considered to be the main source of cfDNA. Several studies have reported a link between cfDNA and inflammatory diseases. Here, we assessed the hypothesis that cfDNA released by obesity-related adipocyte degeneration causes adipose tissue inflammation through recognition by TLR9, contributing to the development of insulin resistance. We examined the association between obesity and the release of cfDNA, and investigated the role of cfDNA in macrophage activation and in the development of adipose tissue inflammation and insulin resistance by using a diet-induced obesity model, a bone marrow transplantation (BMT) model, and an in vivo TLR9 inhibition study involving wild-type and TLR9-deficient (Tlr9-/-) mice. Furthermore, we examined cfDNA level in human plasma to show clinically translatable evidence. Our study may provide a novel mechanism for the development of adipose tissue inflammation and a potential therapeutic target for insulin resistance.

Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9-/-) macrophages. Fat-fed Tlr9-/- mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9-/- mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with visceral obesity and was associated with the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

In recent years a number of research groups have identified statistical relationships between time spent sitting and mortality rate. Some have claimed that longer sitting time correlates with raised mortality rates even for individuals who exercise regularly. Given the large studies showing that even modest levels of activity, such as walking or cleaning the house, associate with better health and lower mortality rates, when taken together this suggests that the problem with sitting is that the sitter is inactive. Here is the latest in the line of studies associating sitting and mortality:

In order to properly assess the damaging effects of sitting, the study analyzed behavioral surveys from 54 countries around the world and matched them with statistics on population size, actuarial table, and overall deaths. Researchers found that sitting time significantly impacted all-cause mortality, accounting for approximately 433,000, or 3.8%, of all deaths across the 54 nations in the study.

Researchers now believe that periods of moderate or vigorous physical activity might not be enough to undo the detrimental effects of extended sitting. While researchers found that sitting contributed to all-cause mortality, they also estimated the impact from reduced sitting time independent of moderate to vigorous physical activity. "It was observed that even modest reductions, such as a 10% reduction in the mean sitting time or a 30-minute absolute decrease of sitting time per day, could have an instant impact in all-cause mortality in the 54 evaluated countries, whereas bolder changes (for instance, 50% decrease or 2 hours fewer) would represent at least three times fewer deaths versus the 10% or 30-minute reduction scenarios. Although sitting is an intrinsic part of human nature, excessive sitting is very common in modern societies. Sedentary behavior is determined by individual, social, and environmental factors, all strongly influenced by the current economic system, including a greater number of labor-saving devices for commuting, at home and work, and urban environment inequalities that force people to travel longer distances and live in areas that lack support for active lifestyles."

The results of this analysis show that reducing sitting time, even by a small amount, can lead to longer lives, but lessening time spent in chairs may also prompt people to be more physically active in general. "Although sitting time represents a smaller impact compared with other risk factors, reducing sitting time might be an important aspect for active lifestyle promotion, especially among people with lower physical activity levels. In other words, reducing sitting time would help people increase their volumes of physical activity along the continuum to higher physical activity levels."

Link: http://www.eurekalert.org/pub_releases/2016-03/ehs-pds032316.php

Researchers have made the accidental discovery that removing the gene ARID1A in mice produces greater regenerative capacity. The team was focused on liver cancer research so most of their observations relate to liver regeneration, but they note that the improvement appears in other tissues as well:

The liver is unique among human solid organs in its robust regenerative capability. A healthy liver can regenerate up to 70 percent of its tissue after injury. However, when the liver has been repeatedly damaged - by chemical toxins or chronic disease - it loses its ability to regenerate. Following repeated injuries, cirrhosis or scar tissue forms, greatly increasing the risk of cancer. In humans, the gene ARID1A is mutated in several cancers, including liver cancer, pancreatic cancer, breast cancer, endometrial cancer, and lung cancer. It is not mutated in every type of cancer, but in a significant number. Those mutations are found in 10 to 20 percent of all cancers, and the mutations render the gene inactive.

Based on this association, the researchers hypothesized that mice lacking Arid1a would develop liver damage and, eventually, liver cancer. They were surprised when the opposite proved to be the case - no liver damage occurred. In fact, livers of the mice regenerated faster and appeared to function better. On observation, livers in the mice without the gene appeared healthier. Blood tests confirmed improved liver function. When researchers deleted the gene in mice with various liver injuries, they found that the livers replaced tissue mass quicker and showed reduced fibrosis in response to chemical injury. Also, other tissues such as wounded skin healed faster in Arid1a-deficient mice.

No drugs are currently available to mimic a lack of this protein, although the researchers are searching for one. "We want to identify small molecules that mimic the effect of these genetic findings. The ideal drug would be one that helps the liver heal while inhibiting the development of cancer. That would be the perfect drug for my patients." Loss of the gene and the protein it expresses may accelerate regeneration by reorganizing how genes are packaged in the genome so that the cells can more easily switch back and forth toward a more regenerative state, sort of like a toggle switch.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2016/march/zhu-liver-regeneration.html

Cryonics has been in the press and the broader online media seemingly more often than not of late. Perhaps it is the season for it. As is the case for many other areas of science and technology in this era of rapid progress, matters in the cryonics industry are on the verge of moving from reasonable but unproven hypothesis to self-evident extrapolation of the uses of a new technology.

The reasonable but unproven hypothesis has been that suitable methods of low-temperature preservation, vitrification being the present standard, will maintain the fine structure of neurons and neural connections sufficiently well that the data of the mind is also preserved. Thus people can be preserved at death, and given the chance at a new life in a future in which restoration becomes technologically feasible. So long as the data is preserved, that restoration remains a possibility. That this data is overwhelmingly static, in the form of encoded structures, is demonstrated by the survival and recovery of cold water drowning victims, among other evidence. The core cryonics hypothesis has held up very well in the face of the past few decades of progress in our understanding of the mechanisms of memory, and progress towards being able to mount initial demonstrations of preserved structure in neural tissue and preserved memory in lower animals.

The phase in which cryonics moves to being an obvious extrapolation of a new medical technology starts when reversible vitrification is used to preserve donor organs indefinitely, removing many of the logistical issues in that industry. When organs are grown from cells to order rather than donated, again reversible vitrification will make the logistics of that tissue engineering a lot easier. This is actually pretty close to realization in the grand scheme of things. Experiments have been carried out in animals with some degree of success, and more researchers are now interested in fixing up the last set of issues in vitrification and thawing protocols that make reversible vitrification hard at present. In a world in which organs are regularly vitrified for storage, then used for transplant years later, it will become pretty obvious to the public at large that storing the brain or the body as a whole is similarly viable.

People who pay more attention to the state of technology still under development are already at that point, of course. If organized well, end of life cryopreservation is a very reasonable wager on the course of the future for someone who will age to death before the advent of sufficiently effective rejuvenation treatments. Few people realize this, unfortunately, and so near all of humanity let themselves fall into oblivion, thinking there is no alternative.

Why Cryonics Makes Sense

We think of the divide between life and death as a distinct boundary, and we believe that at any given point, a person is either definitively alive or definitively dead. Today, dead means the heart has been stopped for 4-6 minutes, because that's how long the brain can go without oxygen before brain death occurs. The brain 'dies' after several minutes without oxygen not because it is immediately destroyed, but because of a cascade of processes that commit it to destruction in the hours that follow restoration of warm blood circulation. Restoring circulation with cool blood instead of warm blood, reopening blocked vessels with high pressure, avoiding excessive oxygenation, and blocking cell death with drugs can prevent this destruction. With new experimental treatments, more than 10 minutes of warm cardiac arrest can now be survived without brain injury. Future technologies for molecular repair may extend the frontiers of resuscitation beyond 60 minutes or more, making today's beliefs about when death occurs obsolete.

In other words, what we think of as "dead" actually means "doomed, under the current circumstances." Someone fifty years ago who suffered from cardiac arrest wasn't dead, they were doomed to die because the medical technology at the time couldn't save them. Today, that person wouldn't be considered dead yet because they wouldn't be doomed yet. Instead, someone today "dies" 4-6 minutes after cardiac arrest, because that happens to be how long someone can currently go before modern technology can no longer help them. Cryonicists view death not as a singular event, but as a process - one that starts when the heart stops beating and ends later at a point called "the information-theoretic criterion for death" when the brain has become so damaged that no amount of present or future technology could restore it to its original state or have any way to retrieve its information.

Here's an interesting way to think about it: Imagine a patient arriving in an ambulance to Hospital A, a typical modern hospital. The patient's heart stopped 15 minutes before the EMTs arrived and he is immediately pronounced dead at the hospital. What if, though, the doctors at Hospital A learned that Hospital B across the street had developed a radical new technology that could revive a patient anytime within 60 minutes after cardiac arrest with no long-term damage? What would the people at Hospital A do? Of course, they would rush the patient across the street to Hospital B to save him. If Hospital B did save the patient, then by definition the patient wouldn't actually have been dead in Hospital A, just pronounced dead because Hospital A viewed him as entirely and without exception doomed.

What cryonicists suggest is that in many cases where today a patient is pronounced dead, they're not dead but rather doomed, and that there is a Hospital B that can save the day - but instead of being in a different place, it's in a different time. It's in the future. That's why cryonicists adamantly assert that cryonics does not deal with dead people - it deals with living people who simply need to be transferred to a future hospital to be saved.

Cryonics and the shifting goal posts of death

The statement "a dead person cannot be revived" seems so obvious that it is hardly worth writing down, but when you look a little deeper, it is not so clear cut. A few decades ago, someone who suffered a cardiac arrest was considered irreversibly dead. Move forward to today, and we routinely bring those people back from the brink. So, in some regards, our definition of what constitutes "dead" has shifted. It is this kind of stance that cryonics researchers often take when faced with dissenters. Their argument, whether you are prepared to run with it or not, is that death has already had its goal posts moved, so who is to say that they cannot be moved again?

Today, brain death, rather than cardiac death, is considered the stamp of finality. But even this, it might be argued, is not entirely infallible. For instance, in 1955, James Lovelock cooled a rat to just above 0°C. Its brain completely stopped its normal business. However, Lovelock managed to reanimate the rodent by warming it back up. Even in a real life situation - cold water drowning - similar findings have been described. A young girl was resuscitated after an astonishing 66 minutes of total submersion in freezing water. After an hour under water, most people would consider the individual irreversibly dead. We now know this is not always the case. Importantly, her memories and personality were still intact. This is not the only case of people "surviving clinical death." Cases like these have spawned a saying in some emergency rooms: "Nobody is dead until warm and dead."

This review looks at a range of investigations into the effects of aging on stem cell populations supporting muscle tissue, and various attempts to restore those populations to active duty. Stem cell populations decline with age, becoming less active and more damaged. In recent years, researchers have demonstrated that a variety of approaches can be used to instruct dormant stem cells to be more active: stem cell transplants, altered GDF11 signaling, and so forth.

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle stem (satellite) and progenitor cells (SMSCs). Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a pre-senescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion.

Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the pre-senescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the pre-senescent state results from loss of autophagy, leading to increased reactive oxygen species (ROS) and epigenetic modification at the CDKN2A locus due to decreased H2Aub, up-regulating cell senescence biomarker p16ink4a. However, the pre-senescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells.

Other work suggests that in humans loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus down regulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to pre-senescence in the very old.

Link: http://dx.doi.org/10.1089/rej.2016.1829

Researchers investigating aging in flies have found that loss of intestinal function is a very strong determinant of degeneration and mortality in that species. Interventions that slow that decline, such as by manipulating intestinal stem cell activity or improving intestinal tissue quality control, also reduce mortality and extend life. There has been some discussion over whether this importance of intestinal function in aging is a characteristic unique to flies, and here the authors of this open access paper argue that it is not, and that there should be more targeted investigation in mammals:

A dramatic increase of intestinal permeability occurs in Drosophila melanogaster during aging in normal condition. The assay presented in this article uses a blue food dye to detect increased intestinal permeability in vivo. A blue coloration throughout the body marked the positive individuals, which were referred to as 'smurfs' from then on. Interestingly, the authors showed that genetic or physiological interventions increasing lifespan in flies significantly decreases the proportion of Smurfs compared to the control population at any given chronological age. This apparent link between the age-related increase of intestinal permeability and lifespan led them to more thoroughly analyze the Smurf phenotype. This phenotype allows the identification of individuals that are about to die of natural death amongst a population of synchronized Drosophila melanogaster individuals and those individuals show numerous other hallmarks of aging. Such a stereotyped way to die is unexpected; this could indicate a physiological phenomenon crucial during normal aging. Here we propose to test the hypothesis that such an important phenomenon should be evolutionarily conserved.

We chose to search for such a 'Smurf transition' in two other Drosophila species, Drosophila mojavensis and Drosophila virilis whose last common ancestor with Drosophila melanogaster existed approximately 50 million years ago, the nematode Caenorhabditis elegans whose divergence time with D. melanogaster is around 750 million years, and finally the vertebrate zebrafish Danio rerio, which diverged from D. melanogaster around 850-950 million years ago. We investigated whether Smurf-like animals could be observed in individuals from populations of these evolutionarily distant organisms. For each tested species, we could identify individuals showing extended dye coloration throughout their bodies. Moreover, we observed heterogeneity in a given population with only a fraction of the individuals exhibiting increased dye level outside the intestine. Thus, at least in old animals, it is possible to identify individuals with increased intestinal permeability.

One of the most striking characteristic of Smurf individuals previously described in Drosophila is the high risk of impending death they exhibit compared to their age-matched counterparts in a given population. So we decided to verify whether Smurf individuals were also committed to die in the other organisms we studied in this article. We showed that the proportion of individuals showing increased intestinal permeability grows linearly - or quasi-linearly - as a function of chronological age in these different organisms as it was previously reported in Drosophila melanogaster. Finally, we validated that, similar to what has been shown in D. melanogaster, the Smurf phenotype is a strong indicator of physiological age since it is a harbinger of natural death occurring during normal aging.

Intestinal dysfunction, as measured by the smurf assay in different species, associated to sharp transitions in gene expression and behavior appears to be a conserved hallmark of impending death. If this phase of aging is as broadly present in living organisms as our present study suggests, highly stereotyped molecularly and physiologically as well as sufficient to explain longevity curves, then we think that identifying the very events responsible for entering into this phase or those characterizing the high risk of impending death associated with that phase could answer fundamental questions about aging and lead to treatments able to significantly improve lifespan/healthspan across a broad range of species.

Link: http://dx.doi.org/10.1038/srep23523

To my eyes professional ethics is a self-defeating field, in that it appears to corrode the ethics of those who participate. The basic problem here is one of incentives, an age-old story. The funding and standing for a professional ethicist depends upon finding a continual supply of ethical issues that can be used to justify the continued employment and budget of said ethicist. When it comes to medicine, however, and for most other fields of human endeavor, there is no such supply. All of the true ethical problems in medicine and medical science were solved long ago and the solutions finessed in great detail across centuries of thought and writing. These ethical problems in medicine are few in number and basically boil down to what to do in limited resource triage situations (the best you can), whether or not to harm people deliberately (no), and whether or not to work towards better medicine (yes). Thus a gainfully employed professional ethicist must invent new, not-actually-real problems pretty much from the get-go, or give up and admit that the job is pointless. Natural selection then ensures that we only see those who prefer the money over the integrity.

We can measure the decay in the ethics of professional ethicists by the degree to which they can contort themselves to produce different answers to those I provided for the few legitimate ethical challenges in medicine above. If you spend any time at all following the progression of aging research and efforts to extend healthy human lives, then you will see a great many ethicists demonstrating the decay of their personal ethics in just this fashion. There are any number of salaried ethicists willing to throw their newly invented logs in front of the wheels of progress in this field, and tell us just how terrible it would be to cure age-related disease and lengthen productive and healthy human lives. The processes of aging and the age-related disease it produces are the greatest cause of pain, suffering, and death in the world by a very large margin. The way to remove all of this pain, suffering, and death is to build therapies that can repair the causes of aging, therefore preventing all resulting disease and disability. That will also extend life, because healthy, youthful people have a very low mortality rate. Yet the cadre of professional ethicists weigh their present position against the lives and livelihoods of billions and go right ahead with their flimsy objections.

That this whole situation exists, that institutions responsible for providing and improving technologies have increasingly indulged a parasitical arm that siphons off funding in order to obstruct the processes of improvement, is yet another sign that the world we live in is far from perfect. It also suggests that human nature leaves much room for improvement in the years to come, once such an engineering project becomes possible. In this article we see an example of the type of "ethics" I find so objectionable, though it isn't as though one has to try hard to find other examples:

The Tricky Ethics of Living Longer

Tortoises typically live well past 100 and might be able to survive even longer. In 2006, a giant tortoise thought to be 255 years old died at India's Calcutta Zoo. We humans have yearned throughout history for longevity and even immortality. Science has already helped us live much longer than our ancestors did, by improving hygiene and protecting us from infectious diseases through antibiotics and vaccines. But current research into extending our lives presents an interesting twist. It also raises ethical questions.

I spoke to experts who foresee a coming revolution in medicine, where we treat age instead of disease. To do this, they are trying to figure out how aging works at the molecular level. The goal isn't exactly immortality. Instead, these scientists have noticed that a variety of diseases, from cancers to Alzheimer's, share aging as a major risk factor. Rather than spending a lot of money to treat each disease individually, why not tackle the root cause? What if there was a pill that slowed how our cells age, letting us avoid age-related illnesses - and also likely extending our lives? It's a safe bet that when most of us contemplate the gaping abyss of mortality, we decide we'd like to postpone that fate as long as possible, while remaining mobile, independent, and mentally sharp. If we must die, let us go peacefully in our sleep, at home, when we're at least 100.

But how might such a revolution ripple across society? Life expectancy already varies greatly. It's tied to education, wealth, and even where you live. According to Alexander Capron, an expert in health policy and ethics at the University of Southern California Gould School of Law, life-extending therapies could exacerbate these differences. For example, if these treatments are expensive, or aren't covered by affordable health care plans, only people with disposable cash will have access. This means people with money and resources will have the choice to live longer. Those who don't, won't.

"We can't cherry-pick the costs or savings to focus on," says Patrick Lin, director of the Ethics + Emerging Sciences Group at California Polytechnic State University. Instead, he says,to fairly examine the ethics involved, we should consider impacts both on the individual and society level. "Yes, healthier people may mean lower health costs and more productivity, but that's a partial picture at best. We'd also have to consider the impact of extended lives on, say, Social Security, pensions, job openings given fewer retirements, crime from unemployment, natural resources, urban density, copyright durations, prison sentences, and many, many other effects."

Another effect to consider is how families pass on their legacies, says Nigel Cameron, president of the Center for Policy on Emerging Technologies. Life extension would mean more time with extended family. But it will also mean that inheritance and property will transfer later and less often, which could put more pressure on younger generations to acquire property independently. Lifespan extension could also influence politics and social change, with different age groups pushing for different policies. "There are big generational differences in economic and social interests," Cameron says. "The whole thing becomes much more extended if people live longer, much more competitive."

Still, the research that could lead to life extension is happening, so the conversation about its implications should, too. "Personally, I'm cautiously optimistic about life extension research, but we need to be careful to manage the hype and not ignore the risks," says Lin. "Will we ever become immortal? I don't know, and no one else can see that far, either. But even extending our lives another 20-100 years or more, to start with, is a game-changer."

Here is another example of recent data on the relationship between levels of physical activity in later life and the health of the brain. With the advent of low-cost accelerometers and more accurate data on activity, it is becoming clear that even the very modest exercise involved in activities such as cleaning or walking shows correlations with health. To to the degree that this relationship involves causation, the important mechanisms likely relate to the status of the vascular system, the rate at which tiny blood vessels suffer structural failure and destroy small portions of brain tissue. That is driven by the pace of arterial stiffening, progression of hypertension, and other factors that are slowed by regular exercise and sped up by the consequences of a sedentary life style, such as higher levels of chronic inflammation caused by visceral fat tissue.

A new study shows that a variety of physical activities from walking to gardening and dancing can improve brain volume and cut the risk of Alzheimer's disease by 50%. The researchers studied a long-term cohort of patients in the 30-year Cardiovascular Health Study, 876 in all, across four research sites in the United States. These participants had longitudinal memory follow up, which also included standard questionnaires about their physical activity habits. The research participants, age 78 on average, also had MRI scans of the brain analyzed by advanced computer algorithms to measure the volumes of brain structures including those implicated in memory and Alzheimer's such as the hippocampus. The physical activities performed by the participants were correlated to the brain volumes and spanned a wide variety of interests from gardening and dancing to riding an exercise cycle at the gym. Weekly caloric output from these activities was summarized.

The results of the analysis showed that increasing physical activity was correlated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus. Individuals experiencing this brain benefit from increasing their physical activity experienced a 50% reduction in their risk of Alzheimer's dementia. Of the roughly 25% in the sample who had mild cognitive impairment associated with Alzheimer's, increasing physical activity also benefitted their brain volumes.

Link: http://www.iospress.nl/ios_news/different-kinds-of-physical-activity-shown-to-improve-brain-volume-and-cut-alzheimers-risk-in-half/

Better methods of detecting the various forms of amyloid as it builds up in tissues with age should result in greater support for development and availability of the means to remove this unwanted form of metabolic waste. Amyloids are present in every individual to some degree, that presence increasing with age, and are known to cause or be associated with numerous age-related diseases. This is one of the fundamental forms of damage that causes aging, yet amyloid levels are rarely assessed in healthy individuals, or even for patients with diseases that are relevant but something other than full-blown amyloidosis. Ideally everyone, healthy or not, should undergo amyloid clearance therapies - like that developed and trialed by Pentraxin for transthyretin amyloid - every few years starting in middle age or earlier.

Researchers have developed a molecular probe that can detect an array of different amyloid deposits in several human tissues. This new probe is extremely sensitive and was used at very low concentrations to correctly identify every positive amyloidosis sample when compared to the traditional clinical tests. The probe also picked up some amyloidosis signals that the traditional methods were unable to detect. This result means that the new probe could be used to detect amyloidosis before symptoms present, leading to faster and hence more effective treatment.

Aggregates of amyloid proteins form and deposit in different tissues which can affect the normal function. As the disease progresses and amyloid deposits grow, tissues become irreversibly damaged. Amyloid deposits can be found in many different organs leading to a wide range of possible symptoms and making diagnosis challenging. To date, the primary mode of diagnosis for amyloidosis has been the Congo red stain. However, evidence from the team shows that their new probe is much more sensitive, being able to detect small amyloid deposits in samples that were previously determined to be amyloid-free.

According to the U.S. Office of Rare Diseases (ORD) amyloidosis is a rare disease, affecting less than 200,000 people in the U.S.. However, the Amyloidosis Foundation suspects that the figures are underreported and that amyloidosis is not that rare - just rarely diagnosed. A more sensitive diagnostic method would help to uncover the reality of the situation. "Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement. It could also be used to identify new types of amyloids and presymptomatic patients who are at risk of developing the disease."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=162338&CultureCode=en

In the open access paper I'll point out today, the authors provide a high level overview of the evidence that suggests immune cells called astrocytes play a primary role in the progression of age-related neurodegenerative conditions. The immune system of the brain is quite different, somewhat more intricate, and more specialized than its equivalents elsewhere in the body, and those systems are themselves very complex and only partially mapped. The brain is shielded from the sort of haphazard exposure to toxins and pathogens that other tissues must face by the existence of the blood-brain barrier, a shield lining the blood vessels that pass through the brain. The portfolio of tasks carried out by the immune system within that barrier has shifted accordingly. In the brain specialized types of immune cell, neuroglia such as microglia and the aforementioned astrocytes, undertake a very broad range of activities beyond simply sweeping up waste and destroying pathogens, and are tightly integrated into the core functions of the brain. They participate in some of the most important and fundamental neural processes, such as the formation and alteration of connections between neurons, for example.

Most of the common diseases of aging have an inflammatory component. Pathology and degeneration is accelerated by the decline of the immune system into a state of ineffective, constant inflammation. The causes of that decline are discussed elsewhere, and include a sort of misconfiguration perhaps brought on by exposure to persistent pathogens such as cytomegalovirus, and the slow and falling rate of generation of replacement immune cells in adults. Effectively addressing these causes seems a very plausible task for the next couple of decades, based on promising studies in animals from the past few years. In the brain, things are going to be much the same at the high level, but different in the details. A lot of research from recent years points to microglia as the agents of neural inflammation, but the authors here suggest that there is just as much evidence for astrocytes to be involved in the generation of a harmful inflammatory state:

Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System

Since the beginning of the 20th century relentlessly progressive neurological diseases have classically been attributed to a primary neuronal dysfunction. This affirmation applies to Parkinson disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among others. Therefore, most investigations have been carried out under this belief, leading to the coining of the term "neurodegeneration." In the 90s, a new era began that considered the possibility of a more important role of the so far neglected neuroglia. This led to different findings opposed to the belief of the astrocytes sole function being neuronal structural support.

Astrocytes have been found to have a much more active role that the one predicted by the earlier guessers. Particularly, they are involved in the ions exchange with neurons, they are organized as a syncytium that allows them to interchange information with other astrocytes residing in a defined net through different types of Ca+++ signals while regulating the release of signaling molecules involved in the production of trophic factors, transmitters and transporters that when released to the extracellular medium will modulate the synaptic activity synchronizing the neuronal functions. Also they are involved in the extracellular K+ uptake, in synaptogenesis and gene expression; adapting, at the same time, the permeability of the blood-brain barrier to the neuronal and synaptic needs.

Slowly but relentlessly, the results of several studies have confirmed the existence of an active role played not only by the astrocytes but also by microglia. Mounting evidence suggests that astrocytes modulate microglial response, through the establishment of a complex cross-talk between both types of cells mediated by the production of different chemokines and cytokines. Therefore, we think that the broader term primary degenerative disorders of the central nervous system (PDD CNS) alludes to the complex pathology of these diseases (in contrast to the classic term neurodegeneration). An early astrocytic dysfunction in the PDDs of the CNS has been broadly observed. We advocate that these observations obtained from different degenerative pathologies, but mostly from experimental animal studies, may be the trees from a forest characterized by primary astrocytic dysfunction as the main process starting them.

Periodontitis, an inflammatory condition of the gums, can spread the effects of chronic inflammation elsewhere in the body via the circulatory system. It is associated with the progression of a number of common age-related conditions that have an inflammatory component, such as cardiovascular disease. Thus it is worth keeping an eye on progress towards therapies capable of effectively treating inflammatory gum disease. Researchers here add more evidence for the association of Alzheimer's disease progression with periodontitis:

A new study has found a link between gum disease and greater rates of cognitive decline in people with early stages of Alzheimer's disease. Periodontitis or gum disease is common in older people and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body, which in turn has been linked to greater rates of cognitive decline in Alzheimer's disease in previous studies.

In the observational study, 59 participants with mild to moderate Alzheimer's disease were cognitively assessed and a blood sample was taken to measure inflammatory markers in their blood. The majority of participants were followed-up at six months when all assessments were repeated. The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer's disease, possibly via mechanisms linked to the body's inflammatory response.

Growing evidence from a number of studies links the body's inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer's disease. In the UK in 2009, around 80% of adults over 55 had evidence of gum disease, whilst 40% of adults aged over 65-74 (and 60% of those aged over 75) had less than 21 of their original 32 teeth, with half of them reporting gum disease before they lost teeth. "A number of studies have shown that having few teeth, possibly as a consequence of earlier gum disease, is associated with a greater risk of developing dementia. We also believe, based on various research findings, that the presence of teeth with active gum disease results in higher body-wide levels of the sorts of inflammatory molecules which have also been associated with an elevated risk of other outcomes such as cognitive decline or cardiovascular disease."

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=161980&CultureCode=en

This is an interesting approach to organ transplant and regrowth, demonstrated initially in rabbits. The researchers believe it may also provide the basis for xenotransplantation between species, but that remains to be seen:

Researchers have discovered a way of freezing embryonic animal kidneys so that they can later be warmed up and grown into full-size organs without the risk of rejection by their recipient. The team found that when precursor kidney tissue from 16-day-old rabbit embryos is implanted in adult rabbits, it develops into an adult kidney, connecting itself to the host's own blood supply. The host doesn't recognise the organ as strange, and permits it to connect to the blood system. The adult rabbits did not reject the foreign kidneys because the embryonic tissue was transplanted before it had started producing the protein that would alert a host's immune system to foreign cells. Researchers believe that when the protein is eventually produced, it matches that of the host instead.

The team then investigated whether it might be possible to create a biobank of potential organs for transplant. Large organs cannot be frozen to prevent decay because water in them turns to ice as they freeze, destroying delicate call structures. But the embryonic precursor kidneys are much smaller, enabling them to use a cryopreservation process called vitrification that can prevent ice formation by pumping antifreeze into an organ before cooling it to -196 °C. This technique is normally only used to freeze small tissues such as human eggs because it is difficult to get the antifreeze around larger, more complicated organs. The team managed to successfully vitrify and store the precursor kidneys for three months in liquid nitrogen. They then warmed the tissue and transplanted it into adult rabbits. Some 25 per cent of the transplants grew into healthy adult organs in the host - not as high as the 50 per cent success rate they achieved with fresh embryonic tissue, but still good.

The results suggest we may one day be able to create a long-term biobank of animal kidneys that provides an unlimited source of organs for transplanting in people. The team is now trialing a similar experiment between rabbits and goats. More than one kidney could potentially be transplanted into larger animals to make up the mass needed for them to act as a native kidney.

Link: https://www.newscientist.com/article/2081623-frozen-rabbit-kidneys-could-solve-organ-shortage-for-transplants

Anders Sandberg is one of the earlier participants in the modern transhumanist movement, perhaps better thought of as a distributed and shifting set of overlapping interest and advocacy groups rather than a movement per se. The core of the transhumanist ideal is the overcoming of limits, the use of technology to expand the choices available within the human condition. The diverse membership of these groups has spread and prospered over the past twenty years, taking influential roles in biotechnology, aging research, cryonics, artificial intelligence, and other related fields. In a sense it is the ideas that matter: the defeat of aging and age-related disease so as to indefinitely extend healthy life; engineering away all of the other causes of pain and suffering; expanding our intelligence; building intelligence; seeking to be far more than we are today. Those of us who propagate these ideas and work towards their realization are in a way water carriers, passing the value along. The more people who do this, the greater the support for transhumanist goals such as achieving effective medical control over aging, the better the prospects become for all of our futures.

Like many of the other futurists who used the early years of the internet to find one another and form a community to talk about the practicality of their visions for a golden future, Anders Sandberg engineered a career from an interest in transcending the limits of the human condition through technological progress. These days he works with the Future of Humanity Institute, itself an outgrowth of a portion of the transhumanist community. This is in large part an advocacy initiative, clothed as academia, seeking to put forward a vision - with supporting evidence - for a far better future to a public that hasn't really given the topic much thought. To the world at large, tomorrow is anticipated to be much the same as today. It is strange that this is the case in a time of such rapid progress in science and technology, but most people expect to live in a future that looks much the same as the present, barring small changes in fashion and culture. The possibilities are so much greater than that, however. For one, we stand on the verge of being able to treat the causes of aging, and many people alive today will as a consequence live for long enough to see aging entirely defeated, rejuvenation robustly achieved, and their lives and healthspans made unlimited in length. That shortly beyond that lies an explosion of intelligence and culture out into the universe, of a size and scope to make our present world seem the smallest mote by comparison, is almost by the by.

Below find a link to the PDF version of a radio essay by Sandberg presented at BBC Radio 3, one portion of a much broader effort to make more people pay attention to what could be done to make the world a better place, and our lives radically different and less limited as a result.

Desperately seeking eternity (PDF)

People have tried to extend their lives since time immemorial. The oldest great work of literature, the epic of Gilgamesh is partially about the king's search for the herb of immortality. Up until recently we did not have any deep understanding of what ageing truly is, so doing anything about it was hard. That has changed radically in recent decades. We now understand why we age, and can in the lab even slow it down in test animals. Some treatments can prolong animal lifespans by up to 40 per cent whether by removing senescent cells, reducing caloric intake, or influencing certain metabolic pathways. While none of the methods are likely to carry over straight to humans, the fact that we have gone from ageing being an immutable fact to something that can be manipulated is already revolutionary.

Even if the first clinical methods for slowing ageing arrive a few decades ahead, that is still good news for the majority of people living today. Especially since slowed ageing gives you more years of medical progress. While nothing is certain, it looks like in the long run ageing may become just another treatable chronic disease. Some would argue that slowing ageing is all about achieving immortality. But treating ageing directly makes sense simply in terms of health: ageing is a direct contributor to heart disease, diabetes, weakened immune system, Alzheimer's and many other maladies. Life extension cannot give us eternal life: besides ageing, we are killed by diseases, accidents and violence. And if we fix those, we are still finite beings in a universe ruled by probability. Sooner or later we will be unlucky and perish. But we can maybe make this probability so low that it does not matter much in practice. The real issue might be what we would do if we had indefinite lifespans.

Every time someone dies, a library burns. The experiences, skills, and relationships painstakingly built across a lifetime disappear forever. We cannot prevent any particular library from eventually having a fire, but we can make sure the fires are rare. Humans are precious, and that is why we should not wish them to age. Some might say we need a change of generations to keep our culture youthful. Yet, to continue the library metaphor, few people think the way of maintaining a successful culture is to burn the archives and art museums. There are better ways of changing things than killing the old guard. The physicist Max Planck said that science advances one funeral at a time, but in practice many radical new ideas do sweep the scientific world faster than scientists are being replaced. In the social arena we have seen struggles to extend human rights succeeding faster and faster, despite people living longer: compare the time it took for female suffrage to go from academic idea to political practice with the time it took gay rights to make the leap from unthinkable to orthodox. At any rate, if long lives actually do slow social changes there are still better ways of speeding it up than letting people die prematurely. We have term limits in politics: maybe we should have them for professors and CEOs too.

I have met 18 year olds claiming they do not want to live beyond 20 because they will be old and decrepit, while my 105 year old grandmother still potters on since dying is simply not done. Some people find new meaning again and again, others feel suicidal about Sunday afternoons. It is not uncommon to envision one's life as a book, and then assume it must have a beginning, a middle and an end. This is reasonable since we tend to construct our identities as narratives: we often tell stories about who we are, what we have done, and where we are going, so thinking of a life this way comes naturally to us. But a book can be a short pamphlet, a thick epic, or maybe a never-ending fantasy series ... which one would we want to be like?

Many people who wish for radical life extension are afraid of dying. This is a bad motivation: sooner or later they will run out of time anyway, and living just to avoid something is a diminished way of life. They are not hoping for something of value, merely the avoidance of loss. The problem with death is not just that it can be painful, but that it also irreversibly prevents any more experience, any more action. Our social bonds are broken. Pain can be dealt with, but these other factors point at what makes life worth living. We should seek to live longer because we love life. We should wish to experience good things, gain wisdom, and interact with people in important ways. A long and healthy life is quite useful for this.

Aging is a global phenomenon in the body, so measures of its progression in different organs tend to correlate well. In some cases this is because there is direct causation involved rather than it being a matter of independent processes that spring from the same root causes. The health of the cardiovascular system is demonstrably connected to the health of the brain. For example, the structural failure of small blood vessels in the brain, driven by increased blood pressure and the processes of stiffening in blood vessel walls, destroys small areas of brain tissue on an ongoing basis. The more such destruction, the worse off the individual, and the greater the age-related loss of mental capacity.

Researchers studied a racially diverse group of older adults and found that having more ideal cardiovascular health factors was associated with better brain processing speed at the study's start and less cognitive decline approximately six years later. At the beginning of the study, 1,033 participants in the Northern Manhattan Study (average age 72; 65 percent Hispanic, 19 percent black and 16 percent white), were tested for memory, thinking and brain processing speed. Brain processing speed measures how quickly a person is able to perform tasks that require focused attention. Approximately six years later, 722 participants repeated the cognitive testing, which allowed researchers to measure performance over time.

The researchers found that having more ideal cardiovascular health factors was associated with better brain processing speed at the initial assessment. The association was strongest for being a non-smoker, having ideal fasting glucose and ideal weight. Having more cardiovascular health factors was associated with less decline over time in processing speed, memory and executive functioning. Executive function in the brain is associated with focusing, time management and other cognitive skills. While this study suggests achieving ideal cardiovascular health measures is beneficial to brain function, future studies are needed to determine the value of routinely assessing and treating risk factors, such as high blood pressure, in order to reduce brain function decline.

Link: http://newsroom.heart.org/news/healthy-heart-equals-healthy-brain

The interactions between molecular damage in cells, repair system activity, the generation of reactive oxygen species (ROS) in mitochondria capable of causing damage, and individual or species longevity are far from simple. The free radical theory of aging and its variants were early and in hindsight overly simplistic views based on the observation that the presence of ROS and their signs of their damage increase with age. However, numerous methods of slowing aging in short-lived animals involve increases in the rate at which mitochondria produce reactive oxygen species. These molecules are signals as well as sources of damage, and an increase can cause repair systems to overcompensate, producing a net gain in cellular maintenance and reduction in overall levels of damage. It isn't just repair: many of the benefits of exercise are also keyed to temporary increases in ROS levels.

Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the ageing process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artefacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect ageing and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan.

A topic highly debated in the field is the role that mitochondrial ROS play in age related and non-age related pathological processes with a mitochondrial component. Are ROS a cause or a consequence of mitochondrial dysfunction? This is a very important question, which needs to be addressed, since it will affect the treatment of those pathologies. Considering all the available evidence, it is plausible to suggest that ROS can have both positive and negative roles depending on the type of the ROS, when, where and how much is produced. Therefore, we can talk about "Good" and "Bad" ROS. "Good" ROS being low reactivity ROS (i.e. superoxide or hydrogen peroxide) produced at specific places, at specific times and in moderate amounts and "Bad" ROS being highly reactive ROS (or low reactive ROS as hydrogen peroxide or superoxide produced at high concentrations) generated continuously and unspecifically. Experimental evidence suggests that boosting ROS production can contribute to the maintenance of cellular homeostasis and positively affect lifespan when induced correctly, whereas if produced in excess or in an unspecific way, they shorten survival and accelerate the onset of age-related disease.

Link: http://dx.doi.org/10.1016/j.bbabio.2016.03.018

The news for today is that NASA's Centennial Challenges Program and the Methuselah Foundation's tissue engineering initiative New Organ have joined forces to develop the Vascular Tissue Challenge, which is currently public in a draft form as an RFI. The intent is to divide a $500,000 purse between up to three teams who can advance the state of the art in tissue engineering by reliably producing thick sections of vascularized living tissue.

I'm sure you've all seen the announcements roll in over the past few years as research groups have built small organoids that function correctly for their organ type: slivers of pancreatic tissue, thymus tissue, kidney tissue, and so forth. It has, I think, been amply demonstrated that the research community has the development of methodologies needed to build complex, functional tissue well in hand. There is a great deal that can be done with even such tiny slices of tissue, ranging from integration into tools that speed research to use as matched tissue patches for patients with damaged organs. A little bit of a pancreas or a liver - or a dozen little bits, or more - is actually quite useful in the context of diseases, age-related and otherwise, that cause progressive damage to those organs.

However, not all is roses and rainbows in the field. Growing much larger sections of tissue from the starting point of cells and entirely artificial scaffolds, with the goal of creating whole organs to order, as needed, and matched to the recipient patient, remains to be accomplished. The proliferation of organoids can be contrasted with the absence of larger solid structures. The challenge here, and this has been the blocking issue for a decade, is that the research community cannot yet reliably create tissue that is equipped with the network of tiny blood vessels needed to keep the cells alive and provisioned with nutrients. Thinner tissues can get by without blood vessels, as fluids will diffuse through their structure, but the blood vessels are absolutely required by any tissue much thicker than a centimeter or so.

This is why decellularization of donor organs has taken off: stripping out the cells is is a way to obtain a scaffold, the natural extracellular matrix, that has the intricate blood vessels and the chemical cues to guide newly introduced cell populations to repopulate and rebuild the correct structures. This cannot yet be done for artificial scaffold materials, such as those turned out by 3-D printers, or at least not in anything more than a very early and limited way. Once microvasculature can be produced in engineered tissue in a robust fashion, however, the gate is flung open and the creation of organs in a variety of ways will happen just a few years later at most. Given all of this, vascularization of tissue is an important goal, and a good place to add incentives into the research process.

Draft Vascular Tissue Challenge

The Vascular Tissue Challenge is a $500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in-vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine taking place both on the Earth and the ISS National Laboratory. Specifically, innovations may enable the growth of de novo tissues and organs on orbit which may address the risks related to traumatic bodily injury, improve general crew health, and enhance crew performance on future, long-duration missions.

The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback.

National Aeronautics and Space Administration (NASA) - Centennial Challenges Program - Vascular Tissue Challenge - Request for Information (RFI)

The Centennial Challenges program is seeking input on a Vascular Tissue challenge being considered for start in 2016. The challenge would require competitors to create a thick tissue with fully functioning vascular systems, similar to the tissue found in the heart, lungs, liver or kidney. This RFI is seeking feedback from potential challengers. Comments must be submitted in electronic form no later than 5:00 pm EDT, April 15, 2016.

The ability to provide oxygen and nutrients to thick human tissue by adequate vascularization of layers of cells to ensure metabolic functions similar to native in-vivo tissues has not been reliably demonstrated. Developing this capability will enable new research initiatives that may bring real solutions to organ disease, skin burns and other medical concerns. NASA's objective for this challenge is to produce viable thick-tissue assays above and beyond the current state of the art technology.

Competitors will be asked to produce an in-vitro vascularized tissue that is more than 1 centimeter in thickness in all dimensions at the launch of the trial and maintains greater than 85% survival of the required parenchymal cells throughout a 30-day period. Tissues must provide adequate blood perfusion without uncontrolled leakage into the bulk tissue to maintain metabolic functionality similar to their in-vivo native cells. Histological measurement of the quality and amount of functional performance will be required to determine survival of parenchymal tissue. Teams must demonstrate 3 successful trials with at least a 75% trial success rate to win an award. In addition to the in-vitro trials, teams must also submit a Spaceflight Experiment Concept that details how they would further advance some aspect of their tissue vascularization research through a microgravity experiment that could be conducted in the U.S. National Laboratory (ISS-NL) onboard the International Space Station.

If you happen to know anyone in the tissue engineering community, please do direct their attention towards this initiative.

An interesting study here shows that lower levels of dopamine D2 receptor (D2R) achieved via genetic engineering in mice lead to a modestly reduced life span. This result appears to be mediated by behavioral changes, such as lesser physical activity, greater food intake, and consequently higher body mass, rather than by any other mechanism.

Dopamine (DA) is known to be implicated in a variety of functions including reward and physical mobility. The DA system has been known to be vulnerable to the effects of aging. Human imaging studies have shown that the rate of D2R loss during aging occurs at approximately 10% per decade. While it is apparent that D2R decreases in both human and rodent brains as a result of physiological deterioration following senescence, the functional consequences of this decline on behavior and lifespan are not fully understood. The D2R ability to modulate reward seeking behavior, motivation, and expectation of a reward, influences feeding behavior. Alterations in the DA reward system can lead to abnormal eating behavior; the down regulation of D2R receptor signaling is thought to reduce sensitivity to reward, providing an incentive to overeat.

An enriched environment (EE) is characterized by sensory, motor and social stimulation relative to standard housing conditions. The incorporation of exercise is an important component of an EE and its benefits have been shown to be a powerful mediator of brain function and behaviour. To determine whether the D2R gene is involved in the mechanism of environmental enrichment, different housing conditions were examined in mice. This study hypothesized that the D2 gene, in the presence of an EE, significantly influenced lifespan, body weight, and locomotor activity.

Results supported the hypothesis. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

These data provide the first evidence of the role of D2R gene on lifespan in mammals. Mice with normal or reduced expression of the D2 gene and housed in an EE showed significant increases in lifespan. However, mice deficient in D2 failed to benefit from an EE. The D2 gene function appears to be a critical mediator linked to the behavior and lifespan effects associated with an EE. D2's mediating role, however is environment-dependent and was not observed in mice raised in DE conditions. The anti-aging and neuroprotective factors associated with exercise may be the key factor as to why Drd2 +/+ and Drd2 +/- EE mice showed increased lifespan in comparison to their DE cohorts.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=8088&path%5B%5D=23838

A growing dysfunction in energy metabolism, such as might be caused by higher levels of mitochondrial damage in cells, has been implicated in the progression of age-related neurodegenerative conditions. The neurons of the brain collectively require a lot of energy to operate, and thus it is reasonable to consider that disruptions in the processes that provide that energy are significant. Such disruptions are not the root causes of neurodegeneration, however, but rather secondary or later effects of an accumulation of the fundamental cell and tissue damage that causes aging. One possible compensatory approach to therapy, a treatment that doesn't address the root causes but instead tries to modestly slow down their consequences, would involve delivering more energy stores to neurons. The researchers here report on a fairly simple proof of concept in mice:

The human brain has a prodigious demand for energy - 20 to 30% of the body's energy budget. In the course of normal aging, in people with neurodegenerative diseases or mental disorders, or in periods of physiological stress, the supply of sugars to the brain may be reduced. This leads to a reduction in the brain's energy reserves, which in turn can lead to cognitive decline and loss of memory. But new research on mice shows that the brain's energy reserves can be increased with a daily dose of pyruvate, a small energy-rich molecule that sits at the hub of most of the energy pathways inside the cell. These results need to be replicated in human subjects, but could ultimately lead to clinical applications.

"In our new study, we show that long-term dietary supplementation with pyruvate increases the energy reserves in the brain, at least in mice, in the form of the molecules glycogen, creatine, and lactate. The mice became more energetic and increased their explorative activity. It appears that these behavioral changes are directly due to the effect of pyruvate on brain function, since we didn't find that these mice had developed greater muscle force or endurance. For example, chronic supplementation with pyruvate facilitated the spatial learning of middle-aged (6- to 12-months-old) mice, made them more interested in the odor of unfamiliar mice, and stimulated them to perform so-called "rearing", an exploratory behavior where mice stand on their hind legs and investigate their surroundings. The dose necessary to achieve these effects was about 800 mg pyruvate per day - which corresponds to about 10 g per day in humans - given to the mice in normal chow over a period of 2.5 to 6 months. A single large dose of pyruvate injected directly into the blood stream had no detectable effect.

Link: http://www.eurekalert.org/pub_releases/2016-03/f-rta031016.php

A legitimate, actual human rejuvenation therapy is one that repairs one of the forms of cell and tissue damage that are collectively the root cause of aging. By root cause I mean that this damage occurs as a result of the normal operation of cellular metabolism, and is not itself caused by another form of damage. The present list includes a few classes of persistent metabolic waste, such as misfolded proteins and sugary cross-links, mitochondrial DNA damage, senescent cells, cancerous nuclear DNA mutations, and loss of necessary cell populations, such as active stem cells and long-lived cells in the central nervous system. While not directly caused by one another, these various forms of root cause damage do interact with one another. One type of damage can speed up the progression of another independent form of damage by harming quality control or repair mechanisms, for example.

Do any real, legitimate rejuvenation therapies exist yet? Why yes, as it happens. In 2015, Pentraxin Therapeutics and GlaxoSmithKline completed a small trial of a therapy capable of partially clearing transthyretin amyloid in human patients. Amyloids are misfolded protein, a type of persistent metabolic waste that accumulates in all of us with age, and which in this case is implicated in the development of cardiovascular disease, among other conditions. The presence of amyloid in older tissues is a form of damage, and clearing it is a form of repair, and thus a narrow and specific form of rejuvenation. A little way behind Pentraxin is Oisin Biotechnology, a new startup with a working gene therapy approach that selectively destroys senescent cells. That has been tested in rats rather than people, but the only reasons it couldn't be used in humans today, right now, are the heavy hand of regulation on the one hand, and a desire for another year or so of work to underline the proof of function on the part of the founders on the other. Beyond these two, there are a few other cases in which thinner slices of the necessary technologies for rejuvenation are under development. For example Gensight is putting a lot of effort into human trials for allotopic expression of a single mitochondrial gene to treat inherited conditions in which that gene is mutated. There are thirteen genes that need this treatment if the technology is to be used for rejuvenation, to completely block the contribution of mitochondrial DNA damage to aging, so in a sense Gensight is building a 1/13th slice of a rejuvenation therapy.

You can't undertake any of these treatments today, however, or at least not unless you are wealthy, connected, and persuasive, in which case you buy early access to the treatment by funding a company to develop it and becoming an insider. Even that is only an option if the people doing the work are willing to go along with it, which isn't always going to be the case. A lot of developers want to walk the regulatory path with clear compliance, which means that it could take a decade or more from start to finish before anyone other than a qualified trial participant undergoes any version of the treatment. That is clearly the case for the Pentraxin work on transthyretin amyloid, which has been locked up in the Big Pharma development and regulatory process for seven years already, and may well be years yet in getting to the clinic. When it does, the odds are it will be restricted for use for specific age-related conditions in their later stages, and it will take further time to break it out into more general availability. This is how things tend to progress in the formal, regulated development process. It takes a very long time for even spectacularly successful technologies to become available to the general public.

This is not what we'd like to see happen for rejuvenation therapies. Adding five or ten entirely unnecessary years between the first functional, proven therapy and availability of that therapy in clinics seems crazy given the immense cost of aging and age-related disease. Ideally the initial developer of a rejuvenation therapy could license the technology to groups willing to spend the excessive time and money needed to go through the regulatory hurdles put in place - largely for no good reason - by the FDA and their equivalents. Then that developer can focus on putting the therapy into clinics immediately through other channels. This is not a novel idea. It is exactly what happened during the early stages of clinical availability of stem cell therapies outside the US and Europe, in the years immediately following the turn of the century. That produced a great deal more data and beneficial results for patients that would have been the case had everyone followed the demands of regulators. It took the FDA a decade to approve any sort of stem cell therapy in the US, and that only happened because those therapies were widely available in many other countries, making regulators in the US look backward and obstructive. That is really the only way to improve regulation, to work around it, make it irrelevant, and make the actions of the bureaucrats involved appear exactly as foolish and malign as they are.

The first set of narrow rejuvenation therapies capable of repairing a slice of the damage that causes aging either work now or are only a year or two away away from working implementations. What are the paths to getting them into clinics and accessible via medical tourism shortly thereafter rather than locked away in the regulatory process for a decade? Two roads spring to mind. The first is to follow in exactly the same footsteps as the stem cell research and development community: every clinic capable of handling stem cell therapies is only a small step away from being able to deliver infusions of enzymes or even gene therapies. Most of the existing institutions of delivery, manufacturing, certification, and training that have come into being over the past decade could be utilized to deliver rejuvenation treatments alongside stem cell therapies. It isn't a big leap, and there are likely many solid and reputable allies to be made along the way. Stem cell therapies are a big business in many parts of the world now, such as India, China, and other Asia-Pacific countries, and the provision of such therapies is a maturing industry with players at every size, from hospitals to individual practices to associations and advocacy groups.

The second option is to engage with the big networks of the "anti-aging" industry, which currently sells exactly nothing (other than perhaps exercise and advice on calorie restriction) worthy of the name. This large and very vocal industry is the result of enthusiasm for intervention in the aging process that started in the 1970s, well in advance of any ability for medical science to produce meaningful results. It is a great example of the way in which it is possible to succeed in business while failing to achieve any of the original goals that drove the launch of that business. Having produced a pipeline and a network, and finding thereafter that there was no such thing as an "anti-aging" treatment at that time, this space became filled with a mix of nonsense, fraud, and useless frippery, pills, potions, and lies. The nonsense won't magically vanish overnight with the advent of real rejuvenation therapies, but if you go dig through the materials available via organizations such as the Life Extension Foundation or the American Academy of Anti-Aging Medicine, you'll see that there are thousands of physicians involved in this business. Of these, many are associated with clinics capable of delivering mass-produced infusions and gene therapies, and have experience with established mechanisms of provision, training, and certification. More to the point this is an industry with a fair degree of centralization in its points of contact, the conferences and industry groups like A4M are good ways for a developer of actual, real rejuvenation treatments to reach this market.

The question here is whether the intangible costs of the second option are worth the benefits. Is the "anti-aging" marketplace so terrible that it is capable of sinking a legitimate rejuvenation therapy and company by mere association? If plastic surgeons or "anti-aging" clinics start to sell senescent cell clearance injections in addition to their normal wares, is that the good chasing out the bad, or the good being corrupted and confused in the public eye so that support for progress in the medical control over aging becomes even harder to obtain? It is hard to say one way or another - it is one of those things that probably depends on the details.

This is an intriguing study in mice in which researchers explore exactly which structures must be regrown and recovered in the brain in order to restore access to memories lost to the progression of Alzheimer's disease - or, indeed, any other form of neurodegeneration. It is a great example of the growing level of control over fine neural structures in living individuals that is made possible by the latest biotechnologies and an increased understanding of the biochemical basis for memory.

Loss of long-term memory for specific learned experiences is a hallmark of early Alzheimer's disease (AD) that is also exhibited by mice genetically engineered to develop AD-like symptoms. Building on their previous work that identified and activated memory cells, researchers have now shown that spines - small knobs on brain-cell dendrites through which synaptic connections are formed - are essential for memory retrieval in these AD mice. Moreover, fiber-optic light stimulation can re-grow lost spines and help mice remember a previous experience.

Mouse memory is often inferred from learned behavior, in this case associating an unpleasant footshock with a particular cage. Remembering and expecting shocks causes mice to freeze in this enclosure but not in a neutral one. Compared with normal mice, AD mice exhibited amnesia and reduced freezing behavior, indicating progressive memory loss. The engrams, or memory traces, of this particular experience are known to be located in the dentate gyrus of the hippocampus, a key brain area for memory processing. During fear conditioning, researchers used a virus to deliver a gene into the dentate gyrus, which labeled active engram cells. This allowed researchers to visually identify the neurons that made up the engram for that specific fear memory. A second virus contained a gene making only these engram neurons sensitive to light. When the engram cells were reactivated with light in the AD mice, memory of the footshock experience became retrievable and freezing behavior was restored.

Memories restored with this method faded away within a day, and the researchers next sought to understand why this happens. They noted a reduction in the number of spines as the mice aged and their Alzheimer's disease progressed. Their waning memory for the fear training was also linked to a loss of these spines. Previous work had shown that spines grow when neurons undergo long-term potentiation, a persistent strengthening of synaptic connectivity that happens naturally in the brain but can also be artificially induced through stimulation. Through repeated stimulation with high-frequency bursts of light to the hippocampal memory circuit in AD mice, the team was able to boost the number of spines to levels indistinguishable from those in control mice. The freezing behavior in the trained task also returned and remained for up to six days. The implication is that restoring lost spines in the hippocampal circuit facilitated retrieval of the specific fear experience and its associated freezing behavior. Light stimulation did not boost the number of spines in normal mice or strengthen the fear memory, nor did indiscriminately shining light in the dentate gyrus result in any long-term memory improvement. Only the precise stimulation of engram cells was able to increase the number of spines and bring about the memory improvement in AD mice.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=162096&CultureCode=en

Researchers have demonstrated a successful and fairly straightforward stem cell therapy for osteoporosis in mice, though it remains a question mark as to exactly how it works under the hood. Osteoporosis is the name given to the age-related loss of bone mass and strength, with the primary proximate cause being a growing imbalance between the activities of osteoblasts that deposit bone and osteoclasts that absorb it. There are other factors involved, such as persistent cross-linking that makes the molecular structure of bone more fragile, but so far the best results in the laboratory have arisen from increasing osteoblast activity, reducing osteoclast activity, or both in conjunction.

With age-related osteoporosis, the inner structure of the bone diminishes, leaving the bone thinner, less dense, and losing its function. But how can an injection of stem cells reverse the ravages of age in the bones? Researchers had in previous research demonstrated a causal effect between mice that developed age-related osteoporosis and low or defective mesenchymal stem cells (MSCs) in these animals. "We reasoned that if defective MSCs are responsible for osteoporosis, transplantation of healthy MSCs should be able to prevent or treat osteoporosis."

To test that theory, the researchers injected osteoporotic mice with MSCs from healthy mice. Stem cells are "progenitor" cells, capable of dividing and changing into all the different cell types in the body. Able to become bone cells, MSCs have a second unique feature, ideal for the development of human therapies: these stem cells can be transplanted from one person to another without the need for matching (needed for blood transfusions, for instance) and without being rejected. After six months post-injection, a quarter of the life span of these animals, the osteoporotic bone had astonishingly given way to healthy, functional bone. "We had hoped for a general increase in bone health. But the huge surprise was to find that the exquisite inner "coral-like" architecture of the bone structure of the injected animals - which is severely compromised in osteoporosis - was restored to normal."

The study could soon give rise to a whole new paradigm for treating or even indefinitely postponing the onset of osteoporosis. While there are no human stem cell trials looking at a systemic treatment for osteoporosis, the long-range results of the study point to the possibility that as little as one dose of stem cells might offer long-term relief. "It's very exciting. We're currently conducting ancillary trials with a research group in the U.S., where elderly patients have been injected with MSCs to study various outcomes. We'll be able to look at those blood samples for biological markers of bone growth and bone reabsorption." If improvements to bone health are observed in these ancillary trials, larger dedicated trials could follow within the next 5 years.

Link: http://www.eurekalert.org/pub_releases/2016-03/uot-sct031716.php

Some very few humans live for decades longer than the average, and the available evidence suggests that at very late age - and ever increasing frailty - genetic variation becomes an increasingly important determinant of longevity. To be clear, almost everyone with a superior genome dies before reaching a century of age: the odds of making it that far are tiny regardless of your genes. But all it takes is a small increase in those tiny odds to ensure that the present population of very old people is weighted in favor of those who are slightly more resilient. So don't imagine that this is something worth recapturing in a therapy. The study of genetics and natural variations in human longevity will, I suspect, be a transitory curio of our short era. We stand in a thin slice of history in which medical technology is advanced enough to catalog genetics and cellular biochemistry, but still too primitive to bring aging under medical control. There isn't much of a gap between those two thresholds of progress; the second follows quite quickly after the first. After rejuvenation therapies are developed, well within the lifetimes of most of those reading this today, after the creation of a comprehensive toolkit to repair all of the forms of cell and tissue damage that cause aging, few people will ever get to the point of being so damaged that their genes are relevant to how long they can survive in that reduced state. There will be little interest in the study of the condition of being aged. How many researchers study how genes affect the chance of surviving smallpox without modern treatments? Not many.

For today, however, the genetics of longevity is one of the more energetic parts of aging research, a field usually the neglected, poorly-funded stepchild of the medical research community. Genetics is a hot topic, and progress in biotechnology is causing both a dramatic fall in cost and dramatic increase in capabilities for the tools used by researchers. Great advances in gathering and understanding genetic data are made with each passing year. When you have a hammer, everything looks like a nail. Hence the existence of initiatives like Human Longevity, Inc., a well-funded young company mixing genetic data with personalized medicine and promising enhanced life spans on the horizon. I don't think they can deliver on that promise. I don't see that chasing human longevity-associated genetic variants is a path to anything other than producing larger databases with better maps of cellular biochemistry. That is an admirable course of action from a pure science perspective, but it won't lead to therapies capable of meaningfully moving the needle on human longevity. Useful treatments for aging, capable of adding decades or more of healthy life, are not going to emerge from understanding the networks of possibly hundreds of genes that make an individual slightly more rather than slightly less likely to live to 100. They are only going to arise from directly addressing the known forms of cell and tissue damage that cause aging.

As this open access paper points out, the genetic networks influencing survival at late ages are large and very complex. Studies attempting to map these networks tend to produce data that cannot be replicated in different populations, indicating very large numbers of relevant genes, each with a tiny individual effect, and all very dependent on one another and on environmental circumstances.

Genetics, lifestyle and longevity: Lessons from centenarians

While the average life expectancy in the US is approaching 80 years, the mean life span of centenarians (and super-centenarians) is about 112. As a group, they represent a distinct region of the demographic distribution among the contemporary human populations. In other words, assuming that the average human generation time is about 25, centenarians are endowed with an extra human generation time. Besides, they are known to have a better health profile relative to the people with normal life span. These distinguishing features of centenarians have prompted an interest among demographers, health scientists and the general public alike, to explore the possibilities of extending the life span of cosmopolitan population to approach that of centenarians. Therefore, we consider their distinct features from an evolutionary, genetic, developmental and environmental perspective, as these factors have been suggested to influence quantitative traits universally. First, centenarians occur at a frequency of about 1.73 and 3.43 per 10000 individuals in the U.S. and Japan respectively; hence they are rare. Second, among genetic factors, certain genotypes/alleles that are known to influence longevity are enriched among centenarians (e.g., Apo C3-CC; FOXO3a-T; CETP-VV; AdipoQ-del/del; TSHr-G and IGFr). Third, others have suggested that longevity may be a function of genomic integrity. Although evidence on this important idea is relatively sparse on centenarians, research has reported low levels of chromosomal aberrations (an index of superior genomic integrity), relative to cosmopolitan populations. It is suggested that the relatively low level of chromosomal aberrations in the "oldest old" people may be both a consequence of their genomic stability and a contributing factor to their attainment of advanced age.

At the genomic level, anywhere between 300-700 genes (or perhaps more) may be influencing longevity. Although this appears to be a large number, in a recent study on human height, which is arguably a less complex trait than longevity, it was reported that 697 variants among 423 genomic regions may be influencing the trait, and speculated that perhaps thousands may be involved. A similar argument could be advanced for longevity, because longevity as a life history and as an indeterminate trait, is influenced by traits that contribute to both viability and reproductive fitness from zygotic stage through adult stages, till death. Note that a number of genes that influence human height also influence longevity (e.g., IGF1 and mTOR) and other life-history traits, such as body weight and sexual maturity, due to pleiotropy. Life history traits often display genetic correlation due to the underlying pleiotropic effects of genes. Further, life history traits maintain allometric relationships, and consequently show trade-offs in their functional aspects. Accordingly, genes that influence longevity could exert both differential and contextual influence on specific traits as well as correlated antecedent traits during the aging process, as shown by divergent patterns of methylation among age groups. These recent discoveries on the developmental regulation of aging, among contrasting age groups, using comparative gene expression, largely compliment previous reports on genotype-phenotype relationships.

The biological basis of exceptional health and longevity among centenarians has remained unclear. The general features of exceptional longevity, however, appears to run in families, and as a group they have a natural tendency to maintain good health much of their lives. Although centenarians are found to occur at higher frequencies in certain geographical locations, their life-style may not be significantly different from individual members of cosmopolitan populations who chose to lead a healthy life-style. It is likely that centenarians differ from each other just as individuals with normal life span do. Yet, individuals with exceptional longevity may interact with environmental and lifestyle factors differently than others. This unique feature may be interpreted as a form of genotype × environment interaction. As a parsimonious explanation, from a genomic perspective, exceptional longevity of centenarians may be attributed to their superior genomic integrity, specific polymorphisms among genes such as ApoC3-CC, FOXO3aT, and CETPVV, and associated molecular genetic and physiological homeostatic mechanisms. It is likely that centenarians arise and are maintained by negative frequency-dependent selection, as this mode of selection has been shown to have slightly superior physiological mechanisms relative to more common genotypes in general populations. There may be other mechanisms, however, and needs further investigation.

It isn't hard to kill cells; "bleach works just fine," as I was told by a researcher some years ago. The challenge lies in killing only a specific set of cells in a living organism, and without greatly harming the organism in the process. Obviously something more discriminating than bleach is called for. The mainstay of the last generation of cancer therapies, chemotherapy, is a fine balance between harming cancer cells as much as possible while harming the patient as little as possible. It isn't a pleasant experience, and it does have significant and lasting negative impact. The best that can be said of it is that it is much better than the alternative. The promise of new technologies allowing delivery of therapeutics to individual cells based on their specific differences in surface or internal chemistry is that existing chemotherapy drugs can be used with minimal doses and near-absent side effects, and yet still be more efficient when it comes to removing cancerous cells. This is one example of many targeted delivery mechanisms under development or in trials:

At the heart of the new therapy is a chemotherapeutic agent called doxorubicin (dox). The drug has been a mainstay of cancer treatment for years, as it jams up DNA in the cell nucleus and prevents tumor cells from dividing. But when it's injected into the bloodstream, the drug can also kill heart muscle cells and cause heart failure. Delivering dox only to tumor cells is therefore highly desirable, but it has been a major challenge. Thus researchers have spent years developing porous silicon particles as drug carriers. The particles' micrometer-scale size and disk-like shape allows them travel unimpeded through normal blood vessels. But when they hit blood vessels around tumors, which are typically malformed and leaky, the particles fall out of the circulation and pool near the tumor. That was step one in delivering chemotherapeutic drugs to their target. But just filling such particles with dox doesn't do much good. Even if a small amount of the drug finds its way inside tumor cells, those cells often have membrane proteins that act as tiny pumps to push the drug back outside the cell before it can do any damage.

To get large amounts of dox inside the metastatic tumor cells and then past the protein pumps, researchers linked numerous dox molecules to stringlike molecules called polymers. They then infused the dox-carrying polymers into their silicon microparticles and injected them into mice that had been implanted with human metastatic liver and lung tumors. The silicon particles congregated in and around tumor sites, and once there the particles slowly degraded over 2 to 4 weeks. As they did so, the silicon particles released the dox-carrying polymer strands. In the watery environment around tumor cells, the strands coiled up into tiny balls, each just 20-80 nanometers across. That size is ideal, because it's the same size as tiny vesicles that are commonly exchanged between neighboring cells as part of their normal chemical communication. In this case, the dox-polymer balls were readily taken up by tumor cells. Once there, a large fraction was carried internally away from the dox-exporting pumps at cell membrane and toward the nucleus.

Not only is the region around the nucleus devoid of dox-removing pumps, but it typically has a more acidic environment than near the cell membrane. The researchers designed the chemical links between dox molecules and the polymer to dissolve under acidic conditions. This releases the dox at the site where its cell killing potency is highest. Up to 50% of cancer-bearing mice given the treatment showed no signs of metastatic tumors 8 months later. The results are promising enough that the researchers are planning to launch clinical trials in cancer patients within a year. The new work holds out hope for improving the effectiveness of other chemotherapy drugs as well. "There's no reason to believe you couldn't make a version of these particles with any chemotherapeutic agent."

Link: http://www.sciencemag.org/news/2016/03/nano-balls-filled-poison-wipe-out-metastatic-cancer-mice

Longevity associated genes are not in fact robustly longevity-associated, as this study demonstrates, the researchers failing to find an association for even the very few gene variants thought to be fairly reliable in other data. The overwhelming majority of associations found between gene variants and human longevity have very small effects and cannot be replicated in different study populations, even in the same region of the world. This means that the impact of any individual gene variant on human longevity is tiny at best and non-existent at worst, and in either case that small effect is very dependent on other factors, either genetic or environmental. This suggests to me that comparative genetics, such as the study of centenarian biochemistry and cellular metabolism, is not a field with the potential to move the needle on human longevity; translating small and dubious effects into therapies capable of reproducing those effects just doesn't make sense when there are other, much better approaches to the treatment of aging.

In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1 / insulin-like growth factor 1 / insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14.

Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health.

Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.

Link: http://dx.doi.org/10.1016/j.exger.2016.03.001

In the paper linked below, the authors report on an attempt to make senescent cells less damaging to surrounding tissues and overall health by modulating their behavior via inhibition of TNF-α, a signaling molecule involved in inflammation. Senescent cells accumulate with age and secrete a mix of molecules - the senescence-associated secretory phenotype (SASP) - that cause all sorts of harmful effects. The more senescent cells there are in any given part of the body, the worse the outcome: chronic inflammation, tissue dysfunction, and raised cancer risk are among the consequences. Accordingly, the presence of senescent cells is known to contribute to the development and pathology of most of the common age-related conditions. Removal of senescent cells has been shown to extend life in mice, but among the researchers who work in this field, there is in fact no great consensus that removal is the best approach. This approach is being taken nonetheless, and two startups, Oisin Biotechnologies and UNITY Biotechnology, are working on commercial development of their approaches to selective destruction of senescent cells. Still, there are those who would rather aim at using pharmacology to adjust the behavior of senescent cells to suppress the worst aspects of their behavior.

For my money, I want to see destruction rather than manipulation. It absolutely and definitely gets rid of whatever bad things senescent cells might be doing, including all the bad things that the research community is still the process of cataloging, or don't yet know about. The recent life span study in mice gives us a good assurance that the useful contributions that senescent cells may be making to our health, such as their roles in wound healing and reduction of cancer risk when they are few in number, are not going to be impacted significantly by periodic clearance. Manipulation of cell behavior, on the other hand, doesn't have an auspicious history of producing more than incremental gains. The way things tend to work is that researchers find a mechanism, often via gene engineering in mice, that produces some beneficial outcome. They then dig through the catalog of approved medicines, herbs, and other odds and ends in search of something that adjusts the same gene or protein level to some degree, while causing side-effects that are not unbearable. At the end of the day, a very diluted effect is the median outcome, achieved at great cost.

So given the option between (a) a straightforward effort that can rid of senescent cells and their effects near-entirely, and which already has methods under development, and (b) the standard lengthy and expensive drug development process that in the end may produce a modest reduction in the harmful output of senescent cells, and which currently has no good drug candidate in the works, the first of those choices sounds a lot better to me. Still, as I mentioned, a fair number of researchers are focused not on removal of senescent cells but rather on tinkering with adjusting the metabolism of senescent cells so as to reduce the impact of the senescence-associated secretory phenotype. Here is one example:

Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

The senescence status of stromal cells, including endothelial cells (ECs), plays a major role in inflammaging, the low-grade, chronic, and systemic inflammatory condition associated to aging. Cellular senescence is related to the acquisition of a discrete phenotype, the so called senescence-associated secretory phenotype (SASP), characterized by the activation of a pro-inflammatory transcriptional program. Accordingly, the pathways involved in SASP acquisition, as the NF-kB and the IL-1/NLRP3 inflammasome pathways are master modulators of the aging rate. Notably, removal of senescent cells in animal models, is able to prolong lifespan and healthspan. Evidence that the number of senescent dermal fibroblasts correlates with the presence of some age-related diseases has also been reported in humans.

Interventions directed at preventing the adverse effects associated with the SASP are being explored The most promising strategies involve delaying cellular senescence; SASP switch-off; and selective removal or killing of existing senescent cells. Even though SASP involves the release of hundreds of molecules, like interleukin (IL)-1, IL-6, IL-8, tumor growth factor (TGF)-β, and tumor necrosis factor (TNF)-α, the most common and best characterized. Some of these cytokines can induce or reinforce the senescent phenotype by acting in autocrine and paracrine manner, spreading senescence via a "bystander effect." However, TNF-α inhibition in relation to EC senescence and SASP acquisition has not been already extensively explored yet. TNF-α can promote senescence in endothelial progenitor cells and human umbilical vein endothelial cell (HUVEC) cultures, and it has well-known adverse effects on endothelial function in vivo. However the molecular basis for these effects has not been fully elucidated yet.

Here we tested whether TNF-α blockade can reduce the acquisition of the senescent phenotype and/or the SASP by HUVECs, an in vitro EC model. We documented that inhibition of TNF-α activity in ECs undergoing replicative senescence attenuated the SASP. Importantly, anti-TNF-α treatment also induced eNOS up-regulation, suggesting an enhanced endothelial function. Interestingly, these significant effects induced in HUVECs undergoing replicative senescence were not associated with significant decrease of classic senescence biomarkers, such as SA-β-Gal, p16/Ink4a, and PAI1.

Some studies have described the possibility of dissociating experimentally the SASP from senescence. Although a number of reports have shown that SASP modulation influences the rate of senescence, differences have been observed depending on the cytokines involved. In our experimental model, i.e. HUVECs undergoing replicative senescence, the number of senescent cells was not significantly affected by continuous anti-TNF-α treatment, suggesting that TNF-α is not closely associated with the arrest of replicative growth. Although it has been demonstrated that IL-1 or TGF-β blockade can attenuate SASP spread in different senescence models, data on anti-TNF-a treatment were scarce and inconclusive. The present findings now indicate that anti-TNF-α treatment can restrain the SASP without significantly affecting senescence signal transmission, either autocrine or paracrine.

In conclusion, anti-inflammatory treatments capable of restraining the SASP could contribute to delay age-related disease onset and progression, especially in patients with an established chronic inflammatory background. Clearly, TNF-α inhibition has too many side effects to be administered as a clinical anti-aging treatment in old patients. However, the present findings are in line with earlier reports that it is possible to dissociate the SASP from senescence, and encourage the search for substances, synthetic or natural, that not only suppress but also restrain the SASP. Our data adds a piece to the complex puzzle of inflammaging, furthering our knowledge of the mechanisms controlling the SASP in ECs and the associated chronic inflammation that can promote the development and progression of the major age-related diseases.

In recent years, researchers have used decellularization to strip cells from rat hearts, leaving behind the intact and intricate extracellular matrix structure, and then rebuilt a functional heart by seeding it with new cells. This approach has the potential to create patient-matched donor organs with minimal issues of immune rejection when transplanted, but there is still work to be done in order to reliably carry out the process in human hearts:

Researchers have taken some initial steps toward the creation of bioengineered human hearts using donor hearts stripped of components that would generate an immune response and cardiac muscle cells generated from induced pluripotent stem cells (iPSCs), which could come from a potential recipient. Using a scaled-up version of the process originally developed in rat hearts, the team decellularized 73 hearts from both brain-dead donors and from those who had undergone cardiac death. Detailed characterization of the remaining cardiac scaffolds confirmed a high retention of matrix proteins and structure free of cardiac cells, the preservation of coronary vascular and microvascular structures, as well as freedom from human leukocyte antigens that could induce rejection. There was little difference between the reactions of organs from the two donor groups to the complex decellularization process.

Instead of using genetic manipulation to generate iPSCs from adult cells, the team used a newer method to reprogram skin cells with messenger RNA factors, which should be both more efficient and less likely to run into regulatory hurdles. They then induced the pluripotent cells to differentiate into cardiac muscle cells or cardiomyocytes, documenting patterns of gene expression that reflected developmental milestones and generating cells in sufficient quantity for possible clinical application. Cardiomyocytes were then reseeded into three-dimensional matrix tissue, first into thin matrix slices and then into 15 mm fibers, which developed into spontaneously contracting tissue after several days in culture.

The last step reflected the first regeneration of human heart muscle from pluripotent stem cells within a cell-free, human whole-heart matrix. The team delivered about 500 million iPSC-derived cardiomyocytes into the left ventricular wall of decellularized hearts. The organs were mounted for 14 days in an automated bioreactor system that both perfused the organ with nutrient solution and applied environmental stressors such as ventricular pressure to reproduce conditions within a living heart. Analysis of the regenerated tissue found dense regions of iPSC-derived cells that had the appearance of immature cardiac muscle tissue and demonstrated functional contraction in response to electrical stimulation. "Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial patch that could replace cardiac tissue damaged due a heart attack or heart failure. Among the next steps that we are pursuing are improving methods to generate even more cardiac cells - recellularizing a whole heart would take tens of billions - optimizing bioreactor-based culture techniques to improve the maturation and function of engineered cardiac tissue, and electronically integrating regenerated tissue to function within the recipient's heart."

Link: http://www.massgeneral.org/News/pressrelease.aspx?id=1910

Researchers here report on one of many attempts to slow aging via manipulation of antioxidant levels in cells, finding that the results are gender-specific. Over the past decade there have been mixed results from animal studies that use gene therapy and other methods to increase antioxidant levels in various parts of the cell. The idea is to reduce oxidative damage associated with aging, but it is not at all obvious that this is the mechanism by which aging is slowed in those approaches that do modestly extend life. The reactive oxidant molecules that cause damage are also signals, so changing the levels of these signals can have all sorts of effects on cellular metabolism, both positive and negative, and not all of which are fully understood at the present time. For example the general introduction of antioxidants throughout cells removes the benefits of exercise, as it blocks the mild increases in oxidative damage that the body reacts to in order to create those benefits. Targeting antioxidants to mitochondria only has produced modestly extended life spans with greater reliability, however.

The gradual accumulation of cell damage plays a very important role in the origin of ageing. There are many sources of cellular damage, however, which ones are really responsible for ageing and which ones are inconsequential for ageing is a question that still lacks an answer. The Oxidative Hypothesis of Ageing - also known as the Free Radicals Hypothesis - was put forward in 1956. Since then, the large majority of attempts to prove that oxidative damage is relevant for ageing have failed, including multiple clinical trials in humans with antioxidant compounds. For this reason, although the accumulation of oxidative damage with ageing is undisputed, most scientists believe that it is a minor, almost irrelevant, cause of ageing.

A group of scientists have tried to increase the global antioxidant capacity of the cells, rather than just one or a few antioxidant enzymes. To achieve this global improvement in the total antioxidant capacity, researches have focused on increasing the levels of NADPH, a relatively simple molecule that is of key importance in antioxidant reactions and that, however, had not been studied to date in relation to ageing. The researchers used a genetic approach to increase NADPH levels. In particular, they generated transgenic mice with an increased expression throughout their bodies of one of the most important enzymes for the production of NADPH, namely, glucose-6-phosphate dehydrogenase (or G6PD). "As anticipated, the cells in these transgenic animals are more resistant to highly toxic artificial oxidative treatments, thus proving that an increase in G6PD really improves antioxidant defences."

Furthermore, when researchers analysed long-lived transgenic animals, they noted that their levels of oxidative damage were lower than in non-transgenic animals of the same age. They also studied the propensity of these animals to develop cancer and found no difference, suggesting that enhancing G6PD activity does not have an important effect on the development of cancer. The greatest surprise for the team was when they measured the ageing process in the transgenic mice: the animals with a high G6PD expression and, therefore, high levels of NADPH, delayed their ageing, metabolised sugar better and presented better movement coordination as they aged. In addition, transgenic females lived 14% longer than non-transgenic mice, while no significant effect on the longevity of males was observed.

Link: https://www.cnio.es/ing/publicaciones/a-global-increase-in-antioxidant-defences-of-the-body-may-delay-ageing-and-its-diseases

Here I'll point out a recent and very readable open access review on the topic of mitochondrial contributions to the aging process. If you'd like a high level tour of present mainstream research community thinking on the numerous mechanisms that link or may link mitochondria to aging, this is a good place to start. Where it falls down, as is often the case, is in the process of moving from the data, that mitochondria contribute to aging, to what to do about the data, meaning strategies for the development of therapies to address mitochondrial dysfunction. When considering that goal, most present research groups immediately reach for pharmaceutical development with an eye to altering mitochondrial activities, such as by artificially recreating some of the calorie restriction response known to both reduce mitochondrial dysfunction and slow aging. The anticipated outcomes are not ambitious - a modest slowing in the progression of dysfunction at best - while the costs and uncertainties of pharmaceutical development to manipulate aspects of cellular metabolism remain as great as ever.

Mitochondria swarm in their hundreds inside each of our cells. They are the remnants of symbiotic bacteria from the earliest era of evolution, over time losing all but a fraction of their original genome. That remnant mitochondrial DNA (mtDNA) passes from mother to offspring, and there are a comparatively small number of varieties across the entire human population, each springing from a single ancestral mutation. Mitochondria multiply like bacteria, and are culled when damaged by quality control mechanisms inside the cell. They also merge, promiscuously swap protein assemblies and DNA, and can even transfer between cells, all of which makes understanding their behavior and the consequences of that behavior quite the challenge. Mitochondria play numerous crucial roles in the cell: they generate fuel for cellular processes in the form of adenosine triphosphate (ATP), and steer forms of programmed cell death such as apoptosis, for example.

In the SENS view of mitochondria in aging, it is the mitochondrial DNA that is critical. This DNA is both less stringently maintained than is our nuclear DNA and more vulnerable to damage. It sits right next to the highly energetic process of ATP production inside each mitochondrion, a process that produces reactive, potentially damaging molecules as a side-effect. Some rare forms of damage to mitochondrial DNA can deny necessary protein machinery to the mitochondrion, and as a result spawn dysfunctional mitochondria that are unfortunately also resilient to removal by quality control mechanisms. The damage multiples every time such a mitochondrion divides and replicates its broken DNA. These damaged mitochondria can quickly take over their cell, turning it into a source of damaging, reactive molecules that can spread throughout tissues and the bloodstream. The count of these cells grows with age: it is all a numbers game, a rare event that happens often enough to create a small class of cells that contribute significantly to age-related disease and dysfunction.

The complete fix for this particular contribution to the aging process, rather than just slowing it down, is to find some way to reliably and globally deliver the missing proteins that are encoded by broken mitochondrial genes. The possible approaches include: gene therapy to deliver new mitochondrial DNA or destroy the broken DNA; delivery of entire fresh mitochondria so that cells can adopt them; direct treatment with the necessary proteins, wrapped in delivery mechanisms that can get them to the mitochondria where they are needed; or the present SENS methodology of allotopic expression in which gene therapy is used to deliver suitably edited versions of mitochondrial genes into the cell nucleus, creating a permanent backup supply of the necessary protein machinery. These are all works in progress, but allotopic expression of single mitochondrial genes to treat inherited mitochondrial disease has, with the help of SENS Research Foundation funding some years ago, now reached the stage of serious biotech industry development. None of this is mentioned in the review paper below, and this is typical of much of the research community, sadly.

The Mitochondrial Basis of Aging

While, from an evolutionary viewpoint, the notion of antagonistic pleiotropy has been exclusively applied to our genetic inheritance, it actually provides a useful framework to understand the role of mitochondria in aging. Perhaps, no structure is so intimately and simultaneously connected to both the energy of youth and the decline of the old. The revelation of these complex and antagonistic functions of mitochondria has slowly transformed how we view this subcellular organelle. Mitochondria can no longer be viewed as simple bioenergetics factories but rather as platforms for intracellular signaling, regulators of innate immunity, and modulators of stem cell activity. In turn, each of these properties provides clues as to how mitochondria might regulate aging and age-related diseases.

It has been long appreciated that aging in model organisms is accompanied by a decline in mitochondrial function and that this decline might, in turn, contribute to the observed age-dependent decline in organ function. Similarly, a decline in mitochondrial function in humans has also been observed; again, this decrement may predispose humans to certain age-related diseases. It is also known that mitochondrial mutations increase in frequency with age in both animal models and in humans, although the levels and kind of mutations appear to differ between tissues and even within tissues. While some have speculated that the increased levels of mitochondrial mutations contribute to aging and age-related diseases, others have questioned whether these mutations ever reach a significant enough level to contribute to the aging process.

Mitochondria as Regulators of Stem Cell Function

While aging is accompanied by a general decline in mitochondrial function in all tissues, the effects of mitochondrial dysfunction might be particularly important within certain specialized cell types. Since a decline in adult stem cell function is thought to contribute to various aspects of aging, the role of mitochondrial dysfunction in stem cell biology has become a subject of increasing interest. One clear connection between mitochondria and stem cell function has come from the analysis of mtDNA mutator mice. Several reports have analyzed the stem cell function of these mice and found a range of defects. It should also be noted, that the level of mitochondrial mutation seen in these models is also dramatically higher than that seen during the normal aging process, which may account for why the observed stem cell defects do not faithfully recapitulate what is seen during normal aging.

Mitochondria and Cellular Senescence

There is a strong link between mitochondrial metabolism, reactive oxygen species (ROS) generation, and the senescent state. Almost four decades ago, it was noted that the lifespan of human cells in culture could be significantly extended by culturing the cells in a low-oxygen environment. Similar relationships have been observed between other regulators of senescence and ROS, including the p53 target and cell-cycle regulator p21, which also appears to regulate senescence in a redox-dependent fashion. All of these observations fit well with the long-standing notions of the free-radical theory of aging that postulated a causal role for ROS in the aging process. Nonetheless, there are a number of observations that suggest that the cellular effects of ROS, with regard to inducing senescence, do not unequivocally transfer to organismal aging.

The Mitochondrial Unfolded Protein Response and Longevity

The mitochondrial unfolded protein response (UPRmt) is a stress response pathway initially characterized in mammalian cells in which there was either a depletion of the mitochondrial genome or accumulation of misfolded proteins within the mitochondria. In either case, it was noted that this mitochondrial perturbation triggered a nuclear transcriptional response that included the increased expression of mitochondrial chaperone proteins. While initially described in mammalian cells, the biochemistry and genetics of this pathway have been predominantly studied in C. elegans. It is now clear that the UPRmt regulates a large set of genes that not only involve protein folding but also involve changes in ROS defenses, metabolism, regulation of iron sulfur cluster assembly, and, modulation of the innate immune response. In general terms, all of these changes allow for a restoration of mitochondrial function while, at the same time, re-wiring the cell to temporarily survive as best as possible without the benefit of full mitochondrial capacity.

Mitophagy in Aging

If misfolded proteins stemming from mtDNA mutations or proteotoxic stress accumulate to a level that exceeds the capacity of the UPRmt, autophagy of mitochondria (mitophagy), or piecemeal autophagy of mitochondrial subdomains, appears to mitigate mitochondrial impairment. Consistent with the suggestion that mitophagy protects animals from loss of mitochondrial function during aging, mitophagy rates decrease in the dentate gyrus with age and upon human huntingtin overexpression.

Mitochondria and Inflammation

One of the hallmarks of aging is the development of a low-grade, chronic, sterile inflammatory state often deemed "inflammaging". The development of this state, characterized in part by increased circulating inflammatory biomarkers such as interleukin (IL)-6 and C-reactive protein, is a known risk factor for increased morbidity and mortality in the elderly. Increasingly, there is a connection between mitochondrial function and the activation of this enhanced age-dependent immune response. Mechanistically, this connection can, perhaps, be traced back to the bacterial origins of the present-day mitochondria. As opposed to nuclear DNA, mtDNA (like bacterial DNA) is not methylated. The immune system has adapted to this subtle difference and has evolved strategies to recognize non-methylated DNA, primarily through members of the Toll-like receptors, including TLR9. Presumably, this response allows rapid activation of the immune system in the setting of bacterial infection. Besides releasing non-methylated DNA, damaged mitochondria, like bacteria, can release formyl peptides that can signal through the formyl peptide receptor-1 to trigger an immune response. Both mtDNA and mitochondrial formylated peptide can be viewed as mitochondrial-derived damage-associated molecular patterns (DAMPs) that are known to stimulate the innate immune system.

Conclusions

Taken together, these observations suggest that mitochondria can be intimately linked to a wide range of processes associated with aging, including senescence and inflammation, as well as the more generalized age-dependent decline in tissue and organ function. In many of the early studies, the association between mitochondria and the aging process was mostly correlative. Increasingly, however, causative connections are being established. This suggests that attempts to rejuvenate mitochondrial function or improve mitochondrial quality control might be an effective strategy to combat aging. Toward this goal, there are a number of ongoing efforts to develop small molecules to therapeutically augment mitochondrial biogenesis. Similarly, raising NAD+ levels in older mice appears to restore mitochondrial function. As such, there is considerable enthusiasm to develop methods to increase NAD+ levels, either through direct supplementation or by altering NAD+ metabolism. Pharmacologic activation of mitophagy is another approach that might be widely beneficial in patients with age-related neurodegenerative disorders or to combat aspects of normal aging. As such, the next decade appears to hold considerable promise for developing a wide range of effective mitochondria-targeted therapies. With such agents, clinical trials can ultimately test the very tenable hypothesis that reversing the decline in mitochondrial function will slow, or even reverse, the rate at which we age.

It is presently technically feasible to build small medical implants made of a mix of electronics, processors, drug manufactories, and tissues, which can be self-regulating or connected via wireless to external computing systems. The heavy hand of regulation in the medical industry ensures that such development in the field is far behind where it might be, particularly in matters of network security for medical technologies, but progress in the labs isn't as constrained - there is still some room there to build on the basis of what is possible rather than what regulators permit. Even in recent years most bioartificial implants under development have been much more device than tissue, such as those intended to replicate some of the functions of the pancreas, for example, but in this case researchers aim at building patches for damaged and aged hearts that are mostly cells with a thin layering of artificial components:

The bionic heart patch combines organic and engineered parts. In fact, its capabilities surpass those of human tissue alone. The patch contracts and expands like human heart tissue but regulates itself like a machine. "Until now, we could only engineer organic cardiac tissue, with mixed results. Now we have produced viable bionic tissue, which ensures that the heart tissue will function properly. We first ensured that the cells would contract in the patch, which explains the need for organic material. But, just as importantly, we needed to verify what was happening in the patch and regulate its function. We also wanted to be able to release drugs from the patch directly onto the heart to improve its integration with the host body."

For the new bionic patch, researchers engineered thick bionic tissue suitable for transplantation. The engineered tissue features electronics that sense tissue function and accordingly provide electrical stimulation. In addition, electroactive polymers are integrated with the electronics. Upon activation, these polymers are able to release medication, such as growth factors or small molecules on demand. "Imagine that a patient is just sitting at home, not feeling well. His physician will be able to log onto his computer and this patient's file - in real time. He can view data sent remotely from sensors embedded in the engineered tissue and assess exactly how his patient is doing. He can intervene to properly pace the heart and activate drugs to regenerate tissue from afar. The longer-term goal is for the cardiac patch to be able to regulate its own welfare. In other words, if it senses inflammation, it will release an anti-inflammatory drug. If it senses a lack of oxygen, it will release molecules that recruit blood-vessel-forming cells to the heart."

Link: http://www.eurekalert.org/pub_releases/2016-03/afot-ccp031416.php

Age-related macular degeneration is a condition that causes progressive blindness. The less common wet variety of macular degeneration is characterized by an excessive and damaging growth of blood vessels in the retina. Researchers here map some of the signals and changes that take place in response to dysfunctional energy metabolism in retinal cells, seeing this as a cause of the condition:

Both wet age-related macular degeneration (AMD) and macular telangiectasia are caused by abnormal growth of misshapen, leaky blood vessels in the eye's retina. It's widely believed this growth is triggered by oxygen deprivation. However, new findings suggest another cause: dysfunctional energy metabolism in the eye that starves the retina's light receptors of fuel. Photoreceptors consume a surprising amount of fuel. They have the highest concentration of mitochondria and use more energy than any other cell in the body. They have to be 'on call' all the time to signal light perception and have to recycle their components constantly. Because of this, photoreceptors have evolved a special system to ensure they get enough fuel. While these cells were assumed to be powered by glucose, the study showed that photoreceptors also need lipids, or fats. They have special receptors to take up fatty acids, as well as a special lipid sensor, FFAR1, that curtails glucose uptake when fatty acids are available.

When blood lipids are elevated, the lipid sensor FFAR1 shuts off glucose uptake inappropriately. The energy-starved photoreceptors then call for new blood vessels to bring them nutrients by secreting large amounts of vascular endothelial growth factor (VEGF). This signaling protein is known to encourage abnormal blood-vessel formation in macular disease. VEGF blockers exist and already being used in AMD, but they have systemic side effects, preventing healthy, necessary growth of blood vessels. "If you go upstream of VEGF and solve the energy problem early, it could be more effective and safer." It may be possible to do that by blocking the lipid sensor, FFAR. In experiments where researchers did this, cells were able to keep taking in glucose and the mice had far fewer diseased vessels. The transporter that brings glucose into cells is another potential target, but is harder to reach with drugs, whereas FFAR inhibitors are already in clinical trials for diabetes.

The researchers believe that fuel starvation contributes to age-related macular disease due not only through lack of fuel but also decreased energy efficiency in mitochondria as people age. Abnormal lipid metabolism and mitochondrial dysfunction are both associated with aging and are important risk factors for AMD. The next steps will be to see if people have lipid sensors similar to those in mice. If so, existing inhibitors could be tried in clinical trials.

Link: http://www.eurekalert.org/pub_releases/2016-03/bch-anv031416.php

Today I'll point out a couple of recent technology press articles in which Aubrey de Grey of the SENS Research Foundation discusses recent progress and a few aspects of the expected near future of rejuvenation therapies. Money, as ever, occupies a large portion of the picture. Funding the right lines of research is critical to progress in medical technology, and the road towards human rejuvenation, towards creating the envisaged therapies capable of repairing the molecular damage that causes aging and age-related disease, is no exception to this rule. Funding, persuasion, public support, and public attention are all intertwined, however. The potential for meaningful progress towards rejuvenation therapies has existed since at least the 1990s, yet has only just started in earnest these past few years. Progress has been incremental and slow, the funding very thin on the ground. This is because little attention was given to aging research, and in a public space dominated by the flim-flam of the "anti-aging" industry, legitimate longevity science simply wasn't taken seriously. To bootstrap a new movement, which is exactly what has taken place for the SENS approach to rejuvenation research over the past decade, you really have to dig in to the ways in which persuasion, publicity, and the availability of funding all depend upon one another. There is a reason that bootstrapping is hard and takes time when starting out with little in the way of either support or resources.

The scientific and advocacy communities have come a long way since I started following the research and writing on the topic. It is easy to forget just how fringe was the idea of undertaking serious efforts to rejuvenate humans ten to fifteen years ago, and how much of a struggle it was to raise even a million dollars over a period of some years to get started on small scientific projects. For all that there remains a lot to accomplish and a long way to go yet towards the goal of the first comprehensive suite of rejuvenation treatments, it is tremendously empowering to see that all the past efforts - the years of hard work for few immediate gains at the outset of the bootstrapping process - have come to something. The wheel is turning and speeding, more people are joining the community and helping out, and there are actual SENS rejuvenation technologies in trials and startup companies, with the likelihood of more to come in the next few years. This is still only the beginning of the story. But for those of us who were striving to get the wheel to move at all some years ago, it is a rewarding time to be in the field.

Aubrey de Grey: Aging Research "Moves on Almost Every Week"

It's an exciting time to be working in ageing research. New findings are coming thick and fast, and although eliminating the process in humans is still some way away, studies regularly confirm what some have suspected for decades: that the mechanisms of ageing can be treated. "It's an amazingly gratifying field to be part of," says biomedical gerontologist Aubrey de Grey, chief science officer and founder of SENS Research Foundation, the leading organisation tackling ageing. "It moves on almost every week at the moment."

At the start of February, for example, a study was published that had hugely significant findings for the field. "There was a big announcement in Nature showing that if you eliminate a certain type of cell from mice, then they live quite a bit longer. Even if you do that elimination rather late; in other words when they're already in middle age." For those following the field, this was exciting news, but for de Grey, it was concrete proof that ageing can be combated. "That's the kind of thing that I've been promoting for a long time, and it's been coming but it's been pretty tricky to actually demonstrate directly. This was really completely unequivocal proof of concept," he says. "So of course it motivates lots of work to identify ways to do the same thing in human beings. These kinds of things are happening all the time now."

Funding for ageing research is forever in short supply. SENS is always asking for donations, and there is always more research to be done than there is money to fund it. However, this is starting to improve, both for SENS and for other institutions engaging in this field of research. In particular, the investment community has shown growing interest in ageing research. February's breakthrough findings were funded by private investors, and SENS, too, is spinning out some of its research into companies. The growing involvement of private investors is, according to de Grey, evidence of the changing perceptions of ageing research. "Not only is the science moving forward, but the appreciation of the science within the investor community is also moving forward. And that is absolutely critical to what we can expect to see in the future."

Reversing old age won't just be for rich people, says visionary biologist

Living longer "is the thing that's going to matter the most to people, Aubrey de Grey says, comparing it to the "It's the economy, stupid," tagline that Bill Clinton used on his road to the White House in 1992. "Ultimately, this is what people are going to vote for," he says. "If it's not available to everybody, then a party that has a manifest commitment to making it for everybody is going to get elected."

Then there are the economics of aging. "At the moment, when people get sick, it's incredibly expensive," de Gray says. "Probably 90% of the medical budget of the industrialized world goes to the diseases and disabilities of old age one way or another. That's trillions and trillions of dollars. If we can stop people from going that way by only spending billions of dollars, it's a big net win."

Additionally, if people can stay able bodied into their 80s, 90s, and beyond, then they can keep contributing their wealth to society, he says. Adding to collective wealth rather than drawing from it - which is why the "graying" of countries like Japan puts so much stress on an economy. "Therapies will pay for themselves in no time at all. and that means from a government's point of view, even the government of a really tax-averse country like the USA, it would be economically suicidal not to frontload the investment to ensure that everyone got these therapies as soon as possible." So living longer wouldn't just be a luxury good; it would be, to borrow from Bill Gates, a global public good.

In many ways the instinctive opinions that people hold on the economics of rejuvenation therapies are just as strange as their instinctive opinions on the desirability of rejuvenation and longer healthy lives. Many people say that they don't want to live a long time, and indeed don't want to live any longer than their parents. Similarly, most people will tell you - without really thinking about it - that longevity therapies would be enormously expensive and only available for the wealthy. This is actually far from the case.

Quite distinct from de Grey's points above, there is the fact that SENS rejuvenation therapies will be largely a matter of mass-produced infusions of small molecule drugs, enzymes, and gene therapies, the same treatment for everyone, given by a bored clinician in a brief visit once every few years. Some may be one-time treatments, such as autologous expression of mitochondrial DNA, leaving you set for life. The first senescent cell clearance treatments presently under clinical development consist of drug combinations and a gene therapy approach. Analogous treatments today, such as the biologics used to treat autoimmunity, or simple stem cell transplants, run to a few thousand per dose even in the dysfunctional US medical system. The economics of production, competition, and scale for medicine of this nature, in which all of the complexity is baked into the manufacturing process, are very different from those of enormously expensive treatments such as organ replacement and other challenging surgeries that require dedicated specialists and long periods of aftercare. Yet people continue to think that longevity therapies will be enormously expensive and reserved for the wealthy, and it seems hard to sway them from this opinion with mere logic.

This popular press article takes a look at some of the people involved in the early stage scientific foundations that will be needed to eventually run a human mind in software. Many of these advocates see mind uploading as a viable end goal for the defeat of aging - to transition away from biology entirely towards emulation of the mind in software. This has always seemed to me to be a potentially dangerous distraction from the business of ensuring personal survival. In most cases the advocates of uploading consider that making a copy of the data of the self is an acceptable form of continuation of identity, but in fact that isn't personal survival at all. The self isn't just data absent context, it is the combination of data and the particular collection of matter than encodes it: thus you are not your copy, these are two individuals made up of two separate collections of matter.

Yes, it is technically possible to transition away from biology in ways that might preserve the self. Consider a slow swapping out of neurons for nanomachines, one by one, for example, a personal Ship of Theseus in which transitions run little differently from the present processes of neurogenesis in the adult brain. That isn't the direction of interest for most of the community presently putting in effort on the very early groundwork needed to abandon our biology, however. Their aim is often simply scanning of the brain, a straight copy.

While many tech moguls dream of changing the way we live with new smart devices or social media apps, one Russian internet millionaire is trying to change nothing less than our destiny, by making it possible to upload a human brain to a computer. "Within the next 30 years," promises Dmitry Itskov, "I am going to make sure that we can all live forever." Itskov is putting a slice of his fortune in to a bold plan he has devised to bypass ageing. He wants to use cutting-edge science to unlock the secrets of the human brain and then upload an individual's mind to a computer, freeing them from the biological constraints of the body. The scientific director of Itskov's 2045 Initiative, Dr Randal Koene - a neuroscientist who worked as a research professor at Boston University's Center for Memory and Brain - laughs off any suggestion Itskov might have lost touch with reality. "All of the evidence seems to say in theory it's possible - it's extremely difficult, but it's possible. The challenge is precisely how to go from a physical substrate of cells that are connected inside this organ, to our mental world, our thoughts, our memories, our feelings."

To try to unlock its workings, many neuroscientists approach the brain as if it were a computer. In this analogy the brain turns inputs, sensory data, into outputs, our behaviour, through computations. This is where the theoretical argument for mind uploading starts. If this process could be mapped, the brain could perhaps be copied in a computer, along with the individual mind it gives rise to. That's the view of Dr Ken Hayworth, a neuroscientist who maps slivers of mouse brain at the Janelia Research Campus in Virginia by day, and by night grapples with the problem of how to upload his mind. Ken believes mapping the connectome - the complex connections of all the neurons in a brain - holds the key, because he believes it encodes all the information that makes us who we are, though this is not proven. "In the same sense that my computer is really just the ones and zeros on my hard drive, and I don't care what happens as long as those ones and zeros make it to the next computer it should be the same thing with me. I don't care if my connectome is implemented in this physical body or a computer simulation controlling a robotic body."

Ken is a realist. "We are pitifully far away from mapping a human connectome." Here Itskov might get some unexpected help, according to Prof Rafael Yuste of Columbia University - who helped bring about the world's biggest neuroscience research project, the Brain Initiative. As part of this $6bn American programme aimed at solving the mysteries of brain disorders like Alzheimer's, he is hoping to map the continual interaction of neurons - the patterns of firing - in the brain over time. Within 15 years Yuste hopes to map - and interpret - the activity of all the neurons in a mouse cortex. But the ultimate aim is to read the activity of the human brain. "If the brain were a digital computer, if you wanted to upload the mind you need to be able to decipher it or download it first. So I think the Brain Initiative is a step that is necessary for this uploading to happen."

Link: http://www.bbc.com/news/magazine-35786771

The folk leading the Major Mouse Testing Program are here interviewed on their work. This volunteer initiative aims to crowdfund mouse life span studies of useful approaches to lengthening healthy life spans in mammals, including SENS rejuvenation research methodologies as they become possible to carry out, such as senescent cell clearance. There are a fair number of such studies that could be carried out, but in most cases the few champions in the research community have struggled to raise funding and engage broader interest. This was the state of affairs for senescent cell clearance up until very recently, but no-one can really argue with the data for life extension in mice via this method that now exists - so it is certainly the case that very promising approaches for treating aging languish for lack of funding, but could be spurred forward by better data in mice.

The gap in the market we're aiming to fill is the bridge between basic research and taking it to clinical trials. People like the SENS Research Foundation are spinning a lot of plates doing the high risk, nitty gritty research that isn't profitable, but crowdfunding can get that done. We want to create a solid gold standard testing platform without the restrictions of government, where any team can come to us for parallel testing and halve development time. The problem with animal testing is there's this disconnect; it's not sexy science basically. A common response is let me know when it's available in humans, but it's not going to be! No animal data means no human testing, regulatory organizations like the FDA, NHS, and EMA all insist on a battery of animal testing before human trials. Period. It's not sexy, it's not available in humans next week, but if MMTP or other projects don't get things done on mice for example, it's never going to get done.

It's not just about the science, too many people claim to support longevity but don't actually do anything to contribute or get things moving. Right now we're pushing to promote ideas among decision makers at a wide range of levels - at the international level like the last World Health Organization Conference in Geneva and at the local level trying to stimulate the same process in multiple countries. There is a big problem with funding today, but if there's even the smallest chance to stimulate movement and make a bigger research impact, we've got to do it.

We can't rely on a traditional model of funding like the FDA, EMA and other government organizations. They may fund some ventures, but it's never going to be the avalanche of support we need to get things done in a timely manner. The pace of progress is glacial in that model. We can't afford to just preach to the choir unfortunately, we need to make bigger waves. Advanced glycation end-products (AGE) breakers for example is one treatment we'd like to explore, and AGEs are closely implicated with diabetes and atherosclerosis, which means we could potentially draw on mainstream and charity support if the data is there to support it. We've got to cast a wide net ultimately or we're not going to go anywhere near fast enough; it's that simple.

We're back to the problem of the mindset here, too many people have this idea that aging isn't amenable to intervention and yet they're quite happy to fund disease research for age-related diseases like Alzheimer's. The money is out there, but we need to be more tactical in how we pursue it. The 1st phase of testing using senolytics to clear senescent cells is quite a difficult concept to sell, but the more we learn and the more robust results we get, the more we can capture hearts and minds. No-one is taking any wages either, which it's why it's so cheap and we can achieve a lot more.

Link: http://www.longevityreporter.org/blog/2016/3/12/an-interview-with-the-major-mouse-testing-program-talking-longevity-advocacy-and-fast-forwarding-progress

Passive immunotherapy involves the delivery of an agent, such as a monoclonal antibody, that spurs the immune system to attack specific targets. This response lasts for as long as the agents are consistently delivered as a therapy, and most are short-lived molecules, meaning that passive immunotherapies are easily halted. This is thus an attractive approach in fields such as cancer treatment and amyloid clearance where there is still a fair degree of uncertainty in the differences between animal models and human patients, and trials that accidentally cause harm are rare but not unheard of. The ability to stop a treatment immediately if results are unexpected is very helpful for all involved.

In recent years researchers have been making progress in the development of useful amyloid antibodies capable of instructing the immune system to clear the amyloid β that is associated with Alzheimer's disease. To take a broader point of view, this is an important class of technology for the near future of rejuvenation therapies after the SENS model. Success against amyloid β using antibodies and passive immunization would mean that success against other forms of extracellular aggregate that contribute to the aging process is also plausible via this methodology. I think that at this point success is just a matter of time, of finding good enough antibodies or related agents, a process that unfortunately isn't turning out to be as rapid or as cheap as anyone would like it to be. In that light it is good that this line of development is attached to a comparatively well-funded field of medical research.

The first paper linked below is a great example of the way in which today's biotechnology is already catching up with the science fiction of a few decades past. Here we have living cells converted into drug manufactories, encapsulated in an implant that secretes the drug at a slow pace, and the whole set in motion to clear some proportion of unwanted metabolic waste so as to slow the pace at which dementia develops - to slow one aspect of aging by consistently removing some fraction of the damage that causes it. All of that engineering is actually the fairly reliable part of the equation, for all that it tends to sound more interesting and impressive than the biochemistry involved in producing antibodies. The challenge in this field is to find a means of control over immune activities that is much, much more effective at clearing unwanted amyloids and other forms of harmful extracellular waste than the present crop of antibodies.

A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml.

In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoforms (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly.

We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.

Here I'll point out recently published results for a cystathionine beta-synthase inhibitor drug candidate. The researchers involved have demonstrated that in rats it greatly reduces cell death in brain tissue following stroke:

Most strokes occur when a disruption of blood flow prevents oxygen and glucose from reaching brain tissue, ultimately killing neurons and other cells. The team found that its molecule, known as 6S, reduced the death of brain tissue by as much as 66 percent when administered to the cerebrum of a rat that had recently suffered a stroke. It also appeared to reduce the inflammation that typically accompanies stroke. "The fact that this inhibitor remained effective when given as post-stroke treatment is encouraging, as this is the norm in the treatment of acute stroke."

The inhibitor works by binding to cystathionine beta-synthase, or CBS - an enzyme that normally helps regulate cellular function but can also trigger production of toxic levels of hydrogen sulfide in the brain. Though hydrogen sulfide is an important signaling molecule at normal concentrations, stroke patients exhibit elevated concentrations believed to initiate the brain damage they often suffer. Researchers modeled their inhibitor on a naturally occurring molecule produced by the CBS enzyme, tailoring the molecule's structure to improve its performance. By swapping out functional groups of atoms known as amines with hydrazines, the team ultimately increased the inhibitor's binding time from less than a second to hours. "We wanted a compound that would bind well, specifically to this enzyme. But we also wanted one that could be synthesized easily. Those are two very different considerations." The team achieved the latter goal, in part, by plucking out the molecule's carbon-sulfur bond and replacing it with a double bond. Slicing that double bond gave the researchers two identical halves of the molecule.

Because the 6S inhibitor has demonstrated its effects in cell cultures and the brain tissue of rats, it represents just an initial step toward developing a stroke-treating drug for humans. However, the proof-of-principle experiments effectively illustrate the concept's promise. The researchers expressed optimism that the synthesis method detailed in the study could streamline the more general production of enzyme-targeting inhibitors. "We started out with a very fundamental-science perspective on understanding the chemistry of this whole class of vitamin B6-dependent enzymes. We're in a good place now, because that science has allowed us to make these inhibitors and many others. We're now working on several enzymes that may represent important targets for translation of the basic inhibitor chemistry into truly therapeutic goals."

Link: http://news.unl.edu/newsrooms/unltoday/article/researchers-build-molecule-to-suppress-stroke-related-enzyme/

In this short editorial, researchers summarize their exploration of a possible causative link between age-related mitochondrial dysfunction and the observed changes in cancer risk over the course of later life. This is interesting, given the assembly of evidence outlined below, but still fairly speculative at this stage:

Aging is associated with increased manifestation of many diseases. In particular, the chances of cancer increase exponentially starting from middle age. At the same time, there is a convincing evidence that in the case of certain tissues/organs the increase of cancer incidence is followed by a plateau or even a decrease of reported cases. As a rule, the decrease starts at the age above 80 years. What could be the reason for such a decline? Possibly, only a small proportion of human population is susceptible to the certain types of cancer and most of such people die at the age of 80 or younger. If so, the age group above 80 will be depleted for people prone to the cancers. Alternatively, several biological explanations for such a decrease were suggested: for instance, age-dependent decrease of angiogenesis can suppress tumor growth.

We propose that mitochondrial dysfunction is also responsible for the age-dependent changes of cancer incidences. First, mitochondrial oxidative capacity and ATP production decrease with age. The reasons for the mitochondrial dysfunction are the mutations of mitochondrial DNA (mtDNA) and a continuous expansion of mtDNAs with large deletions. Second, in aged mammals the clonal expansion is likely to be a primary source of abnormal mtDNAs rather than de novo mutations. How could mitochondria dysfunction interfere with cancer incidence and progression? On one hand, mild mitochondrial dysfunctions can be carcinogenic due to increased mitochondrial reactive oxygen species-mediated inflammation or due to inhibition of apoptosis. On the other hand, the severe ones can inhibit the proliferation of cancerous cells. It has been shown that the cells lacking mtDNA have lower tumorogenic potential compared to the ones with the mild mutations or even with intact mtDNA. This is surprising, because for their energy needs cancer cells tend to rely on glycolysis instead of oxidative phosphorylation. Our study with model eukaryotic cells - baker's yeast - provides an explanation: we found that the loss of mtDNA activates a signaling cascade that tightens the S-phase arrest of the cells caused by inactivation of telomerase. Importantly, this effect was not due to alterations in ATP supply. We speculate that such mitochondria-dependent signaling pathways play a significant role in the regulation of cell cycle progression in higher eukaryotes.

If so, it provides an explanation for the age-dependency of cancer incidences. During the development and aging of multicellular organisms various mutations appear in mtDNAs. Some of them have severe tumorogenic capacity and eventually lead to cancerous transformation of the host cells. We speculate that, with age, the severe mutations (i.e. common deletions of mtDNA) expand and prevail over the mild ones, strengthening the S-phase arrest and thus decreasing cancer incidences. Interestingly, this hypothesis explains why, during evolution, mtDNA of some higher eukaryotes (including humans) did not get rid of the repeat regions which are prone to recombination leading to the common deletions. In other words, the intrinsic instability of mtDNA may serve as a cancer-prevention mechanism.

Link: http://www.impactaging.com/papers/v8/n3/full/100923.html

The practice of calorie restriction has been shown to reliably and robustly extend life in a variety of species. It has been used for decades now as a tool to investigate the relationships between metabolism, genetic variation, cellular biochemistry, and aging. Does the life extension produced in response to calorie restriction mean that it slows aging, postpones aging, or both? What does the distinction between slowing and postponing aging even mean at the most detailed level of consideration? Attempting to answer this question means engaging with definitions of aging, whether statistical or physiological, that are all still fairly open to debate. This is well illustrated by the open access paper linked below.

Over the past twenty years researchers have discovered and demonstrated many interventions that extend healthy, mean, and maximum life spans in varied combinations and degrees in short-lived species such as nematode worms, fruit flies, and mice. The plasticity of life span in response to altered environmental, genetic, and metabolic states is inversely related to the unmodified life expectancy of the organism in question. The longer the life span, the less it changes. So while nematodes that normally live for a few weeks have been engineered to gain as much as a tenfold increase in length of life, in mice that normally live a few years the record for artificial life extension stubbornly remains stuck at the 60-70% increase achieved more than a decade ago. The researchers involved used genetic knockout of the growth hormone receptor, and by good fortune there is a small human population descended from a comparatively recent ancestor who have inherited a very similar loss of function mutation. They, much as expected, don't seem to have any obvious gain in life expectancy. We are a long-lived species in comparison to mice, and therefore our plasticity of life span in response to these sorts of alterations is much lower.

Why does plasticity of longevity scale in this way? Calorie restriction may provide the answer. The calorie restriction response most likely evolved very early in the history of life because it provides survival advantages in periods of famine. Famine takes place on seasonal or shorter time frames, and a season is a sizable chunk of the life of a mouse, but much less so for a human. Thus only the mouse evolves the ability to greatly extend life when calorie intake falls, despite the fact that both mice and humans exhibit quite similar short-term alterations in metabolic state in response to calorie restriction. Calorie restriction in mice can extend life by 40% or more, while in humans it certainly doesn't produce anywhere near that gain. There is no rigorous estimate for longevity added in humans practicing calorie restriction, and such an estimate is unlikely to emerge any time soon, but the much less rigorous process of theorizing and modeling suggests 5% as a reasonable ballpark. Anything much larger than that would appear as a strong statistical signal in many historical data sets that are known to show no such signs.

It is worth bearing in mind that when we seek to build therapies to treat aging as a medical condition, to bring it under control, the ideal goal is to postpone it, not slow it. A therapy that can postpone aging is a therapy that can be reused later to postpone aging some more. A therapy that only slows aging has no such option: it has a flat maximum benefit to life span. Postponing aging, provided it works well enough and doesn't let any aspect of aging leak though to accumulate, has an unlimited upside in terms of the years of healthy life it can add. This is one of the reasons why I'm very focused on repair of damage after the SENS model as the path ahead for the treatment of aging. Repair of the forms of cell and tissue damage that cause aging can in principle produce rejuvenation and indefinite postponement of aging, provided it can be made comprehensive enough. In comparison, work aimed at modestly slowing aging by developing drugs to beneficially alter metabolic state, meaning slowing the pace at which damage accumulates rather than repairing existing damage, has no such upside and will be of very limited utility to people who are already old and damaged.

Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

Extensive experiments have demonstrated that caloric restriction and genetic disruption of growth hormone signaling can profoundly counteract aging in mice. Caloric restriction - or dietary restriction - is an environmental intervention, whereby the usual ad libitum dietary intake is limited to an intake of 30-40% less. Mice subjected to caloric restriction can live up to 60% longer, suffer less often and at higher ages from age-associated disorders, and exhibit less molecular stress and damage. Disruption of growth hormone signaling is a genetic intervention, whereby the production of growth hormone-releasing hormone, growth hormone, or the receptor of growth hormone is impaired, so that the effects of growth hormone are annulled. Mice with disrupted growth hormone signaling can live up to 70% longer, suffer less often and at higher ages from age-associated disorders, have youthful metabolic characteristics such as a higher insulin sensitivity, and have an enhanced resistance against molecular-genetic stress and damage.

However, since age-dependent survival and life expectancy do not reveal at which ages and to what extent the risk of death increases, they conceal the effects on aging. Age-dependent mortality rates are generally fitted to the Gompertz model, after which they increase linearly with age on a logarithmic scale. The linear increase of such a modeled mortality rate is classically interpreted as an aging rate. However, the use of the Gompertz model constrains mortality rates to increase linearly on a logarithmic scale, which may not correspond with the increases in the crude age-dependent mortality rates, especially in relatively small populations. Therefore, alternative methods are needed to accurately examine the effects of interventions such as caloric restriction and genetic disruption of growth hormone signaling on age-dependent mortality rates.

According to the classical method, these interventions negligibly and non-consistently affected the aging rates. By contrast, according to the alternative method studied here, the aging rates of mice subjected to caloric restriction or disruption of growth hormone signaling increased at higher ages and to higher levels as compared with mice not subjected to these interventions. A key question in research on aging is whether increases in life expectancy reflect a postponement or a slowing of aging. The answer to this question is pivotal to gain insight in the mechanisms of aging, to identify interventions that modulate these mechanisms, and to predict the effects of such interventions on aging. However, with respect to caloric restriction and disruption of growth hormone signaling, a clear answer to this question is lacking. While caloric restriction has long been assumed to slow aging, it is debated whether it postpones aging instead. Likewise, some presume that genetic disruption of growth hormone signaling slows aging, whereas others pose that it rather postpones aging.

Our method interprets these interventions to affect the aging rates in an age-dependent manner: aging was slowed at lower ages, postponed until higher ages, but quickened at higher ages. Such a pattern resembles a compression of aging, whereby aging is postponed as well as intensified, reflected by a risk of death that increases sharply at a high age. A compression of aging also becomes apparent from the life expectancies of the mice: these interventions bring about an increase in median life expectancy that is two to four times larger than the increase in maximal life expectancy, indicating a sharper increase in the risk of death at a higher age. This effect was shared by caloric restriction and genetic disruption of growth hormone signaling. This conclusion warrants a reevaluation of previous studies on the effects of these interventions on murine aging with the use of the alternative method.

In this open access review paper, researchers discuss the associations and possible contribution of advanced glycation end-product (AGE) accumulation to the age-related decline in motor function, though given that they focus on short-lived forms of AGE and omit mention of glucosepane, I suspect that the relevance of their conclusions is limited. The differences between types of AGE are important, and they can't all be lumped together based on the study of just one type. In particular the contribution to aging from AGEs that cross-link versus AGEs that promote inflammation is quite distinct.

Where do AGEs come from? They are a class of waste produced by the normal operation of cellular metabolism, and which can also arrive in the diet. They accumulate in tissues with advancing age. There are various types of AGE, but the important ones are the long-lasting varieties based on glucosepane that the body cannot effectively break down. They form cross-links in the extracellular matrix, degrading tissue function by altering its structural properties, as is the case in age-related loss of elasticity in skin and blood vessels. Other classes of AGEs - such as N(6)-carboxymethyllysine (CML) - are probably involved in different ways in the progression of age-related disease and especially in metabolic dysfunctions such as type 2 diabetes, as they can increase chronic inflammation through their interactions with cells. These types are better studied than glucosepane, but they can be broken down and cleared by our biochemistry, their levels are quite dynamic over short time frames, and it isn't completely clear as to the degree to which their accumulation is secondary to other forms of age-related dysfunction, or even to diet and lifestyle choices.To tackle the inexorable increase in glucosepane cross-links, however, it is definitely the case that a viable strategy is the development of therapies to clear these damaging and unwanted molecules.

Diminishing motor function is commonly observed in the elderly population and is associated with a wide range of adverse health consequences. Advanced Glycation End products (AGE's) may contribute to age-related decline in the function of cells and tissues in normal ageing. Although the negative effect of AGE's on the biomechanical properties of musculoskeletal tissues and the central nervous system have been previously described, the evidence regarding the effect on motor function is fragmented, and a systematic review on this topic is lacking. Therefore, a systematic review was conducted from a total of eight studies describing AGE's related to physical functioning, physical performance, and musculoskeletal outcome which reveals a positive association between high AGE's levels and declined walking abilities, inferior activities of daily living (ADL), decreased muscle properties (strength, power and mass) and increased physical frailty.

The available literature on musculoskeletal outcomes support the hypothesis that high AGEs levels are associated with a decline in muscle function. However, the correlations and calculated effect sizes indicate only a moderate relationship. It is known that AGEs can affect muscle function through a variety of pathways. In fact, AGEs can alter the biomechanical properties of muscle tissue, increasing stiffness and reducing elasticity through cross-linking and upregulated inflammation by RAGE binding and endothelial dysfunction in the intra-muscular microcirculation. This is also consistent with studies on sarcopenia in which decreased muscle mass and strength is explained by an overall increase in inflammatory burden. Examining the studies in this review that report decline in walking abilities, it is suggested by the authors that this decline is also attributed to the effects of AGEs on muscle tissue, thereby impairing muscle function. It has been considered that impaired muscle function - through AGEs-induced muscle damage - can contribute to decline in walking abilities and ADL and can also contribute to physical frailty.

It is important to realise that, in this review, decline in motor function was primarily associated with elevated CML levels. Association with circulating CML was determined in four studies, and a relation with tissue CML was found in one study. One study reported an association with Pentosidine and two other studies with non-specified skin tissue fluorescent AGEs. It is suggested that fluorescent and non-fluorescent AGE's such as CML behave similarly and fluorescence may be employed as a marker for the total skin tissue AGEs pool. Although CML is a dominant AGE in blood circulation and correlates with other AGEs, it is possible that the association between AGE's and motor function outcome could be different if crosslinking AGEs such as Pentosidine were assessed.

The vast majority of participants included in this review were elderly people older than 64 years. Interestingly, in two studies, the participants were middle-aged between 37 and 56 years. This indicates that the negative effect of AGEs on motor function already begins during midlife and, as AGE levels increase with ageing, could be an important factor in age related decline in motor function. A high AGE level, as a biomarker, therefore, could predict a decline in motor function later in life. This could also imply that preventive interventions should start as soon as possible as part of healthy ageing. In accordance with the results of this review, it would be interesting to investigate whether motor function can be improved by reducing AGE levels. Intensive glycaemic control may be a method to decrease AGEs formation. CML levels correlate to dietary consumption, therefore, dietary intake is a possible factor that can be influenced.

Link: http://dx.doi.org/10.1186/s11556-016-0163-1

Researchers are making progress in the tissue engineering of components of the eye, an area of development that is less hindered by the challenge of producing blood vessel networks than is the case for most other tissue types:

Discs made of multiple types of eye tissue have been grown from human stem cells - and that tissue has been used to restore sight in rabbits. The work suggests that induced pluripotent stem (iPS) cells - stem cells generated from adult cells - could one day be harnessed to provide replacement corneal or lens tissue for human eyes. The discs also could be used to study how eye tissue and congenital eye diseases develop. A second, unrelated paper describes a surgical procedure that activates the body's own stem cells to regenerate a clear, functioning lens in the eyes of babies born with cataracts.

In the first study, a team cultivated human iPS cells to produce discs that contained several types of eye tissue. The cells grew in distinct regions so that researchers could extract and purify specific types, including those found in the cornea, retina and lens. The team was able to remove cells from one region of a disc to grow sheets of corneal epithelium that the researchers then successfully transplanted into rabbits with defective corneas. Previous studies have generated retinal or corneal tissue using iPS cells, but none has produced such different types of eye cell in a single experiment. Cells made from the recipient's own cells using the disc method could one day supply tissue to repair damaged eyes without the threat of rejection by the immune system. But much remains to be done before any such therapy could be tested in humans.

By contrast, the cataract paper could have an almost immediate impact on treatment. The technique described does not involve culturing cells outside the body or transplanting material that would require regulatory approval. "This is just a change in a surgical procedure. They are not putting in an artificial lens: they are just letting the lens regrow." The research was inspired by a typical side effect of implanting artificial lenses to treat cataracts: the new lenses often become cloudy as the recipient's own cells grow over them. A team decided to find out whether this regrowth signalled that the body is capable of regenerating an entire lens. The scientists began a series of animal studies to assess whether lens epithelial stem/progenitor cells (LECs) that exist naturally in a fully formed mammalian eye can produce a new lens. Encouraged by the results, the team developed a surgical technique and tested it in rabbits, macaque monkeys and, finally, 12 human infants.

In the new method, surgeons slice a 1.5-millimetre opening in the side of the lens capsule to remove the diseased lens, prompting the eye's LECs to grow a new one. In initial tests, this approach produced a much lower rate of complications - 17% - than the 92% seen after typical cataract surgery. And the lenses generated did not grow opaque as artificial lenses tend to do. The first infant treated using the method underwent surgery two years ago and still has good vision.

Link: http://www.nature.com/news/sci-fi-eye-experiments-improve-vision-in-children-and-rabbits-1.19535

Functional electrical stimulation has been used as the basis for therapies and prosthetics in cases of paralysis. In theory it can help slow degeneration of paralyzed limbs by exercising muscles, or in some lesser cases bypass damaged nerves sufficiently well to allow very limited function of otherwise paralyzed muscles. As prosthetic systems become more sophisticated, "limited function" increases in scope: consider the proof of concept from last year in which a paraplegic with spinal cord injury walked a few steps. This is still a long way from robust methods of bypassing damaged nerves, however. It is most likely that progress in regenerative medicine will enable repair of even very severe nerve damage before artificial nerve bypasses arrive at the point of enabling paraplegic patients to use their paralyzed limbs in a natural way.

Elsewhere, electrical stimulation of various sorts is used in a variety of therapies for a variety of conditions, and has been for some time - though the evidence for benefits and understanding of mechanisms involved is lacking in many cases. Looking forward to the future, some research groups are exploring the role of electric fields and signals in tissue growth, in regeneration, and in related uses in tissue engineering, as well as potentially providing a basis for selectively disabling cancer cells. But for today I'll point out a few recent research articles that focus firstly on whether or not electrical stimulation of muscles can be of use as a compensatory treatment for age-related muscle wasting, and secondly on electrical stimulation of the brain as a way to increase neuroplasticity - again a way to compensate in part for losses that occur due to aging. As is frequently the case in research, these are not approaches that address any of the root causes of degeneration, but rather try to add more capacity or resilience to impacted tissues. This will always be an inferior approach, capable of producing only lesser benefits, but the cost-benefit analysis for undertaking the work may still be favorable in many cases.

Brain Boost: ONR Global Sponsors Research to Improve Memory through Electricity

Researchers have significantly boosted the memory and mental performance of laboratory mice through electrical stimulation. The study involved the use of Transcranial Direct Current Stimulation, or tDCS, on the mice. A noninvasive technique for brain stimulation, tDCS is applied using two small electrodes placed on the scalp, delivering short bursts of extremely low-intensity electrical currents. "We already have promising results in animal models of Alzheimer's disease. In the near future, we will continue this research and extend analyses of tDCS to other brain areas and functions."

After exposing the mice to single 20-minute tDCS sessions, the researchers saw signs of improved memory and brain plasticity (the ability to form new connections between neurons when learning new information), which lasted at least a week. This intellectual boost was demonstrated by the enhanced performance of the mice during tests requiring them to navigate a water maze and distinguish between known and unknown objects. Although tDCS has been used for years to treat patients suffering from conditions such as stroke, depression and bipolar disorder, there are few studies supporting a direct link between tDCS and improved plasticity. More important, the researchers identified the actual molecular trigger behind the bolstered memory and plasticity - increased production of brain-derived neurotrophic factor (BDNF), a protein essential to brain growth. BDNF is synthesized naturally by neurons and is crucial to neuronal development and specialization.

Biology of Muscle Atrophy and of its Recovery by FES in Aging and Mobility Impairments: Roots and By-Products

We have presented strong evidence that the atrophy which accompanies aging is to some extent caused by loss of innervation. We compared muscle biopsies of sedentary seniors to those of life long active seniors, and show that these groups indeed have a different distribution of muscle fiber diameter and fiber type. The senior sportsmen have many more slow fiber-type groupings than the sedentary people which provides strong evidence of denervation-reinnervation events in muscle fibers.

In extreme examples of muscle degeneration accompanying nerve disconnection, we have gathered data supporting the idea that electrical stimulation of denervated muscles can retain and even regain muscle. We show here that, if people are compliant, atrophy can be reversed. A further example of activity-related muscle adaptation is provided by the fact that mitochondrial distribution and density are significantly changed by functional electrical stimulation (FES) in horse muscle biopsies relative to those not receiving treatment. All together, the data indicate that FES is a good way to modify behaviors of muscle fibers by increasing the contraction load per day. Indeed, it should be possible to defer the muscle decline that occurs in aging people and in those who have become unable to participate in physical activities. Thus, FES should be considered for use in rehabilitation centers, nursing facilities and in critical care units when patients are completely inactive even for short periods of time.

Molecular and Cellular Mechanisms of Muscle Aging and Sarcopenia and Effects of Electrical Stimulation in Seniors

One of the problems associated with aging is that some people cannot move because of pathological conditions like pain, osteoarthritis and so on. Is there an alternative approach instead of physical exercise for these people? Researchers designed a specific way of analyzing electrical stimulation to address the question: can electrical stimulation mimic the effect of physical exercise? In particular, a stimulator for neuromuscular electrical stimulation was designed, especially suiting the requirements of elderly people with diminished fine motor skill. What was demonstrated is that electrical stimulation did improve muscle performance. The increase in muscle strength was associated with an increase of muscle fibers and most importantly with an increase of fast fibers, which are related to the power of the skeletal muscle. We asked: what is the mechanism associated with this increase of muscle strength and increase in muscle mass?

Since IGF-1 is one of the factors that are activated during physical exercise, we verified whether electrical stimulation was able to induce an increase in IGF-1 expression. At first, we analyzed the expression of the different types (isoforms) of IGF-1. All of them were up regulated after electrical stimulation. Then we analyze some downstream pathways activated by IGF-1. We demonstrated that electrical stimulation stimulates not only anabolic pathways, but negatively modulates muscle catabolism. Another component that we analyze is collagen expression. There is remodeling, not only during physical exercise but also in electrical stimulation of extracellular matrix (ECM). Of note histology did not reveal any accumulation of fibrotic tissue in electrical stimulated muscles. To further support the morphological evidences, we analyzed one of the important controllers of fibrosis, namely miR29. The electrical stimulation regulates miR29, which might block the accumulation of fibrosis. We then analyzed the number of satellite cells that can be activated by electrical stimulation. We wanted to verify whether electrical stimulation, similarly to exercise, can increase the activity of these cells. Electrical stimulation indeed increased the number of satellite cells.

In conclusion, what we demonstrated is that electrical stimulation, which can be applied to people that cannot carry out normal physical activity, modulates similar factors associated with physical exercise. All of these data might help to design therapeutic strategies to counteract muscle atrophy associated with aging.

Researchers have demonstrated that introducing a gel scaffold material of the type used in tissue engineering into living tissues can improve the ability to regenerate at some forms of injury and compensate for some forms of age-related degeneration. Here they test this approach on peripheral artery disease, in which narrowing of major blood vessels due to atherosclerosis means insufficient oxygen and nutrients are delivered to tissues. This causes a wide range of dysfunction, leading eventually to critical limb ischemia and amputation or worse. Spurring tissue regrowth and remodeling via the introduction of scaffolding material doesn't address the underlying causes of the condition, the harmful processes that generate fatty deposits inside blood vessel walls that narrow them, but it can partially compensate by spurring adaptation and increased blood vessel size:

Bioengineers and physicians have developed a potential new therapy for critical limb ischemia, a condition that causes extremely poor circulation in the limbs. The therapy consists of injecting in the affected area a gel derived from the natural scaffolding, or extracellular matrix, in skeletal muscle tissue. The team tested the procedure in a rat model of the disease and found that it promotes muscle remodeling and improves blood flow.

Researchers had already shown that injection of a gel derived from cardiac muscle tissue extracted from pigs could help repair the heart after a heart attack. The tissue is stripped of cells, leaving behind a scaffold of the extracellular matrix from cardiac muscle, which acts a regenerative environment where cells can grow again. Using this same concept, the team now are turning their attention to peripheral artery disease and critical limb ischemia. They developed a material that was derived from the skeletal muscle of pigs to treat damaged skeletal muscle in these patients. Researchers injected the gel into the affected area in a rat model of the disease seven days post-surgery and monitored blood flow in the rats' limbs up to 35 days after injection. Researchers found that the hydrogel increased the diameter of the rats' larger blood vessels, called arterioles. The increased diameter led to improved blood flow in the limbs. By day 35, the size and structure of muscle fibers in the rats treated with the hydrogel was comparable to that in healthy rats.

The gel, which forms a fibrous scaffold upon injection, also attracted muscle stem cells to the affected area. Gene expression analysis showed that inflammatory response and cell death decreased while blood vessel and muscle development pathways increased in rats injected with the gel. Next steps include looking at other disease models in animals and refining preclinical safety protocols and quality control for manufacturing.

Link: http://jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=1894

In recent years, tissue engineers have made great progress in 3-D printing very small sections of a wide variety of functional tissue types. Printing tissue masses that include the intricate blood vessel networks needed to support larger volumes remains a challenge, however. Progress on this front has been slow, as illustrated by the fact that this reported research is a step forward in terms of size and complexity:

Researchers have invented a method for 3D bioprinting thick vascularized tissue constructs composed of human stem cells, extracellular matrix, and circulatory channels lined with endothelial blood vessel cells. The resulting network of vasculature contained within these deep tissues enables fluids, nutrients and cell growth factors to be controllably perfused uniformly throughout the tissue. To date, scaling up human tissues built of a variety of cell types has been limited by a lack of robust methods for embedding life-sustaining vascular networks. Building on earlier work, researchers have now increased the tissue thickness threshold by nearly tenfold, setting the stage for future advances in tissue engineering and repair.

In the study, the team showed that their 3D bioprinted tissues could sustain and function as living tissue architectures for upwards of six weeks. They demonstrated the 3D printing of one centimeter-thick tissue containing human bone marrow stem cells surrounded by connective tissue. By pumping bone growth factors through the supporting vasculature lined with the same endothelial cells found in our blood vessels, the team induced cell development toward bone cells over the course of one month. The novel 3D bioprinting method uses a customizable, printed silicone mold to house and plumb the printed tissue structure. Inside this mold, a grid of vascular channels is printed first, over which ink containing living stem cells is then printed. The inks are self-supporting and strong enough to hold shape as the structure's size increases with each layer of deposition. At intersections meeting within the foundational vascular grid, vertical vascular pillars are printed, which interconnect a pervasive network of microvessels throughout all dimensions of the stem cell-laden tissue. After printing, a liquid composed of fibroblasts and extracellular matrix fills in the open regions around the 3D printed tissue, cross linking the entire structure. The resulting soft tissue structure is replete with blood vessels, and via a single inlet and outlet on opposite ends of the chip, can be immediately perfused with nutrients to ensure survival of the cells.

Link: http://wyss.harvard.edu/viewpressrelease/250

It has to be said, it is pretty rare for researchers to find a genetic effect as large as a halving of disease risk in human studies. We'll have to see if this particular case holds up in replication studies, but for the moment researchers are claiming that a mutation in the angiopoietin-like 4 (ANGPTL4) gene reduces risk of heart attack by 50%, and that to initial inspection this mutation doesn't seem to bear any detrimental side-effects. If this is in fact the case, we can add this to the growing list of potentially desirable gene therapies that are now well within the technical capabilities of most laboratories in this new age of CRISPR and low-cost, reliable genetic editing. At this point there are probably a score or more speculative changes that may be worth carrying out on the basis of animal studies or the existence of healthy human mutants, but only two or three, such as myostatin knockout, that are backed by sufficient evidence and experience to seem viable and low risk for immediate clinical translation.

Somewhere out there, right now, people with an interest, people with scientific knowledge, and people with money are exchanging missives and chewing over business plans that involve producing and selling packages of gene therapies for human enhancement. Some of these will include viable compensatory treatments for specific aspects of age-related degeneration; myostatin knockout to reduce loss of muscle mass and strength in aging, for example, or adding lysosomal receptors to increase cellular maintenance and slow loss of organ function. As the cost of gene therapy continues to fall, even as its reliability and capabilities increase by leaps and bounds, we're going to see the same thing happen for this field as happened for stem cell research fifteen years ago. Many groups and clinics will choose to circumvent the more restrictive regulatory systems of the US and Europe. They will offer therapies in other regions based on the technical ability to do so, and where there is a reasonable expectation of success and benefit. My prediction is that this process of commercial and medical exploration will be well underway five years from now.

Mutated gene safeguards against heart attacks

For the large-scale study at hand, the scientists analyzed 13,000 different genes from a pool of 200,000 participants - both heart attack patients and healthy control persons. They were on the lookout for correlations between gene mutations and coronary artery disease. For a number of genes, the researchers registered a correlation, including the ANGPTL4 (angiopoietin-like 4) gene. In addition, subjects with the mutated ANGPTL4 gene had significantly lower triglyceride values in their blood. "The blood fat triglyceride serves as an energy store for the body. However, as with LDL cholesterol, elevated values lead to an increased risk of cardiovascular disease. Low values, by contrast, lower the risk. For most patients the focus still lies on cholesterol. A differentiation is always made between the healthy HDL and the harmful LDL cholesterol variants. However, in the mean time we know that the HDL values always run inversely proportional to those of the triglycerides and that HDL itself actually tends to behave in a neutral manner. The triglycerides, on the other hand, are the second important blood fat, alongside the harmful LDL cholesterol. The only reason HDL blood values are still measured is because, together with HDL and triglyceride values, they can be used to derive the LDL values, which cannot be measured directly."

The current study now shows that the concentration of triglycerides in the blood are influenced not only by nutrition and predisposition, but also by the ANGPTL4 gene. "At the core of our data is the lipoprotein lipase (LPL) enzyme. It causes the decomposition of triglycerides in the blood." Normally, ANGPTL4 hems the LPL enzyme, causing blood fat values to rise. The mutations identified by the researchers disable the function of this gene and thereby ensure that the triglyceride value drops significantly. "At the same time, we discovered that the body does not even need the ANGPTL4 gene and manages wonderfully without it. It seems to be superfluous." Shutting down the gene or inhibiting the LPL enzyme in another manner may ultimately protect against coronary disease. "Based on our results, medications now need to be developed that neutralize the effect of the ANGPTL4 gene, thereby reducing the risk of a heart attack. Other researchers have already done this successfully in animal tests. They drastically reduced the blood fat levels in monkeys that received a neutralizing antibody against ANGPTL4. This feeds the hope that antibody preparations with a similar effect can soon be used successfully in humans."

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing. Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL. The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol. We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization. Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

To provide confirmatory orthogonal evidence that a loss of ANGPTL4 function is associated with a decreased risk of coronary artery disease, we searched for loss-of-function mutations in this gene. We found that ANGPTL4 loss-of-function mutations were associated with substantially lower triglyceride levels (35% lower than in persons who were not carriers of a loss-of-function mutation), and we also found that these loss-of-function alleles were associated with a 53% lower risk of coronary artery disease. The identification of additional ANGPTL4 inactivating mutation carriers provides further evidence of the association between a loss of ANGPTL4 function and lower triglyceride levels and a reduced risk of coronary artery disease.

Researchers have developed a means of reversing periodontitis, inflammation of the gums, in an animal model. This is of interest in the context of aging as periodontitis is widespread in the population, and inflammation in the gums doesn't remain isolated: it spreads to contribute to the progression of much more dangerous conditions such as atherosclerosis. A clinical therapy that eliminates periodontitis entirely would be a very positive advance.

Periodontitis, a gum disease present in nearly half of all adults in the United States, involves inflammation, bleeding and bone loss. In its severe form, it is associated with systemic inflammatory conditions such as atherosclerosis and rheumatoid arthritis. Few treatment options exist beyond dental scaling and root planing, done in an attempt to reduce plaque and inflammation. Now, however, researchers have employed an inhibitor of a protein called C3, a component of the body's complement system, which is involved in immunity and inflammatory responses. Delivering this inhibitor, Cp40, to the periodontal tissue just once a week reversed naturally occurring chronic periodontitis inflammation in a preclinical model. "Even after one treatment, you could see a big difference in inflammation. After six weeks, we saw reversals in inflammation, both clinically and by looking at cellular and molecular measures of osteoclast formation and inflammatory cytokines. The results were so clean, so impressive. The next step is to pursue Phase 1 trials in humans."

This study builds on earlier work which identified C3 as a promising target for treating periodontal disease. C3, or the third component of the complement system, is a key part of signaling cascades that trigger inflammation and activate the innate immune system. Their previous research, which used an inducible model of periodontal disease, found that Cp40 could reduce signs of the disease. To get closer to a natural scenario, however, the current work was conducted on animals that naturally had developed chronic periodontitis. Initially the research team tried administering Cp40 three times a week, but after seeing significant reductions in inflammation, they tried giving it only once a week to a different group and saw the same good results. This study delivered the drug via a local injection to avoid any potential systemic effects from inhibiting a component of the immune system. There were no adverse effects reported. "Some people have been concerned that blocking complement would lead to more infections but that is not the case here. We're stopping the inflammation in the gums and thereby killing the bacteria that need inflammatory tissue breakdown proteins to survive."

Link: https://news.upenn.edu/news/penn-team-reverses-signs-naturally-occurring-chronic-periodontitis

Neurogenesis, the creation of new neurons in the brain, slows with age. This is most likely an important contributing factor in the age-related loss of neural plasticity, the ability of the central nervous system to change, adapt, and to a limited degree repair itself. Here researchers show that they can increase the pace of neurogenesis in old mice by raising the level of fibroblast growth factor (FGF) signaling:

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear.

Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis.

Link: http://dx.doi.org/10.1523/JNEUROSCI.1469-15.2015

Researchers have found that, unusually, entering a senescent state actually improves some measures of performance in the beta cells of the pancreas responsible for producing insulin. Senescent cells are those that have removed themselves from the cycle of replication, either because they have reached the Hayflick limit, or prior to that point in reaction to molecular damage or a toxic local environment. A senescent cell may destroy itself via programmed cell death mechanisms or it may be destroyed by the immune system, but while it remains in place it behaves badly, secreting a harmful mix of molecules that change surrounding cellular behavior and remodel tissue structures. Aging brings a growing number of these senescent cells in all tissues, lingering long past the point at which they should have been destroyed. Their harmful effects grow sizable and contribute to the pathology of most age-related conditions. Thus cellular senescence is a cause of aging, age-related disease, and death. Even if all of the other mechanisms that cause aging were hand-waved away, increasing numbers of senescent cells alone would be enough to kill us eventually.

Biology is complex, however, and it is rare for any given process to do just one thing, or for any mechanism to be important in just one way. Evolution likes reuse, and cellular senescence has a variety of forms and has evolved into a variety of roles. It may have started as a process of embryonic development, a way to halt growth in order to define the shape of extremities such as fingers. The transient creation of senescent cells is also involved in wound healing, however, and senescence in response to damage and toxins likely serves to reduce the risk of cancer, or at least initially. Large numbers of senescent cells cause significant chronic inflammation, among other issues, and that eventually overwhelms any cancer-prevention benefit resulting from preventing replication in cells at a greater risk of suffering cancerous mutations.

Given all of this, it shouldn't be completely surprising to find more places and circumstances in the body in which cellular senescence produces benefits along the way towards ultimately helping to kill us. That we find such benefits isn't a good reason to pull back from efforts to produce therapies that can clear senescent cells from the body, and thereby prevent their contribution to aging, of course, but they do serve to remind us that nothing is ever simple when it comes to living organisms.

Cellular Aging Process Unexpectedly Enhances Insulin Secretion

New research shows that a cellular program that causes aging can also bring unexpected benefits in the function of pancreatic beta cells and the production of insulin in mice and humans. The researchers examined the activity of a gene named p16, which is known to activate a program called senescence in cells. Senescence prevents cells from dividing, and is therefore important in preventing cancer. The activity of the p16 gene increases in human and mouse pancreatic beta cells during aging and limits their potential to divide. This activity is thus seen as having a negative effect - the lack of ability of these cells to divide can contribute to diabetes, since beta cells are the cells responsible for secreting insulin when blood glucose levels are high, and their loss causes diabetes. However, it was unknown whether senescent beta cells could continue functioning at all.

To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence actually improve the primary function of beta cells: the secretion of insulin upon glucose stimulation. Because insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better. The researchers further found that activation of p16 and senescence in beta cells of mice that suffer from diabetes enhanced insulin secretion, thereby partly reversing the disease and improving the health of the mice. Similar experiments conducted in human cells strongly suggest that senescence-induced enhancement of insulin secretion is conserved between mice and humans, and point to the p16 gene as its main driver in both organisms.

p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit.

Expression of p16Ink4a in beta cells induces hallmarks of senescence - including cell enlargement, and greater glucose uptake and mitochondrial activity - which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

Specialized components of the immune system present in the brain, such as microglia, are integral to many of the processes involved in or degraded by neurodegenerative conditions. For example, microglia may be a primary cause of the chronic inflammation found in older brain tissue, and which contributes to the pathology of a range of conditions, including Alzheimer's disease. The study noted here focuses on a different aspect of the role of microglia, a way in which they participate in the normal operation of the brain in conjunction with neurons: the researchers involved show that microglia play a necessary role in altering the connections between neurons. This will no doubt be of interest to the field of aging research, as the plasticity of neural connections diminishes with age, and it will be interesting and potentially useful to know the degree to which this is a problem of neurons versus a problem of the immune system.

A new study shows that cells normally associated with protecting the brain from infection and injury also play an important role in rewiring the connections between nerve cells. While this discovery sheds new light on the mechanics of neuroplasticity, it could also help explain diseases like dementia, which may arise when this process breaks down and connections between brain cells are not formed or removed correctly. "We have long considered the reorganization of the brain's network of connections as solely the domain of neurons. These findings show that a precisely choreographed interaction between multiple cells types is necessary to carry out the formation and destruction of connections that allow proper signaling in the brain."

The study is another example of a dramatic shift in scientists' understanding of the role that the immune system, specifically cells called microglia, plays in maintaining brain function. Microglia have been long understood to be the sentinels of the central nervous system, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up dead cell tissue. However, scientists are now beginning to appreciate that, in addition to serving as the brain's first line of defense, these cells also have a nurturing side, particularly as it relates to the connections between neurons. The formation and removal of the physical connections between neurons is a critical part of maintaining a healthy brain and the process of creating new pathways and networks among brain cells enables us to absorb, learn, and memorize new information.

While this constant reorganization of neural networks - called neuroplasticity - has been well understood for some time, the basic mechanisms by which connections between brain cells are made and broken has eluded scientists. Performing experiments in mice, the researchers employed a well-established model of measuring neuroplasticity by observing how cells reorganize their connections when visual information received by the brain is reduced from two eyes to one. The researchers found that in the mice's brains microglia responded rapidly to changes in neuronal activity as the brain adapted to processing information from only one eye. They observed that the microglia targeted the synaptic cleft - the business end of the connection that transmits signals between neurons. The microglia "pulled up" the appropriate connections, physically disconnecting one neuron from another, while leaving other important connections intact. "These findings demonstrate that microglia are a dynamic and integral component of the complex machinery that allows neurons to reorganize their connections in the healthy mature brain. While more work needs to be done to fully understand this process, this study may help us understand how genetics or disruption of the immune system contributes to neurological disorders."

Link: https://www.urmc.rochester.edu/news/story/4516/the-brains-gardeners-immune-cells-prune-connections-between-neurons.aspx

Researchers are working on a method of targeting stellate cells in the liver to prevent them from causing fibrosis when overactivated in response to infections, autoimmunity, and other causes of liver disease:

Liver fibrosis and its more severe form, cirrhosis, are caused by scar tissue that forms in the liver. The progressive stiffening of the liver, a hallmark of the disorders, occurs when a type of liver cell known as the hepatic stellate cell is "activated" and overproduces the stringy network of proteins called the extracellular matrix that binds cells together. Being able to turn cirrhosis around, especially in its late stages, would be a great boon, because liver fibrosis and cirrhosis can be asymptomatic for decades. Many patients only seek treatment when their disease becomes very advanced, at which point liver transplant is their only option.

Scientists have known for more than a decade that a protein called tumor necrosis factor-related apoptosis-inducing ligand - TRAIL, for short - can specifically kill activated hepatic stellate cells that overproduce the extracellular matrix, sparing healthy cells in the liver. However, TRAIL has thus far proven unsuccessful for clinical use because in animal studies, enzymes in the bloodstream quickly degrade it before it has time to work. Seeking a way to extend TRAIL's half-life, or the time that it remains intact in the bloodstream, researchers coated TRAIL with polyethylene glycol (PEG), a synthetic polymer. Initial experiments showed that this "PEGylated" TRAIL had a half-life of between eight and nine hours in monkeys, compared to less than 30 minutes for the unmodified protein. When the scientists intravenously dosed rats that had liver fibrosis with the modified TRAIL for 10 days, the animals' activated hepatic stellate cells died off. By fighting these bad cells, signs of fibrosis began to diminish. Further investigation showed that multiple genes associated with fibrosis had reduced activity, and the proteins produced by these genes faded away.

Findings were similar in rats with advanced cirrhosis. Additionally, when the researchers examined the rodents' liver tissue under a microscope, they found that animals treated with PEGylated TRAIL had fewer deposits of collagen and other extracellular matrix proteins, offering some evidence that the disease had actually been reversed. The research team hopes to develop PEGylated TRAIL for clinical trials in human patients in the next two years. Some preliminary data suggest that the modified protein could also treat other fibrotic diseases as well, such as pancreatic or lung fibrosis, which also have no effective treatment.

Link: http://www.eurekalert.org/pub_releases/2016-03/jhm-mpr030216.php

Cells use the bloodstream as a way to communicate with one another, and blood in an old individual has many differences when compared to that of a young individual. The amounts of numerous important signal molecules are different, for example. By the evidence to date, obtained from parabiosis studies in which the circulatory systems of an old and a young individual are linked, this appears to be connected to the age-related decline in stem cell activity, and probably to many other systems as well. These signal molecules are just one class of change in the blood over the course of aging, however. Here is another: fragments of DNA sequences, the nucleic acids that make up DNA, are another type of molecule found in the bloodstream in greater amounts in old individuals. Researchers are presently debating whether and how this molecular debris might cause harm.

These circulating nucleic acids are thought to arise from the destruction of cells, though given that cells are capable of creating and releasing quite complex structures into the surrounding tissues - consider extracellular vesicles for example - it is perhaps plausible that dysfunctional cells could be exporting nucleic acids while still intact. The theorized problem caused by extracellular nucleic acids is that cells will take them up and integrate them into their DNA, and that this could be a significant source of stochastic mutational damage.

This might be considered a part of the broader argument as to whether nuclear DNA damage is significant in aging over a normal human life span in any way other than generating an increased risk of cancer. It is indisputably the case that mutational damage occurs, and is a distinguishing feature of old tissues, each cell with its own unique pattern of damage. What is hard to prove is that this actually causes significant problems in and of itself, absent any of the other changes of aging. A large enough level of mutation will definitely change the behavior of cells in ways that degrade tissue function, but is the present mutation rate in aging anywhere near high enough to get to that point? The studies needed to definitively answer that question have yet to take place.

The dark side of circulating nucleic acids

Billions of cells in the adult human body are eliminated daily through cell death processes, such as apoptosis and necrosis; especially necrotic cells, which unlike apoptotic cells are not generally removed cleanly by phagocytosis, are thought to be a source of degraded DNA fragments released to the blood plasma or serum as cell-free DNA or circulating free DNA (cfDNA). Some aspects of the biology of cfDNA are still unexplored and several key questions remain. One question with high relevance to aging is whether or not cfDNA fragments can behave as mobile genetic elements, illegitimately integrating in the chromosomal DNA of healthy cells in its own host, thereby contributing to genome instability and possibly causing age-related functional decline and age-related pathophysiological processes.

Recently evidence was provided that the integration of cell-free nucleic acid with host cells occurs in vivo as well as in vitro. Mice were injected intravenously with human cfDNA and Cfs and analysis of heart, lung, liver, and brain of the mice sacrificed 7 days after injection revealed genomic localization of nucleic acids, with Cfs localizing more efficiently than cfDNA. Of note, genomic integration of Cfs in the mouse brain indicated that chromatin particles are able to cross the blood-brain barrier. This recent work offers a fascinating new mechanism of age-related mutagenesis, highlighting the fate and effects of free nucleic acids within our body. However, many questions remain. Probably the most interesting question is whether cfDNA truly behaves as mobile genetic elements under normal conditions. That is, rather than extracting concentrated cfDNA from heterogenic serum samples and intravenously injecting that in the mouse, integration of its own cfDNA should be studied, for example, as a function of age. Because integrated DNA fragments can then no longer be uniquely aligned as foreign DNA to a reference sequence, single cells or clones should be studied for insertion events as compared to the germline sequence, which is considerably more difficult than screening for reads containing human sequences.

While still lacking in important details, this recent work opens up the intriguing prospect of a new, endogenous source of genome instability that could well contribute to increased genome mosaicism with age. In this respect, cfDNA could act similarly to the previously described age-related derepression of endogenous retrotransposons in the somatic genome during aging. In this respect, there is evidence that cfDNA becomes increasingly frequent in the circulation as a function of age, for example, due to increased vulnerability of aged and damaged cells to cell death. Its activation of the DNA damage response could increase the level of genome instability considerably, contributing to aging-related degenerative processes, such as cellular senescence, cancer, and inflammation. Further research on the biological and pathological roles of cell-free nucleic acids will help to elucidate its importance as an intrinsic mechanism of aging.

The cryonics industry offers low-temperature preservation of the body and brain on death, and this is presently the only alternative to the grave and oblivion for those who will age to death prior to the advent of rejuvenation therapies. Preservation of the structures holding the data of the mind provides a chance at life again in a future in which technology has advanced to the point at which restoration of a preserved individual becomes practical. The media these days treats cryonics with a lot more respect than used to be the case, though they still tend to dumb things down by talking about freezing rather than vitrification with cryoprotectants - a very important distinction when talking about tissue preservation. I think that this change in attitudes is in part because the development of vitrification techniques for use in the organ preservation and transplant industry is much more evidently making progress and gathering support in the research community. Since that is an accepted field of research, and meanwhile researchers are demonstrating preservation of fine structure in vitrified brain tissue, it becomes hard for journalists to dismiss cryonics out of hand.

In a nondescript industrial office park in San Leandro, a little city on the outskirts of Oakland, sits the headquarters of a business named Trans Time. The walls in the foyer of the building are filled with posters about anti-aging research. There's a lab with microscopes and beakers that look like they've been around since Trans Time opened in 1974, and a white room with an operating table. In the very back of the office, you'll find a large canister of liquid nitrogen, and a handful of 10-foot-tall metal vats that look like huge coffee Thermoses. Visitors aren't allowed to look inside these vats, but if you could, you'd see that one of them contains three human corpses - or, as the facility refers to them, "patients."

With just three patients frozen in its tanks, Trans Time is a scrappy little cryonics competitor. (The last person to enter one of Trans Time's vats was the company's founder, Paul Segall, a Berkeley Ph.D who co-founded the publicly-traded medical company BioTime. He died of a brain aneurism in 2003.) The two largest cryonics facilities are Alcor, in Arizona, and the Cryonics Institute, in Michigan; that's where you'll find most of the 300 or so people who are currently frozen. There's also KrioRus in Russia, which has 45 people on ice. And there are over 2,000 people worldwide who have signed up to be frozen, but haven't died yet.

Greg Fahy is a cryobiologist at 21st Century Medicine, a scientific institution based in southern California that has received funding from the National Institutes of Health to work on cryonically preserving organs. And he thinks the sci-fi fantasy of bringing frozen bodies back to life may not be as far-fetched as we think. "We're getting pretty good at this. We can load a kidney up with cryoprotectant and save it. We now know we can remove a piece of the brain and preserve it with perfection, and then put it back and it will still operate." Fahy, who has experimented successfully with cryonic preservation in rabbits and rats, thinks it may one day work in humans, too. "There's nothing about brain tissue that prevents it from being cryonically preserved."

In fact, Fahy said, the biggest obstacle to successful cryonic reanimation might be the law, not science. Most cryonics experts agree that cryonic preservation would work best on bodies that aren't yet dead, and haven't begun to decompose. But under current law, cryonics facilities are prohibited from freezing their patients while they're alive. (Doing so would be considered assisted suicide, or possibly murder.) "There may need to be legal changes that need to be made to allow cryonic preservation before deterioration begins."

Cryonics, itself, represents a kind of faith - a faith that scientific progress will continue unabated, and will eventually be able to solve even death itself. Cryonicists believe so strongly in our scientific future that many think that people who bury, cremate or compost their bodies instead of freezing them are, essentially, committing suicide.

Link: http://fusion.net/video/256864/real-future-episode-9-cryonics/

Mitochondrially targeted antioxidant compound SkQ1, a plastinquinone, has at this point been moving through the commercial development pipeline for a decade or so. This is par for the course in medicine, sad to say. Engaging with the regulatory system is a slow, slow process, and requires such a large amount of money that organizing the funding itself often requires years of groundwork and initiatives.

SkQ1 has been shown to modestly extend life in laboratory animals, and along the way have also proven to be a useful therapy for a range of inflammatory conditions of the eye. They work by soaking up damaging oxidative molecules where they are produced, in the mitochondria, before they can cause harm to cell structures, particular the nearby mitochondrial DNA. That said, any significant alteration to the net rate of production of oxidative molecules affects the regulation of many cellular activities. A lot of unrelated methods of slowing aging in laboratory species involve either reducing or raising the rate of production of oxidative molecules by mitochondria, for example. So it isn't just a matter of preventing damage, but also of changing cellular behavior. Since it has a demonstrated ability to reduce inflammation, it is probably useful as a treatment for a range of conditions in which inflammation is an important contributing cause.

In any case, it looks like work is progressing past the initial availability of therapies for eye conditions towards formulations of SkQ1 in pill form. A lot of people in the broader longevity advocacy community will be interested in this, but bear in mind that, like all approaches so far shown to slow aging in short-lived animals, it will probably have only much smaller effects in long-lived species such as our own. Reducing the rate of mitochondrial damage caused by oxidative molecules isn't in the same class of expected outcome as repairing that damage or completely preventing its consequences, as is the goal of SENS strategies such as allotopic expression of mitochondrial DNA.

Mitotech S.A., a Luxembourg based clinical stage biotechnology company, announced a successful completion of its pre-clinical program and a start of clinical development for systemic drug Plastomitin based on Mitotech's lead compound SkQ1. SkQ1 is a small molecule engineered specifically for reducing oxidative stress inside mitochondria. Previously, SkQ1 demonstrated efficacy and safety in a double-masked placebo-controlled Phase 2 study of an eye drop formulation - Visomitin - in the U.S.

"This is a very exciting new step for our company. Our strategy assumes parallel development of a variety of formulations for our lead compound SkQ1 targeting a spectrum of age-related disorders. Visomitin had been the most advanced drug in our pipeline and already reached Phase III stage for dry eye indication in the U.S. Ophthalmic field, where we have been pursuing uveitis in addition to dry eye syndrome, remains the forefront area of development for Mitotech. At the same time, this new milestone brings us to clinical level of development for a variety of indications outside ophthalmic field. Mitotech is now in a great position to tackle critical disorders associated with aging such as neurodegenerative and metabolic diseases. Here at Mitotech we feel that we are approaching a major clinical breakthrough that could help many patients around the world."

"SkQ1 has demonstrated efficacy when administered systemically in a whole spectrum of preclinical studies. The very unique mechanism of action of the molecule has proved its benefit in models of rare genetic diseases as well as in models of more common age-related disorders. We see enormous potential in this novel mode of action and our clinical team worked very diligently on getting Plastomitin to its first clinical trial. Mitotech's goal is to progress with this new clinical program as efficiently as we did with the ophthalmic program and to deliver Plastomitin to patients within the next few years."

Link: http://www.mitotechpharma.com/news/Mitotech-SA-to%20initiate-its-first-clinical-study-of-a-systemic-formulation-of-SkQ1

Calorie restriction is a growing area of research these days, linked to diverse fields ranging from aging to diabetes to pharmaceutical development, and above all to the overarching quest to produce a grand map of cellular metabolism. Calorie restriction is of greatest interest outside the scientific community for the fact that it reliably slows aging and extends healthy life in most species and lineages tested to date. This effect, like all methods of slowing aging through altered metabolic state, is much more pronounced in short-lived species. The additional life gained as a proportion of life span falls as the species life span increases: we all know that calorie restriction in humans, while it produces impressive short-term benefits for basically healthy individuals that have yet to be matched by medical science, doesn't extend human life span by 40% or more as it does in mice. We would have noticed by now.

Messing with metabolism, however it is done, isn't a great approach to life extension. It has a limited upside, and has proven very hard and very expensive to achieve successfully via drug development. Calorie restriction itself already exists, however, is reliable, and even though it has a limited upside, it is free. Just as for exercise, it seems silly not to take advantage. The cost-benefit analysis for metabolic alteration via drugs is terrible because it will cost an enormous amount of time and money to produce results, and those resources would be better devoted to SENS rejuvenation research. The cost-benefit analysis for calorie restriction is completely different because it costs nothing and is here now - something for nothing, even if it is not much of a benefit in the grand scheme of things.

Moving away from considerations of enhanced longevity, inside the scientific community calorie restriction is perhaps of greatest interest as a reliable tool with which to interrogate the operation of cellular metabolism. The ability to reliably adjust that operation into a different stable state is very useful if the aim is to try to understand the function of this complex system. Two operating states provides points of comparison and analysis that don't exist for one state. This is of particular interest in aging research, and calorie restriction is used by some groups in much the same way as comparisons between species with different life spans: to try to identify important mechanisms relevant to aging and understand how the operation of metabolism determines natural variations in life span.

Nevertheless, some research groups are attempting to refine the application of calorie restriction as a formal treatment, largely to augment existing approaches to diabetes and cancer, as that is where the ability to raise funding best overlaps with potential benefits for patients. This involves a lot more careful categorization of short-term results for human calorie restriction, and a classification of different types of calorie restriction, some of which don't involve a reduction in overall calorie intake at all, but rather focus on timing and dietary content, such as intermittent fasting or protein restriction. The first of the papers linked here is a review along these lines:

Dietary restriction with and without caloric restriction for healthy aging

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20-40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

Newer antidiabetic drugs and calorie restriction mimicry

In rhesus monkeys unsurprisingly one of the most potent mechanisms of longevity was the reduction of cardiovascular risk factors and glucose intolerance in calorie-restricted monkeys. In the University of Wisconsin cohort, none of the individual calories restricted animals developed any degree of glucose impairment at the time of the interim analysis in contrast with the control monkeys who developed diabetes in a fairly good number. The animal data suggests the long-term CR in adult animals is a potent way to prevent the development of glucose impairment.

There are no comparable human studies with CR. Type 2 diabetes mellitus in humans is currently described as a progressive disease with a pathophysiology that involves over eight different organ systems. However, this understanding of disease does not really give a valid explanation to the reversibility and induction of normal glucose tolerance in patients with type 2 diabetes who undergo bariatric surgery. The improvements in glucose control happen within a few days after surgery much before there is any significant reduction in body weight. There are many explanations offered for early improvement in glucose tolerance like changes in gut hormone profile, changes in gut bacteria, etc., Both these overlook the most logical explanation for the phenomenon which is an acute profound decrease in calorie intake.

However, considering the difficulties in getting healthy adults to limit food intake science has focused on understanding the biochemical processes that accompany calorie restriction (CR) to formulate drugs that would mimic the effects of CR without the need to actually restrict calories. Drugs in this emerging therapeutic field are called CR mimetics. Some of the currently used anti-diabetic agents may have some CR mimetic like effects. This review focuses on the CR mimetic properties of the currently available anti-diabetic agents.

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction

Women live on average longer than men, but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the ageing gut in Drosophila. The intestinal epithelium of the ageing female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in ageing females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like ageing pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. Hunger signaling, circadian rhythms and their downstream effects are far more complex than the results described here. Although limited by using a knowledge based signaling network, we were able to gain insights into the potential mechanisms underpinning the action of CR. Associations between gene expression and physiological outcomes such as body temperature and food anticipatory activity established by linear models and correlations are obviously only descriptive and causality cannot be assumed. Nevertheless these individual mice have been subjected to an unprecedented level of phenotyping allowing us to tie together the complex transcriptomic changes to alterations in body composition, circulating hormones and physiological outcomes.

Overall, our study has demonstrated that increasing levels of CR lead to a graded expression of genes involved in both hunger signaling and circadian rhythms. The expression of genes in these pathways wwere correlated with circulating levels of leptin, insulin, TNF-α and IGF-1, but not resistin or IL-6. We also demonstrated the phenotypic responses to CR (body temperature and physical activity) were significantly associated with the key hunger and core clock genes. Our results suggest that under CR modulation of the hunger and circadian signaling pathways, in response to altered levels of circulating hormones, drive some of the key phenotypic outcomes, such as activity and body temperature, which are probably important components of the longevity effects of CR.

There are many ways to extend life in short-lived nematode worms, but most overlap, being different ways to manipulate the same few core mechanisms. Everything in cellular biology connects to everything else, so isn't at all unexpected for there to be a dozen indirect ways to alter levels of any one particular protein, or alter the behavior of any one particular pathway. Much of the present focus in the aging research community involves mapping all of these methods so as to pin down the list of those core mechanisms, the most important ways in which metabolism determines variations in longevity between individuals and species. This actually has very little relevance to the future of human longevity and the development of rejuvenation treatments: those will emerge from efforts to repair the cell and tissue damage known to cause aging, an approach that will produce rejuvenation, not from altering the operation of metabolism to merely slightly slow down aging.

"We found that longevity can be extended by increasing the amount of a protein called arginine kinase-1 (ARGK-1). ARGK-1 maintains ATP availability within cells, and we suspect that increased levels trigger a fuel sensor, regulating energy homeostasis and extending lifespan." The research team identified ARGK-1 by comparing protein levels in normal worms to those in worms lacking S6 kinase (S6K), a genetic change that extends worm lifespan by at least 25%. Reduction of S6K proteins also extends lifespan significantly in several other organisms, including laboratory mice, showing that this pathway that controls aging is evolutionarily conserved. "ARGK-1 caught our attention because levels in S6K mutant worms were more than 30 times higher compared to normal worms. When we created normal worms that overexpressed ARGK-1, they also lived significantly longer, meaning that ARGK-1 on its own can extend life."

ARGK-1 and its mammalian equivalent, creatine kinase, are enzymes that transport energy in the form of phosphoarginine or phosphocreatine to various locations within cells. The research team found that, as in worms, creatine kinase levels are increased in the brains of mice lacking a similar S6K protein. "Our main goal in studying aging is not to find ways to extend human lifespan, but to understand the processes by which our cells and tissues become less functional over time. Such insight might allow us to develop better preventive care that improves overall health at advanced ages, or interventions that can slow or perhaps even prevent the progression of diseases associated with aging. For example, in cancer, some tumors highly activate S6K to feed tumor growth. Further work to understand the relationship between creatine kinase and S6K may lead to new avenues to pursue novel drugs for age-related diseases, including cancer."

Link: http://beaker.sbpdiscovery.org/2016/02/fine-tuning-cellular-energy-increases-longevity/

This is an illustrative example of the continued exploration of modest life extension via metabolic manipulation in short-lived animals. A lot of effort is spent on sifting through the existing catalog of known and approved drugs for those that might impact life span, something I consider to be a waste of time and effort from the point of view of producing therapies to extend life in humans. It is an important part of purely scientific efforts to map the interaction of metabolism and aging, however:

To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan.

To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Link: http://dx.plos.org/10.1371/journal.pgen.1005866

In the open access paper I'll point out today, a group of researchers who focus on the phenomenon of cellular senescence present their argument for cellular senescence to be the central process in aging. It has to be said that I'm bullish on the clearance of senescent cells as a strong first step towards a toolkit of therapies for human rejuvenation, especially now that startup companies are working on it, but it is important to recognize that the accumulation of senescent cells is just one of a number of fairly independent mechanisms that contribute to aging. Yes, the damage caused by these mechanisms interacts, but the sources of that damage are very different. Removing one only helps to the degree that you have removed one. The others will still get you, because all of them are associated with at least one fatal age-related disease. You can take a look at the introduction to the SENS vision for rejuvenation therapies for a list of the forms of cell and tissue damage that contribute to degenerative aging.

I think we've all heard the fable of the blind men and the elephant deployed in connection with aging research. The life sciences are overwhelmingly populated by specialists, as biochemistry and medicine are both so very complex that productive work requires a narrow focus. Investigating one tiny area of cellular biochemistry can be the focus of an entire career. Even when you can see what you are doing, when poised two centimeters from an elephant's face, the creature is essentially a trunk - and maybe some other stuff back there that obviously can't be as important as the giant trunk occupying your field of vision. The elephant of aging is surrounded by hundreds of researchers, each of whom is focused intently upon a small piece of the whole. There are far too few generalists working to link parts of the field and make otherwise disconnected researchers aware that they are looking at the same biochemistry through different lenses.

In any case, this is a very long-winded way of saying that one should be cautious about any analysis that places one particular mechanism at the center of aging. It isn't at all clear to me that aging has a center, and the research community is still unable to say with confidence that any one of the the forms of cell and tissue damage listed in the SENS view of aging is more or less important than the others. The way we will find out which of the forms of age-related damage is the most important is by firstly developing the means to repair that damage and then secondly watching the results of repair therapies in animal models - which is exactly what is happening at the moment for senescent cell clearance. The try it and see approach will get to answers a lot faster than any of the much more analytical alternatives.

Cellular Senescence as the Causal Nexus of Aging

In 1881 the evolutionary biologist August Weismann proposed that "Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting but finite." How did he arrive at such a bold conclusion? Weismann observed that during evolution, simple multicellular organisms such as Pandorina Morum, which were immortal, gradually evolved into mortal organisms such as Volvox Minor. The absolutely crucial difference between these two organisms is that while Pandorina's cells were undifferentiated and divided without limit, Volvox's cells had differentiated into two very different types: the Somatic (body) cells, and the Germ (reproductive) cells. Thus, while the germ line has retained the capacity for infinite renewal, the body cells have not; they age and expire. While Weismann's hypotheses were remarkably prescient, at that time neither DNA nor cultured cells were sufficiently understood to allow his theory to be adequately tested. In fact, it was not until nearly one hundred years later, following the development of sophisticated animal cell culture protocols, that he was proven correct: it was shown that somatic cells grown in culture have limited growth potential. After approximately forty passages, human cells stop proliferating and undergo cellular senescence.

Besides Weismann's evolutionary theory, many additional theories have been proposed to explain the complexity of aging. These include the antagonistic pleiotropy theory, the free radical theory, age-associated shortening of telomeres, development of insulin resistance, decreased immune function, the mitochondrial theory, as well as deregulation of the circadian clock. While these theories indicate functional diversity in the etiology of aging, it must be stressed that each one relies on the concept of internal alterations in individual cells, and does not explain how the microscopic cellular damage manifests as macroscopic aging and tissue breakdown in the organism (with a few exceptions, such as changes in hormone function and declines in immune function). Theories of mutation accumulation and antagonistic pleiotropy address the genetic causes of aging, and environmental stress or lack of it contributes to modulation of the epigenome as well as physiological alterations in different tissues of the whole organism, but each theory revolves around the functional competence of different components of cells and again does not explain how this manifests as macroscopic organismal aging. Experimental evidence unifying the interactions of some components has started to emerge, but we propose that all of the changes described by diverse theories ultimately converge on the cellular senescence theory.

Since aging is a progressive condition that steadily advances from invisible to visible and localized to ubiquitous, the central question as to the direct cause of the entire process is key. The answer has been elusive due to its complex nature. Our model proposes that the process of aging results from a sequential passage through three distinct phases and can be described by the following blueprint: (1) molecular damage which results in (2) cessation of proliferation leading to cellular senescence followed by (3) body-wide aging of the organism. The first step occurs when localized, microscopic damage accumulates to a point where the burden to repair overwhelms the system. Despite the tissue source or broad input of molecular damage, crossing of this threshold results in the second phase, the crux of the entire process - arrest of cellular proliferation, acquisition of the senescence-associated secretory phenotype (SASP), and imminent cellular senescence. Once this occurs, the third phase of aging begins. This final phase is marked by tissue dysfunction and breakdown that results in the visible signs of comprehensive organismal aging.

The incremental advance proposed by our model is that while there are many undisputed factors that trigger the onset of cellular senescence and result in cessation of proliferation and SASP, the first phase in the model (cumulative molecular damage) is a precursor, rather than a final cause of aging. The complexity normally imposed by countless variables (i.e., age of onset, site of damage, affected cell type, mechanism of damage, and even species) that need to be overcome is rendered manageable by eliminating the first phase in the aging schematic. And since organismal aging can be artificially and reversibly induced by blocking and restarting cellular proliferation, this indicates that the second phase in the model - cessation of proliferation followed by cellular senescence - clearly represents the essential cause of aging. Placing cellular senescence in the pivotal junction between cause and effect, the causal nexus, to yield an integrated model of aging will serve to advance identification of crucial targets for future therapeutic investigation. By identifying cellular senescence as the causal nexus of aging, the process of treating, reversing and possibly even eventually eliminating this once inevitable outcome draws closer to reality.

Researchers here investigate one of the mechanisms by which the immune system recognizes senescent cells, targeting them for destruction. Accumulating numbers of senescent cells are one of the contributing causes of aging, and the age-related decline of the immune system probably accelerates this process in later life. In theory, given a good enough understanding of the biochemistry involved, it should be possible to greatly increase the efficiency with which the immune system destroys senescent cells. This is not the direction taken by the first companies to work on senescent cell clearance technologies, however, so this approach may never be developed, as it will prove to be unnecessary.

Senescent cells are specifically recognized and eliminated by natural killer (NK) cells. In this study we investigated the mechanisms which control the recognition of senescent cells by NK cells. We found that senescent cells up-regulate the expression of NKG2D ligands MICA and ULBP2 regardless of the senescence-inducing stimuli. The mechanisms regulating the expression of NKG2D ligands in senescent cells are partly attributed to a DNA damage response and activation of ERK activity. MICA and ULBP2 were found to be localized at the cell membrane where they can interact with NK cells to mediate efficient killing of senescent cells. Interaction of the ligands with the NKG2D receptor on the NK cells is necessary for the recognition of senescent cells by the NK cells in vitro. Importantly, NKG2D receptor-ligand interaction is essential for efficient elimination of senescent cells in vivo and thus for restraining fibrosis development. Overall, our findings demonstrate that NKG2D ligands on senescent cells are necessary for efficient recognition and elimination of senescent cells in vitro and during tissue damage in vivo.

The increase in expression of NKG2D ligands, particularly MICA and ULBP2, is likely a general feature of human senescent cells. A number of other studies have demonstrated the expression of MICA and/or ULBP2 in senescent cells derived from different cell types. Furthermore, senescent cells also acquire unique NKG2D ligand expression profiles consisting of several additional NKG2D ligands that result from differences between cell types (or cell-strains) and the mechanism by which senescence was induced. The repertoire of NKG2D ligands in mice is vast and similar to human cells, however based on sequence comparisons, mouse ligands are not homologous to the human ligands. Of note, NKG2D ligands are present on mouse cells that become senescent following p53 reactivation, and participate in the interaction of these cells with NK cells. In addition to their expression in senescent cells, NKG2D ligands are upregulated in other cell contexts related to cellular stress, including cancer, virally infected cells or following DNA damage. Therefore, the expression of these ligands might be part of a general stress response of cells that is utilized by senescent cells.

Our findings add to the emerging conceptual idea that the senescent program might represent a change in cell state that is associated with conversion to an immunogenic phenotype, functioning to remove damaged cells by immune clearance rather than through apoptosis. In addition to the upregulation of NKG2D ligands, the secretion of chemoattractants or the expression of adhesion molecules are further examples by which senescent cells become immunogenic. Immune clearance of senescent cells is likely beneficial in complex organisms where the regenerative capacity is dependent on non-resident stem cell populations and therefore temporal preservation of tissue architecture is necessary. Elimination of senescent cells following short-term insults, mediated by immune clearance, has physiological functions in tumor suppression and wound healing. Moreover, inefficient clearance might lead to the long-term persistence of senescent cells in tissues that has been associated with promotion of cancer development, ageing and age-related disease. Therefore, understanding the normal processes and mechanisms by which senescent cells are eliminated by the immune system will enable the formulation of conjectures concerning the mechanism responsible for impaired senescent cells elimination in later life. Such an understanding could lead to novel therapeutic strategies that enhance elimination of senescent cells by the immune system to improve tissue repair, cancer therapy and prevent deleterious effects of accumulation of senescent cells.

Link: http://www.impactaging.com/papers/v8/n2/full/100897.html

One of the interesting results that has emerged from the growing use of accelerometers in studies of exercise is that even small differences in activity levels have an noticeable correlation with mortality rates and life expectancy:

Even for people who already exercised, swapping out just a few minutes of sedentary time with some sort of movement was associated with reduced mortality. Researchers looked at data from approximately 3,000 people aged 50 to 79 who participated in the National Health and Nutrition Examination Survey (NHANES). For the study, subjects wore ultra-sensitive activity trackers, called accelerometers, for seven days. For these same people, the agency then tracked mortality for the next eight years. The results were striking. The least active people were five times more likely to die during that period than the most active people and three times more likely than those in the middle range for activity. "When we compare people who exercise the same amount, those who sit less and move around more tend to live longer. The folks who were walking around, washing the dishes, sweeping the floor tended to live longer than the people who were sitting at a desk."

Previous activity-tracking studies have drawn similar conclusions. But such studies usually ask participants to monitor their own exercise frequency and quantity, numbers they notoriously over-report. Also, the trackers used for NHANES have a higher level of precision than what's typically employed. "Because the device captures the intensity of activity so frequently, every minute, we can actually make a distinction between people who spent two hours a day doing those activities versus people who spent an hour and a half." To account for chronic conditions or illness influencing mortality rates, researchers statistically controlled for factors like diagnosed medical conditions, smoking, age and gender. They also completed a secondary examination from which they entirely excluded participants with chronic conditions. Though the scientists didn't discover any magic threshold for the amount a person needs to move to improve mortality, they did learn that even adding just 10 minutes per day of light activity could make a difference. Replacing 30 minutes of sedentary time with light or moderate-to-vigorous physical activity produced even better results.

Link: https://news.upenn.edu/news/new-penn-study-links-moving-more-decreased-mortality

You might recall that last year longevity science advocate Maria Konovalenko raised more than $50,000 via crowdfunding to create the Longevity Cookbook, an examination of the state of research and development for aging and longevity. My impression from the materials at the time was that this will be something analogous to Kurzweil and Grossman's Fantastic Voyage, in which a mix of the irrelevant and the interesting are presented. In that work, diet, supplements, and existing pharmaceuticals, all of which are near completely irrelevant to the future of human life extension, are given a lot of space, and discussed alongside some of the latest lines of research that might in the future be relevant once developed into clinical therapies, such as the SENS research programs. The public fixates on diet and supplements, encouraged by relentless "anti-aging" industry propaganda, and much of the aging research community focuses on slow and expensive pharmaceutical development aimed at metabolic adjustment that might, one day, slightly slow the pace of aging. None of that will add a decade of additional healthy years to human life any time soon, but it certainly sucks up all of the oxygen in the room when it comes to talking about human longevity.

The only path ahead that can produce radical life extension in the near future, an addition of decades or more, is the path of damage repair: SENS-like therapies capable of fixing the fundamental forms of cell and tissue damage that cause aging. Senescent cell clearance, removal of metabolic wastes, and so forth. The work needed to produce these therapies has far less support and funding, and receives far less attention than slow and expensive efforts to slightly slow down the pace of aging via metabolic tinkering, however. Nonetheless, SENS rejuvenation therapies are the future, because they are the only way to succeed in this game. Sooner or later all of the other approaches and hobbies will fall by the wayside because they cannot extend life. They will be discarded in favor of the SENS approaches that work, on an ongoing basis as the data is produced.

Work on the Longevity Cookbook is proceeding apace, and I see that an excepted chapter is now available to read online. It is focused on pharmacology, one of the areas where I think that the current mainstream research focus is of little relevance to the end goal of greatly enhanced human longevity. Obviously small molecule and enzyme development has tremendous promise for rejuvenation based on clearance of specific forms of metabolic waste, such as amyloids, cross-links, and lipofuscin constituents, but that isn't what is taking place in the industry. Similarly, outside of cancer research, there isn't a great deal of effort put towards pharmacology for destruction of other types of unwanted or harmful cells, such as senescent cells or errant immune cells. Most pharmacological work related to aging and longevity involves scanning existing drug catalogs for things that might do a little good by altering metabolism into a state more like that of the calorie restriction response: researchers would be pretty excited to obtain a two year statistical gain in life span in humans via this strategy. Not a useful approach to my eyes, since it has a high cost and poor expected outcomes even if wildly successful. That doesn't stop it from being interesting, but bear in mind the low expectation value given the past decade of work on dead ends like sirtuins.

Longevity Cookbook: Pharmacological Extension of Lifespan

Can we impact lifespan with pharmaceuticals? The average lifespan of humans has increased unevenly throughout history, but since the beginning of the industrial revolution it has taken rapid and steady strides upward. Much of this increase has been due to better sanitation, nutrition and living standards. Improvements in medicine, such as vaccines and antibiotics, have been very successful in combating infectious disease. This used to be the main cause of death for humanity but we have been so successful in combating them (world wide) that the main causes of death are now chronic age-related disease and cancer. These are what we hope to tackle now.

We will not cover all of the compounds that have been studied to extend lifespan, but those that I find most promising or most interesting. We will also discuss compounds that possibly work through different mechanisms. This could mean that we are neglecting some potentially important compounds, so we will try to explain what we think constitutes good evidence for a compound being promising. Extending lifespan in a model organism is certainly an important factor.

Combinatorial interventions are used for treating different diseases in the clinic. In cancer therapies, combinatorial treatments are used with success. The cancer can be attacked from different angles with multiple targeted therapies and cytotoxic agents. So what is the difference between testing one compound and testing a combination of compounds? At some level a single compound may act as a combination of compounds. Single compounds can bind to many targets. But aren't those off-target effects just creating negative side effects? Often that may be true, but some compounds might work well, precisely because they have multiple targets.

If two compounds can extend lifespan separately, together they must be even better, right? Well, it might not be that simple. The only published combination of compounds that has successfully extended lifespan to my knowledge is valproic acid and trimethadione in C. elegans. On their own, valproic acid extended the mean lifespan by 35% and trimethadione extended it by 45% at optimal dose. Together they extended the mean lifespan by 61%. This same study from the Kornfeld lab also shows that combining two compounds that on their own extend lifespan, can produce toxic effects. This was the case when mixing ethosuximide with trimethadione. So why is this? One explanation can be that they are both acting on the same pathway. Too much of a good thing is not always good.

So how do we know which compounds will work well together? The truth is we don't really know. We can try to make educated guesses though. Perhaps targeting different pathways is the way to go. However, sometimes targeting the same pathway can yield very potent effects with genetics. The insulin/IGF1 signaling pathway can be targeted from different angles in C. elegans yielding very long lived worms. There is also the possibility that two compounds targeting the same pathway can maximize the beneficial outcome while minimizing the side effects. Targeting different pathways can also work very well. In C. elegans the TOR and insulin signaling pathway were targeted genetically to produce a worm with nearly 5 times its normal lifespan.

Rapamycin and metformin are two drugs that could potentially work well together to extend longevity. A side effect of rapamycin is insulin resistance but metformin improves this condition. A combination of rapamycin and metformin treatment was started by the NIA Interventions Testing Program in 2011. No results are yet published, but rumor has it, it's working. One combination of compounds that was reported to be working in mice to combat one aspect of aging is quercetin and dasatinib. The combination is for killing senescent cells. They were each effective in killing senescent cells in different tissues but worked better together. No lifespan was measured, but health was improved. The mice were able to run farther on a treadmill.

Testing different compounds in combination is certainly a daunting task. How many compounds do you want in your longevity cocktail? Lets say we want to test 100 promising geroprotectors in combination. Perhaps we are assaying lifespan of C. elegans in a 96-well format. If we are just doing pairwise combinations it is almost manageable. 10,000 combinations performed in triplicate make 30,000 wells to be assayed. Only very large effects will be noticed in these types of screens if we are to eliminate false positives. If we are combining 3 or 4 compounds together in our screen we need to assess 3,000,000 or 300,000,000 wells respectively. In this setup, we are only using one concentration per compound. We have seen that sometimes concentrations of drugs need to be lowered when used together with another drug. A way to get around some of the problem is to first do a pairwise screen and use your best combination as the base for the next screen. This way you can keep adding compounds to your cocktail with a manageable amount of screening. This will of course miss some combinations that would be in the massive 300,000,000 well screen but some compromises always have to be made.

One of the main problems with research in general is the reliability of the data. Many times a finding is not repeatable when tried by another lab. This is usually not due to fraud or anything as nefarious as that. It is mainly that research is hard and there are many ways to fool yourself. One way to easily fool yourself is to use too small a sample size. This is quite common. Using a small sample size when looking at lifespan increases the chance that a long-lived or short-lived population was picked by chance. Generally around 100 animals should give around 80% chance of detecting a 10% difference in lifespan. By detecting I mean the difference being statistically significant (if they indeed are). But not only large sample sizes and statistical significance are important. Large effects are generally more reproducible than small effects. What I like to see is a large effect with a large sample size with a good statistically significant result. It is always nice to see if can be replicated by other groups. However, many small badly designed studies do not equal one large well-designed study.

This scientific editorial summarizes and provides links to many of the papers published of late on the topic of whether or not aging should be classified as a disease. This is primarily a question of regulation and advocacy, and how those issues interact with the pace of progress and the ability to bring more money to bear on research into treating aging as a medical condition. That present regulatory systems don't recognize aging as a medical condition has greatly impacted the ability to raise funds at all levels of development. Given the present state of the science, with the first actual, real rejuvenation treatments already under clinical development in startups, there is much more willingness in the scientific community to call for funding and work towards changing the present system.

The quest to increase healthy lifespan is becoming a pressing economic priority required to preserve the current standards of living. Rapidly increasing dependency ratios and unfunded social security and healthcare liabilities are an enormous and growing burden on the economies of developed countries. But the situation, if handled properly, is not hopeless; with advances in anti-aging treatments and preventative care, the negative economic impact of aging could be at very least reduced, while increases in productive longevity in developed countries could actually stimulate significant economic growth. One of the impediments to industry transformation is the way aging is treated. While no doubt exists that aging is a complex multifactorial process leading to a progressive decline in function with no single cause or treatment, the issue of whether aging can be classified as a disease is widely debated by gerontologists, medical doctors, demographers, philosophers, policy makers, and the general public. This disagreement has until now hindered classification of aging as a disease and, consequently, the fitting of potential treatment options into established research, regulatory, insurance, and marketing frameworks.

Some prominent biogerontologists have provided comprehensive weighted responses explaining the dangers of separation of aging from disease and benefits of proactive preventative approaches that are likely to result from recognizing the pathological nature of aging. In spite of the many breakthroughs providing proof of concept for successful interventions in aging in model organisms, human progress has been surprisingly slow. One major cause of inaction is a widely held, but flawed, conceptual framework concerning the relationship between aging and disease that categorizes the former as "natural" and the latter as "abnormal". One comprehensive review of the many arguments for and against classifying aging as a disease with a definite and eloquent recommendation that calls for a complete quote: "We must draw aside the rosy veil of tradition and face aging for what it is, and in all its horror: the greatest disease of them all."

Bulterijs et al. explained the many benefits of classifying aging a disease, while Stambler provided a historical perspective arguing that acknowledging the possibility of successful intervention into the aging process, in other words treating aging as a curable disease, has been a long and highly respected tradition of biomedical thought. Dubnikov and Cohen provided an overview of multiple theories of aging and recommended further research to understand the relationship between aging and disease. Advocates for longevity research provided new survey data indicating that the majority (74.4%) of Americans are interested to live to 120 or longer if health was guaranteed, but only 57.4% wished to live that long if it wasn't, contradicting previous surveys that used different approaches to surveying the general population and generally indicated negative attitudes toward increased longevity and longevity-boosting interventions.

The main international agency responsible for disease classification is the World Health Organization (WHO), which maintains and publishes the International Statistical Classification of Diseases and Related Health Problems (ICD) since 1948. The 10th revision of the ICD, referred as ICD-10, was first published in 1992, and the 11th revision (ICD-11) is expected to be released in 2018. WHO classifies aging as a disease in the ICD-10 with the R54 code. However, this code is generally regarded by the Global Burden of Disease (GBD) statisticians as a "garbage code" and cannot be considered to be actionable. Actionable classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. In order to classify aging with an actionable code or set of codes linked to specific age-related diseases, we propose an international task force to be organized to develop and communicate proposals to the WHO at the national and international levels.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754422/

To the degree that rejuvenation therapies are successfully developed, retirement will become a thing of the past. It and all of its surrounding institutions and traditions exist because, in the environment of today's medical technology, everyone eventually becomes too frail to work and maintain their own lives. When health can be sustained for far longer, people will continue to work and engage with the world for far longer, but that longevity opens up many other options for lifestyle and planning besides simply working indefinitely. For example, saving and investment over much longer timeframes will ultimately allow anyone to take a few decades out of the normal flow of work here and there to do whatever it is that they desire before returning to gainful employment.

This article isn't a particularly deep or insightful discussion of the topic of retirement and longevity, and, given the source, isn't all that applicable to people of modest means and ordinary employment, but I point it out its existence as an indication of the degree to which the concepts of radical life extension are spreading in the media and the public at large. The more that people think about this sort of thing, and realize that the science makes it plausible for the near future, the more support we find for the necessary research and development.

While the new longevity Americans now savor seems to offer nothing but an upside - you're cheating death longer, right? - the downside of retirement, if it can be called that, is the absolute need to do more planning and budget in many more expenditures. And that's just for starters, because no one knows how long "longevity" will eventually extend, given the scientific world's ongoing research into stem cells. With stem cells, engineered tissues and organs may someday replace our disintegrating originals. "You could get an 'oil change,' an upgrade to your cells every few years. If, 20 or 30 years into the future, your heart is defective, maybe you can grow a new heart in a dish. The underlying biology and access to cells is getting there."

It's hard for anyone to put a number on it. Depending on whom you talk to, those estimated ages of longevity - again, 81.4 years for men and 84.3 for women, according to 2011 actuarial tables - may be just so much hokum. As the science of human longevity continues to accelerate, this will likely translate into improved life expectancy across the board.

Heart disease, cancer and other terminal illnesses can all be traced back to the natural wear and tear that comes with living. As we age, our bodies break down: Tissues and organs become defective and the likelihood increases that our cells will fail us. "Ninety percent of us will die of diseases that do not kill 20-year-olds," says George Church, a professor of genetics at Harvard Medical School. Advances in medicine - which over the past century raised the average lifespan in the United States from 47 to 77 - simply delay the inevitable certainty that we will grow old and, eventually, die. But what if we could reverse aging? According to Church, "That's already happening." Remember those stem cells? Other body parts are figuring into the mix, too. To be clear, Church is talking about mice. Still, the research is compelling.

Such experiments, along with advancements in regenerative medicine, stem cell therapy and gene editing, mean that in a hazy but potentially not-too-distant future, we will no longer die from natural causes. Death, in other words, will be relegated to the realms outside age and disease. Plan to live longer than you expect to. After all, the anecdotal evidence out there supports it.

Link: http://www.entrepreneur.com/article/271456