Fight Aging!

FIGHT AGING! NEWSLETTER
April 4th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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CONTENTS

• DNA Debris From Dying Fat Cells Causes Chronic Inflammation
• An Interesting Theoretical Paper on the Nature of Aging
• Recent Papers Linked by the Theme of Exercise and Aging
• Developing the Art of Group Buy Medical Tourism: 100 People Traveling to Pay 10-20,000 for a Rejuvenation Therapy
• Further Progress in Tissue Engineering of Skin
• Latest Headlines from Fight Aging!
  • ARID1A Gene Knockout Improves Regeneration in Mice
  • Recent Research on Time Spent Sitting and Mortality Rates
  • Kurzweil's View in Brief, in His Own Words
  • Arterial Stiffening and Resulting Damage Starts Early in Aging
  • Evidence for FKBP1b Decline in Aging to Disrupt Calcium Metabolism in the Brain, Leading to Cognitive Decline
  • Modifications of Collagen Cause Age-Related Decline in Structural Function of the Extracellular Matrix
  • Deriving an Anti-Amyloid Drug from Phage Biochemistry
  • Towards Bioprinted Sections of Jawbone and Gum Tissue
  • A Third Demographic Dividend
  • The Popular Science Press on Nanomedical Robotics Designs

FURTHER PROGRESS IN TISSUE ENGINEERING OF SKIN
https://www.fightaging.org/archives/2016/04/further-progress-in-tissue-engineering-of-skin/

Over the past decade, promising inroads have been made in the production of "good enough" engineered skin tissue, and it has advanced to the point at which production methodologies can be automated, building skin from a patient's own cells. The varied forms of tissue generated by these approaches differ from natural skin in many ways: they do not have the same layering of specialized cell types, and lack blood vessel networks and other features of skin such as hair follicles, sweat glands, and lymphatic systems. Still, they can successfully replace lost skin and integrate with a recipient patient's tissues. This represents a big improvement in the quality of treatment and the prognosis for burn victims and other patients who have lost large sections of skin.

As is usually the case, the technologies at the end of the research pipeline closest to realization are considerably less advanced than the work still in progress in the laboratory. We live in an age of rapid progress, and the newly launched technology is already heading towards obsolescence. Even as forms of first generation tissue engineered pseudo-skin become available as an option for hospitals and clinics, the research community is closing in on the production of much more natural and fully-featured skin, again produced from a patient's own cells. Once realized and deployed, this will represent another leap ahead for the treatment of injured and lost skin. In the publication and publicity materials noted here, researchers report on achieving the goal of complex, more fully featured skin in mice:

This Lab-Grown Skin Grows Hair and Can Sweat

Scientists have developed a new method to grow 3D layers of skin and hair cells from stem cells - which are genetically engineered from adult tissue. The scientists' lab-grown skin includes all three layers of skin cells, as well as sweat glands, hair follicles, and your skin's oil-producing glands called sebaceous glands. That's far and away more complex than the next best attempt to artificially regenerate skin, which only includes two types of skin cells. To test their new skin, the researchers took a DNA sample from an adult nude mouse, built a chunk of skin with it, and successfully implanted skin back in the mouse, where it thrived and grew hair. The skin and hair prospered over the entire 70 day period it was meant to last.

To build their multi-layered suite of skin cells, the researchers first collect a small sample of adult tissue. This can be as simple as taking a drop of blood. Although, for their mice, the team scrapes away a tiny bit of mouse's gums. The scientists are then able to genetically engineer those adult cells to revert into stem cells that share the donor's DNA, called induced pluripotent stem cells, or iPS cells. The team found a way to nurture those iPS cells to generate into a package of skin and hair cells. This is done by growing the stem cells in en environment infused with the right combination of chemical signals. This tricks the iPS cells into thinking they need to start forming skin, which can then be harvested in chucks containing between one and two dozen hair follicles. Using this same adult-derived stem cell process, the researchers are also now looking at ways to regenerate various parts of your mouth, including teeth and salivary glands.

Bioengineering a 3D integumentary organ system from iPS cells using an in vivo transplantation model

The integumentary organ system is a complex system that plays important roles in waterproofing, cushioning, protecting deeper tissues, excreting waste, and thermoregulation. The integumentary organs include the skin and its appendages (hair, sebaceous glands, sweat glands, feathers, and nails). We developed a novel in vivo transplantation model designated as a clustering-dependent embryoid body transplantation method and generated a bioengineered three-dimensional (3D) integumentary organ system, including appendage organs such as hair follicles and sebaceous glands, from induced pluripotent stem cells. This bioengineered 3D integumentary organ system was fully functional following transplantation into nude mice and could be properly connected to surrounding host tissues, such as the epidermis, arrector pili muscles, and nerve fibers, without tumorigenesis. The bioengineered hair follicles in the 3D integumentary organ system also showed proper hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches.

DEVELOPING THE ART OF GROUP BUY MEDICAL TOURISM: 100 PEOPLE TRAVELING TO PAY 10-20,000 FOR A REJUVENATION THERAPY
https://www.fightaging.org/archives/2016/03/developing-the-art-of-group-buy-medical-tourism-100-people-traveling-to-pay-10-20000-for-a-rejuvenation-therapy/

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.

RECENT PAPERS LINKED BY THE THEME OF EXERCISE AND AGING
https://www.fightaging.org/archives/2016/03/recent-papers-linked-by-the-theme-of-exercise-and-aging/

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.

AN INTERESTING THEORETICAL PAPER ON THE NATURE OF AGING
https://www.fightaging.org/archives/2016/03/an-interesting-theoretical-paper-on-the-nature-of-aging/

Today I'll point out an open acess 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.

DNA DEBRIS FROM DYING FAT CELLS CAUSES CHRONIC INFLAMMATION
https://www.fightaging.org/archives/2016/03/dna-debris-from-dying-fat-cells-causes-chronic-inflammation/

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.

LATEST HEADLINES FROM FIGHT AGING!

THE POPULAR SCIENCE PRESS ON NANOMEDICAL ROBOTICS DESIGNS
https://www.fightaging.org/archives/2016/04/the-popular-science-press-on-nanomedical-robotics-designs/

It is already possible to design and computationally model nanomedical devices, complex molecular machines intended to operate in large numbers in our tissues for extended periods of time, even if it is not yet possible to manufacture and use them in the large numbers needed. This design and modeling has been going on for quite some time in some portions of the research community, in fact. You might recall the respirocyte as an early design, a device to multiply the oxygen carrying capacity of blood a hundredfold or more. This is only one of a growing stable of designs, many of which are intended to carry out repair of the damage of aging since there has long been an overlap between advocates for life extension and advocates for molecular nanotechnology. This is groundwork for the medical technology of the 2030s and beyond, as constructing and using such machines in large enough numbers to matter will require, at the very least, precision molecular manufacturing - which is the large hurdle - and a range of incremental advances in wireless command and control systems.

Futurists have long speculated that nanotechnology - the engineering of materials and devices at the molecular scale - will revolutionise virtually every field it touches, medicine being no exception. Here's what to expect when you have fleets of molecule-sized robots coursing through your veins. To learn more about the potential for medical nanotech, I contacted Frank Boehm, author of the recently released book, Nanomedical Device and Systems Design: Challenges, Possibilities, Visions.

Let me tell you about one conceptual nanomedical diagnostic concept to give you an idea. It's what I call the Vascular Cartographic Scanning Nanodevice (VCSN) - a sophisticated and autonomous one micron wide nanomedical device for imaging living organisms. I envisage that thousands of VCSN devices would work in massively parallel fashion to scan and image the entire human vasculature, down to the capillary level (3 microns). The acquired spatial data would then enable physicians and surgeons to "fly through" the entire circulatory system using a joystick and computer display. These ultrahigh resolution medical images would allow for the detailed inspection of every portion of the system to discover plaque deposits and to precisely determine arterial/venous wall thicknesses, and hence, whether the patient might be at risk for a potential aneurysm, particularly within the brain.

We could use these devices to significantly enhance the human immune system. I describe one such class of conceptual nanodevice, which I have dubbed the "sentinel." Once nanomedicine matures, the human immune system might be augmented with the capacity to rapidly identify and eradicate threats, like chemical toxins or pathogenic micoorganisms. Autonomous micron-scale "sentinel" class nanodevices, imbued with comprehensive data on all known toxins and pathogens, might continually "patrol" the human vasculature and lymphatic system for the presence of invasive species. They could also penetrate into tissues. And if an unknown intrusive agent is discovered, a default protocol would be spontaneously launched to ensure their complete destruction via chemical, oxidative, hyperthermic, or highly localised nanomechanical disassembly. These Sentinels could operate in conjunction with the innate human immune system, serving as exceptionally sensitive "first responders" to rapidly identify, engage, disable, and degrade all manner of foreign entities.

Extension of the human lifespan could be facilitated through the removal of a substance called lipofuscin from certain types of non-dividing cells, including the brain, heart, liver, kidneys and eyes. Lipofuscin is a metabolic end product that accumulates primarily within lysosomes (the garbage disposal organelles within cells). It's thought that when lipofuscin accumulates to certain levels, it begins to negatively impact cell function, which eventually manifests in many age related conditions. I imagine a procedure in which dedicated "Defuscin" type nanodevices are deployed - they would enter cells and then the lysosomes to bind with and remove lipofuscin through an enzymatic or nanomechanical digest and discharge protocol, a fundamental concept that was originally proposed by Robert Freitas.

A THIRD DEMOGRAPHIC DIVIDEND
https://www.fightaging.org/archives/2016/04/a-third-demographic-dividend/

I have criticized the Longevity Dividend view on extending healthy life for a lack of ambition, for focusing on expensive and slow ways to obtain tiny gains in life expectancy through the manipulation of metabolism. Calorie restriction mimetic development and the forthcoming metformin clinical trial are representative of this school of thought. Here, however, is a view of what to do about aging that makes the Longevity Dividend seem radical. It is focused entirely on policy, provision of existing medical technology, and non-medical prevention strategies such as lifestyle choices to modestly reduce risk of age-related disease - as for the World Health Organization reports it derives from, it is a bureaucratic vision of doing something about aging without doing anything about aging. In this era of tremendous and transformative progress in biotechnology, it seems like burying one's head in the sand to talk at length about improving the state of aging without making medical research and development the primary focus.

Most countries of the world are emerging from the first or are in various stages of the second demographic transition. The first transition is from an agrarian society with high mortality and fertility rates to one where mortality, starting with child mortality, falls; this is followed by declines in fertility. As the "bulge" of children surviving ages into employability, the labor supply becomes greater than the dependent population of children, potentially creating economic growth. This results in what is called a first demographic dividend. This period is time limited. The stage that follows is one in which persisting declines in mortality lead to a population that is living longer. Combined with low fertility, the age structure changes with higher proportions of the population at older ages. Evidence indicates that longevity induces the accumulation of capital, including individual savings in anticipation of retirement. A country's wealth rises. This is termed the second demographic dividend. If policies are constructive and effective, the second dividend can lead to sustained positive economic outcomes.

Mounting evidence suggests that the second demographic dividend does not encompass, by itself, the full potential benefit that society could derive from a larger population of older and aging adults. Additional and sustainable benefits could arise if people arrive at old age healthy and if the large, unrealized social capital of older adults can be activated, conferring benefits both economically and in other measures of societal well-being.

To accomplish this would require a new frame of goal setting for successfully aging societies with investments needed in (a) education, (b) disease prevention and health promotion so that the people arrive at older age healthier and stay healthier longer, and (c) new social institutions and roles to enable paid work by older adults or new high impact generative roles, bringing new social capital to solve major unmet societal needs, while enhancing well-being for the older adults who are accomplishing this. Proposed here is the idea that such investments could lead to a third demographic dividend for aging societies, in addition to the increased wealth of the second demographic dividend.

TOWARDS BIOPRINTED SECTIONS OF JAWBONE AND GUM TISSUE
https://www.fightaging.org/archives/2016/03/towards-bioprinted-sections-of-jawbone-and-gum-tissue/

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.

DERIVING AN ANTI-AMYLOID DRUG FROM PHAGE BIOCHEMISTRY
https://www.fightaging.org/archives/2016/03/deriving-an-anti-amyloid-drug-from-phage-biochemistry/

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.

MODIFICATIONS OF COLLAGEN CAUSE AGE-RELATED DECLINE IN STRUCTURAL FUNCTION OF THE EXTRACELLULAR MATRIX
https://www.fightaging.org/archives/2016/03/modifications-of-collagen-cause-age-related-decline-in-structural-function-of-the-extracellular-matrix/

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.

EVIDENCE FOR FKBP1B DECLINE IN AGING TO DISRUPT CALCIUM METABOLISM IN THE BRAIN, LEADING TO COGNITIVE DECLINE
https://www.fightaging.org/archives/2016/03/evidence-for-fkbp1b-decline-in-aging-to-disrupt-calcium-metabolism-in-the-brain-leading-to-cognitive-decline/

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.

ARTERIAL STIFFENING AND RESULTING DAMAGE STARTS EARLY IN AGING
https://www.fightaging.org/archives/2016/03/arterial-stiffening-and-resulting-damage-starts-early-in-aging/

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."

KURZWEIL'S VIEW IN BRIEF, IN HIS OWN WORDS
https://www.fightaging.org/archives/2016/03/kurzweils-view-in-brief-in-his-own-words/

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 unit cost 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.

RECENT RESEARCH ON TIME SPENT SITTING AND MORTALITY RATES
https://www.fightaging.org/archives/2016/03/recent-research-on-time-spent-sitting-and-mortality-rates/

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."

ARID1A GENE KNOCKOUT IMPROVES REGENERATION IN MICE
https://www.fightaging.org/archives/2016/03/arid1a-gene-knockout-improves-regeneration-in-mice/

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.