Fight Aging! Newsletter, October 12th 2015

October 12th 2015

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

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  • Fundraising Posters: Spread the Word that We're Matching SENS Donations
  • The Long Road Ahead to Exercise Mimetics
  • A View of the Importance of Neurogenesis
  • The Arcane
  • Recent Research on Aging-Related Genes and Proteins
  • Latest Headlines from Fight Aging!
    • A Look at the Work of David Sinclair
    • On the Road to Measuring the Mutational Damage of Aging
    • An Efficient Method of Creating Photoreceptor Cells for Transplantation to Treat Degenerative Blindness
    • Is Alzheimer's Disease Effectively a Type 3 Diabetes?
    • CRISPR Gene Editing and Xenotransplantation
    • Study Suggests More Moderate Exercise is Better
    • Lab-Grown Intestinal Tissue Regenerates Gut Lining in Dogs
    • AC5 Knockout in Mice Increases Exercise Performance as Well as Extending Life
    • Eliminating Rejuvenation in Cellular Reprogramming
    • A Role for LAP2α in Progeria


Last week we launched the Fight Aging! fundraiser for SENS rejuvenation research programs, work on the biotechnologies needed to repair the cellular and molecular damage that causes aging and all age-related disease. Do we want to see meaningful progress towards the defeat of degenerative aging in our lifetime? Yes, yes we do. We will be matching all donations to the SENS Research Foundation until either the end of the year or our 125,000 matching fund runs out - whichever happens first. Obviously we'd love to see the community hit this target, as that would mean an extra quarter of a million for the best lines of early stage research into ending frailty and disease in aging. As of today, 94 donors have given 22,542 since the fundraiser launched on the 1st. A good start!

The SENS Research Foundation has a track record of producing results, as I outlined recently. The philanthropy of past years has blossomed into a first round of startups, clinical development, and greater ongoing funding: Gensight is commercializing an approach to mitochondrial repair, Oisin Biotech is working on senescent cell clearance, and Human Rejuvenation Technologies was formed to further develop the use of bacterial enzymes to remove of some of the metabolic waste compounds that contribute to atherosclerosis. The wheel is turning and now is the time for greater efforts, to remove the hurdles and fund the groundwork needed for the next round of biotechnologies for human rejuvenation.

I ran up a pair of new fundraising posters over the weekend, sticking to this year's simple motif of text and color, suitable for signs and more visible from a distance. This year's fundraiser is a stretch goal for our community, based on how we've been doing over the past couple of years. We need to get out there and wave the flag, track down new supporters and expand our corner of the world, the small community interested in actually getting something done about aging.


Today I'll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion in funding and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I'm not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

Excessive caloric intake and limited physical activity contribute to the current explosion of 'modern' chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these 'modern' chronic diseases.

Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.

Exercise in a bottle could become a reality

Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world's first comprehensive exercise blueprint. "Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn't a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise." The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.

"Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise."


Neurogenesis is name given to the creation of new neurons in the central nervous system, and particularly the brain. Only within the last thirty years, quite recently in the grand scheme of things, have researchers proved that neurogenesis occurs at a low level in adults, that the brain is not a fixed set of long-lived and non-dividing cells, but is augmented with new arrivals on an ongoing basis. Once verified, this became a topic of considerable interest for the growing fields of regenerative medicine and stem cell research. Can the rate of neurogenesis be safely increased, and will this produce benefits for patients suffering neurodegenerative conditions, or postpone the onset of such conditions? Can investigation of neurogenesis be used to guide improvements in first generation stem cell therapies based on transplanted cells?

With more research into the biology of the brain, aided by the rapid improvement in the tools of biotechnology since the 1990s, there is an increased realization of the importance of adult neurogenesis. Few evolved processes exist without serving multiple ends, and this one is no exception in that regard. More than a mere repair and replacement mechanism, neurogenesis in adults is necessary to the correct functioning of the brain. Couple that to the discovery that rates of neurogenesis decline with age, and the processes of slow growth and change in the brain become ever more attractive as an area of medical research. It is worth noting that some of the recent work emerging from parabiosis studies, in which alterations are made to levels of some of the molecular signals in the circulatory system, have shown preliminary signs of being able to reduce the age-related decline in neurogenesis.

The article linked below is a good read, and goes some way to providing the high-level context and background to explain why research into neurogenesis is so important to those parts of the life science community focused on aging, age-related diseases of the brain, neurobiology, and regenerative medicine. Clearly there is a lot more to be done before an initial set of therapies emerge via the traditional drug development approach, and those therapies will likely be pretty marginal at the outset if history is any guide, but it is an interesting field to watch.

Brain Gain: Young Neurons in the Adult Human Brain are Likely Critical to its Function

At a lab meeting in the mid-1990s a neuroscientist told his team that he wanted to determine whether new neurons are produced in the brains of adult humans. At the time, adult neurogenesis was well established in rodents, and there had been hints that primate brains also spawned new neurons later in life. But reports of neurogenesis in the adult human brain were sparse and had not been replicated. Soon enough, a clear picture emerged: the human hippocampus, a brain area critical to learning and memory and often the first region damaged in Alzheimer's patients, showed evidence of adult neurogenesis. In November 1998, the group published its findings. "When it came out, it caught the fancy of the public as well as the scientific community. It had a big impact, because it really confirmed neurogenesis occurs in humans."

Fifteen years later, in 2013, the field got its second (and only other) documentation of new neurons being born in the adult human hippocampus - and this time learned that neurogenesis may continue for most of one's life. Neuroscientistists took advantage of nuclear bomb tests carried out during the Cold War. Atmospheric levels of carbon-14 have been declining at a known rate since such testing was banned in 1963, and researchers were able to date the birth of neurons in the brains of deceased patients by measuring the amount of carbon-14 in the cells' DNA.

In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited. "For a period of about four or five weeks, while the newborn neurons are maturing, they're hyperexcitable. They'll fire at anything, because they're young, they're uninhibited, and they're integrating into the circuit."

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals' performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment.

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people - namely, that adult neurogenesis plays some role in learning and memory. "Given that the dentate gyrus is so highly conserved and that the mechanisms of its function are so similar between the species - and given that neurogenesis is there in humans - I would predict that the general principle is the same." And if it's true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information - an ability that is often impaired among people with neurodegenerative diseases - it's natural to wonder whether promoting neurogenesis could affect the course of Alzheimer's disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life - known from animal models to increase neurogenesis - are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer's. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression.

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists say yes. "I think the field is moving toward that. Neurogenesis is not something de novo that we don't have at all - that would be much harder. Here, we know it happens; we just need to enhance it."


Here I am going to ramble a little about patterns of human behavior. "Arcane" is one of those words sorely abused by generations of people involved in the most fanciful of modern pastimes, which is to say the creation of alternative magical and religious beliefs and practices, both in earnest and for fun. As a consequence it has gathered a broad wake of connotations and cultural baggage. Cut all that away and it has an unbiased, simple, and straightforward meaning, however. To be arcane is to be obscure, to be hidden, to be known only to a few.

We humans have evolved a strong urge to pattern recognition. It is a key part of our intelligence as it applies to the business of surviving the rigors of natural selection. Clearly the benefits of identifying and acting on real patterns far outweighed the disadvantages of incorrectly seeing patterns that are not real. How else to explain magical thinking, the tendency for people to fit everything they observe into simple models of cause and effect regardless of accuracy, and then search for the truth later, if at all? The world about us is so very complex that there will always be things that any given group of people cannot understand or model accurately with the resources at their disposal, but put in that situation they will build the models anyway, because that is more comfortable than acknowledging ignorance. So we have religion, magical traditions, the ridiculous marketing that emerges from the snakeoil "anti-aging" marketplace, and generations of people attaching extra saddlebags of meaning to workhorse words such as "arcane," "esoteric," and the like.

Every present culture has very deep roots, stretching back at least centuries into eras in which it was universally accepted that an arcane world lies underneath the mundane, steering it, providing the rules that make sense of what seems senseless. In search of patterns, any patterns, people looked for guidance to whomever was bold enough to claim to see into the arcane world, and since we are a hierarchical species, like our fellow primates, that form of leadership was institutionalized into power structures very early on. Thus we have a history of shamans, priesthoods, temples, the Hero's Journey, and the endless, ever more baroque theology that commenced as soon as things advanced to the point of fighting with words and concepts rather than weapons. All of that lies underneath the thin veneer of modernism, a bone mountain, the legacy of the dead.

Now, here is an interesting thing about modern science and technology: its complexity and importance has in effect created a real arcane world that lies alongside the mundane, steering its future, determining who will live and who will die, what changes and what persists, how the rules of everyday life will differ tomorrow. The present state of technology is the greatest determinant of how we live our mundane lives, and technological progress is the greatest determinant of what tomorrow will bring. Yet few people choose to undertake the work needed to peer from their daily grind into the arcana of technology, even in this age of enormously rapid change, in which the formative lives of each new generation are appreciably different from those of their parents.

Medicine and medical research, especially into aging, shape the rules that will determine the portents for the rest of our lives. How long will we live, will we suffer, what must we do to have the best odds of success? Two thousand years ago people went to priests and burned offerings. A thousand years ago they petitioned physicians who had more in common with priests than with today's practitioners. Today they go clinics and understand about as much of the underpinnings of what they are told to do, for all that it is a lot more effective. The behaviors and organizations laid down to deal with the imaginary arcana of mysticism and religion continue for the real arcana of technology. Very few people go beyond talking to researchers to lift the veil and seek to understand why medicine is the way it is, why the answers to their questions are what they are. They accept the patterns that are explained in shorthand, and are comforted by them, right or wrong. That the patterns offered are better and more effective because of the changing tides of the arcane world of medical research is almost beside the point.

It is always too easy to castigate, however. We who do look further, who place ourselves with a foot in the arcane and a foot in the mundane, drifting from day to day activities on the one hand to presenting the logical outcome of human agelessness resulting from effectively treating aging as a medical condition on the other - we can forget just how distantly removed from all this we once were, or how much of an accident it is that we are where we are today. Ponder just how little thought you gave to medicine and where it came from when you were young, immersed in the mundane: back when you thought aging was set in stone, and the sum of the world was school, shopping, relationships, the changing of the seasons, a job, a hobby. The sum of an unremarkable, unique life. That is most people, unaware of what actually sways their futures.

All of this is why you see similar patterns of human organization at the high level emerging at the boundary of medical science and the world at large as at the boundary of organized religion and the world at large. The data is vastly different, and the importance vastly different. But the same underlying incentives and facets of human nature are at work, driving the small decisions that snowball into organizations and initiatives. For preference I'd like to see this change. The arcane world of medical research, and particularly that related to ending frailty and disease in aging, cannot continue to be as arcane as it is today if we are to see the growth we need in funding and support. The scale of applied resources and pace of progress that is justified by the grand panoply of suffering caused by disease and aging is hard to sustain when no-one thinks about medicine until they are sick. Research and development of new therapies is slow, and leaving education and support for that process until it is needed is leaving it far too late to make a difference.

If we could just bootstrap medicine to much the same position in the public eye as the automobile or the personal computer, where there is some breakdown of the veil between the arcane world of progress and development and the mundane world of use, even that would be a great gain. Unfortunately doing this is an uphill battle against our own evolutionary history and evolved preferences: threatened by complexity, and worse, by the time needed to make a dent in that complexity, most people retreat and direct their limited attention elsewhere. It is a hard sell to persuade anyone to outlay their precious time to understand something that will be important a decade or two from now. In effect those of us closer to the inside of the veil of the arcane for medical research are something like reverse Cassandras: knowing that wondrous, golden futures lie ahead, if only people will listen, understand, and help. More are taking notice with each passing year, but it still far more slowly than they might. Changing the world is not easy.


Below find links to a few recent papers relating to the genetics and epigenetics of aging. Aging is a byproduct of the normal operation of cellular metabolism, due to damage generated and not repaired. Many genes will have some impact on the progression of aging because they govern the operation of metabolism and thus influence the pace at which unrepaired damage accumulates. As time progresses and the damage of aging builds up, cells react to that damage with changes to the epigenetic regulation of the production of proteins. Thus old individuals have more of some proteins and less of others in circulation and present in various tissues, changing the way in which cells and tissues function. Some of this is compensation, and aging would be faster and worse without it, but some of it is just more dysfunction piled on top of that caused directly by damage to cells and their component parts.

Much of the aging research field is involved in cataloging: firstly finding genes associated with the pace of aging by dint of altering them one by one in short-lived and well-characterized species such as yeast or nematode worms, and secondly finding genes whose output of proteins changes with age by precisely measuring the molecules present blood and other bodily fluids at various different ages. Gathering information about how exactly aging progresses at the detail level still has a higher priority for most researchers in comparison to moving beyond that to try to treat aging.

There are some necessary tools that will emerge from cataloging efforts, however. One is a good biomarker of biological age, a measurement that must be cheap and easy to carry out given simple patient samples such as skin or saliva, and comprehensive enough to pick up the beneficial effects of a partial rejuvenation therapy soon after it is applied. For rejuvenation based on repair of cell and tissue damage after the SENS model, researchers can always identify how much of the specific form of damage has been repaired by their treatment, but there is still the need to link that to some reliable and accepted measure of overall biological age for the organism as a whole. Without that biomarker the only way to prove that rejuvenation has happened is to wait and see: run the life span study, which even in mice requires years and millions in funding, never mind in longer-lived mammals. The need for life span studies as proof is a real drag on the pace of progress.

Identification of ageing-associated naturally occurring peptides in human urine

In a first small scale study, we investigated the urinary proteome in a cohort of 324 healthy individuals between 2 to 73 years of age showing the feasibility to obtain high resolution molecular information from readily available body fluids such as urine. Meanwhile, we have accumulated multiple high-resolution urine peptidomics datasets that enable the investigation of ageing-associated changes in a large cohort. In the present study, we therefore investigated the unique urinary proteome profiles of 11,560 individuals in an attempt to identify specific ageing-associated alterations and investigate pathological derailment of normal ageing. This showed that perturbations in collagen homeostasis, trafficking of toll-like receptors and endosomal pathways were associated to healthy ageing, while degradation of insulin-like growth factor-binding proteins was uniquely identified in pathological ageing.

Length of paternal lifespan is manifested in the DNA methylome of their nonagenarian progeny

The heritability of lifespan (age at death) has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age. Healthy aging is also heritable, and the offspring of long-lived parents show delayed onset of aging-associated diseases. Much of the research studying the heritability of lifespan has focused on extreme age (nonagenarians, centenarians, supercentenarians), but recently it has been shown that every decade of parental age after the age of 65 reduces the mortality and incidence of cancer of their offspring. Even though the heritability of the lifespan is acknowledged, only one genomic locus (on chromosome 3) and a few genetic variants, such as in APOE and FOXO3, have consistently been shown to be associated with longevity. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.

We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch-genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.

The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan

The heat-shock protein 70 (Hsp70) acts as a cellular defense mechanism its expression being induced under stressful conditions. Aging has been related to an impairment in this induction. However, an extended longevity has been associated with its increased expression. According to the oxidation-inflammation theory of aging, chronic oxidative stress and inflammatory stress situations (with higher levels of oxidant and inflammatory compounds and lower antioxidant and anti-inflammatory defenses) are the basis of the age-related alterations of body cells. Since oxidation and inflammation are interlinked processes, and Hsp70 has been shown to confer protection against the harmful effects of oxidative stress as well as modulating the inflammatory status, it could play a role as a regulator of the rate of aging.

Mapping the Genes that Increase Lifespan

Following an exhaustive, ten-year effort, scientists have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. "This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is. It also sets up a framework to define the entire network that influences aging in this organism." Researchers began the painstaking process by examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing. "We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides. We had several microscopes running all the time."

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control. "Calorie restriction has been known to extend lifespan for a long time. The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes."


Monday, October 5, 2015

This article paints a picture of David Sinclair as one of the important researchers in the move towards treating aging as a medical condition. I'd say that he's certainly good at publicity and fundraising, and has more than done his part to make drug development for the treatment of aging plausible in the eyes of the public, but it is a pity that all of this is coupled to lines of research (such as the investigation and manipulation of sirtuins) that to my eyes have no hope of producing meaningful therapies. Even if sirtuin-based therapies could do all that the original hype promised, the end result would be a marginal, slight slowing of the aging process. As an end goal for the investment of billions and years of time, that simply isn't worth it when there are far better approaches to the problem such as SENS that can in principle lead to actual rejuvenation and the addition of decades of healthy life.

Today, Sinclair's work on slowing the ageing process, and even reversing some aspects of it, could lead to the most significant set of medical breakthroughs since the discovery of antibiotics nearly a century ago. At the heart of what motivates him is a deceptively simple notion: if the greatest driver of disease in old age is old age itself, then why not find a cure for ageing, which he describes as being "the greatest problem of our time". Sinclair's statement is borne out by the World Health Organisation's Global Burden of Disease Project, which estimates that the number of years lost to premature death or compromised by disability in 2010 was 2.5 billion, meaning that about a third of potential human life goes to waste. The toll from crime, wars and genocides does not come close to matching this. Yet, as Sinclair points out, just one per cent of medical research funding is spent on understanding why we age and even less on doing something about it. His goal is to find the "master control switch" that can regulate the pathways that contribute to ageing itself. "It could be one pill for 20 diseases at once. It would be the most profitable drug ever made."

Extending the generally accepted limits of human life is now being taken seriously by some of the world's top scientists. Backed by wealthy philanthropists and tech giants such as Google, billions are being poured into longevity research. Press releases and PowerPoint presentations come laced with terms such as health-span, not lifespan. The elderly, we are told, will become the wellderly. There will be fewer bedridden geriatrics taxing our overstretched medical systems. The ever-growing list of billionaires funding research into longevity includes PayPal co-founder Peter Thiel, who has set up Breakout Labs, a non-profit organisation that supports early-stage companies, and Oracle founder Larry Ellison, who has donated more than 430 million to ageing research.

Sinclair is decidedly reticent when it comes to passing judgment on the work of other scientists such as Craig Venter at Human Longevity Inc. and Cynthia Kenyon at Calico: "I think it's going to take a lot of resources to find the needle in the haystack, but it's helpful that more people are getting involved in ageing research. If Craig and his associates tackle it from the sequencing side and we tackle it from the fundamental biology side and Google's Calico attacks it from bioinformatics side, then there's more chance of finding the right medicines." Circumspection is embedded in Sinclair's DNA. He speaks slowly and deliberately, giving his audiences time to absorb both the complex science behind his discoveries and to underline what motivates him. "How sad would it be if we, after 10,000 generations, we were the last ones to live a normal lifespan? Imagine if we were born one generation too early to reap the benefits of this technology."

Monday, October 5, 2015

Researchers are now able to compare the mutational damage to nuclear DNA in individual long-lived cells such as neurons, which is a step towards measuring how much of this damage there is and how it varies over time and from cell to cell. That in turn is a step towards getting a handle on whether or not this damage has any meaningful effect over the course of a human life span beyond raising the risk of cancer. For example is the presence of stochastic mutational damage causing large enough alterations in the day to day operation of metabolism across enough cells to matter? There is some debate on this issue, and certainly a lack of good enough data to nail down a proof one way or another.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. "We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated." It's not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease.

Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible. However, technology has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron's genome and scour it for places where that cell's genetic code differed from that of other cells.

The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual's heart. What they found was that every neuron's genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What's more, the nature of the variation was not quite what the scientists had expected. "We expected these mutations to look like cancer mutations, in that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes. To what extent do these mutations normally shape the development of the brain, in a negative way or a positive way? To what extent do we have a patch of brain that doesn't work quite right, but not so much that we would call it a disease? That's a big open question."

Tuesday, October 6, 2015

An important factor in the speed of development, cost, and availability of future stem cell therapies is the existence of an efficient, reliable way to create large numbers of the specific cell types needed. This is one of the main limiting factors for many areas of medical development in cell-based regenerative medicine. Here, researchers establish a methodology for generation of photoreceptor cells that could be used to rebuild retinal tissue, which is good news for progress towards regenerative therapies for conditions such as macular degeneration:

Age-related macular degeneration (ARMD) is due to the degeneration of the macula, which is the central part of the retina that enables the majority of eyesight. This degeneration is caused by the destruction of the cones and cells in the retinal pigment epithelium (RPE), a tissue that is responsible for the reparation of the visual cells in the retina and for the elimination of cells that are too worn out. However, there is only so much reparation that can be done as we are born with a fixed number of cones. They therefore cannot naturally be replaced. Moreover, as we age, the RPE's maintenance is less and less effective - waste accumulates, forming deposits.

A research team has developed a highly effective in vitro technique for producing light sensitive retina cells from human embryonic stem cells. "Our method has the capacity to differentiate 80% of the stem cells into pure cones. Within 45 days, the cones that we allowed to grow towards confluence spontaneously formed organised retinal tissue that was 150 microns thick. This has never been achieved before."

In order to verify the technique, researchers injected clusters of retinal cells into the eyes of healthy mice. The transplanted photoreceptors migrated naturally within the retina of their host. "Cone transplant represents a therapeutic solution for retinal pathologies caused by the degeneration of photoreceptor cells. To date, it has been difficult to obtain great quantities of human cones." The discovery offers a way to overcome this problem, offering hope that treatments may be developed for currently non-curable degenerative diseases, like Stargardt disease and ARMD. "Researchers have been trying to achieve this kind of trial for years. Thanks to our simple and effective approach, any laboratory in the world will now be able to create masses of photoreceptors. Even if there's a long way to go before launching clinical trials, this means, in theory, that will be eventually be able to treat countless patients."

Tuesday, October 6, 2015

For some years a faction of researchers have argued that Alzheimer's disease really should be considered a type 3 diabetes, based on the shared risk factors and what is known of the way that it ties into the mechanisms associated with insulin resistance. It is certainly the case that based on epidemiological data Alzheimer's, like type 2 diabetes, is enough of a lifestyle disease that you should add it to the list of very good reasons not let yourself become fat and sedentary. But is the connection with insulin metabolism relevant enough to class Alzheimer's as a form of diabetes, or is this just a good example of the way in which everything connects to everything else in the operation of our cellular biology?

Aging is known to be one of the top risk factors for both Alzheimer's disease (AD) and Type 2 Diabetes (T2D). The pathologies of these disorders are somewhat understood, with AD being associated with the accumulations of amyloid-β plaques and/or phosphorylated tau tangles (two proteins involved in neuron structure and development) and T2D being associated with resistance to insulin (the growth factor that controls glucose uptake by cells). For many years these two diseases have been treated separately, with few overlaps. In more recent years, however, the overlap between them has become more prominently recognized. The rate of AD in diabetic individuals is elevated, and it may be worth considering these two "separate" disorders as a related problem.

The first suggestion of AD being a previously unrecognized type of diabetes was in 2005, where it was noted that insulin signaling and insulin-like growth factor (IGF) expression were greatly affected in the instance of AD. It has since been shown that in the instance of AD, IGF, insulin receptor, and insulin expression are all reduced in the temporal cortex and hippocampus of the brain. Further, as AD progresses the levels of these gene transcripts continue to decrease. These inhibited insulin-related signals result in a deficiency and similar symptoms to those shown in other cases of diabetes. This deficiency also contributes to a vicious cycle, as impaired insulin receptor expression can contribute to further AD-like pathology such as hyperphosphorylation of tau and increased amyloid-β deposits as well as decreased clearance of these deposits from the brain.

Although seldom considered a metabolic disorder, it is clear that AD is metabolically affected in a similar fashion to diabetes. Although frequently treated separately, the same basic principles which are used for diagnosing an individual as diabetic may also be applied to understand some of the mechanisms affected in AD. As such, it may be appropriate to consider AD as a type of diabetes of the brain.

Wednesday, October 7, 2015

The present best approach to enabling xenotransplantation of pig organs into human patients is decellularization: strip all the cells and repopulate the extracellular matrix scaffold of the organ with human cells. However, with the existence of cheap and efficient genetic alteration based on CRISPR it may be possible to edit all of the genes in pig cells that produce problem proteins instead of replacing these cells. My first thought on this is that decellularization is still a better option; after any reasonable number of genetic edits on pig cells the result remains an organ built out of edited pig cells, not human cells, and not matched to the patient. Still, this is an interesting demonstration of the cost-effectiveness of CRISPR, making genetic alterations in much larger batches than have been achieved to date:

For decades, scientists and doctors have dreamed of creating a steady supply of human organs for transplantation by growing them in pigs. But concerns about rejection by the human immune system and infection by viruses embedded in the pig genome have stymied research. By modifying more than 60 genes from pig embryos - ten times more than have been edited in any other animal - researchers believe they may have produced a suitable non-human organ donor.

The researchers used CRISPR gene-editing technology to inactivate 62 porcine endogenous retroviruses (PERVs) in pig embryos. These viruses are embedded in all pigs' genomes and cannot be treated or neutralized. It is feared that they could cause disease in human transplant recipients. They also modified more than 20 genes in a separate set of embryos, including genes encoding proteins that sit on the surface of pig cells and are known to trigger the human immune system or cause blood clotting. Eventually, pigs intended for organ transplants will have both these modifications and the PERV deletions.

A biotech company founded to produce pigs for organ transplantation, eGenesis in Boston, is now trying to make the process as inexpensive as possible. The team released few details about how they managed to remove so many pig genes. But both sets of edited pig embryos are almost ready to implant into mother pigs. eGenesis has procured a facility at Harvard Medical School where the pigs will be implanted and raised in isolation from pathogens.

Wednesday, October 7, 2015

Researchers here crunch the numbers to suggest that people who exercise for longer are better off in terms of risk of suffering age-related cardiovascular disease. One of the emerging themes in epidemiology in recent years is an attempt to pin down the dose-response curve for exercise. How is long term health and life expectancy affected for different levels of exercise, and do these differences reflect correlation or causation? Is it a matter of people obtaining health benefits through exercise or a matter of more healthy people tending to exercise more? These are hard questions to answer for human populations, but as technology lowers the cost of obtaining and using large data sets, ever more research groups are taking a stab at it. As with all such statistical studies, it is wise to wait for more data and the work of different teams before taking anything published by one group at face value, however:

Doubling or quadrupling the minimum federally recommended levels of physical activity lowered the risk of developing heart failure by 20 percent and 35 percent, respectively, according to researchers. "Walking 30 minutes a day as recommended in the U.S. physical activity guidelines, may not be good enough - significantly more physical activity may be necessary to reduce the risk of heart failure." The researchers found that the current U.S. physical activity guidelines recommendation of a minimum of at least 150 minutes of moderate intensity physical activity a week was associated with only a modest reduction in heart failure risk, and suggest that higher levels of physical activity, up to twice the minimum recommended dose, is needed to reduce the risk of heart failure.

They also found a "dose-dependent" inverse association between physical activity and heart failure, that is, higher levels of physical activity were associated with a lower risk of heart failure. This relationship was consistent across all age, sex, race, and geographic location based subgroups studied. Although the role of physical activity in coronary heart disease - the narrowing of the arteries that causes heart attacks - has been comprehensively studied, this study focused exclusively on the quantitative relationship between the amount, or specific "dose" of regular physical activity and the risk of heart failure.

The researchers pooled data from 12 studies from United States and Europe that collectively included 370,460 individuals with varying levels of physical activity at baseline and 20,203 heart failure events over a mean follow-up of 15 years. Physical activity was measured by self-reported levels of activity by study participants using standard questionnaires. "Future physical activity guidelines should take these findings into consideration, and potentially provide stronger recommendations regarding the value of higher amounts of physical activity for the prevention of heart failure."

Thursday, October 8, 2015

Over the last five years considerable progress has been made in the tissue engineering of intestines. Researchers have created sections of intestine, grown intestine organoids, and regenerated damage to intestines in laboratory animals. Here is the latest example:

Working with gut stem cells from humans and mice, scientists have successfully grown healthy intestine atop a 3-D scaffold made of a substance used in surgical sutures. The tube-shaped scaffold was a big first step on the quest to develop an implantable replacement intestine. But the new work pushes that effort further because it shows how stem cells, when mixed with immune and connective tissue cells, can grow into normal gut tissue around the scaffold and function inside a living mammal. Researchers caution that a fully functioning replacement intestine for humans is far off, but they say their results have laid the critical groundwork to do so. "Our experiments show that the architecture and function of our lab-made intestine strikingly resemble those of the healthy human gut, giving us real hope that our model could be used as the backbone for replacement intestine."

In an initial set of experiments researchers took stem cells from the colons of babies undergoing intestinal surgeries and from mice, then added immune cells called macrophages, the body's scavengers that seek out and engulf debris along with foreign and diseased cells. To this mix, they added cells called fibroblasts, whose function is to form collagen and other connective substances that bind tissues and organs together. The idea, the scientists say, was to create a mixture that closely mimics the natural composition of the gut. In another set of experiments, researchers added probiotic bacteria to the newly created intestinal tissue. Doing so further amplified the growth and differentiation of new gut cells, specifically the growth of Paneth cells responsible for production of infection-fighting proteins that guard against intestinal infections.

Next, researchers implanted the newly created intestine into the bellies of mice. In a matter of days, the implanted intestine began producing new intestinal stem cells and stimulated the growth of new blood vessels around the implant. That observation, researchers say, affirmed the ability of the 3-D intestine to spur the growth of new tissue not only in lab dishes, but also in living organisms. In a final step, the investigators implanted pieces of the newly created intestine - about 1.6 inches in length - into the lower portion of dog colons lacking parts of their intestinal lining. For two months, the dogs underwent periodic colonoscopies and intestinal biopsies. Strikingly, the guts of dogs with implanted intestines healed completely within eight weeks. By contrast, dogs that didn't get intestinal implants experienced continued inflammation and scarring of their guts.

Thursday, October 8, 2015

Here I'll point out some of the latest work on adenylate cyclase 5 (AC5), a longevity gene in mammals, which is now shown to boost exercise performance as well as longevity in mice. It is an open question as to the degree to which the longevity effects are secondary to the exercise effects. The authors of this paper note that there has been little study of exercise effects for most of the other methods of enhancing longevity in laboratory mice, which is an interesting oversight. Perhaps this will change with a growing interest in the development of exercise mimetic drugs.

Disruption of AC5, such as through gene knockout, is one of the many methods shown to modestly slow aging and extend healthy life in mice. As for all of these approaches, much work is yet needed to understand exactly how it works under the hood. The present high level understanding of single gene longevity enhancements in laboratory animals varies from sketchy theory to fairly robust outline, and getting any further than that is proving to be a slow, expensive, and time-consuming business. Every mechanism influences every other mechanism inside a cell, nothing happens in isolation, and so understanding any one life-extending genetic alteration blurs at the edges into the much, much larger project of understanding the enormous complexity of cellular biochemistry as a whole.

The major finding of this investigation is that disruption of AC5, which actually decreases sympathetic tone, increases exercise performance. This is novel, as the most common mechanism mediating enhanced exercise is via increased sympathetic stimulation and catecholamines, resulting in increased AC activity and augmented cardiac output. This was not the mechanism in AC5 knockout mice, where AC activity is actually reduced, and there was no greater increase in cardiac output during exercise compared with WT mice, based on direct measurements of ascending aortic blood flow with implanted ultrasonic flow probes and heart rate in chronically instrumented mice. Further confirming the lack of a cardiac mechanism, the cardiac-specific AC5 knockout did not exhibit enhanced exercise. Accordingly, the mechanism resided at the level of the exercising skeletal muscles, which was confirmed, when we found that exercise performance was also elevated in the skeletal muscle-specific AC5 knockout.

Another key finding of the current investigation was demonstrating that protection against oxidative stress, by increased MnSOD levels and activity in AC5-deficient skeletal muscles, is also involved in the mechanism of enhanced exercise capacity in AC5 knockout mice, as exercise capacity of AC5 knockout mice was significantly attenuated in AC5 knockout / MnSOD heterozygous knockout bigenic mice. One question that arose is whether these effects of enhanced exercise in AC5 KO mice are simply due to a decrease in AC, which might be evoked in a knockout from any of the 9 AC isoforms, or are they due to unique signaling in AC5. To address this question, we examined exercise in 10 AC6 KO mice and 7 wild type controls. The AC6 KO mice did not show increased distance or speed with exercise compared to their wild type. Therefore, the enhanced exercise was not simply due to a reduction in AC, but was rather unique to the AC5 KO and its signaling pathway noted above.

Exercise plays an essential role in longevity, in general, and healthful aging, in particular, as it protects not only against obesity, diabetes, and cardiovascular disease, but also reduces the risk of cancer and improves bone health and even mental diseases that impair aging. Therefore, the demonstration of improved exercise performance in the AC5 knockout model is particularly germane, as this is also a model for longevity, and protects against cardiovascular stress, diabetes, and obesity. In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.

Friday, October 9, 2015

Researchers here demonstrate a method of generating reprogrammed cell lines from old patients that retain the age-related changes and damage in the cells, a useful tool for further research. The technique of induced pluripotency has in recent years been used to generate cells of arbitrary specific types from, for example, a patient skin cell sample: the skin cells are reprogrammed to be pluripotent, and then differentiated into the desired cell type. Reprogramming to pluripotency has been shown to rejuvenate some of the aspects of old cell lineages, such as by clearing out damaged mitochondria, and removing age-related epigenetic markers, possibly reflecting other forms of repair. This may be related to the early stage of embryonic development in which age-related damage is abruptly repaired, the cells reset to a youthful state. This is all very interesting to some factions of the research community, but frustrating for those scientists who are trying to build patient-matched models of old tissue to better understand what is going wrong in age-related diseases.

For the first time, scientists can use skin samples from older patients to create brain cells without rolling back the youthfulness clock in the cells first. The new technique, which yields cells resembling those found in older people's brains, will be a boon to scientists studying age-related diseases like Alzheimer's and Parkinson's. "This lets us keep age-related signatures in the cells so that we can more easily study the effects of aging on the brain. By using this powerful approach, we can begin to answer many questions about the physiology and molecular machinery of human nerve cells - not just around healthy aging but pathological aging as well."

Over the past few years, researchers have increasingly turned to stem cells to study various diseases in humans. For example, scientists can take patients' skin cells and turn them into induced pluripotent stem cells, which have the ability to become any cell in the body. From there, researchers can prompt the stem cells to turn into brain cells for further study. But this process - even when taking skin cells from an older human - doesn't guarantee stem cells with 'older' properties. "As researchers started using these cells more, it became clear that during the process of reprogramming to create stem cells the cell was also rejuvenated in other ways."

Researchers decided to try another approach, turning to an even newer technique that lets them directly convert skin cells to neurons, creating what's called an induced neuron without passing through a pluripotent state. They collected skin cells from 19 people, aged from birth to 89, and prompted them to turn into brain cells using both the induced pluripotent stem cell technique and the direct conversion approach. Then, they compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains. When the induced pluripotent stem cell method was used, as expected, the patterns in the neurons were indistinguishable between young and old derived samples. But brain cells that had been created using the direct conversion technique had different patterns of gene expression depending on whether they were created from young donors or older adults. For instance, levels of a nuclear pore protein called RanBP17 - whose decline is linked to nuclear transport defects that play a role in neurodegenerative diseases - were lower in the neurons derived from older patients.

Friday, October 9, 2015

It remains an open question as to the degree to which the mechanisms that cause progeria are relevant in normal aging. They are present at very low levels in old people, a very different picture from the upheaval and dysfunction taking place in the cells of progeria patients. Are those low levels meaningful over the course of a normal human life span, and in comparison to the known causes of degenerative aging? Time will tell, but it can't hurt to keep an eye on progress in progeria research, which seems to be on the verge of a more effective class of therapies:

Though researchers identified the abnormal protein behind progeria - progerin - the exact way in which it causes the accelerated aging remains elusive. Progerin, a protein present in very high concentration in progeria cells, is known to be responsible for many of the characteristics of the disease. It is a mutant version of lamin A, a protein crucial for the stability of the nucleus and involved in many essential nuclear functions. "A few years ago, we and others found that progeria cells have much less LAP2α than normal cells. LAP2α is a protein that interacts with lamin A to regulate cell proliferation, the process that produces new cells. Interestingly, LAP2α levels also decrease during normal aging. The cells that produce progerin had really low LAP2α levels compared to normal cells. But when we re-introduced LAP2α we could completely rescue the proliferation defect of the progeria cell line. The same actually happened in cells from patient samples."

Further experiments revealed a real surprise: LAP2α functions very differently in progeria cells compared to normal cells. Usually it binds to a distinct nuclear pool of lamin A and slows proliferation, so low LAP2α levels result in hyperproliferation. But in progeria the opposite is the case, cells proliferate much slower and prematurely enter the cellular aging process. The reason for this is that progeria cells do not have the nuclear lamin A pool. This hinted that LAP2α uses a different route to exercise its function in progeria cells. In the end, data from previous experiments gave the researchers the clue to solve the puzzle. "Cells are surrounded by material that structurally supports them. It is called extracellular matrix or in short ECM. It was reported before that progerin negatively affects the production of ECM proteins, leading to a disrupted cellular environment and slower proliferation. Now we connected this to the low LAP2α levels and when we reintroduced LAP2α into progeria cells they again produced normal ECM and proliferated normally and didn't enter the cellular aging process."

The study's insights why and how progerin impairs the production of ECM proteins and normal proliferation opens new avenues towards the development of more specific therapeutic strategies for the treatment of progeria. As the premature aging disease resembles in many aspects normal aging, the results also allow drawing conclusions on the cellular processes during normal aging.


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