Fight Aging!

Philanthropy has an important role in funding medical research, and thus crowdfunding will have an equally important role in the years ahead: it is collaborative philanthropy, the diverse will of the public, organized and made real. The falling cost of early stage biotechnology research means that the suite of prototype technologies needed to arrest degenerative aging in mammals, preventing all age-related disease through periodic repair of the cell and tissue damage that causes aging, might be as little as a billion dollars and ten years of work away from where we stand today. If we all get our act together.

Many hands make light work, and getting our act together is the point of Lifespan.io. This new non-profit crowdfunding initiative officially launched last week, showcasing a SENS mitochondrial research project that is a third of the way towards being funded as of today. Lifespan.io is an outgrowth of the Life Extension Advocacy Foundation (LEAF), and the staff and volunteers seek to attract funding for the most important of early staging longevity research, speeding the advent of prototype rejuvenation therapies. This is certainly the time for it: today is still early in a great transformation in aging research, leaving behind the look but don't touch approaches and the palliative treatment of late stage symptoms without any hope of lasting cures. The near future is brightened by the promise of direct intervention in the underlying causes of aging and age-related disease, and thus the prospect of being able to cure not just age-related disease but the very process of aging itself.

The LEAF and Lifespan.io president, Keith Comito, was kind enough to send me his thoughts on where this initiative comes from and where it is going. We're all of us on our own journeys through this space of development and potential in medicine; more traveling companions are always welcome:

My team and I created Lifespan.io because we strongly believe that centralizing crowdfunding efforts in this field will help to create a powerful grassroots movement for the extension of healthy human lifespan. It can do this by not only building a focused community of passionate serial donors who can fund research directly, but also by providing an accessible gateway for the public at large to be introduced to the idea of life extension.

Lifespan.io can also be a powerful tool in positively shaping the dialogue surrounding life extending technologies going forward. The argument against life extension used to be that it was impossible and a waste of time, but now the critique is changing to one that takes on shades of income inequality: this technology might be possible, but it will be available only for the rich. Lifespan.io can serve as a counter-force to this; giving the everyday person agency in the progression of this technology - democratizing relevant research and making the results open to the public.

In the near future we also plan to support Lifespan.io with various forms of content, such as thought-provoking videos focused on engaging the broader public. Through this we can help reframe certain aspects of the ongoing conversation about transhumanist ideals such as life extension, which at times can be divisive, to a more positive one by genuinely inviting dialogue on the science and the societal issues relating to life extension, as well as providing a path for those who wish to become informed and involved. Personally I believe that many people can be reached on the issue if we speak with compassion and intelligence. Extending healthy life is not just for scientists or transhumanists - it is human; it is what we have always done since the very first poultices and medicines.

Realizing our work sits within a continuum of human development and thought both connects us to the past and empowers the drive to keep reaching for an even greater future. Ever since The Epic of Gilgamesh humanity has dreamed of this goal - it is exciting that right now we are in this unique moment of history where literally anyone can carry the torch forward, and help find the flower of rejuvenation Gilgamesh sought. You get the chance to be part of the first Hero's Journey, and that's pretty awesome. Call me optimistic, but I think we can inspire others to feel that excitement too.

Personally, I've always been interested in self-enhancement, and slowly that led me to seek out information on the concept of life extension. This eventually led me to Aubrey de Grey's book Ending Aging which made me aware that meaningful progress in this area was feasible in our lifetime. I reached out to him and we bounced some emails back and forth about creating a New York based organization to further this research. This started out as a discussion group that met once a month for about a year, the remnants of which coalesced into LEAF.

I believe a little reframing could go a long way towards reaching the everyman, instead of alienating him. As one example, I think "Do you want to live forever?" is the wrong question to ask, because of how cognitive biases affect the way we think of aging. Better to ask "Do you want to be alive tomorrow? And, do you expect the answer to that question to change tomorrow?" It is in essence the same question, but phrased in a way that mitigates the inherent cognitive bias. I think that if we can illustrate how combating aging is really about affording greater choice to everyone, we can reach more people than we think. Even if an individual doesn't want to live longer or be free from terrible age-related diseases, the odds are that someone they know, someone they love, would like the freedom to have that choice - I believe most people could be convinced that giving their loved ones that choice is a good thing.

An official release from the SENS Research Foundation on the recent Rejuvenation Biotechnology 2015 conference:

The Rejuvenation Biotechnology conference brings together experts from research, academia, industry, policy, finance and regulatory fields to share ideas - and the latest research and developments - on diseases that are impacting the aging population on a global scale, such as Alzheimer's disease, cancer, and cardiovascular disease. The Rejuvenation Biotechnology Conference creates a forum for thought leaders from multiple disease communities to consider the wider potential of novel strategies for early intervention, while evaluating the feasibility of preventive and combinatorial medicine applications to treat all aging-related diseases.

"For the second year in a row, the Rejuvenation Biotechnology Conference achieved its mission of bringing together a global community to transform the treatment of age-related diseases. With the explosive growth this past year in research into the underlying causes of the diseases of aging, we have an even greater opportunity to continue to accelerate the construction of the Rejuvenation Biotechnology industry. SENS Research Foundation will continue to grow our outreach efforts through conferences and general advocacy, because we believe that a world free of age-related disease is possible."

The theme for this year's Rejuvenation Biotechnology Conference was "Bringing Together a Global Community to Transform the Treatment of Age-Related Diseases". Tracks included "Age-Related Diseases," "Therapeutic Approaches," and "Translation to Treatment," the latter of which included investigation into economics, investment, industry, regulatory issues, and the impact of digitization on healthcare. The conference featured over 50 leading speakers from industry, academia, government, and the financial community. Highlights included keynoters Chas Bountra, SGC Oxford Chief Scientist, Professor of Translational Medicine, Nuffield Department of Clinical Medicine, and Associate Member, Department of Pharmacology, University of Oxford, who spoke on "Transforming the Discovery of New Medicines," and Frances Colón, Acting Science and Technology Adviser to the Secretary of State of the United States, who spoke on "Science and Technology for Diplomacy." Among the additional speakers were representatives of leading biotech firms including Sanofi, Sartorius Stedim, Fate Therapeutics, Biolatris, Sangamo BioSciences Inc., and Asterias Biotherapeutics, Inc. as well as CIRM, Stanford University, Scripps Institute and the Harvard Stem Cell Institute and other leading universities.

Link: http://sens.org/outreach/rejuvenation-biotechnology-conference-2015/media-kit/press-release

Researchers here demonstrate extended life spans in rats as a result of life-long regular transplantation of stem cells. The specific mechanisms are unknown, but the researchers suggest that the proximate causes involve altered levels of various signal molecules leading to better operation and maintenance of native cells and tissues. Given that one study can't measure everything of interest, this should probably be taken as a preliminary set of suppositions, though reasonable given what is known of stem cell therapies at this point. Following on from this work it is definitely the case that more life span studies should take place for stem cell treatments.

Aging brings about the progressive decline in cognitive function and physical activity, along with losses of stem cell population and function. Although transplantation of muscle-derived stem/progenitor cells extended the health span and life span of progeria mice, such effects in normal animals were not confirmed.

Human amniotic membrane-derived mesenchymal stem cells (AMMSCs) or adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously transplanted to 10-month-old male F344 rats once a month throughout their lives. Transplantation of AMMSCs and ADMSCs improved cognitive and physical functions of naturally aging rats, extending life span by 23.4% and 31.3%, respectively. The stem cell therapy increased the concentration of acetylcholine and recovered neurotrophic factors in the brain and muscles, leading to restoration of microtubule-associated protein 2, cholinergic and dopaminergic nervous systems, microvessels, muscle mass, and antioxidative capacity.

The results indicate that repeated transplantation of AMMSCs and ADMSCs elongate both health span and life span, which could be a starting point for antiaging or rejuvenation effects of allogeneic or autologous stem cells with minimum immune rejection.

Link: http://dx.doi.org/10.5966/sctm.2015-0011

Here you'll find links to a selection of recent papers on Alzheimer's disease with no particular central thesis: merely a sampling of representative research results. Alzheimer's research is as much investigation of cellular metabolism and the biochemistry of the brain as it is research into the disease itself. Scientists strive to understand everything that might put the mechanisms of disease development into context. Our neural biochemistry is enormously complex, and thus so is any form of dysfunction in the many interacting systems of the brain. Since there is still so much blank space still left on the comprehensive map of human biochemistry, there are many competing theories to explain the development and pathology of Alzheimer's disease (AD), in part or in whole. Theories proliferate in times of uncertainty, and since therapies emerging from the dominant branch of theories based on amyloid accumulation are still in search of meaningful results, there is plenty of room for heresy, hypothesis, and debate.

It is perhaps ironic that aging has such simple and well-cataloged roots, a few forms of cell and tissue damage that occur as a result of the normal operation of metabolism, and yet the research community spends all of its time working backwards from enormously complicated end states of diseases, where a great deal of time and money are required to make even modest advances in understanding. This makes more sense if one assumes that the goal is less one of treatment and more one of understanding human biochemistry: Alzheimer's disease is the narrow end of the wedge to obtain funding to develop that understanding. That may be part of the problem, that the incentives and the goals for much of the research establishment are not necessarily aligned with rapid progress towards effective treatments. The output of traditional investigation followed by drug discovery is almost entirely marginal treatments that tinker with some aspect of cellular behavior in the late-stage disease process, a far cry from the most effective approach of tackling root causes.

Yet at the same time Alzheimer's research is actually one of the few fields where it is possible to say that at least some within the community work on ways to attack fundamental forms of damage, in the form of amyloid clearance. With enough money and enough different competing research groups, someone somewhere will be close to doing the right thing. Clearance of amyloid is a capability that will be needed for rejuvenation therapies, since the presence of amyloid is a distinguishing difference between old tissues and young tissues. A robust way to clear amyloid in Alzheimer's should require little work to adapt to other forms of amyloid in the body, at which point we might start to see a greater understanding developed as to exactly how and why these deposits contribute to degenerative aging. The fastest way to enlightenment and practical results is often to remove the potential cause of a problem, rather than to keep analyzing the system as it is.

The papers below are illustrative of these points, being representative of several types of output generated by the Alzheimer's research community. Theories abound, as do suggested forms of compensatory treatment, and books can be written to provide an overview of even just aspects of Alzheimer's development in the full context of how the brain works. It is a very complicated business, and some of the approaches to treating Alzheimer's patients are now more than a decade old, still gathering data in search of any benefit.

Nerve Growth Factor Gene Therapy - Activation of Neuronal Responses in Alzheimer Disease

In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.

Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side. Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.

These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects.

In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.

Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles

Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by aging and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease.

The Role of Oxidative Damage in the Pathogenesis and Progression of Alzheimer's Disease and Vascular Dementia

Oxidative stress (OS) has been demonstrated to be involved in the pathogenesis of the two major types of dementia: Alzheimer's disease (AD) and vascular dementia (VaD). Evidence of OS and OS-related damage in AD is largely reported in the literature. Moreover, OS is not only linked to VaD, but also to all its risk factors. Several researches have been conducted in order to investigate whether antioxidant therapy exerts a role in the prevention and treatment of AD and VaD. Another research field is that pertaining to the heat shock proteins (Hsps), that has provided promising findings. However, the role of OS antioxidant defence system and more generally stress responses is very complex. Hence, research on this topic should be improved in order to reach further knowledge and discover new therapeutic strategies to face a disorder with such a high burden which is dementia.

Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease

Mitochondrial dysfunction and neuroinflammation occur in Alzheimer's disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While, mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.

Aubrey de Grey is the co-founder of the SENS Research Foundation, a non-profit organization focused on speeding up development of the biotechnologies needed for human rejuvenation. The underlying model behind the research programs funded is that aging is caused by forms of cell and tissue damage that are currently well defined and understood. Periodic repair of that damage will allow for effective treatment of age-related disease and ultimately indefinite extension of healthy life spans. The only thing separating us from rejuvenation therapies is the matter of building the necessary treatments, a process of a few decades all told were it adequately funded - which is, sadly, still not the case, and one of the reasons why advocacy and grassroots fundraising is so important.

THE INSIGHT: That leads me into the next question: Google has created the California Life Company (Calico), the hedge-fund billionaire Joon Yun has launched the Palo Alto Longevity Prize, so there seems to be a lot of movement in this area. What I'm really fascinated by is - a lot of people are investing a lot of time and money into this area of defeating ageing - if you do implement this 7-stage plan and you see breakthroughs in this area, what's to say that something else, some other large obstacle, doesn't come up? Are you relatively sure that if this 7-stage plan is implemented it will create an open passageway for a longer life?

AUBREY DE GREY: That's a great question. I'm going to give a slightly complicated answer to it - really a two-part answer: the point about the approach that we're taking now is that it's based on this classification of the types of damage that occur in the body and eventually contribute to ill health of old age - classification into seven major categories - and that classification is important because within each category we have a generic approach, a generic therapeutic strategy that should be able to work against every example within that category. So, then your question really divides into two questions. The first question is: are we going to identify new types of damage that fit into the existing classification? The second part of your question is: are we going to find new types of damage that don't fit into the classification - type number 8, and so on?

The answer to the first question is: absolutely, we're going to find more of those; we've been seeing more of those turn-up over the years - throughout the time that I've been working in this area. But, the fact that they fit into the classification means that they're not a problem. It means that, yes, we're going to have to carry on developing additional therapies to address these additional types of damage, but that's kind of okay, because the difficulty of developing those additional therapies will be very slight as a result of the fact that they will be minor variations of the therapies that we already developed to address the examples of that category, that we already knew about.

So, now we move onto the second part of the question, of are we going to identify damage-type number 8, and so on - ones that don't fit into the classification. That's a very important question, but the evidence is looking very good that it's not going to happen. First of all, we can just look and say, "Has it happened anytime recently?" and the answer is absolutely not. SENS has been around for 15 years and, in fact, all of the types of damage that SENS discusses have been well studied and known about for more than 30 years. That's a very long time for nothing to be discovered that breaks the classification.

THE INSIGHT: Have you at any point in your career had an anxious response from governments about your work, like it being a national security threat?

AUBREY DE GREY: No, the government don't behave in that way, because everyone in the government is caught in this trap that I talk about so often, where they're desperate to continue to pretend that any talk of radical life extension is just science-fiction; they don't want to think about it. The reason they don't want to think about it is the reason why the general public don't want to think about it and the reason why quite a lot of scientists don't want to think about it: namely, they don't want to get their hopes up. They really don't want to reengage a psychological battle that they have already lost, that they have already submitted to. They have already made their peace with ageing and the inevitability of declining health, old-age and eventual death; getting into a mode of thinking where maybe science will come along and prevent that from happening or maybe it wont, that's a mindset that disturbs a lot of people; that's a mindset a lot of people would prefer not to even engage in, if the alternative is to continue to believe that the whole thing is science-fiction. It's fatalistic but it's calming.

THE INSIGHT: I'm interested in the psychology of people, I guess you can put them into two camps: one doesn't have an inherent understanding of what you're doing or saying, and the other camp willingly resign themselves to living a relatively short life. You've talked to a whole wealth of people and come across many counter-opinions, have any of them had any merit to you, have any of them made you take a step back and question your approach?

AUBREY DE GREY: Really, no. It's quite depressing. At first, really, I was my own only affective critic for the feasibility - certainly never a case or example of an opinion that amounted to a good argument against the desirability of any of this work; that was always 100% clear to me, that it would be crazy to consider this to be a bad idea. It was just a question of how to go about it. All of the stupid things that people say, like, "Where would we put all the people?" or, "How would we pay the pensions?" or, "Is it only for the rich?" or, "Wont dictators live forever?" and so on, all of these things... it's just painful. Especially since most of these things have been perfectly well answered by other people well before I even came along. So, it's extraordinarily frustrating that people are so wedded to the process of putting this out of their minds, by however embarrassing their means; coming up with the most pathetic arguments, immediately switching their brains off before realising their arguments might indeed be pathetic.

THE INSIGHT: I'd be fascinated to know what your dialogue has been like with pharmaceutical companies and why they have not been more forthcoming?

AUBREY DE GREY: So, there's a somewhat different scenario, because that problem of believing that the whole thing is never going to happen is still true, but there are various other aspects that influence the attitude of... well, beyond big-pharma, the medical industry in general. One thing is, they want to make money; they're worried about quarterly balance sheets, they want to make money now; they don't want to make money 20 years from now. They also don't know that the particular approaches that we're taking are the ones that are going to work; they want to buy up ideas that have already gone through and have been through clinical trials, and then run with them and capitalise on them. They know perfectly well that when things are at the pre-clinical stage - especially when they're only in a conceptual stage and haven't even been tested in mice - that the hit-rate is really low, even when the concept is correct, such that the concept has to be retried multiple times before one comes up with an actual substantiation of the concept that works.

Link: http://www.theinsight.co/aubrey-de-grey-fountain-of-youth

Researchers here model the relationship between genetic regulation and aging with an eye towards trying to fit the outcomes in both negligibly senescent and "normally aging" species. It is known that advancing age brings with it epigenetic dysregulation, meaning significant changes in the levels of various proteins produced from their genetic blueprints, and therefore significant changes in cell behavior. Researchers differ on what this means and how close it is to the root causes of aging. In the theories in which aging is an accumulation of damage, then epigenetic changes are far downstream in the chain of cause and consequence; they are a reaction to rising levels of cell and tissue damage.

Several animal species are considered to exhibit what is called negligible senescence, i.e. they do not show signs of functional decline or any increase of mortality with age. Recent studies in naked mole rat and long-lived sea urchins showed that these species do not alter their gene-expression profiles with age as much as other organisms do. This is consistent with exceptional endurance of naked mole rat tissues to various genotoxic stresses. We conjectured, therefore, that the lifelong transcriptional stability of an organism may be a key determinant of longevity.

We analyzed the stability of a simple genetic-network model and found that under most common circumstances, such a gene network is inherently unstable. Over a time it undergoes an exponential accumulation of gene-regulation deviations leading to death. However, should the repair systems be sufficiently effective, the gene network can stabilize so that gene damage remains constrained along with mortality of the organism. We investigate the relationship between stress-resistance and aging and suggest that the unstable regime may provide a mathematical basis for the Gompertz "law" of aging in many species. At the same time, this model accounts for the apparently age-independent mortality observed in some exceptionally long-lived animals.

Link: http://dx.doi.org/10.1038/srep13589

Global trends in life expectancy, at birth, at 30, and at 60, continue onward and upward at a fairly slow but steady pace: approximately two years every decade for life expectancy at birth and a year every decade for remaining life expectancy at 60. The research linked below crunches the numbers for the much of the world from 1990 to 2013, an extension of similar past studies to include more recent data. The authors show that lives are longer and age-related illness less severe, but the period of time spent in disability or illness has grown.

We are machines. Very complex machines, but nonetheless collections of matter subject to the same physical and statistical laws regarding component failure and damage as a car or an electronic device. Aging is damage, and a substantial portion of the trend in life extension is caused by an incidental, unintentional slowing of the pace at which that damage accrues. This slowing results from diverse causes, including control of infectious disease and reduction of the life-long burden imposed by infection, increased wealth and consequently greater access to medical care of all types, and an improved capacity to treat age-related medical conditions as they emerge. None of this is aimed at aging per se, and the historical trend in rising life expectancy has been slow precisely because there has been neither the ability nor the attempt to meaningfully intervene in the aging process.

What happens when you slow down the pace at which damage accumulates in a machine? You extend all the phases of its life span, both fully functional and in decline. At a given age its average level of dysfunction is lower than it would otherwise have been and it lasts longer as a result - but that also means it is spending more time with at least some dsyfunction before finally failing. The story should be little different for us, which is why I've long been fairly skeptical of the concept of compression of morbidity, wherein some factions of the research community suggest it should be possible to engineer a long period of good health followed by a rapid decline. In their defense, there are species, such as naked mole rats and salmon, that have exactly this shape to their lives, so it is clearly possible in principle. But in humans, with the way we work, intervention in aging means slowing down or repairing the damage, and slowing it down has this outcome of a longer period of a slower decline.

The future of health and longevity will look nothing like the past, however. The trend will not continue: it will leap to the upside in a much faster gain in longevity. This is because are now entering a transitional period in which researchers aim at the deliberate treatment of the mechanisms of aging, the underlying cause of age-related disease, rather than continuing expensive and ultimately futile efforts to patch over disease symptoms and proximate mechanisms. This is a night and day change in the entire approach to medicine, and upsets many regulatory frameworks and established business models, which means it has taken time and a lot of effort to get to the point at which enough people are on board to make it happen. We are close to the tipping point these days, but the vast majority of the money and the research community remains stuck in the past, working on strategies in medicine for age-related conditions that are now outmoded. Change is painfully slow in heavily regulated fields like medicine, and I expect that this transitional period will continue well past the point at which the first partial rejuvenation treatments are proven in the clinic, such as senescent cell clearance.

If we want to see the trends change, and the slowly lengthening period of slowly lessening disability be replaced by sudden leaps in life expectancy, accompanied by outright cures for many age-related conditions, then we have to make repair of the damage of aging a priority. Not merely slowing down the pace at which that damage accumulates as a side-effect of the operation of normal metabolism, but creating targeted biotechnologies capable of deliberate repair of the points of failure. More than enough is known today in order to do this, it is just a matter of finding the money and the will to proceed.

Life expectancy climbs worldwide but people spend more years living with illness and disability

Global life expectancy has risen by more than six years since 1990 as healthy life expectancy grows; ischemic heart disease, lower respiratory infections, and stroke cause the most health loss around the world. People around the world are living longer, even in some of the poorest countries, but a complex mix of fatal and nonfatal ailments causes a tremendous amount of health loss, according to a new analysis of all major diseases and injuries in 188 countries. Global life expectancy at birth for both sexes rose by 6.2 years (from 65.3 in 1990 to 71.5 in 2013), while healthy life expectancy, or HALE, at birth rose by 5.4 years (from 56.9 in 1990 to 62.3 in 2013).

The study's researchers use DALYs, or disability-adjusted life years, to compare the health of different populations and health conditions across time. One DALY equals one lost year of healthy life and is measured by the sum of years of life lost to early death and years lived with disability. The leading global causes of health loss, as measured by DALYs, in 2013 were ischemic heart disease, lower respiratory infections, stroke, low back and neck pain, and road injuries. For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers and age-standardized rates declined between 1990 and 2013. While the number of DALYs for non-communicable diseases have increased during this period, age-standardized rates have declined. The number of DALYs due to communicable, maternal, neonatal, and nutritional disorders has declined steadily, from 1.19 billion in 1990 to 769.3 million in 2013, while DALYs from non-communicable diseases have increased steadily, rising from 1.08 billion to 1.43 billion over the same period.

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition

The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries.

Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

The liver is the most regenerative of mammalian organs, so liver transplantation is the natural first candidate for replacement by some form of cell therapy, delivering cells that will regrow lost and damaged tissue. The details are important in these types of treatment, as seemingly small differences in the methodology of creating and transplanting cells leads to a wide variation in outcomes. A great deal of effort is devoted to finding exactly the right methodology for each tissue type in order to coax cells into carrying out regeneration, and here researchers demonstrate progress for liver tissue in rats:

Liver transplantation is currently the only established treatment for patients with end stage liver failure. However, this treatment is limited by the shortage of donors and the conditional integrity and suitability of the available organs. Transplanting donor hepatocytes (liver cells) into the liver as an alternative to liver transplantation also has drawbacks as the rate of survival of primary hepatocytes is limited and often severe complications can result from the transplantation procedure.

In an effort to find potential therapeutic alternatives to whole liver transplantation and improve the outcomes of hepatocyte transplantation, this study tested the therapeutic efficacy and feasibility of transplanting multi-layered sheets of hepatocytes and fibroblasts (connective tissue cells) into the subcutaneous cavity of laboratory rats modeled with end stage liver failure. The results of the study demonstrated that the cells in the multi-layered hepatocyte sheets survived better than cells transplanted by traditional methods and that the cells proliferated, maintaining liver function in the test animals for at least two months.

The researchers called the fibroblasts "feeder cells" that helped preserve the "high viability and functionality" of the hepatocytes in both in vitro and in vivo studies. The researchers also noted that in other methods of hepatocyte transplantation such as intrasplenic (through the spleen) or intraportal, only a small number of hepatocytes can be transplanted at one time, and many die. By contrast, the transplanted cell sheets showed "dramatically higher albumin expression levels" in vivo one month after transplantation into the subcutaneous cavity.

"Hypoxia is a major cause of poor hepatocyte survival. Therefore, immediately after transplantation, all transplanted cells are supplied with oxygen only from surface diffusion because of the lack of capillary vessels when other methods of transplantation are used." However, in the current study it was observed that merely one week after transplantation, the hepatocyte sheets were permeated with multiple capillary vessels. That the hepatocytes were close to blood vessels confirmed that vascularization is crucial for their survival and function.

Link: http://www.eurekalert.org/pub_releases/2015-08/ctco-ctp082615.php

Birds, like bats, have high metabolic rates due to the demands of flight but are also long-lived in comparison to similarly sized members of other species. This has a lot to do with mitochondria and membrane fatty acid composition, as shown by the evidence in the paper linked below. The membrane pacemaker theory of aging tells us that the genetically determined ratios of specific fatty acids in cell membranes determine resistance to oxidative damage, as well as other important properties in the operation of metabolism that are particularly relevant to mitochondrial function and the ways in which mitochondria become damaged in aging. From a practical point of view, this is one of the things that should steer our attention towards mitochondrial DNA damage as an important contribution to aging, and cause us to prioritize research on methods of repair of that damage.

The evolution of lifespan is a central question in evolutionary biology, begging the question why there is so large variation among taxa. Specifically, a central quest is to unravel proximate causes of ageing. Here we show that the degree of unsaturation of liver fatty acids predicts maximum lifespan in 107 bird species. In these birds, the degree of fatty acid unsaturation is positively related to maximum lifespan across species. This is due to a positive effect of monounsaturated fatty acid content, while polyunsaturated fatty acid content negatively correlates with maximum lifespan. Furthermore, fatty acid chain length unsuspectedly increases with maximum lifespan independently of degree of unsaturation. These findings tune theories on the proximate causes of ageing while providing evidence that the evolution of lifespan in birds occurs in association with fatty acid profiles. This finding suggests that studies of proximate and ultimate questions may facilitate our understanding of these central evolutionary questions.

Link: http://dx.doi.org/10.1111/evo.12754

Here I'll point out a twenty minute podcast interview with Aubrey de Grey of the SENS Research Foundation and Brian Kennedy of the Buck Institute for Research on Aging. This was recorded at the recent Rejuvenation Biotechnology 2015 conference, hosted by the SENS Research Foundation in the Bay Area, where both institutions are based. The SENS Research Foundation remains perhaps the world's only organization focused wholly on developing the fundamental biotechnologies needed for near future rejuvenation therapies capable of actually reversing the course of aging. A little of the work taking place at the Buck Institute is funded in part by the SENS Research Foundation, such as the research programs in the Campisi Lab aiming at the end goal of senescent cell clearance therapies, but for the most part the Buck Institute funds much more modest and mainstream goals in aging research, meaning attempts to slightly slow the aging process through traditional approaches of investigating cellular metabolism and drug discovery.

Brian Kennedy and Aubrey de Grey on their Converging Approaches to Aging Research

Last week we attended the 2015 Rejuvenation Biotechnology Conference where we heard about the latest developments in aging research. We were fortunate enough to sit down with two of the major figures in the field of aging research, Aubrey de Grey, CSO of the SENS Research Foundation and Brian Kennedy, CEO of the Buck Institute for Research on Aging. Brian and Aubrey gone about their work in different ways but say that their approaches are now converging as the momentum behind aging research increases. How do the two see the field since Calico and Human Longevity emerged? What developments in the past year stand out to them? Join us for an exclusive interview with two of the aging field's visionary leaders.

I put in a fair attempt to extract coherent text from the audio via software, but it wasn't on the cards today, or at least not via the standard recourse of feeding it to CMU Sphinx. If anyone else has better luck, let me know. In the meanwhile, here is a transcription of the middle of the interview, which might be of more interest to those of you who have followed the evolution of SENS since the early days.

Moderator: Let's try to hone in on the difference between you two and your view of aging, and what should be done. I mean, you know each other, so maybe you could just speak up.

AdG: Ok, well, so the big thing, the big innovation that I introduced fifteen years ago was the idea that we might actually find it easier in the long run to postpone substantially the ill-health of old age in human beings by not slowing down the rate at which the body creates damage to itself as a side-effect of normal metabolic processes, but rather by periodically repairing that damage after it has been created - but of course before it gets to a level that is so bad for us that we start going downhill.

Moderator: Ok, so one focused on repair...

Aubrey: That's right, that was the idea I brought forward. And the basis for that idea came, in large part, from areas of biology that had never previously been associated with the biology of aging. So that meant of course that the people who were working in the biology of aging were completely unfamiliar with those areas. It took a long time for me to actually make that case, and only because I had to bring together a lot of scientists who had never talked to one another before, and generally get people to pay attention to areas of biology that they had previously thought were not relevant to their work.

Brian: I think there has been some convergence on our end from the point of view that we've been following the genetics of aging, and have identified a lot of genes that impact the aging process. It seems clear that while some of them may prevent the onset of damage, a lot of them can actually induce repair mechanisms to clean up the damage that exists. So I think that at least superficially there was a significant difference in what we were saying ten years ago - and in reality there was some difference too - but there has been a lot of convergence on both sides so that I doubt that our messages are all that much different now.

Aubrey: Right, I think that a lot of the differences were more perceived and not so real, and I think the mutual education that has gone on in the meantime has clarified that, and besides there isn't all that much difference in terms of the emphasis that goes on. But I think it is also very important to note that one thing where convergence has been extremely strong is not so much on the science, but on the communication of the science. I think that now that everybody in the field is comfortable with saying that aging is really actually quite bad for you and we ought to try and do something about it...

Moderator: And that it's modifiable.

Brian: Yes.

Aubrey: Yes, and that we can do something about it, that's right. Now we all really speaking from the same hymn sheet, even that actual sort of words we're using here are converging. Brian gave an example today, in that he's talking of longevity as a side-effect of good health, and that's exactly the same thing that I've been saying.

Moderator: There is a big difference in the accents. Now how did you two meet?

Brian: It was certainly at the aging meetings, and we met at one of them.

Aubrey: The biogerontology community is actually pretty small, even now, and it was smaller ten years, twenty years ago.

Moderator: So you met ten years ago?

Aubrey de Grey: At least fifteen, I would say.

Brian: Yes, probably right.

Moderator: So was that like, wow somebody else gets it, or?

Brian: I think that there was a period where we had to get comfortable with each other. Speaking my side from the field as a whole, I think that Aubrey's message was... there was a lot of insight, and also it was also more aggressive than we were used to, so at the time we had to figure out how to deal with each other.

Moderator: Did that make you kind of bolster up, get some more courage?

Brian: It created different responses in different people in the field, but what I think is that we need multiple voices - there's no reason that the field should be speaking with only one voice. When you have different ideas and you have some people that are more grounded in saying "this is what the data has already shown" and other people that are more visionary I think it is good.

Aubrey: All that is certainly true, I agree with all of that. I think one thing that made it difficult for me to find common ground, common rhetorical ground especially, with the community back then, was something that I have been calling longevity sticker shock. Specifically that if I'm right about the science, that actually the most promising approach to postponing the ill health of old age consists of periodic preventative repair, repairing damage rather than slowing down the creation of damage, then what that implies for longevity is rather dramatically different. Slowing down the accumulation of damage, you'll get a modest increase in longevity, and that increase will be less if you start later. But if you are repairing damage every so often then you are buying time much more effectively. I pointed out way back in 2003 or 2004 that this led to a concept I call longevity escape velocity, that via really very imperfect but improving treatments one might be able to stay indefinitely ahead of the process of aging by keeping damage below pathogenic levels. This of course implies that the longevity consequences would be very dramatic. I, perhaps slightly naively, pointed this out and said, look, it's perfectly reasonable to think that there are people alive today who will live to a thousand, because that's how long you would live if you just didn't have an increased risk of death per year as we do today. And a lot people ran away very rapidly, shall we say.

Brian: Yes, it was the number. I think that at the time, that message appealed to a very small segment of the population, of which there were prominent people who were good to appeal to, but the public didn't understand enough to get to the point of your message, I think.

Aubrey: That's right, yes.

Moderator: And that's changed?

Brian: I think, well, I still don't go around talking about escape velocity. I think it is an interesting concept, but I represent a very large institute conducting NIH-funded research, and what I saying is that I don't know what is possible in the future, but I know what is possible in the short term. If we can start extending healthspan using strategies that we are developing today, the benefits of that are huge. The long-term consequences we just don't know; it could be that you're right, but I want to get those first incremental steps so that we can really get everyone excited about the approach.

Aubrey: You touched on a really important point at the beginning of that answer, which was the funding sources. When I started talking in those terms, I started getting the attention of people who wouldn't dream of funding someone like Brian because Brian's too...he's not aiming high enough, in their view. People like Peter Thiel, for example, they just want to live forever and that's that. So when I come along and I explain longevity escape velocity, they'll say "that sounds like what I want to deal with," whereas conversely, as Brian points out, if he starts talking like that in grant applications to the NIH, it isn't going to be good for his chances.

Moderator: What response have both of you had to the entrance of Calico, the Google company, and Human Longevity, Craig Venter's new company?

Aubrey: It's a complicated question. I'll talk about Human Longevity first. In my opinion they are not really working on what we're working on. They are working on personalized medicine, trying to optimize therapies that essentially already exist using analysis of large amounts of genetic data.

Moderator: So a similar company to other companies that are out there, with a fancier name?

Aubrey: I would say that definitely their hearts are in the right place, but they are a regular, perfectly normal company. They want to make profits fairly soon. Calico have set themselves up as a completely unusual company with the goal of doing something very long-term, however long it takes, they want to actually fix aging. They said so - Larry Page was perfectly clear about that. The question is how are they going about it, and that's getting really interesting. The first thing that they've done, which I feel is an absolutely spectacularly good move, is to bifurcate their work into a relatively short-term track and a long-term track. The short term track involves drug discovery for age-related diseases, doing deals with big companies like Abbvie, and so on. That's all very wonderful and all very lucrative in the relatively short term, and has more or less nothing to do with the mission for which Calico was set up - but it is a fabulous way to insulate the stuff that they do that is to do with why Calico was set up from shareholder pressure. It gets a little more complicated though. So then on the long term side, the stuff being led by David Botstein and Cynthia Kenyon, the question is how are they going about their mission. Of course an awful lot of this unknown because they are a secretive company, but from the perspective of whom they are hiring, and what kinds of work those people have done in the past, one can certainly say that they are not just focusing on one approach. They are interested in diversity. My only real concern is that they may be emphasizing a curiosity-driven long term exploratory approach to an unnecessary degree. I'm all for finding out more and more about aging, but I'm also all for using what we've already found out to the best of our ability to try stuff and see what we can do. I should emphasize that this is only my impression from a very limited amount of information available, but my impression is that it is perhaps turning into an excessively curiosity-driven, excessively basic science, inadequately translational outfit. And that's kind of what I feared when Botstein came along in the first place, because he's on record as saying he doesn't have a translational bone in his body. Now Brian could obviously say a lot more if he wants to, as he's done a deal with Calico.

Brian: Let me start by saying that I think its great that these big companies are getting into the game. Almost no matter what happens that is going to help the field get more people, more private sector people involved, maybe get Big Pharma involved, and so I think it is a good thing. I can't say too much about Calico because we have a relationship with them, but I will say that I think it is an interesting challenge when all of a sudden a lot of money is on the table, and very good people are hired to say "go solve this problem," and they haven't been thinking about that problem until a month ago. So I think what we're going to see with Calico is that they're going to continue to evolve as they go forward, and I think it will be very interesting to see the kinds of stuff they choose to do, and it may be very different two years or three years from now.

Moderator: You were saying in the panel we were just at that you thought it was a game-changer.

Brian: I think it adds great momentum, and I think it will be equally important to really get Big Pharma to get into this game too. It is easy to say you've got a ton of money, but what is a ton of money? If you're going to start doing real clinical trials, phase III clinical trials, it takes more than a ton of money; Big Pharma has to come in. Getting Abbvie involved is a good step, but it would also be good if everyone else starts saying this is the place to be.

Here researchers study natural variations in GDF-11 and myostatin levels, finding correlations with health outcomes in heart disease patients. This is one of a number of lines of research emerging from the search for cell signals that differ between old and young tissues, and that might be altered to induce old cell populations to behave more like young cell populations despite the damage they have suffered. In recent years researchers have demonstrated the use of GDF-11 to spur greater levels tissue maintenance in aged mice, for example:

Individuals previously diagnosed with heart disease may be less likely to experience heart failure, heart attacks, or stroke, or to die from these events, if they have higher blood levels of two very closely related proteins. One of these proteins, known as GDF11, has attracted great interest since 2013, when researchers showed that it could rejuvenate old mice. Based on these findings, scientists have speculated that drugs that increase GDF11 levels might reverse physiological manifestations of aging that lead to heart failure in people.

The study population included 1,899 men and women with heart disease who ranged in age from 40 to 85 (average 69 years). Because they already had been diagnosed with stable ischemic heart disease, in which blood supply to the heart is reduced due to coronary artery disease, the participants were at elevated risk for stroke, heart attack, hospitalization for heart failure, and death. Hundreds of the participants experienced one or more of these outcomes during the course of the study, in which they were monitored for nearly nine years.

Researchers used a lab test to measure combined blood levels of GDF11 and a very similar protein called myostatin - the test could not distinguish between the two, because they are quite similar both structurally and functionally. The scientists determined that research subjects who had relatively high blood levels of these two proteins at the beginning of the study - in the top 25 percent of all participants - were less than half as likely to die from any cause, in comparison to participants whose blood levels ranked them in the bottom 25 percent. Those in the highest 25 percent also experienced fewer adverse health events associated with heart disease. "We also found that combined levels of GDF11 and myostatin in humans decline with advancing age, but that the rate of this decline varies among individuals."

In mouse studies published in 2013 researchers found that four weeks of GDF11 treatment in old mice that restored the youthful level of this protein reversed potentially harmful thickening of heart muscle. In humans this thickening of heart muscle, known as ventricular hypertrophy, is associated with aging and contributes to heart failure and death. In the new study, the researchers used standard clinical imaging tests to measure ventricular hypertrophy and found that participants with lower levels of the GDF11 and myostatin proteins were more prone to having thickened heart muscle. "This association with less ventricular hypertrophy and death suggests the possibility that GDF11 might act similarly in humans as in mice. Restoring GDF11 or myostatin to their higher, youthful levels might potentially serve as a so-called 'fountain-of-youth' treatment, but far more work remains to be done,"

Link: https://www.ucsf.edu/news/2015/08/131386/study-fountain-youth-protein-points-possible-human-health-benefit

Type 2 diabetes patients have a considerably greater risk of suffering Alzheimer's disease, as well as many other age-related conditions. It is commonly theorized that this is because the underlying risk factors are the same, which is to say that a sedentary lifestyle and excess fat tissue leading to metabolic syndrome contributes to the development of both conditions. Researchers here propose that type 2 diabetes results in increased generation of the amyloid-β involved in Alzheimer's, because it also has an associated amyloid, and because various different types of amyloid can spur a faster pace of creation of one another once they start accumulating. At this point the evidence is still fairly tenuous, however:

Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (Aβ) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism.

Proximity ligation assay was used for colocalization studies of IAPP and Aβ in islet amyloid in type 2 diabetic patients and Aβ deposits in brains of patients with Alzheimer disease. Aβ reactivity was not detected in islet amyloid although islet β cells express AβPP and convertases necessary for Aβ production. By contrast, IAPP and proIAPP were detected in cerebral and vascular Aβ deposits, and presence of proximity ligation signal at both locations showed that the peptides were less than 40nm apart. It is not clear whether IAPP present in brain originates from pancreas or is locally produced. Heterologous seeding between IAPP and Aβ shown here may represent a molecular link between type 2 diabetes and Alzheimer disease.

Link: http://dx.doi.org/10.1016/j.ajpath.2014.11.016

This is a year of much grassroots fundraising for longevity science, it seems, with more new projects launched and more new faces joining the community of supporters. All of these developments are collectively, hopefully, yet another sign that faster growth and more publicity are yet to come: the tipping point for public acceptance of efforts to treat aging as a medical condition is somewhere near, just around the corner. Ten years from now, people will conveniently forget that they were ever opposed to the development of therapies for aging. How silly that would be, like opposing cancer research or heart disease treatments, like self-sabotage. Who would think such a thing?

Here at Fight Aging! we're preparing to launch our 2015 SENS rejuvenation research fundraiser on October 1st, which coincidentally is also Longevity Day and the International Day of Older Persons. The crowdfunding site Lifespan.io launched recently, and their first project is a part of the SENS research programs aimed at bypassing mitochondrial DNA damage so as to remove that contributing cause of degenerative aging. Drop by and give them a few dollars: it's just the starting point for that team of crowdfunding developers, and I expect to see interesting things from them in the years ahead.

Similarly, a fundraising effort is presently coming together with the aim of raising philanthropic donations for development of the anti-virus technology DRACO. This is an approach that can be applied to near any virus in mammals, as it targets cells in which viruses are replicating rather than the viral particles themselves. DRACO has been featured at SENS conferences in the past, and is an excellent example of a technology that is too radically different from the present status quo to have an easy time in fundraising, even when backed by studies that would be more than enough to raise money were the results produced by the output of the standard drug discovery process.

Hence the work of a small group of volunteers putting together initiatives like killingsickness, and aiming at starting a crowdfunding campaign starting on October 1st this year. It's a busy time.

killingsickness

As you already know, DRACOs research and development may lead to a cure for virtually all viruses. More importantly, DRACOs may end suffering and save millions of lives! Unfortunately, this has received only limited funding to date and so DRACOs research and development will only happen with your help! We will launch an IndieGoGo campaign October 1, 2015 and we hope you will donate. We do know you have a lot questions first, and we want to answer them! To that point, please comment with your key questions and we will develop and post an FAQ's here and on the IndieGoGo campaign page.

About DRACO

The DRACO approach and results have been called "visionary" by the White House and named one of the best inventions of the year by Time magazine. However, research on DRACO has entered the well-known "Valley of Death," in which a lack of funding prevents DRACO and many other promising new drugs from being developed further and advancing toward human medical trials. With your help, we would like to raise enough funding to help DRACO successfully pass through the Valley of Death and advance toward human trials.

In cell culture, DRACO is reported to have broad-spectrum efficacy against many infectious viruses, including Marburg marburgvirus and Zaire ebolavirus, dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus. Although DRACOs have not yet been tested against other viruses, their broad-spectrum activity may mean that they might also be effective against HIV, HSV (cold sores and genital herpes), herpes zoster virus (chickenpox/shingles), HTLV, Ebola, MERS, SARS, avian influenza (bird flu), and other major viruses. DRACOs might be effective against viruses that are currently untreatable, or that can currently only be controlled but not cured by existing drugs. Because of their broad-spectrum activity, DRACOs might be useful in treating viruses that have become resistant to existing antiviral drugs, or even in promptly treating outbreaks of newly emerged viruses (like MERS).

Looking beyond the consideration of this one technology, and this effort to bypass the issues afflicting funding of early stage research, I see this and other similar efforts as representative of an ongoing and important change in the research ecosystem. The falling cost of communication, still on its way down towards the vicinity of zero, is fundamentally changing all aspects of human interaction and collaboration. The need for organizations to act as middlemen in funding the least costly, most risky, and earliest stage research is evaporating: the people with the interest and incentive to fund this work can collaborate among themselves, talk to the researchers directly, and set up their own fundraising efforts.

All of this produces a much greater incentive to educate ourselves about research and medicine, so as to better pick the winners, and to be able to make a difference to our own futures. It is the same incentive as drives us to understand diet and exercise. That incentive will play out over the next decade or two to produce a funding landscape, a dynamic interaction between laboratory staff, researchers, and the public, that is very different from what we see today - at least in the areas that really matter to the pace of progress, which is to say the innovation that occurs in early stage research that is very hard to fund adequately through traditional channels.

Here I'll point out a review of dozens of studies shows that the balance of evidence points to greater longevity in successful professional athletes. This is one part of a still open question on exercise and long-term health: is it actually better to exercise much more than the recommended moderate levels? There is conflicting evidence from various different types of epidemiological study. The data on professional athletes unfortunately does not show causation, so it may well be that they live longer because more robust individuals tend become professional athletes. In that case had they chosen a different life path, and kept up with regular moderate exercise, they would have had much the same higher than average life expectancy.

Understanding of an athlete's lifespan is limited with a much more sophisticated knowledge of their competitive careers and little knowledge of post-career outcomes. In this review, we consider the relationship between participation at elite levels of sport and mortality risk relative to other athletes and age- and sex-matched controls from the general population. Our objective was to identify, collate, and disseminate a comprehensive list of risk factors associated with longevity and trends and causes of mortality among elite athletes.

Fifty-four peer-reviewed publications and three articles from online sources met the criteria for inclusion. An overwhelming majority of studies included in this review reported favorable lifespan longevities for athletes compared to their age- and sex-matched controls from the general population. In fact, only two studies reported lower lifespan longevities in athletes relative to the controls. Although our overall understanding of modifiable and non-modifiable factors that contribute to mortality risk in elite athletes remains limited, in part due to methodological and data source inconsistencies, some trends emerged from our investigation. In particular, our review supports previous conclusions that aerobic and mixed-sport athletes have superior longevity outcomes relative to more anaerobic sport athletes. In addition, playing position and weight, as well as education and race, appeared to be consistent indicators of mortality risk, whereas other mechanisms such as handedness, precocity, and names and initials appeared to be less consistent and/or examined.

As a variety of confounders may impact longevity, the reasons for the differences in lifespans between elite athletes and the general population are likely to be multifactorial. There are several possible explanations of increased survival in the elite athlete cohort; namely, participation in higher volumes of exercise training leading to higher physical fitness levels, the likelihood that elite athletes are comprised of the healthiest and fittest individuals, and the maintenance of active and healthy lifestyles later in life. The extents to which these confounders contribute to mortality risk are still largely unknown however, as survival statistics may undermine the interplay of complex socioeconomic factors. For example, medical care accessibility made available by higher income may improve the life expectancy of athletes when compared to other groups. Further, plenty of corroborating evidence suggests health-care services alone do not result in improved health outcomes, but a variety of social factors such as education and employment produce these widespread biases in health. As a result, the historical investigations of elite athletes and longevity outcomes need to be cautiously interpreted and discussed in the contexts of a variety of possible influential factors of mortality.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534511/

In species capable of regrowing limbs and organs, such as salamanders and zebrafish, tissues form a blastema at the site of regeneration. This mass of cells recapitulates much of the behavior of embryonic development, including the complex signal interactions that steer the construction of replacement tissue. How exactly are the correct structures produced? Researchers hope that understanding the underlying processes will enable the inducement of similar cellular activity to heal injuries and age-damaged tissues in our species. That better understanding may also have other applications, such as in ongoing efforts to find a robust way to build complex blood vessel networks to support engineered tissue, which at the moment is one of the limiting factors preventing the creation of entire organs from a patient's own cells:

When parts of the zebrafish tailfin are injured by predators, or are experimentally amputated, the lost tissue is replaced within three weeks. Zebrafish fins consist of a skin that is stabilized by a skeleton of bony fin rays; similar to an umbrella that is supported by metallic stretchers. Fin rays are formed by bone-producing cells, the osteoblasts. In order to rebuild an amputated fin, a large number of new osteoblasts have to be formed by cell divisions from existing osteoblasts.

Retinoic acid is required to regulate the addition of bone material in growing fish. During regeneration, mature osteoblasts have to revert to an immature osteoblast precursor, which enables the switch from bone synthesis to cell division. The switch requires retinoic acid levels to drop below a critical concentration. However, upon amputation the tissue beneath the wound initiates a massive bout of retinoic acid synthesis that is required to mobilize cell division in the fin stump. How do mature osteoblasts circumvent this dilemma? The answer: osteoblasts that participate in regeneration transiently produce Cyp26b1, an enzyme that destroys and inactivates retinoic acid. Protected by this process, osteoblasts are able to rewind their developmental clocks, thus turning into precursor cells that contribute to a pool of undifferentiated cells, the blastema. Cells in the blastema pass through a number of cell divisions to provide the building blocks for the regenerated fin.

However, these cell divisions are supported by high concentrations of retinoic acid, which poses the next predicament: The reversion to become a mature osteoblast is inhibited by high levels of retinoic acid. Connective tissue in those areas of the blastema from which new mature osteoblasts eventually emerge produces the retinoic acid killer Cyp26b1. This lowers the local concentration of retinoic acid, so that osteoblast precursors are again able to mature and produce new fin rays. Other parts of the blastema, which replenish the supply of cells needed for regeneration to occur, continue to produce retinoic acid. "This is an elegant mechanism that ensures a gradient of cells experiencing high and low levels of retinoic acid. This allows two processes to run in parallel during regeneration: Proliferation for the production of all cells that replace the lost structure and redifferentiation of osteoblasts where the skeleton re-emerges."

How is the exact shape of the fin skeleton regenerated? In order to form new fin rays, newly formed osteoblasts have to align at the correct positions. Osteoblasts are ultimately guided to target regions by a signaling protein called Sonic Hedgehog. This is produced locally in the epidermis, a skin-like layer that covers the fin and the blastema. However, signal production only occurs in locally restricted cells that are free of retinoic acid. Such epidermal cells produce Cyp26a1, an enzyme that is functionally similar to Cyp26b1. Lastly, it emerged that osteoblasts themselves exert a piloting function for other cell types, particularly mesenchymal cells and blood vessels that also have to be directed to appropriate destinations during the rebuilding process. "The re-emergence of the skeletal pattern relies on a navigation system with interacting parts. Initially, retinoic acid is inactivated where new rays are to form. This allows the local production of a signal that pilots immature osteoblasts to areas where existing fin rays are to be extended. Interestingly, over the course of regeneration other cell types in the blastema are informed by osteoblast precursors to respect the boundaries between emerging fin rays."

Link: http://www.eurekalert.org/pub_releases/2015-08/ub-hzr082415.php

To go along with a few posts from last week, here is a longer report from this year's Rejuvenation Biotechnology conference, hosted by the SENS Research Foundation. There are some interesting tidbits in the section on thymus regeneration, which is an approach to immune system rejuvenation that promises to be very helpful, even if not capable of solving all of the problems of the aging immune system in and of itself. A sizable component of the frailty of aging arises because the immune system becomes dysregulated and incompetent, its complement of cells capable of destroying pathogens reduced to very low levels, replaced by other types of immune cell that do little to help in this situation. Regeneration of the thymus is one of a number of possible ways to introduce much larger numbers of fresh new immune cells into an old body, thereby patching this problem to at least an initial degree:

Report from Rejuvenation Biotech 2015

Georg Hollander presented a cogent and enlightening exegesis of the thymus, from basic function to ongoing projects. The thymus is a small gland under the breastbone that is responsible for a crucial function of the immune system: training white blood cells (T-cells) to distinguish between self and other, so they can consistently attack the latter and spare the former. In adulthood, the thymus atrophies ("thymic involution"), and in old age there is almost no thymus left, with the disastrous result that T-cells not only fail to protect our bodies from invaders, but treat our bodies as the enemy, leading to autoimmunity. The training is performed by web-like epithelial cells, shaped like crumpled blankets, each epithelial cell in contact with up to 60 developing T-cells. Epithelial cells must express every single protein in the genome, and there is a transcription factor called AIRE that binds to DNA, promoting "promiscuous expression." Curiously, AIRE works best for genes that are normally turned off by methylation or acetylation. 15% of genes are expressed only in the presence of AIRE. There are microRNAs that are also necessary for promiscuous expression of all genes.

Hollander has been working on the hypothesis that each epithelial cell succeeds in programming only a random subset of the genome, so if you have fewer epithelial cells late in life, the cells collectively will not express every single gene in the body; there will be holes in the set of all genes represented in the thymus, and as a result there will be autoimmunity. He said we need a minimum 200-300 epithelial cells for a fully-functioning thymus that protects the body against itself.

At Wake Forest Inst, John Jackson is working on growing epithelial cells in a petri dish, then forming them on a scaffold, integrating blood vessels (vascularization) and structural (stromal) cells. His intern Blake Johnson made remarkable progress in a single summer toward creating a functional mouse thymus. Mice (like other small animals) have much larger thymi in relation to body size; and (like humans), they lose most of their thymic volume over their short lifetimes, with the result that their immune systems are disabled and they are vulnerable especially to cancer.

FOXN1 may be a key to reactivating the tired thymus. Greg Fahy of 21st Century Medicine is conducting a tiny clinical trial in the coming year, using growth hormone and other blood factors to regrow the thymus in people 50-65 yo. (Enrollment is closed; they are not seeking test subjects.)

The author here is more or less on the other side of what I consider to be a very important divide in how best to approach longevity research. I'd separate the research world between those who want to alter the operation of metabolism to make the damage of aging accrue more slowly, which is roughly the current mainstream, and those who want to leave metabolism working exactly as it is but periodically repair the damage. I favor the latter approach, the author the former.

To me attempts to rebuild a new state for the operation of cellular metabolism, while ensuring it to be safe and effective, looks both very hard and very expensive. We can look back at the the vast sums of money and years of work poured into efforts to make some headway, and with very little to show for it other than a massive increase in the size of databases and the scope of what is yet to be understood. Metabolism is fantastically complicated. It is still the case that researchers cannot definitively explain how the most reliable intervention to slow aging actually works: a full accounting of how calorie restriction improves health and extends life still lies somewhere in the future. Billions of dollars have been spent on attempts to understand and replicate these effects, and yet even if successful a calorie restriction mimetic drug far better than all of the possible candidates touted today will still have only modest effects on human life span.

The repair approach on the other hand is unbounded in its potential benefits. Repair well enough and aging can be reversed or indefinitely postponed: your only limit is the effectiveness of the technology. This is still the disruptive minority interest in the field, but I predict that change lies ahead as research programs following this path produce much larger and more reliable benefits to health and longevity than are achieved through the traditional drug discovery process when applied to aging. We have seen the first steps on this path of late in the form of senescent cell clearance and progress towards clinical implementation of allotopic expression to work around mitochondrial DNA damage.

Obviously there are no clear cut lines in life, and grey areas abound in a field this complex. The author's terminology is useful, I think, though I differ on which path is the better one. It seems to me that some significant forms of damage in the aging body cannot be repaired by the biochemistry we have, no matter what signals we issue to change cell behavior, such as some forms of cross-link that degrade tissue structure and elasticity:

Very broadly, there are two approaches to anti-aging medicine, which might be called "bioengineering" and "endocrinology". The question is, how much of the change that takes place with age can the body reverse with its internal resources, given the appropriate chemical signals (that's endocrinology)? And how much remains that must be rebuilt or replaced with prosthetics (bioengineering)? From the beginning, SENS has emphasized the bioengineering approach - its middle name is "engineering". I am more optimistic about what the body might be able to do on its own, if only we can master its biochemical language.

Significant advances have been made in bioengineering in the 15 year history of SENS. A prosthetic limb no longer needs to be a peg leg, but can be designed to respond to neural signals. Prosthetic eyes and ears have come down from the clouds into the realm of the feasible. The first organs grown cell-by-cell on scaffolds in the lab have been re-implanted successfully in human patients.

But even more stunning and promising breakthroughs have appeared in the realm of chemical signaling. In 2000, before the Bush Ban, all stem cell research depended on embryonic stem cells harvested from foetal tissue; but turning muscle or skin cells back into stem cells has turned out to be surprisingly easy (though the process is still being refined). "Epigenetics" was an abstract noun in 2000, and it is now the fastest-growing area of biological science. Epigenetic signaling may be the organizing principle of whole-body aging. Signal proteins have been identified that turn on whole systems of genes that retard aging. Better yet, pathways that promote inflammation (e.g. TGF-β, NFkB) can be blocked, while some blood factors turn on regenerative pathways, with the promise of rejuvenation.

Hormesis is the process whereby a little damage leads to a lasting increase in the activities of cellular repair mechanisms, with the outcome of a net gain in systems integrity and function. Hormesis is involved in a majority of the interventions shown to modestly slow aging in at least some short-lived species, such as low level radiation treatment. Here researchers add to the data on radiation hormesis and life span in flies, showing life extension of 3% to 7% that varied by gender but, perhaps surprisingly, not by dose:

Although there are many common mechanisms of response of organism and cell to irradiation and other stresses (thermal, oxidative, etc.), their principal difference is a significant role of DNA damage on the biological effects of ionizing radiation. However, these differences are attributed mostly to high dose rates. In the case of low dose radiation, direct effects of irradiation such as clustered DNA damage and DNA double strand breaks are minimal, whereas indirect DNA damages caused by the induction of reactive oxygen species become the primary result. In high doses, adverse effects accumulate in the tissues in a deterministic manner that depends linearly on the dose, but in low doses the effects are stochastic, non-linear on the dose, and depend mainly on the efficiency of the stress response's protective mechanisms.

Therefore, low doses of radiation can be regarded as moderate stress, which is known to induce hormesis. Indeed, in our previous work, and in the work of other authors it has been revealed, that relatively low dose exposure (20-75 cGy) of fruit flies on immature preimaginal stages in some cases has long-term effects that lead to an increased life span and resistance to other stresses, such as hyperthermia. It is known that preimaginal stages of Drosophila have comparable radiosensitivity to mammals. At the same time, adult individuals, due to the postmitotic state of most tissues, are about 100 times more radioresistant. Other researchers have revealed that irradiation of Drosophila individuals in the imago stage in doses from 0.1 to 400 Gy causes a statistically significant effect on lifespan and gene expression only if the dose is higher than 100 Gy. At the same time, in our recent work on comparing the effects of irradiation in the adult Drosophila male and female at the 20 cGy dose rate, we observed some differentially expressed genes.

Although some changes in life extensity in males were identified (the effect of hormesis after the exposure to 5, 10 and 40 cGy) as well as in females (the effect of hormesis after the exposure to 5 and 40 cGy), they were not caused by the organism "physiological" changes. This means that the observed changes in life expectancy are not related to the changes of organism physiological functions after the exposure to low doses of ionizing radiation. The identified changes in gene expression are not dose-dependent, there is not any proportionality between dose and its impact on expression. These results reflect nonlinear effects of low dose radiation and sex-specific radio-resistance of the postmitotic cell state of Drosophila melanogaster imago.

Link: http://dx.doi.org/10.1371/journal.pone.0133840

Researchers here investigate a way to generate more oligodendrocytes in the brain, the cells responsible for creating the myelin sheathing essential to correct function of the nervous system. The presence of more of these cells improves the pace of myelin generation, which may form the basis for therapies to treat the medical conditions that involve accelerated loss of myelin. It is also the case that some loss of myelin maintenance will occur for all of us in old age due to growing cellular dysfunction and damage. This likely contributes to cognitive decline and other manifestations of old age, so it is worth keeping any eye on the development of potential treatments in this area.

Scientists found that deleting from the adult brain a protein necessary for early development actually fosters the growth of cells that generate myelin, the important protective coating neurons need to function. The research on lab animals provides new insight into how critical brain cells are generated. The finding may lead to improved treatments for brain injury, demyelinating diseases, certain developmental diseases and brain tumors. Researchers studied Nuclear Factor I X (NFIX), a transcription factor - a protein that turns genes on and off. NFIX is required for normal development of the early brain and it's known that losing NFIX before birth results in a number of rare human diseases, characterized by severe developmental and physiological defects. However, the new study shows that the loss of NFIX is necessary at a certain point in order for some brain cells to develop normally.

Oligodendrocytes surround neurons, which transmit electrical signals in the brain, protecting them from damage and speeding the transmission of those signals. The research shows that as neural stem cells differentiate into oligodendrocytes, the expression of NFIX decreases, apparently an essential step in the normal formation of the myelin-making cells. "In terms of a treatment, this could lead to the development of a small molecule that could be used to shut off NFIX activity in MS patients, thus promoting the growth of more oligodendrocytes." This study and previous ones have found that loss of NFIX could also increase the growth of adult neural stem cells, which, in turn, generate new neurons in adult animals. "This could also help us find ways to stimulate new neuron production in diseases where neurons die, such as in Alzheimer's and Parkinson's diseases and in spinal cord injury." The researchers' next step is to learn which genes are regulated by NFIX, and the best way to promote this increase in both oligodendrocytes and neural stem cells.

Link: http://www.buffalo.edu/news/releases/2015/08/018.html

Researchers have found a genetic alteration that slows the progression and fatal consequences of atherosclerosis in a mouse lineage engineered to have an accelerated progression of the disease. As is usually the case in such studies, the primary goal is insight into disease mechanisms, gathering knowledge that may later aid in the development of therapies. It is not necessarily the case that finding a way to slow atherosclerosis in an animal model has relevance to the actual condition: there are many examples of promising research results turning out to be a roundabout way of fixing the breakage in the animal model lineage that causes individuals to develop the condition rapidly and reliably. In normal individuals it then turns out to be useless. This is more often the case in poorly understood areas of biochemistry, given that as knowledge is gained it becomes easier to sift out the more relevant mechanisms, those applicable to the real condition.

Atherosclerosis is a particular unpleasant and prevalent cardiovascular condition that in and of itself causes few overt symptoms until it suddenly kills you. It is an outgrowth of cardiovascular dysfunction in general, however, and is thus usually accompanied by all of the other signs of degeneration in heart and blood vessels: tissue stiffness, hypertension, heart failure, and so forth. The physical damage of atherosclerosis consists of fatty deposits and inflammatory injuries in blood vessel walls, spawned at least in part by the effects of oxidized LDL cholesterol on cell populations in blood vessels, but the increasing stiffness of blood vessel walls and resulting increased pressure of blood flow doesn't help matters by putting additional stresses on these tissues. It is thought that mitochondrial DNA damage is the original cause of much that damaged cholesterol, while the accumulation of persistent cross-links in the extracellular matrix are a primary culprit in blood vessel stiffness.

Once the fatty deposits of atherosclerosis get started, they grow in a positive feedback loop: the damage spurs inflammation, attracting macrophages that attempt to clean up the waste, but which ingest too much fat and become foam cells. These in turn cause more inflammation, produce more fatty debris, and attract more macrophages. The role of inflammation here means that any treatment that reduces the chronic inflammation accompanying aging is likely to be beneficial, but it can't solve the problem. All it can do is slow things down a bit. Prior to the development of self-sustaining fatty deposits, serious damage to blood vessel walls, and restructuring of blood vessels and the heart in response to stiffness and hypertension, it is in principle possible to prevent atherosclerosis and arterial stiffness from ever developing through some combination of SENS therapies targeting mitochondrial DNA damage and cross-links. All the more reason to develop these therapies, but those people already old when they arrive will also need means of safely clearing out the fatty debris of atherosclerotic plaques. That is what kills, when a section finally breaks off to clog a vital blood vessel.

The link below is to the abstract as the full paper, while open access, is still only available in PDF format. It is an interesting look at some of the mechanisms driving the progression of atherosclerosis, and a good example of the way in which most medical research focuses on intervening in later stages of the disease. The proposed intervention here doesn't treat the root causes of the condition at all, but rather seeks to slow down the feedback loop of its later development. As a strategy this will always be less effective and more costly, but here as elsewhere it remains the primary approach for the research community.

RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality

Atherosclerosis is one of the major causes of human death in modern society. A high blood cholesterol level resulting from cholesterol metabolism dysfunction is a key known contributing factor for premature atherosclerosis. Using a mouse model of high blood cholesterol, we show that a specific activation marker of a programmed necrosis mediated by the kinase receptor-interacting protein 3 (RIP3) can be detected in the core of atherosclerotic plaques. Mice lacking the RIP3 gene showed a significant reduction of proinflammatory monocytes in the blood and delayed mortality. This study suggests that RIP3-mediated necrotic cell death is part of a self-amplifying proinflammatory cycle that contributes to the premature death of animals with the pro-atherosclerosis trait.

Monocyte cells enter atherosclerotic plaques and subsequently differentiate into macrophages, which, after engulfing cholesterol crystals and becoming foam cells, die in situ to form the necrotic core of the plaques. These dead cells then send out damage-associated molecular patter (DAMP) signals to attract and mobilize more monocytes, completing a vicious cycle that accelerates disease progression. Thus the particular mode of death of these macrophages - apoptosis or necrosis - can be a critical determinant for the initiation of inflammation, because necrotic death releases the cellular contents that constitute the DAMP signal to the blood stream, whereas apoptotic cell debris is engulfed by macrophages without leaking out of the cell.

Recently, the molecular mechanism of a form of programmed cell death termed "necroptosis" was characterized. This form of cell death can be triggered by the TNF family of cytokines and by ligands of Toll-like receptors 3 and 4. The activated TNF receptor recruits receptor-interacting kinase 1 (RIP1) which in turn binds and activates a closely related kinase, RIP3, to form a necrosis-inducing protein complex. The activated RIP3 is marked by phosphorylation that allows it to bind and activate its downstream effector, a pseudokinase known as "mixed lineage kinase domain-like protein," MLKL. MLKL then is phosphorylated by RIP3 and shifts into an oligomerized state that allows it to form membrane-disrupting pores, ultimately resulting in necrotic death.

After we developed a monoclonal antibody that specifically recognizes the phosphorylated RIP3, we studied the role of necroptosis in atherosclerotic plaque areas by using this antibody to probe the signal of necroptosis activation. We further investigated the role of necroptosis in systematic inflammation by analyzing a panel of proinflammatory cytokines and immune cells in ApoE single-knockout and ApoE/RIP3 double-knockout mice. Finally, we addressed the consequences of necroptosis in the animals by comparing the lifespans of ApoE single-knockout and ApoE/RIP3 double-knockout mice fed either a high-cholesterol or a normal diet. It is clear that high blood cholesterol in the ApoE single-knockout mice is sufficient to cause atherosclerotic plaque formation, even without the systematic inflammation contributed by RIP3-mediated necrosis. However, disease progression, as measured by plaque area and thickness, was significantly slowed in the absence of necroptosis. We believe this slowing of disease progression results from an interruption of the vicious cycle of necroptosis-induced inflammation in lesion sites such as atherosclerotic plaques.

The most interesting result from this study is that mice without RIP3-mediated cell death not only manifested much less severe lesions in multiple tissues but also had significantly delayed mortality. What causes necroptosis in the atherosclerotic plaques remains to be determined. It is likely that cholesterol crystals and local higher concentrations of inflammatory cytokines contribute to the death of macrophages. Nevertheless, by using the small molecules specifically targeting necroptosis, which are being developed, it should be possible to alleviate the symptoms and prolong the lives of patients suffering from atherosclerosis.

Researchers here fill in some of the gaps regarding the action of the INDY gene on longevity in nematode worms, suggesting that its effects largely arise due to its influence on the nematode version of AMPK, now also well known to be involved in the relationship between metabolism and natural variations in longevity. INDY (I'm Not Dead Yet) was one of the earliest longevity genes to be discovered, uncovered in fly studies. It is a mark of the complexity of cellular biochemistry, in which every system interacts with every other system, that researchers are still tracing mechanisms and signals to establish how exactly manipulations of INDY work to extend longevity.

Reduced expression of the Indy gene in Drosophila melanogaster promotes longevity in most studies. The underlying mechanisms recapitulate multiple characteristics of caloric restriction, i.e. reduced in body fat, insulin like proteins, and increased mitochondrial biogenesis, along with the activation of FOXO and the co-transcriptional regulator PGC-1α. Interestingly, food intake in the long lived, Indy mutant flies is not reduced. Knocking down the Indy homolog CeNAC2 in C. elegans also promotes a moderate increase in lifespan in one study, while another study failed to observe the phenotype. Whether or not the knockdown of CeNAC2 really promotes longevity and by which mechanism remains unclear.

Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independents, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied.

Knockdown of Indy/CeNAC2 increased life span by 22±3 % compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2.

Link: http://www.impactaging.com/papers/v7/n8/full/100791.html

Here is one of many studies to show a strong association between regular physical activity throughout life and better health and longevity when reaching old age. Human epidemiological studies like this one can largely only show correlation due to the way in which they are structured, but the equivalent life span studies in animals do show causation, in that the explanation for this correlation is that exercise acts to extend healthy life span:

We examined whether physical activity in early adulthood, late midlife, and old age as well as cumulative physical activity history are associated with changes in physical functioning and mortality in old age. Data are from 1,149 participants aged 65 years or older enrolled in the InCHIANTI study who were followed up from 1998-2000 to 2007-2008. At baseline, participants recalled their physical activity levels at ages 20-40, 40-60, and in the previous year, and they were categorized as physically inactive, moderately active, and physically active. Physical performance was assessed with the Short Physical Performance Battery and self-reported mobility disability was evaluated at the 3-, 6- and 9-year follow-up. Mortality follow-up was assessed until the end of 2010.

Physical inactivity at baseline was associated with greater decline in Short Physical Performance Battery score and greater rate of incident mobility disability (hazard ratio 4.66) and mortality (hazard ratio 2.18) compared to physically active participants at baseline. Being physically active throughout adulthood was associated with smaller decline in physical performance as well as with lower risk of incident mobility disability and premature death compared with those who had been less active during their adult life. We conclude that higher cumulative physical activity over the life course was associated with less decline in physical performance and reduced rate of incident mobility disability and mortality in older ages.

Link: http://dx.doi.org/10.1093/gerona/glv111

The Rejuvenation Biotechnology 2015 conference started yesterday, hosted by the SENS Research Foundation in San Francisco. This is the second in a conference series intended to help build the bridges between scientists and developers, the lab and the industry. We are nearing the point at which some first generation rejuvenation therapies based on the SENS vision of damage repair become ready for practical clinical development. Senescent cell clearance has been demonstrated to some degree via drugs in mice, and at least one startup company has been seed funded to create a first pass at a viable therapy for humans. Similarly allotopic expression to eliminate the consequences of mitochondrial DNA damage is under commercial development already for inherited mitochondrial diseases, and once robustly deployed that technology will need comparatively little adaptation to be used as a therapy for aging.

A smooth hand-off from laboratory to developer doesn't just magically happen, however, no matter how compelling the potential therapy. It requires network, connections, and a two-way flow of education and awareness. Even the obvious steps in creating technological progress must be organized well in advance. Given all of this, the focus of the Rejuvenation Biotechnology conference series is as much on business and economics as it is on the science of rejuvenation and the programs taking place in the laboratory. The message is being delivered to a broad audience of movers and shakers in the business community: opportunity is knocking, the potential to treat aging as a medical condition is near. Be ready, and better yet, invest in speeding development, because your competitors are going to wake up one day soon and do exactly that. Those who get there first are going to make a lot of money selling treatments that are applicable to everyone, and which greatly improve health for everyone.

It is usually the case that good coverage of SENS conferences only emerges after the fact, alongside video of the presentations, but this year there is a little liveblogging taking place:

Live blogging from RB2015  - Rejuvenation Biotechnology Conference

Fantastic keynote talk by Chas Bountra, Structural Genomics Consortium Oxford Chief Scientist. We must transform the way we discover medicines. The biggest challenge is identifying proteins we need to modulate. Too much secrecy and competition are slowing down drug discovery. As an example, take cancer in the UK: in the next 12 months, 315,000 people will be diagnosed. That is one person every 19 seconds. Half of us in the room will get diagnosed with cancer in our lifetime. The way we discover drugs is too costly, too risky, and too slow: available for solid tumors produced an increase in overall survival by only 2.1 months, and only 30 out of 71 drugs for solid tumors produced clinically meaningful improvements. Average cost per drug launched: $12Bn. In 2003 there were 529 molecules in development for cancer (phase 1-3 clinical trials). In 2013 they looked at what happened to them: 45 made it to market, 95 were still in development, 389 have been terminated (took to the clinic and terminated). It's also very slow. It took 6-30 years to take an idea into patients.

Too much secrecy, competition, duplication and wastage. We bring together multiple clinicians, academic groups, pharma companies, patient groups and CROs. We're funded by government, private, philantropic and charity funds. We're working to come up with new targets so the industry can take the molecules to the markeplace. We're trying to create a new ecosystem, which will generate more novel, more effective medicine, more quickly, and more affordably. Let's remember that, regrettably, all of us will be patients one day.

RB2015  -  Liam Grover: Designing materials to maximise regeneration

We develop novel methods for tissue regeneration by considering the biology at the implant site in addition to the influence it will have on a biomaterial. Cell response is important, but many overlook the fact that cell response is guided through the extracellular matrix, and matrix assembly is often ignored. Material/tissue interactions have not been fully exploited in regenerative medicine, and critically the translation of "simple materials" to the clinic has a lower cost in effort and money than the translation of cell therapies - meaning a larger short-term economic payback.

Keynote Address: Science and Technology for Diplomacy

Frances Colón is the Acting Science and Technology Adviser to the Secretary of State, United States Department of State. In an animated talk spanning science, technology, diplomacy and policy, Frances provided an inside look at the intersection between science and politics.

Colón was asked about how the State plans to deal with issues that are perceived as 'non-crisis' issues, such as aging. She stated that 90% of the issues they deal with are crises like infectious outbreaks and simply do not have the bandwidth to tackle these other issues, despite the fact that the older population is growing rapidly across the globe. Her advice was to speak loudly, clearly and frequently (from diverse communities) to US Congressmen and organizations like the NSF. Speaking as a scientist in the aging field, I concur with my collegues here and hope that age-related diseases make it on the to-do list of public policy makers.

An attendee noted that getting a policy initiated with the current Obama administration may be our best best since he has actively gone after a 'non-crisis' issue like climate change. Finally, Colón encourages scientists to be vocal about their work and passions - so that our collective voice grows louder and can lead to real policy change.

Researchers here show that a greater number of senescent cells in skin correlates with a greater loss of skin elasticity. As we age, skin becomes less elastic. Damage to the structures of the extracellular matrix that determines this and other physical properties of tissue occurs due to a number of processes, such as cross-linking and the activities of senescent cells. Developing methods to remove cross-links and clear senescent cells would allow the production of therapies to reverse these and numerous other issues associated with aging:

Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders.

The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.

In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face.

Link: http://dx.doi.org/10.1093/gerona/glv114

In the research noted below, scientists have made initial inroads into the induced dedifferentiation of human cells. This is an attempt to recapture the behavior of tissues in highly regenerative species such as salamanders, and success here may be a step towards generating much greater regeneration of injuries and aged tissues suffering a lack of maintenance. Over the past decade considerable effort has gone into better understanding the precise mechanisms by which species such as salamanders and zebrafish can fully regenerate limbs and organ tissue. Part of the answer appears to be a different relationship between immune cells called macrophages and tissue regeneration, and the dynamics of cellular senescence may also play a role, but of primary interest is that the cells in these species respond to injury by dedifferentiating to form a blastema capable of regrowth. It remains to be seen whether this process can be safely recreated in humans:

A research team has adapted the astonishing capacity of animals such as newts to regenerate lost tissues and organs caused when they have a limb severed. Cells in newts can change in response to injury - a process known as dedifferentiation. The cells aggregate and return to a stem cell-like state to allow them to increase in numbers and generate the specialised cells needed for new tissue formation. But this form of tissue regeneration does not occur in humans, so the researchers recreated similar conditions in the laboratory by growing human cells as 3D aggregates.

The scientists cultivate the spheroid clusters of cells, which are just visible to the naked eye, in tiny cavities. The process involves reverting cells to an embryonic state. In doing so, the cells eat their own constituents and consequently reduce in size. "Using this technique, we have shown that human cells can also be dedifferentiated to an early embryonic stage. They are then capable of generating new tissues. We were able to use pharmaceuticals to induce cell self-eating effects and stimulate dedifferentiation though not as effectively as 3D culture, so we need to do more work on this. The next stage is to find out more about the dedifferentiation process so that we can find the right treatment to encourage tissue repair in the damaged joint. That is our aim."

Link: http://www.york.ac.uk/news-and-events/news/2015/research/newts-osteoarthritis/

You can't just throw stem cells or signal proteins to change the behavior of existing cells at injured tissue and expect reliably good results. A great deal of craft and sophistication goes into even the first generation stem cell transplant treatments, and the need for this complexity is demonstrated by the variability of outcomes seen in stem cell trials. The results are all over the map even for treatments that use the same types of cell to spur regeneration the same types of tissues. There are all sorts of factors at work: how the cells are cultured, how they are supported after being delivered into tissues, what signals are provided along with the cells, whether or not the cells are further engineered before being introduced into the patient, and so forth. The same is true for therapies that do not involve cell transplants, but instead deliver signal molecules to attempt to spur native cells to do the work of healing.

The research results linked below well illustrate this point, as the scientists demonstrate a selection of methods and combinations of methods for heart regeneration in rats. There are large differences in the outcomes, both in the degree of regeneration of healthy tissue (good) and in the generation of scar tissue rather than healthy tissue (bad). The results demonstrate that small changes in technique that alter the timing of the introduction of supporting molecules can have large effects on cell behavior and the bottom line of healing.

In practice this means that it is hard to write off any one particular approach to signal therapies and cell therapies in regenerative medicine as a dead end just because the results to date have been less than promising. It may be that all that is needed is one more adjustment to the delivery method, or the biomaterials, or the signals and factors delivered with the cells. Unfortunately finding the flecks of gold amidst all of the sand is a slow and painful process, even with the large-scale funding presently pouring into this field. There is an enormous space of possible approaches to try, growing rapidly as fundamental research delivers new information on relevant cellular mechanisms, but very few of them are of any real use. The difference in quality between a mediocre and a good approach is large, so settling for mediocre results in return for evading a large amount of work is not a viable trade-off. On that note, I think that you'll find the stained cross-sectional images of regenerated heart tissue from the publicity materials to be particularly interesting:

Repairing The Heart With A Protein-Hydrogel Combo

Even if a person survives a heart attack, the lack of blood flow damages tissue, which often leads to heart failure. Now researchers have developed a new approach to therapy that combines two experimental techniques for reviving heart tissue after a heart attack. One approach is to inject a scaffolding material to reinforce the weakened muscle wall. Another is to inject stem cells or growth factors to help repair the damaged tissue. The researchers devised a special trick to deliver a growth protein trapped within a hydrogel. The gel protects the protein, keeps it at the heart attack site, and supports the damaged walls of the heart right after a heart attack. They used a tissue-signaling protein called Sonic hedgehog that is known to protect cardiac cells and help them grow by inducing the formation of blood vessels.

The researchers mixed it with negatively charged heparin, which is a widely used anticoagulant, and a polycation, which attaches to the oppositely charged heparin molecules to form micrometer-sized liquid droplets. Next, they combined the droplets with a polyethylene glycol gel. The gel targets the signaling protein to damaged tissue because it degrades in the presence of an inflammatory enzyme secreted after a heart attack.

To test the new strategy, the researchers induced heart attacks in rats, and divided the animals into four groups. One group got an injection of the new combination material at the site of the heart attack, while the others got injections of only the protein-containing droplets, only the hydrogel, or saline. After two and four weeks, echocardiograms showed that hearts treated with the combination therapy pumped more blood per beat. The team also examined cross sections of hearts removed four weeks after treatment. Rats treated with the hydrogel-protein combination had at least 25% less scar tissue than those in the other groups.

Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction

Numerous technologies have been evaluated for alleviating or reversing the damage caused by cardiac ischemia. These technologies fall into two general categories: bioactive therapies and structural "bulking" therapies. The former aims to provide the resources and signals necessary for tissue preservation and regeneration, and several therapeutic approaches including stem cells, growth factors, and gene therapy have been evaluated in U.S. controlled clinical trials. On the other hand, the primary aim of structural therapies is to reinforce the damaged heart wall and thereby alleviate wall stress to prevent wall thinning and ventricular dilation. Clinical trials have been initiated to evaluate intramyocardial injections of alginate and cell-seeded collagen. However, no biological or structural therapy has shown enough promise to receive USFDA approval for treatment of MI. Therefore, new approaches need to be developed and those that combine both bioactive and structural components are particularly appealing

To this end, we developed a bioactive therapy of sustained release of the morphogen Sonic hedgehog (Shh) and the anti-inflammatory cytokine interleukin-10 (IL-10) from a coacervate delivery vehicle. This is combined with a structural therapy consisting of a biodegradable polyethylene glycol (PEG) hydrogel, harnessing the benefits of both components. Upon injection into the hearts of rats after heart attack, we found that each component synergistically improved the benefit of the other. Furthermore, their combination was critical to preserve heart function. These findings indicate that, when combined, growth factor delivery and an injectable hydrogel represent a promising therapeutic approach for treatment after heart attack.

The first project up at the newly launched longevity science crowdfunding site Lifespan.io is a mitochondrial research program to be carried out by a SENS Research Foundation scientist. This follows on from a crowdfunded initial stage in 2013 and continuing research from the past couple of years. The project is effectively an extension and expansion of the work of Gensight on allotopic expression of mitochondrial genes to cover all of the genes of interest in the mitochondria. When successful this will offer a way to bypass and eliminate the contribution of mitochondrial DNA damage to degenerative aging.

This is also a big experiment for the SENS Research Foundation: does this form of fundraising, styled after Kickstarter and Experiment, work for our community? Does it help to pull in new donors and present our goals to people who haven't yet heard of this research? Is it more or less effective than the ad-hoc methods we've used over the past decade? Further, are we at the point at which the community can run multiple distinct fundraising programs each year and still be successful in all of them? The only way to find the limits of fundraising is to keep pushing. Personally, I just pledged a few hundred dollars.

At the SENS Research Foundation, we are in the early stages of creating an innovative system to repair these mitochondrial mutations. If this project is successful we will have demonstrated, for the first time, a mechanism that can provide your cells with a modified backup copy of the entire mitochondrial genome. This genome would then reside within the protective confines of the cell's nucleus, thereby mitigating damage to the mitochondrial genome. In fact, during the long course of evolution, this gradual transfer of genetic information into the nucleus has already occurred with the majority of mitochondrial genome, leaving behind a mere 13 genes within the mitochondria. Demonstrating the effectiveness of this technology would be a major milestone in the prevention and reversal of aging in the human body.

We are also developing a unique method for guiding the products of these nuclear encoded mitochondrial genes back into the mitochondria, where they can then properly function. Over the last decade, engineering this last step has been the major bottleneck in achieving effective results. In our novel system, the mRNA from an engineered mitochondrial gene is guided back to the mitochondrial surface, where it is then translated into a protein by the organelle's co-translational import system. Once imported, it is then incorporated into the correct location within the inner mitochondrial membrane. Our precise targeting is achieved by adding a specific sequence "tag" to both ends of the mRNA. These tags then serve to guide the information containing mRNA molecule to the mitochondrial surface. Our prior research indicates that our system of tagging yields in a significantly higher efficiency of import to mitochondria than any previously published research.

In the first part of this project we will use cells that have been derived from a patient with a rare mitochondrial disease that are completely null for the mitochondrial ATP8 gene i.e. they make no ATP8 protein. We will attempt to effectively fix these cells by inserting our better engineered versions of ATP8 into the nuclear genome, rather than the mitochondrial genome, and then use our tagging system to help guide the functional protein back into the mitochondria. During the second part of this project we will then proceed to translate this technology to the remaining 12 mitochondrial genes. We have already begun recoding several of these genes in the form of cDNA constructs that can then be used to transfect our test cells.

Link: https://www.lifespan.io/campaigns/sens-mitochondrial-repair-project/

Our community began to crowdfund projects in longevity science, such as the ongoing SENS research programs, long before Kickstarter and the rest of the young crowdfunding industry came into being. It is inevitable and helpful that people will take the lessons of for-profit crowdfunding and try to apply them to general research funding at the small scale, as is happening at Experiment, and also inevitable that crowdfunding platforms devoted to aging and longevity research will arise, such as LabCures and now the newly launched Lifespan.io:

Lifespan.io is a project of the Life Extension Advocacy Foundation non-profit company, and is a mission driven crowdfunding platform dedicated solely to longevity research projects. We believe that centralizing and enhancing such efforts will create a strong community of contributors and researches who will help extend healthy human lifespans, both through both direct funding as well as shifting public perception in favor of this important humanitarian goal. Conquering the negative effects of aging is one of the oldest dreams of humanity, and now through the steady progress of science, we are poised to fulfill that dream.

Whether this occurs in 20 years or 200 is largely a question of funding. The best way to accelerate this process is by mobilizing those who desire the option of a longer and healthier life into a cohesive social force - crowdfunding relevant research and advocating for its benefits to society. On lifespan.io researchers post projects related to longevity or age related disease, and receive funds from contributors to fulfill their goals. Contributors, in turn, are able to exercise agency in the development of potentially life changing research, as well as receiving rewards specified by the project creators. We care about the success of and will actively support every project on our site; you won't just be one in a crowd. As we grow, the fruits of our success will be focused on furthering our shared mission.

Link: https://www.lifespan.io

What is frailty, the state of being physically frail? As is the case for the related - but not identical - state of being old we know it if we see it, but a single rigorous and commonly agreed upon measurable definition of frailty remains elusive. Not for lack of trying, of course; there are numerous published and proposed scales of measurement, and debate over their utility. The paper referenced here argues for a better language and categorization of frailty in aging, pointing out that that the present clinical applications of scientific knowledge are not what they might be, while new approaches are at this point just as likely to muddy the waters as clear things up.

The treatment of aging and its many degenerative conditions by the medical profession has a foot in two worlds. There is the established world of observation, simple measures of function used for decades, the judgement calls of medical professionals based on sparse data, the acceptance that there is little that can be done but assess the downward spiral. Within this world there is still as much reluctance to measure aging in common practice, as there is a movement towards better use of existing tools to pin down aging and be more rigorous. That old way of doing things now coexists with increasingly sophisticated by quite narrow applications of modern biotechnology that accurately measure aspects of, and to some degree treat, specific age-related dysfunctions. Despite representing sizable steps forward these new technologies have yet to give rise to a biomarker for biological age - a rigorous measure of damage and dsyfunction - despite some promising ongoing lines of research such as analysis of DNA methylation patterns. Such a biomarker would produce unambiguous results based on the state of cellular biochemistry rather than the present commonly used measures such as grip strength, recollection, or walking ability.

The practice of medicine is constantly in transition in this age of rapid progress in biotechnology. Papers such as the work referenced here are one manifestation of the tensions and necessary organization involved in the departure of old, established practice taking place concurrently with the advent of unfinished works-in-progress that will one day become the future standard of care.

Frailty: a tale of two concepts

Frailty in older adults is most often defined as a late-life vulnerability to adverse health outcomes. Although frailty consensus work has focused on physical frailty, a theoretically based construct built around a core group of activity-based and strength-based measurements, the frailty index (FI), has emerged as a useful strategy to measure risk for mortality and other adverse health outcomes in older adults. The FI utilizes simple counts of up to 71 co-morbidities, laboratory measures, and social and functional declines (termed deficits) to construct a score. Proponents of this approach have noted that the component measures are interchangeable, the approach can be applied in bedbound or ambulatory populations, and fewer variables can successfully predict mortality than originally proposed.

In the present study, the authors develop an aging-related biological index that utilizes 40 biological measures found to be age-associated in the Newcastle 85+ study. This index contains measures ranging from telomere length to induced cytokine production from isolated lymphocytes to the components of a complete blood count. Although prior studies of older adults have developed indices focused on clinical laboratory measurements, the authors are to be commended for working toward the development of an index that attempts to assess biological age and associated risk through biological measurements. Their findings regarding the complementarity of clinical and biological measures for predicting mortality risk are potentially important: One can imagine, for example, the identification of older adults who "look" healthy but may benefit from interventions to address significant latent risk factors.

The approach is pragmatic in that measures can be for the most part interchanged with other measures without substantial change in the predictive ability of the tools. There are likely a large number of age-related aggregated biological precursors that drive frailty and late-life decline, and the systemic effects as measured by risk to adverse outcomes can in part be detected through an index approach. Hence the approach can be used to predict outcomes, and the combination of FI and a biomarker-based frailty index (FI-B) seems to hold considerable promise to this end. The approach also likely allows the tracking of vulnerability in a reasonable way.

Despite this flexibility in measurement and substantial predictive ability of a high index score, notable obstacles remain if this approach is to be further developed as a true biological aging index or measure of systemic effects. For example, it is not clear that systemic effects are being measured unless index components are selected and validated vis a vis a system. Moreover, including a preponderance of age-associated clinical measures may result in an assessment of chronic disease states rather than aging per se. The FI-B construction, and the authors' characterization of frailty as "a state of increased risk, compared with others of the same age," suggests that any marker conferring risk of mortality (or possibly other adverse geriatric outcomes) contributes usefully to frailty measurement. We, and others who consider frailty as a specific physiological state with a definable phenotypic presentation, would disagree.

The specificity embedded within the phenotype approach offers benefits if the goal is to elucidate mechanisms and physiological etiology. To approach such a goal scientifically, theories describing plausible processes by which frailty arises, and how they are linked to one another, are needed. Indices (psychometrically: as opposed to "scales") fail to provide this. Moreover, the more heterogeneously a large collection of variables arises, the higher the risk of masking a key driver that can be targeted by specific interventions. In sum, various conceptualizations of frailty have complementary strengths; however, if etiology is to be elucidated and targeted interventions are to be pursued, we believe the field would benefit from more strongly distinguishing disparate concepts which currently share the single label of "frailty."

There is considerable debate over the origin and ongoing role of post-reproductive life span in evolution. If evolution is driven by reproductive success, why do the individuals of some species live on far past the capacity to reproduce? Our own species is an exceptional example of the type; we are very long-lived in comparison to other mammals, and have a long period of post-reproductive life. Why is this the case? You might look at the grandmother hypothesis for one possible answer to that question, thought it is far from being the only answer. In general one should expect anything involving biology to be intricate, complex, and composed of many separate mechanisms. In this paper researchers explore the concept that post-reproductive lifespans might serve as an aid to adaptation, for example. It is a good reminder that much of the debate over the evolution of aging is quite abstract and technical, based on the use of models and the limitations and bounds of effectiveness of those models:

Post-reproductive lifespan is a life history trait that is typical of some mammals, and is especially developed in humans who can live for decades after having given birth to their last offspring. To our knowledge, the role that survival beyond the last reproductive age may play in population genetics models of adaptive evolution has not been investigated yet. This is probably because models with ideally infinite census size are insensitive to the presence of post-reproductive individuals.

It is well known that post-reproductive lifespan reduces the population effective size, which is a parameter inversely proportional to the genetic change in a finite population due to random sampling of gametes through generations; i.e. drift. The classic model for populations without age structure suggests that a reduction in effective size goes to the detriment of fixation chances of a beneficial mutation. Hence, one would intuitively be led to infer that a more prolonged post-reproductive lifespan slows adaptive evolution in a population. In the present paper, we will show that this intuition is wrong and explain why it is so.

We compare two separate, stationary populations living in a constant environment that are equivalent except for the average time their respective members spend in the post-reproductive stage of life. Using a recently derived approximation, we show that fixation of a beneficial mutation is more likely in the population with greater post-reproductive longevity. This finding is surprising, as the population with more prolonged post-reproductive lifespan has smaller effective size and the classic population-genetic model would suggest that decreasing effective size reduces fixation chances of beneficial mutations. Yet, as we explain, in the age-structured case, when effective size gets smaller because of longer post-reproductive lifespan but census size is kept equal, a beneficial mutation has a higher likelihood to get fixed because it finds itself at higher initial frequency.

Link: http://dx.doi.org/10.1371/journal.pone.0133820

Here I'll point out a review of some of the species researchers use in the study of aging, coupled with a call to expand that list to fill in known gaps and shortcomings. Despite the large differences between lower animals and humans, aging is a near universal phenomenon. It originated in its presently dominant form very early in the evolution of life, and thus many relevant cellular mechanisms are the same or at least very similar even in widely divergent species. Since lower animals used in aging research are short-lived, it is far less costly to conduct exploratory life span experiments and alterations of metabolism. Nonetheless, there are sizable challenges inherent in trying to learn about human aging via the investigation of insects and worms, and here it is proposed the some of these problems can be overcome by adding additional points of comparison, such as hydra, sea urchins, sea squirts, and the like:

Although the nematode, the fruit fly models, and yeast have led to major advances in aging research, the gaps that exist in these models make a compelling case for additional, potentially invertebrate, model systems to identify longevity genes, whose roles have yet to be studied, and to investigate the role of additional cellular pathways in aging.

Both the nematode and the fruit fly models have critical shortcomings including the following: (a) both nematode and fruit fly belong to Ecdysozoa, a superphylum, which has undergone extensive gene loss since their divergence from their common ancestor with humans and thus a large fraction of human orthologs are missing; (b) larvae from these two species can enter a non-aging stage in response to stress, which suggests that modulation of lifespan observed in corresponding adult organisms may be mediated by stress response mechanisms that have no equivalent in humans; (c) except for the Drosophila gut, the somatic adult tissues of these two organisms have limited regenerative capabilities with scarce to null cell proliferation; finally, (d) nematodes and fruit flies poorly mimic the processes involving stem cell renewal and tissue repair mechanisms that maintain tissue homeostasis in mammals. Thus, new invertebrate models with proliferating cells in the adult, as well as in those with extensive regenerative capacity, have the potential to be informative on the perils of life-long cell division and mechanisms of tissue regeneration and homeostasis.

Given this background, researchers have begun to make new inroads in the study of aging and longevity in several new model systems. We provide here a brief outline of the advantages of several of the newest invertebrate model systems for the study of aging. Although we continue to witness remarkable progress in aging research using invertebrate models, major limitations and challenges remain in the use of these new models for research in aging biology. These limitations include: (a) technologies to mass culture cells from these models are still lacking; (b) progress has been slow in fine tuning genetic and molecular tools and methodologies, including RNAi and transgenic approaches, for use in these models; (c) very few age-related phenotypes that are functions of specific cellular and molecular pathways in these systems have been identified; and, (d) information on cellular, molecular, and physiological mechanisms in tissue aging and homeostasis, including the role of stem cells and senescence, is still very meager in these new model systems.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464166/

I'm pleased to note that the book A History of Life Extensionism in the Twentieth Century is now freely available online, a step that everyone who publishes should undertake. After the initial wave of sales is done there is simply no reason to leave a book locked up: everyone who wants to pay to read it already has, and everyone who wants to read it for free will simply download a copy whether or not formally permitted to do so. Both author and audience are far better served by making it easier to read published works.

In this case, A History of Life Extensionism in the Twentieth Century was published last year as the culmination of several years of research and writing on the topic by author Ilia Stambler. His book covers many past contributions to the culture of medicine and views on longevity, influences that lead us to where we stand today, but are perhaps too easily overlooked by those of us focused on the near future. It is a fascinating read. Beyond this work Stambler is active in a number of longevity advocacy movements; you might recall his contributions to the position papers published following last year's International Conference on Aging and Disease, for example.

One of the more interesting things one sees from the references explored in A History of Life Extensionism in the Twentieth Century is just how strikingly similar the proposals and debates on extended longevity were a century or more ago. Many of the commentaries that dealt with motivations for the defeat of age-related disease could be republished today largely unchanged and still fit right in. The important difference between then and now is that we are today able to make meaningful progress towards the goal of rejuvenation treatments: we can create detailed plans built on solid science such as the SENS research programs, knowing that building them has a high expectation of producing large benefits to human health and longevity. This is a new age of biotechnology, but it never hurts to look back at the bigger picture of how we came to be where we are now.

A History of Life-Extensionism In The Twentieth Century

This work explores the history of life-extensionism in the 20th century. The term life-extensionism is meant to describe an ideological system professing that radical life extension (far beyond the present life expectancy) is desirable on ethical grounds and is possible to achieve through conscious scientific efforts. This work examines major lines of life-extensionist thought, in chronological order, over the course of the 20th century, while focusing on central seminal works representative of each trend and period, by such authors as Elie Metchnikoff, Bernard Shaw, Alexis Carrel, Alexander Bogomolets and others. Their works are considered in their social and intellectual context, as parts of a larger contemporary social and ideological discourse, associated with major political upheavals and social and economic patterns.

This work pursues three major aims. The first is to attempt to identify and trace throughout the century several generic biomedical methods whose development or applications were associated with radical hopes for life-extension. Beyond mere hopefulness, this work argues, the desire to radically prolong human life often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery. It will be shown that novel fields of biomedical science often had their origin in far-reaching pursuits of radical life extension. The dynamic dichotomy between reductionist and holistic methods will be emphasized.

The second goal is to investigate the ideological and socio-economic backgrounds of the proponents of radical life extension, in order to determine how ideology and economic conditions motivated the life-extensionists and how it affected the science they pursued. For that purpose, the biographies and key writings of several prominent longevity advocates are studied. Their specific ideological premises (attitudes toward religion and progress, pessimism or optimism regarding human perfectibility, and ethical imperatives) as well as their socioeconomic conditions (the ability to conduct and disseminate research in a specific social or economic milieu) are examined in an attempt to find out what conditions have encouraged or discouraged life-extensionist thought. This research argues for the inherent adjustability of life-extensionism, as a particular form of scientific enterprise, to particular prevalent state ideologies.

The third, more general, aim is to collect a broad register of life-extensionist works, and, based on that register, to establish common traits and goals definitive of life-extensionism, such as valuation of life and constancy, despite all the diversity of methods and ideologies professed. This work will contribute to the understanding of extreme expectations associated with biomedical progress that have been scarcely investigated by biomedical history.

Here I'll point out a long article that ties together technological advances that increase human longevity with some of the broader modern issues of progress, change, and opposition to progress that are important in modern societies.

Stagnation and stasis are ever the goal of much of our politics: a thousand Canutes standing athwart the tide. People are reflexively conservative, even in times of great change brought on by technological progress, and that is reflected in regulation and other forms of obstruction that slow down beneficial change. Nowhere is this more apparent than in medicine, one of the most heavily regulated areas of research and development. We are in the midst of a biotechnology revolution, capabilities advancing by leaps and bounds in the laboratory, and costs plummeting, yet the delivery of new clinical therapies is becoming slower and more expensive year after year. The costs imposed by regulation have doubled in the past decade, and for no good reason.

Stasis is the path to destruction, the eventual collapse of a society under the weight of regulation and coercive redistribution. Continued and accelerating progress is the path to a golden future, and medical technologies to enhance longevity while also defeating age-related frailty and disease will play an important role in putting us on this road:

Technological progress, particularly radical extension of the human lifespan through periodic rejuvenation that can restore the body to a more youthful condition, is also the only hope for remedying unsustainable expenditures of national governments, which are presently primarily intended to support people's income and healthcare needs in old age. Rejuvenation biotechnology of the sort championed by Dr. Aubrey de Grey's SENS Research Foundation could be developed with sufficient investment into the research, and could become disseminated by biotechnology entrepreneurs, ensuring that older people do not become decrepit or incapable of productive work as they age.

Many people who receive rejuvenation treatments will not want to retire - at least not from all work - if they still feel the vitality of youth. They will seek out activities to support human well-being and high living standards, even if they have saved enough money to consider it unnecessary to take a regular 8-to-5 job. With the vitality of youth combined with the experience of age, these people will be able to make sophisticated, persistent contributions to human civilization and will tend to plan for the longer term, as compared to most people today.

Fortunately, there are glimmers of hope that the path of gradual embrace of ever-accelerating progress will be the one taken in the early-21st-century Western world. The best outcome would be for an existing elite to facilitate mechanisms for its own evolution by offering people of merit but from humble backgrounds a place in real decision-making. Some of that evolution can occur through market competition - new, upstart businesses displacing incumbents and gradually amassing significant resources themselves. The best instantiation of this in the United States today is the Silicon Valley entrepreneurial culture - which, incidentally, now tends to finance longevity research.

These developments are evidence that the United States today is characterized not by one elite, but by several - and the old "Paper Belt" elite is clearly in conflict with the new Silicon Valley elite. Differences in the breadth of vision among elites matter. For instance, breakthroughs in human longevity could actually be a great boon for medical providers and the first pharmaceutical companies that offer effective products/treatments. Even the most ambitious proponents of life extension do not think it possible to develop a magic immortality pill. Rather, the treatments involved (which will be quite expensive at first) would require periodic regeneration of the cells and tissues within a person's body - essentially resetting the biological clock every decade or so, while further innovation uncovers ways to reverse the damage more cheaply, safely, and effectively. This is a field ripe with opportunities for enterprising doctors, researchers, and engineers (while, at the same time, certainly endangering many extant business models). Some government officials, if they are sufficiently perceptive, could also be persuaded to support these changes - if only because they could prevent a catastrophic collapse of Social Security and Medicare.

The key to achieving a freer, more prosperous, and longer-lived future is to educate both elites and the general public to accurately weigh the opportunities and risks of emerging technologies. Too many individuals today, both elites and ordinary people, view technological progress with suspicion, conjuring in their minds every possible dystopian scenario and every possible malfunction, inconvenience, lost possibility, moral reservation, or aesthetic dislike they can muster against breakthroughs in life extension, artificial intelligence, robotics, autonomous vehicles, genetic engineering, nanotechnology, and many other areas of advancement that could vastly benefit us all. If we have a modicum of technological progress, the West might be able to muddle through the next several decades. If we have an acceleration of technological progress, the West will leave its current problems in the dust.

Link: http://www.rationalargumentator.com/index/blog/2015/08/imperative-of-progress/

As a companion piece to last week's post on the miserable, parasitic institution of modern bioethics, here are a few apropos comments from Steven Pinker:

Have you had a friend or relative who died prematurely or endured years of suffering from a physical or psychiatric disease, such as cancer, heart disease, Alzheimer's, Huntington's, Parkinson's, or schizophrenia? Of course you have: the cost of disease is felt by every living human. The Global Burden of Disease Project has tried to quantify it by estimating the number of years lost to premature death or compromised by disability. In 2010 it was 2.5 billion, which means that about a third of potential human life and flourishing goes to waste. The toll from crime, wars, and genocides does not come anywhere close.

Physical suffering and early death have long been considered an ineluctable part of the human condition. But human ingenuity is changing that apparent fate. Advances in drugs, surgery, and epidemiology have brought reductions in years lost to more recalcitrant diseases in every age range and in richer as well as poorer countries. As the treatments get cheaper and poor countries get richer, these gains will spread. Biomedical research, then, promises vast increases in life, health, and flourishing. Just imagine how much happier you would be if a prematurely deceased loved one were alive, or a debilitated one were vigorous -- and multiply that good by several billion, in perpetuity. Given this potential bonanza, the primary moral goal for today's bioethics can be summarized in a single sentence. Get out of the way. A truly ethical bioethics should not bog down research in red tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as "dignity," "sacredness," or "social justice." Nor should it thwart research that has likely benefits now or in the near future by sowing panic about speculative harms in the distant future.

Some say that it's simple prudence to pause and consider the long-term implications of research before it rushes headlong into changing the human condition. But this is an illusion. First, slowing down research has a massive human cost. Even a one-year delay in implementing an effective treatment could spell death, suffering, or disability for millions of people. Second, technological prediction beyond a horizon of a few years is so futile that any policy based on it is almost certain to do more harm than good. Biomedical advances will always be incremental and hard-won, and foreseeable harms can be dealt with as they arise. The human body is staggeringly complex, vulnerable to entropy, shaped by evolution for youthful vigor at the expense of longevity, and governed by intricate feedback loops which ensure that any intervention will be compensated for by other parts of the system. Biomedical research will always be closer to Sisyphus than a runaway train -- and the last thing we need is a lobby of so-called ethicists helping to push the rock down the hill.

Link: https://www.bostonglobe.com/opinion/2015/07/31/the-moral-imperative-for-bioethics/JmEkoyzlTAu9oQV76JrK9N/story.html

In the paper referenced here researchers dig more deeply into the effects of statins on cellular metabolism, and in particular its effects on stem cell activities. Statins act to reduce cholesterol levels in the blood and are widely used to attempt to slow the onset of cardiovascular diseases, particularly atherosclerosis. The consensus view of the evidence suggests that overall the outcome of statin use is modestly positive, but there are always outlier studies, such as those suggesting statin use causes more harm than it prevents to the cardiovascular system. Like all drugs in widespread use today statins have very broad effects on the operation of cellular metabolism, and far from all of these effects are completely understood.

Still, statins were selected to be one of the components of a proposed polypill program aiming to slightly slow the later stages of aging. Trials have been carried out or are underway, but the proponents of polypills are still a fair way distant from implementing the original vision of blanket prescription of low doses of statins and a range of other drugs for everyone over the age of fifty. If we're lucky, this and all other similar programs will be overtaken by circumstances, rendered irrelevant by progress in rejuvenation therapies. Tinkering with metabolism and mining the world for drugs that might slightly slow aging isn't the path forward, but it is certainly expensive and time-consuming.

That both beneficial and harmful actions result from the interaction of drugs with tissues is well illustrated in this examination of statins, but the actual biochemistry involved is an unusually constrained case. A single type of change, a reduction in the ability of stem cells to deliver a supply of new cells into tissues, spirals out to bring both benefits and harms. These occur on different timescales and for different aspects of the integrity of the cardiovascular system. A drug can be seen as beneficial if slows a rapid cause of death but speeds up a slower cause of death, as might be argued is happening in the case of statins. Much of the downside will be masked because many people will die due to other causes along the way. With the advance of biotechnology and greater knowledge of cellular biochemistry some drugs will no doubt be altered to successfully split apart beneficial and harmful actions. This is underway for rapamycin, to pick one example, but I think it less likely to happen here.

This is also a good illustration of the point that altering the operation of metabolism away from its present evolved state always comes with trade-offs. Our biology is too complex for any other outcome: every system is connected in some way to every other system. Nothing can be altered in isolation, nothing can be easily switched around. The only approach to medicine free from considerations of benefit versus harm is to aim at repair of the root cause damage that causes age-related system failures in cells and tissues. Strive to maintain the metabolism we have when we are young through periodic repair, in other words, don't try to build a new system that can slightly better cope with being damaged. The former is the easier path, with much larger potential gains in health and longevity, while the latter is far harder and cannot produce anything more than a modest slowing of aging. Yet most research follows the latter path. It is a crazy world we live in.

New Research Shows Why Statins Should Be Viewed as a Double-Edged Sword

Atherosclerosis develops when plaques build up inside blood vessels, which can lead to heart attack, stroke and death. Statins lower the risk by blocking cholesterol production in the liver, reducing a person's "bad" cholesterol. The immune cells macrophages play a major role in plaque formation and rupture in atherosclerosis. Macrophages ingest fat deposits along the blood vessel wall and attract more macrophages, other cells and inflammation-related proteins to the injury site. The enhanced inflammation builds up the plaque within the vessel wall and further narrows the artery. Macrophages also release enzymes that weaken the fibrous cap that separates the plaque from the blood flow, increasing the likelihood that the plaque breaks open. Plaque ruptures lead to blood clots that result in strokes and heart attacks.

Macrophages primarily develop from stem cells that reside in the bone marrow, but can also develop from mesenchymal stem cells (MSCs), which are found throughout the body. While bone marrow stem cells mainly become blood cells, MSCs can become all cell types, including bone, cartilage, muscle cells and macrophages. In this study, the research team found that long-term statin use prevented MSCs from turning into macrophages, which could decrease inflammation and improve plaque stability in patients with cardiovascular disease. However, statins also prevented MSCs from becoming bone and cartilage cells. Statins increased aging and death rate of MSCs and reduced DNA repair abilities of MSCs. "While the effect on macrophage differentiation explains the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects."

The Impact of Statins on Biological Characteristics of Stem Cells Provides a Novel Explanation for Their Pleotropic Beneficial and Adverse Clinical Effects

Statins reduce atherosclerotic events and cardiovascular mortality. Their side effects include memory loss, myopathy, cataract formation, and increased risk of diabetes. As cardiovascular mortality relates to plaque instability, which depends on the integrity of the fibrous cap, we hypothesize that the inhibition of the potential of Mesenchymal Stem Cells (MSCs) to differentiate into macrophages would help to explain the long known, but less understood "Non Lipid Associated" or pleiotropic benefit of statins on cardiovascular mortality. While the effect on macrophage differentiation explain the beneficial side of statins, their impact on other biologic properties of stem cells provides a novel explanation for their adverse clinical effects.

The liver is the most regenerative of organs, capable of regrowing lost sections even in mammals. Here researchers identify a novel population of cells that contributes to that capacity for regrowth, and which might prove to be the basis for regenerative therapies:

The mechanisms that allow the liver to repair and regenerate itself have long been a matter of debate. Of all major organs, the liver has the highest capacity to regenerate -- that's why many liver diseases, including cirrhosis and hepatitis, can often be cured by transplanting a piece of liver from a healthy donor. The liver's regenerative properties were previously credited to a population of adult stem cells known as oval cells. But recent studies concluded that oval cells don't give rise to hepatocytes; instead, they develop into bile duct cells. These findings prompted researchers to begin looking elsewhere for the source of new hepatocytes in liver regeneration.

Researchers traced the cells responsible for replenishing hepatocytes following chronic liver injury induced by exposure to carbon tetrachloride, a common environmental toxin. That's when they found a unique population of hepatocytes located in one specific area of the liver, called the portal triad. These special hepatocytes, the researchers found, undergo extensive proliferation and replenish liver mass after chronic liver injuries. Since the cells are similar to normal hepatocytes, but express low levels of bile duct cell-specific genes, the researchers called them "hybrid hepatocytes."

Meanwhile, many other research labs around the world are working on ways to use induced pluripotent stem cells (iPSCs) to repopulate diseased livers and prevent liver failure. While iPSCs hold a lot of promise for regenerative medicine, it can be difficult to ensure that they stop proliferating when their therapeutic job is done. As a result, iPSCs carry a high risk of giving rise to tumors. To test the safety of hybrid hepatocytes, the team examined three different mouse models of liver cancer. They found no signs of hybrid hepatocytes in any of the tumors, leading the researchers to conclude that these cells don't contribute to liver cancer caused by obesity-induced hepatitis or chemical carcinogens. "Although hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure. Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation."

Link: http://health.ucsd.edu/news/releases/Pages/2015-08-13-cells-regenerate-liver-without-tumors.aspx

The sad truth about Google's Calico initiative is that, for all the hype at the outset, what is going on under the hood looks very much like building a standard issue Big Pharma institution to work on commercializing drug discovery programs that won't make much of a difference to aging. The charitable view of that picture is that they are setting up a sustainable revenue stream in order to later investigate more relevant and interesting things. The more realistic view is that they intend to invest in what is currently the mainstream of aging research, a matter of trying to slightly alter the operation of metabolism to slightly slow down the aging process, and will never go beyond that. There are scores of larger companies capable of doing relevant and interesting things in aging, but they never go beyond tinkering with drug discovery to produce marginal therapies; once a revenue stream and mode of operation is established there is little incentive to do more.

This all suggests that the way in which disruptive ventures working on methods of rejuvenation gain traction with Calico is no different than the methods of gaining traction with the rest of Big Pharma: bootstrap the production of technology demonstrations that work. Gain support through the slow process of networking and incremental progress in research. Become the mainstream. Large scale funding is unimaginative and almost never backs radical new directions until all the excitement is done and the new new thing is obviously taking over. That is simply the way things are, and it is why our grassroots efforts to raise research funding and gain greater attention to the cause continue to be very important.

For the first year of its existence, all we knew about Calico was that the company had 'moonshot goals' and a team of scientific superstars. However, in September 2014 it finally sprang into action by announcing two research collaborations. The first was with AbbVie (a global, research-based biopharmaceutical company) and aimed to 'accelerate the discovery, development and commercialization of new therapies.' The two companies then immediately invested in the creation of a new research and development facility in San Francisco focused on aging and age-related diseases. Initially, AbbVie and Calico provided $250 million each to fund this project, and it was agreed that both sides would potentially contribute an additional $500 million in the future. The two also agreed to share the costs and profits equally.

The second collaboration was with the UT Southwestern Medical Center and 2M, to advance research and drug development for neurodegenerative disorders caused by the aging and death of nerve cells. Basically, Calico managed to muscle in on a deal which already been made between UT Southwestern and 2M concerning the licensing of P7C3 compounds (which had the potential to combat neurodegeneration). 2M and Calico entered into a new license agreement under which Calico took chief responsibility for developing and commercializing the compounds resulting from the research program. Calico no doubt persuaded 2M to agree to the new deal by promising to fund research laboratories in the Dallas area (where 2M is based) and elsewhere to support the program.

All went quiet again until March 2015, when The Broad Institute of MIT and Harvard entered into a partnership with Calico, concerning the genetics of aging and early-stage drug discovery. The partnership aimed to support several efforts at the Broad to advance the understanding of age-related diseases and to propel the translation of these findings into new therapeutics. The Institute agreed to use its genetics expertise and novel drug-discovery tools in pursuit of goals shared with Calico.

In the same month Calico formed a partnership with QB3, a University of California institute specialising in the advancement of biotechnological innovation. The purpose of this partnership was to conduct research into longevity and age-related diseases and, in the process of doing so, foster an interdisciplinary community of scientists in the relevant fields. Funding from Calico was to support QB3 research projects focused on aging; some in collaboration with Calico, others led solely by QB3. In exchange for providing the funds, Calico acquired the option to claim exclusive rights to discoveries made under the sponsored research agreement.

The third partnership made in March was with UC San Francisco (UCSF) (a University of California health sciences campus), on a project to develop potential therapies for cognitive decline. Under the agreement, Calico received an exclusive license to technology discovered in the laboratory of Peter Walter, Professor of Biochemistry and Biophysics at UCSF. This technology could potentially address the damage to cells caused by the Integrated Stress Response (ISR) mechanism. For an an undisclosed up-front fee, UCSF allowed Calico to take responsibility for further research, development and commercialization of the resulting therapeutics.

By April 2015 it was clear that Calico was splashing the cash in order to facilitate the formation of partnerships. For this reason, Calico started to become more tight-lipped about the financial aspect of its deals. In fact, they categorically refused to disclose the financial terms of a new partnership with the Buck Institute for Research on Aging. This partnership was to support research into longevity and age-related diseases. Calico was permitted to cherry-pick innovative research projects at the Institute and, in exchange for funding, obtain exclusive rights to the discoveries made.

Calico's most recent partnership was announced in July 2015 with AncestryDNA (an industry leader in consumer genetics). This partnership aimed to investigate the heredity of human lifespan. The two companies planned to evaluate anonymized data from millions of public family trees, as well as AncestryDNA's database of over one million genetic samples. Calico would then use the findings from the analysis to develop and commercialize potential therapeutics. Again, Calico refused to disclose just how much it had parted with in order to get its hands on AncestryDNA's data.

Looking at Calico's impressive array of employees and collaborations, it would seem, at the moment, that Calico is merely trying to make money using other people's knowledge. However, Chief Science Officer at SENS, Aubrey de Grey, claims that this is just a facade: "they are doing a bunch of highly lucrative irrelevant short-term stuff that lets them get on with unlucrative critical long-term stuff without distraction."

Link: http://lifemag.org/article/solving-the-mystery-of-calico

This is the barnstorming era of biotechnology, in which researchers continually demonstrate new and interesting ways to re-engineer cellular biochemistry. Many of these initiatives are very intriguing and tackle issues of age-related dysfunction, but nonetheless probably won't lead to the development of therapies that make it to widespread clinical use. The example here is one of these, I think. Researchers have found a way to use a gene therapy to introduce some of the functionality of photoreceptor cells into the retinal neurons that lie behind the layer of photoreceptors, and have demonstrated the results in mice. The result is that in cases of blindness where near all normal photoreceptors are lost, the converted neurons take up some of the slack to send signals to the brain. Formerly blind mice given the treatment exhibit the ability to pick up changes in movement and shade in their surroundings.

Given that outcome, why do I think that this has only a modest future? A combination of a few factors. Firstly, it is quite early stage research, so one should expect it to take a decade or so for it to progress to the point at which someone is mounting clinical trials. Secondly it is a form of restructuring and compensation: it is not restoring original cell populations in the retina, but rather creating new hybrids and a new variant architecture of vision, a state of affairs that will introduce all sorts of complexities not present in straight regeneration. The combination of these two points means that this type of approach will, I think, lose out to forms of regenerative medicine capable of restoring the original population of photoreceptors and supporting tissue in the retina. That research is further along at this point and has more funding behind it.

(Further, assuming that we longevity advocates get our act together in the next decade or two all of these approaches will become unneeded for most people due to the advent of SENS therapies that periodically clear out the accumulations of metabolic waste that contribute to photoreceptor cell death).

This all said, partial restoration of visual ability via gene therapy would probably compete well with partial restoration of visual ability via electrode grid retinal implants, were they at the same level of clinical development. Both aim to add new architecture in order to push signals to the optic nerve, but are otherwise very different, with equally different potential paths towards improvement of quality. That path is known for electrode grids - add ever more electrodes to gain better resolution, and attempt to better mimic the effect of real photoreceptor signaling on retinal neurons - but improvement is an open question for gene therapy to convert neurons into photoreceptors. Still, gene therapy doesn't require surgery and a camera device in order to work, and avoiding surgery is always a big plus.

Restoration of Vision with Ectopic Expression of Human Rod Opsin

Inherited retinal degenerations (retinal dystrophies), such as retinitis pigmentosa, affect 1:2,500 people worldwide. Irrespective of etiology, most affect the outer retina and lead to progressive and permanent loss of photoreception. Severe visual impairment is common in advanced stages of the degeneration, and these conditions are currently incurable. However, despite the loss of outer retinal photoreceptors, inner retinal neurons, including bipolar and ganglion cells, can survive and retain their ability to send visual information to the brain. These neurons therefore, represent promising targets for emerging optogenetic therapies that aim to convert them into photoreceptors and recreate the photosensitivity that has been lost during degeneration.

Pioneering work has shown that electrophysiological responses to light can be restored to animal models of retinal degeneration by introducing a variety of optogenetic actuators to the surviving inner retina.These interventions can also support behavioral light responses including, in some cases, maze navigation or optokinetic reflexes reliant upon detection of spatial patterns or fast temporal modulations (flicker). However, in most cases, these actuators function only under very bright light, and, to date, no clinically achievable optogenetic intervention has recreated spatiotemporal discrimination at commonly encountered light levels.

Here, we set out to determine whether it is possible to recreate vision in blind mice using ectopic expression of a natural human protein, rod opsin. We expressed human rod opsin in surviving inner retinal neurons of a mouse model of aggressive retinal degeneration with near complete loss of rod and cone photoreceptors (rd1) by intravitreal administration of clinically approved adeno-associated virus (AAV) vector, AAV2/2. Widespread light-evoked changes in firing were observed in neurons of the retina and dorsal lateral geniculate nucleus (dLGN) in treated mice. These responses could be elicited using physiologically encountered light levels and under natural light-adapted conditions. Behavioral studies indicated that the treated mice had regained the ability to detect modest changes in brightness, relatively fast flickers, spatial patterns, and naturalistic movie scenes.

Naked mole rats live nine times longer than similarly sized rodents and show little sign of age-related decline across the majority of that span. Researchers are very interested in finding out why this is the case. Here a team is looking at levels of autophagy in the naked mole rat, a collection of cellular maintenance mechanisms that direct damaged cell structures to be engulfed by lysosomes for recycling. More active autophagy is seen in many of the methods shown to slow aging in mammals, and most likely contributes by reducing the presence and impact of forms of cellular damage such as mitochondrial DNA mutations.

Like all important cellular mechanisms autophagy falters with age, and this harms long-lived cell populations such as those of the central nervous system by allowing damage to accumulate. In mice and humans we can point to growing levels of the hardy garbage compounds known collectively as lipofuscin. These clutter up cellular lysosomes and degrade their function, providing one important cause of failing autophagy, as well as a target for efforts to produce drugs capable of breaking down lipofuscin. In naked mole rats, however, autophagy is maintained at high levels into late age, though at present the precise reasons why remain to be uncovered:

The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained healthspan. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extended human healthspan and lifespan.

The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared to shorter-lived rodents. Using a proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies.

Link: http://dx.doi.org/10.1016/j.bbadis.2015.08.002

Researchers continue to explore the mechanisms of regeneration in search of both a greater understanding of why it falters in aging, as well as ways to enhance the normal processes of healing. Here they have focused on the role of double-stranded RNA and toll-like receptor 3 in triggering skin regeneration in response to damage:

Researchers have identified a novel cell signaling pathway in mice through which mammals - presumably including people - can regenerate hair follicles and skin while healing from wounds. "Medications that turn on this protein have the powerful potential to decrease scarring as healing of wounds takes place, thereby promoting skin and hair follicle regeneration. A lot of human disability is from scarring. After a heart attack, we're really good at replacing the blood flow, but it's the scar on the heart afterward that's the real problem. We and others in the field of regenerative medicine are interested in how to enhance or trigger regeneration in such situations."

Damaged skin releases double-stranded RNA (dsRNA) - genetic information normally carried by some viruses - that is sensed by a protein called toll-like receptor 3 (TLR3). TLR3, which in other contexts plays a fundamental role in recognizing some disease-causing organisms and activating the immune system, during wounding also activates the genes IL6 and STAT3 to promote hair follicle regeneration. TLR3 also activates other molecules involved in hair development, including the Wnt and Shh signaling pathways and a gene called EDAR, which makes the protein ectodysplasin and plays an important role in skin development.

Researchers compared the protein expression of certain genes in healed wounds in two groups of mice. One group was genetically proficient in wound-induced hair neogenesis, a process in mice and rabbits in which skin and hair follicles regenerate after wounds. The other inbred group of mice was noted to lack this ability. Expression of TLR3 was three times higher in the mice that were better able to regenerate hair. In other experiments, the team found that the expression of TLR3 was five times higher in scratched human skin cell samples compared to healthy skin cell samples, that adding synthetic dsRNA to mouse skin wounds led to a greater number of regenerated follicles, that adding a substance that breaks up dsRNA decreased the number of regenerated follicles, and that regeneration was nearly abolished in mice deficient in TLR3.

It has long been known that skin damage can trigger regeneration. Several cosmetic dermatological procedures, such as chemical peels, dermabrasion and laser treatments, have been used to do that for decades: "One implication from our work is that all of those different rejuvenation techniques are likely working through dsRNA pathways. It may also be that dsRNA could be directly used to stimulate rejuvenation in aging or hair follicle growth in burn patients to regain structures that have been lost."

Link: http://www.hopkinsmedicine.org/news/media/releases/researchers_identify_drug_candidate_for_skin_hair_regeneration_among_scarred_victims_of_burns_and_trauma

Here I'll point out a few recent papers from the bioethics community on the topic of longevity and medical science. We are approaching the advent of therapies capable of effectively treating the underlying causes of the aging process, and for reasons we all still argue about this seems to require a lot more wailing and gnashing of teeth than, say, the prospects of developing a cure for cancer or heart disease. You won't see deep soul-searching treatises on how terrible it would be it cancer were done away with, at least not from people who like to avoid mockery, but treatments for aging appear to be fair game.

I should say here that I don't think highly of bioethics. The modern institution of bioethics is much like politics, in that it is a parasitical line of business that exists only to divert resources away from productive uses. Bioethicists as a group thrive on slowing down progress and inflicting additional costs on development: their funding comes from manufacturing problems where no problems exist, and the incentives follow on from that in a very straightforward manner. In short, bioethics is unneeded. It has no useful role. Yet, like the roil of politics, there it is, a bunch of people devoted to making vital activities such as medical development harder and more expensive. (This stands in contrast with the past of medical ethics as largely pragmatic business of formalizing triage and experiment when you cannot save everyone. Unfortunately once institutions become well established they inevitably drift in the direction of securing growth and perpetuation at the cost of their original goals. Hence bioethics).

Some truly reprehensible concepts are trafficked around in bioethics circles regarding aging, longevity, and medicine. The duty to die, the "fair innings" argument for cutting off provision of medicine to the old, suppression of research that might extend life, and so on and so forth. Meanwhile the average fellow in the street is suspicious or disinterested in living longer for entirely different reasons, but were he born a century from now, he would accept his indefinite future healthy life span without question. It's all a matter of culture. When it comes to the talking heads, there is no status quo so horrible that it won't be defended. We don't have to look far to see that; just count the hundred thousand lives lost every day to aging, and the ongoing suffering of hundreds of millions of others that is swept behind the curtains.

Of course one can also find bioethics writers, usually not of the professional sort, who write more favorably on the topic of enhanced longevity through medical science. Even so, the framing of the discussion is all too often one of rules and allowances: who should be permitted, who should be forbidden. Freedom and choice is something of a lost art as our governments grow bloated and every aspect of life is regulated by disinterested bureaucrats. In medicine particularly all that is not explicitly allowed is forbidden, and the effects of the modern biotechnology revolution are muted and suppressed by the enormous and growing costs imposed upon turning laboratory work into therapies.

Longevity and compression of morbidity from a neuroscience perspective: Do we have a duty to die by a certain age?

The search for longevity, if not for immortality itself, has been as old as recorded history. The great strides made in the standard of living and the advances in scientific medicine, have resulted in unprecedented increases in longevity, concomitant with improved quality of life. Thanks to medical progress senior citizens, particularly octogenarians, have become the fastest growing segment of the population and the number of centenarians is increasing, even though in the last two decades, spurred by the bioethics movement, the priority assigned to the prolongation of lifespan has taken a back seat to the containment of health care costs.

Four Ways Life Extension will Change Our Relationship with Death

Discussions of life extension ethics have focused mainly on whether an extended life would be desirable to have, and on the social consequences of widely available life extension. I want to explore a different range of issues: four ways in which the advent of life extension will change our relationship with death, not only for those who live extended lives, but also for those who cannot or choose not to. Although I believe that, on balance, the reasons in favor of developing life extension outweigh the reasons against doing so (something I won't argue for here), most of these changes probably count as reasons against doing so.

First, the advent of life extension will alter the human condition for those who live extended lives, and not merely by postponing death. Second, it will make death worse for those who lack access to life extension, even if those people live just as long as they do now. Third, for those who have access to life extension but prefer to live a normal lifespan because they think that has advantages, the advent of life extension will somewhat reduce some of those advantages, even if they never use life extension. Fourth, refusing life extension turns out to be a form of suicide, and this will force those who have access to life extension but turn it down to choose between an extended life they don't want and a form of suicide they may (probably mistakenly) consider immoral.

Slowed ageing, welfare, and population problems

Biological studies have demonstrated that it is possible to slow the ageing process and extend lifespan in a wide variety of organisms, perhaps including humans. Making use of the findings of these studies, this article examines two problems concerning the effect of life extension on population size and welfare. The first - the problem of overpopulation - is that as a result of life extension too many people will co-exist at the same time, resulting in decreases in average welfare. The second - the problem of underpopulation - is that life extension will result in too few people existing across time, resulting in decreases in total welfare. I argue that overpopulation is highly unlikely to result from technologies that slow ageing. Moreover, I claim that the problem of underpopulation relies on claims about life extension that are false in the case of life extension by slowed ageing. The upshot of these arguments is that the population problems discussed provide scant reason to oppose life extension by slowed ageing.

Lastly, as for all political and philosophical fields of discussion there are bioethics debates that run right off the rails and into never-never land. At some point reality is left behind and those involved might as well be building their own sort of secular theology for all the relationship it bears to practical concerns. The paper referenced below is a particular egregious example, but there are many others that come and go on a regular basis.

The Tortoise Transformation as a Prospect for Life Extension

The value of extending the human lifespan remains a key philosophical debate in bioethics. In building a case against the extension of the species-typical human life, Nicolas Agar considers the prospect of transforming human beings near the end of their lives into Galapagos tortoises, which would then live on decades longer. A central question at stake in this transformation is the persistence of human consciousness as a condition of the value of the transformation. Agar entertains the idea that consciousness could persist in some measure, but he thinks little is to be gained from the transformation because the experiences available to tortoises pale in comparison to those available to human beings. Moreover, he thinks persisting human consciousness and values would degrade over time, being remade by tortoise needs and environment. The value available in the transformation would not, then, make the additional years of life desirable. Agar's account does not, however, dispose of the tortoise transformation as a defensible preference. Some people might still want this kind of transformation for symbolic reasons, but it would probably be better that no human consciousness persist, since that consciousness would be inexpressible as such. Even so, it is not irrational to prefer various kinds of lifespan extension even if they involve significant modifications to human consciousness and values.

The paper linked below looks at overlaps in the underlying mechanisms by which exercise and selective breeding can extend fly life spans, and is typical of much of the mainstream of aging research these days. A great deal of the field still involves finding natural ways to extend life and then digging through the biochemistry to gain more knowledge of its operational parameters. It is all very interesting, but we shouldn't expect these research programs to result in methods of significantly extending life in humans; the goal here is understand the relationship between the enormously complex operation of metabolism and natural variations in life span.

Aging is damage, and so natural variations in life span relate to the pace at which damage accumulates over time. Since living organisms self-repair, this is not a straightforward process, and there is room for decades of research yet for those interested in the fine details of every part of the downward spiral. In many ways a damaged, old metabolism is even more complicated that the correctly functioning younger version. When the research community does get around to building meaningful rejuvenation therapies, such as those detailed in the SENS proposals, they will not be created atop the knowledge of how metabolism determines longevity. The goal will be to halt and reverse degenerative processes through damage repair rather than trying to alter metabolism to slightly slow down the pace of damage accumulation. The nature of that damage and how to repair it are already well known, and the work left is to build the necessary technologies. How exactly damage spirals out to create dysfunction is a big empty space on the map, but if the damage can be repaired then researchers don't need that knowledge in order to create rejuvenation therapies.

Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training.

We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.

Link: http://www.impactaging.com/papers/v7/n8/full/100789.html

There are two paths to xenotransplantation, the use of animal organs from species such as pigs in human medicine. The first is decellularization, clearing out all of the cells from the organ and then repopulating it with cell types derived from the patient's stem cells. The second is genetic engineering of a donor lineage, such as the transgenic pigs mentioned in this article. In both cases this is a sizable incremental improvement on the present day situation in transplant medicine, either minimizing immune rejection issues or removing limits on the availability of donor organs. Bear in mind, however, that xenotransplantation and decellularization are only stepping stones on the way to future technologies of organ tissue engineering and regenerative medicine capable of organ repair in situ; these are unlikely to have a long life spans as active technologies given the present pace of progress.

Researchers have been shattering records in xenotransplantation, or between-species organ transplants. The researchers say they have kept a pig heart alive in a baboon for 945 days and also reported the longest-ever kidney swap between these species, lasting 136 days. The experiments used organs from pigs "humanized" with the addition of as many as five human genes, a strategy designed to stop organ rejection. The GM pigs are being produced by Revivicor, a division of the biotechnology company United Therapeutics. That company's founder and co-CEO, Martine Rothblatt, is a noted futurist who four years ago began spending millions to supply researchers with pig organs and has quickly become the largest commercial backer of xenotransplantation research. Rothblatt says her goal is to create "an unlimited supply of transplantable organs" and to carry out the first successful pig-to-human lung transplant within a few years.

The problem with xenotransplantation is that animal organs set off a ferocious immune response. Even powerful drugs to block the immune attack can't entirely stop it. All human tests of pig organs have ended quickly, and badly. Researchers continue to work with pigs because they're in ready supply, and the organs of young pigs are about the right size. In order to beat the rejection problem, researchers began trying to genetically modify the animals. One major step came in 2003 with pigs whose organs lacked a sugar molecule that normally lines their blood vessels. That molecule was the major culprit behind what's called hyperacute rejection, which had almost instantaneously destroyed transplanted pig organs. Removing the sugar molecule helped. But it wasn't enough. Tests in monkeys showed that other forms of organ rejection still damaged the pig tissue, albeit more slowly. To combat these effects, researchers have made pigs with more and more human genes. For instance, one gene that's been added produces the human version of thrombomodulin, a molecule that prevents clotting in blood vessels. Although pigs have their own version of thrombomodulin, it's the wrong shape and doesn't work correctly with human blood.

Transplant surgeons say one of the largest obstacles they face is the immense cost of carrying out xenotransplant experiments. A single transplant surgery costs $100,000 and involves eight people. Then there's the cost of keeping the primates, the red tape of animal regulations, and limited government grants. That's where Rothblatt's personal interest and her fortune have made a difference, they say. "She is the one that has rejuvenated the field. She has the money and a personal attachment. She wants to get it done fast."

Link: http://www.technologyreview.com/news/540076/surgeons-smash-records-with-pig-to-primate-organ-transplants/

Proteins, the basis for all cellular machines, are very complex structures. Their properties depend upon correct folding, and so misfolded proteins are essentially broken, unable to perform their functions. Some forms of misfolded or otherwise damaged proteins can precipitate from cell and tissue fluids to form solid aggregates. The presence of these aggregates is a form of damage, and cellular quality control mechanisms toil constantly to recycle or repair broken proteins. Clearly these mechanisms fail or are overwhelmed with advancing age, as growing levels of aggregated and misfolded proteins are one of the hallmarks of old tissue. Researchers are investigating in ever greater detail how exactly cells act to clear aggregates, with the goal of finding ways to enhance these evolved processes. The research noted in this post is one example among many, in which the scientists look beyond chaperone proteins, such as heat shock proteins, that are responsible for enabling correct folding and prevention of aggregates, and focus on how the activities of these chaperones are coordinated.

The presence of many of types of aggregate are associated with specific age-related conditions, especially neurodegenerative diseases such as Parkinson's disease (aggregates of α-synuclein) and Alzheimer's disease (aggregates of one of the many types of amyloid). The evidence for aggregates as a direct cause of pathology varies in quality, but there is nonetheless considerable funding and energy directed towards the development of therapies to clear these aggregates. In Alzheimer's disease, for example, forms of immunotherapy are under development to attempt to manipulate immune cells into attacking and recycling the damaged proteins making up aggregates.

At this point the prospects for effective treatments via enhancement of existing cellular quality control mechanisms, as opposed to other forms of clearance such as immunotherapy, seem more distant. It is clearly an interesting proposal, as many ways of slowing aging in laboratory species have been shown to be accompanied by increased activity of chaperone proteins, clearance of damaged proteins, and recycling of cellular components. Calorie restriction is among these, to pick one example. Despite more than a decade of serious interest in finding therapies to boost the activity of quality control processes there is as of yet little progress towards clinical trials or drug candidates, however. Perhaps that will change when a new and more tractable point of influence is discovered in the relevant areas of cellular biochemistry, or perhaps it is another of those areas where progress is a matter of hard work and funding, but too few research groups are presently interested in this approach to generate real traction. For my part, I am more in favor of targeted clearance from the outside via strategies such as immunotherapy rather than attempting to alter existing cellular operations; the latter tends to be much harder to accomplish safely and without side-effects. On the other hand, more competition and diversity in research strategies is usually a good thing.

How Human Cells Can Dissolve Damaging Protein Aggregates

Proteins in all cells - from bacteria to human - are folded in their native state. Proteins are first manufactured as long, sequential chains of amino acids and must assume a specific three-dimensional structure, i.e., fold, to be functional. This correctly folded state, or protein homeostasis, is at constant risk from external and internal influences. Damaged proteins lose their structure, unfold and then tend to clump together. If such aggregates form, they can damage the cells and even cause the cells to die, which we see in neurodegenerative diseases such as Alzheimer's and Parkinson's, and even in ageing processes. The formation of protein aggregates in different organs of the human body is associated with a large number of diseases, including metabolic disorders.

"Dissolving protein aggregates is a critical step in recycling defective proteins and providing protection against stress-induced cell damage. We had several clues as to the main players in this process, but we didn't know exactly how it worked." The researchers succeeded in identifying a previously unknown, multi-component protein complex that efficiently solubilizes stress-induced protein aggregates in vitro. This complex consists of molecular folding helpers, the chaperones, which in this case belong to the heat shock protein 70 (Hsp70) class. These are proteins that aid other proteins in the folding process.

The researchers also studied the co-chaperones that regulate Hsp70 activity in the protein complex. The co-chaperones of the so-called J-protein family are key, in that they "lure" the Hsp70 folding helpers to the protein aggregates and activate them precisely at their target. "The key finding of our work is that two types of these J-proteins must dynamically interact to maximally activate the Hsp70 helper proteins to dissolve the protein aggregates. Only this launches the potent cellular activity to reverse these aggregates. Now we are faced with the challenge of understanding the physiological role and the potential of the newly discovered mechanism well enough to apply these findings from basic research and develop novel strategies for therapeutic interventions."

Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states. Healthy metazoan cells effectively eliminate intracellular protein aggregates, indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems, and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro. This unresolved conundrum is central to protein quality control biology.

Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.

The open access paper linked here reviews evidence for the contribution of dietary advanced glycation end-products (AGEs) to aging. There is in fact some debate over the degree to which AGEs from the diet are important in aging versus AGEs generated within and between cells. There are many types of AGE capable of forming cross-links in the extracellular matrix. These cross-links degrade tissue structure and function, and while most are short-lived and soon broken down, the less common long-lived varieties build up over the years to contribute to age-related disease and degeneration. The overwhelming majority of cross-links in old human tissues involve glucosepane, a long-lived AGE that doesn't appear to arrive in significant amounts from the diet. The SENS Research Foundation is funding programs to find a way to safely break down glucosepane since our evolved biochemistry isn't capable of performing that job. AGEs don't just form cross-links, however. They can also spur chronic inflammation and other bad cellular behavior by interacting with the receptor for AGEs, RAGE. This is an area in which short-lived AGEs and dietary AGEs might be contributing meaningfully to aging, and is certainly a day to day concern for people with diabetes, for example.

An important mechanism by which lifestyle influences loss of health and function is oxidative stress. Oxidative stress results in oxidized cell macromolecules and disturbs cell signal transduction, especially insulin-mediated metabolic responses. Metabolic insulin resistance remains a poorly understood phenomenon of cell stress associated with aging and chronic degenerative diseases. Medical approaches focus on management of hyperglycemia, often at the expense of insulin-dependent cell stress. Systemic advanced glycation end-products (AGEs) formed endogenously or acquired from high temperature-cooked foods and tobacco products are powerful pro-oxidants. Emerging research reveals the compelling contribution of dietary AGEs (dAGEs) to systemic load of AGEs, cell stress and insulin resistance.

Advanced glycation end-products promote oxidative damage to proteins, lipids and nucleotides. Aging and chronic diseases are strongly associated with markers for oxidative stress, especially advanced glycation end-products, and resistance to peripheral insulin-mediated glucose uptake. High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512899/

Researchers have in the past demonstrated that the children of very long-lived individuals tend to themselves have greater longevity. Thus is isn't surprising to see evidence of better measures of health as well, such as in thus study where the offspring of centenarians have less inflammation and longer telomeres. Aging is a process of accumulating damage to cells and tissues, and both chronic inflammation and telomere shortening are largely or completely a reflection of that damage and its direct consequences, and in turn go on cause their own further consequences. Rising levels of inflammation, for example, are in part caused by immune system dysfunction and the effects of cross-link forming advanced glycation end-products on cell activities.

"Centenarians and supercentenarians are different - put simply, they age slower. They can ward off diseases for much longer than the general population." In groups of people aged 105 and over (semi-supercentenarians), those 100 to 104 (centenarians), those nearly 100 and their offspring, the team measured a number of health markers which they believe contribute towards successful ageing, including blood cell numbers, metabolism, liver and kidney function, inflammation and telomere length.

Scientists expected to see a continuous shortening of telomeres with age, however what they found was that the children of centenarians, who have a good chance of becoming centenarians themselves, maintained their telomeres at a 'youthful' level corresponding to about 60 years of age even when they became 80 or older. "Our data reveals that once you're really old, telomere length does not predict further successful ageing. However, it does show that those who have a good chance to become centenarians and those older than 100 maintain their telomeres better than the general population, which suggests that keeping telomeres long may be necessary or at least helpful to reach extreme old age."

Centenarian offspring maintained lower levels of markers for chronic inflammation. These levels increased in everybody with age including centenarians and older, but those who were successful in keeping them low had the best chance to maintain good cognition, independence and stay alive for longer. "It has long been known that chronic inflammation is associated with the ageing process in younger, more 'normal' populations, but it's only very recently we could mechanistically prove that inflammation actually causes accelerated ageing in mice. "This study, showing for the first time that inflammation levels predict successful ageing even in the extreme old, makes a strong case to assume that chronic inflammation drives human ageing too. Our study showed that over a wide age range, including unprecedentedly large numbers of the extremely old, inflammation is an important driver of ageing that might be something we can develop a pharmacological treatment for. Accordingly, designing novel, safe anti-inflammatory or immune-modulating medication has major potential to improve healthy lifespan."

I think that there are some cart and horse issues in the conclusions drawn here by the researchers involved. This is the case in much of modern medicine for age-related conditions: development focuses on addressing proximate causes and consequences of root causes rather than on the root causes themselves. It is trying to clean up the spill from a broken pipe without fixing the pipe, or trying to make an old, worn car run more effectively by being very diligent in changing the oil. Present research and development strategies result in expensive treatments that do comparatively little, and this must change if we are to see greater progress towards effective treatments for aging.

Link: http://www.ncl.ac.uk/press.office/press.release/item/scientists-crack-the-secret-of-the-centenarians

Here I'll point you to a recent open access review paper on the use of adult stem cells in the production of cartilage tissue. Cartilage regenerates poorly, and wear and tear in the load-bearing cartilage of joints over the course of aging is the cause of considerable disability and suffering. Any cartilage injuries accumulated along the way only make things worse.

Cartilage is a highly structured tissue, in which the precise arrangement of cells and extracellular matrix molecules provides the mechanical properties necessary to its function. This was perhaps less appreciated than it should have been, at least until researchers started trying in earnest to grow cartilage from stem cells. The complex molecular structure of cartilage has made it a real challenge to engineer this tissue, and only very recently have researchers made inroads into getting the structure right, such as through the mesenchymal condensation technique. Even so production of all of the varied types of cartilage tissue - elastic, hyaline, and fibrocartilage - is yet to be reliably accomplished. It is worth noting that, all this aside, cartilage is one of the "easy" tissues to engineer, being comparatively uniform and lacking in blood vessel networks. Forming and integrating blood vessels is one of the big challenges in building tissues of any significant size, and there is still no good, robust solution to that problem. Until researchers can manage cartilage, muscle, skin, and the like, it is premature to expect much more complex internal organs to be reliably grown from a patient's cells alone.

That said, the process of decellularization will soon allow patient-matched organs to be reliably created from donor organs, and probably even using organs from other species such as pigs. This approach to tissue engineering makes use of the extracellular matrix of the donor organ, stripped of its cells, to guide the patient's cells to reform an organ in the correct fashion. While it is possible to produce a functional organ this way, and this has been demonstrated for a few organs in mice and rats, the research community is still a long way away from being able to fabricate such a matrix or guide its creation by cells. Ultimately we wish to see organ engineering decoupled from the need for donors, which is why decellularization is only a stepping stone to later goals.

Looking back in the Fight Aging! archives, I noticed a very similar review from late 2011 that covers much the same ground as the paper linked below. Four years isn't all that much time in medical research, so the two reviews are much the same in content at a high level. One noteworthy difference is that the number of ongoing, official, by-the-regulations clinical trials for regrowth or regeneration of cartilage has grown considerably in the past few years. But take a look and see what you think; it is clear that this is a field still in the comparatively early stages of developing a practical technology platform for regenerative treatments.

Use of Adult Stem Cells for Cartilage Tissue Engineering: Current Status and Future Developments

Although initially considered as a tissue with a simple structure, reproducing the finely balanced structural interactions of cartilage has proven to be difficult. Articular cartilage is a stable tissue that functions for decades to keep normal joint movement possible. It is a hyaline tissue with no blood, lymphatic or nerve supply. It contains a single type of cells, called chondrocytes, maintained in an abundant connective tissue. This extracellular matrix is composed of collagen fibers, mainly type II collagen, and proteoglycan aggregates, mainly aggrecan, attached along a filament of hyaluronic acid. Collagens provide tensile strength, while proteoglycans are responsible for the compressive strength. The whole forms a viscoelastic structure well suited for both functions of cartilage: the absorption and distribution of forces and the sliding of the joint surfaces with a very low coefficient of friction.

During life, articular cartilage defects may happen and form areas of damaged or missing cartilage. These defects are often caused by acute trauma. Biochemical changes due to age may also stimulate the degradation of cartilage matrix and at term lead to chronic diseases such as osteoarthritis. These defects are the most often irreversible, since articular cartilage has very limited self-repair capability. Cartilage is an attractive candidate for use in tissue-engineering therapies since this tissue is avascular and has a limited capacity for repair.

The use of autologous chondrocyte implantation may represent a promising technology for cartilage repair in orthopedic research. However, we and other investigators have established that, during monolayer expansion of chondrocytes in vitro, this cell population loses its phenotype, as illustrated by a switch in collagen production from type II (typical of hyaline cartilage) toward types I and III (typical of fibrocartilage). The result of these phenotype changes is the production of an extracellular matrix with inferior biomechanical properties. In addition, the limited capacity of the donor site to provide a large amount of chondrocytes, as well as donor site morbidity, are major obstacles for autologous chondrocytes. Therefore, use of stem cells, such as mesenchymal stem cells (MSCs), may be preferred. MSCs can be relatively easily harvested and the procedures using them are less invasive or destructive than articular cartilage harvesting procedures.

Growth factors are essential to induce chondrogenic differentiation of adult stem cells. However, to promote/maintain cartilage differentiation/phenotype in culture, another critical requirement is to provide a 3D microenvironment. Indeed, research has demonstrated that MSCs hardly differentiate into cartilage cell lineage in a 2D culture system. For applications of cartilage tissue replacement, most investigators preferred transplantation of cells combined with scaffold. So, a huge expansion in biomaterial technologies and scaffolds took place to create functional tissue replacement to treat cartilage defects or osteoarthritis. Numerous biomaterials and scaffolds are being developed, influenced by the knowledge of the anatomical and structural complexity of articular cartilage.

Many clinical trials have been registered at regarding application of stem cells for regenerating cartilage. About 40 studies (phase 1 to 3) are in progress or are completed worldwide. Most of them aim to repair cartilage defects or treat degenerative damage, in knee, ankle, or hip, due to osteoarthritis. Some preliminary results have been published and are promising. In spite of the above-mentioned potential, there are some pitfalls associated with MSC application for articular cartilage regeneration. One is the qualities and mechanic properties of neoformed cartilage, and the second is the fabrication of anatomically relevant 3D engineered tissue and its integration into surrounding native joint tissues.

Scientists have of late been making progress in understanding the role of TDP-43 accumulation in the nerve cell degeneration and death that characterizes amyotrophic lateral sclerosis (ALS) and some forms of frontotemporal dementia (FTD). Potential drug targets have emerged that may allow better clearing of unwanted TDP-43 through cellular quality control mechanisms, for example. The researchers quoted here have a different approach in mind, however, focusing on the use of other proteins that can perform the vital cellular functions that are disrupted when too much TDP-43 is present, but which are not themselves affected by high levels of TDP-43:

TDP-43 is normally responsible for keeping unwanted stretches of the genetic material RNA, called cryptic exons, from being used by nerve cells to make proteins. When TDP-43 bunches up inside those cells, it malfunctions, lifting the brakes on cryptic exons and causing a cascade of events that kills brain or spinal cord cells. Researchers deleted the gene for TDP-43 from both lab-grown mouse and human cells and detected abnormal processing of strands of RNA, genetic material responsible for coding and decoding DNA blueprint instructions for making proteins. Specifically, they found that cryptic exons - segments of RNA usually blocked by cells from becoming part of the final RNA used to make a protein - were in fact working as blueprints. With the cryptic exons included rather than blocked, proteins involved in key processes in the studied cells were abnormal.

When the researchers studied brain autopsies from patients with ALS and FTD, they confirmed that not only were there buildups of TDP-43, but also cryptic exons in the degenerated brain cells. In the brains of healthy people, however, they saw no cryptic exons. This finding, the investigators say, suggests that when TDP-43 is clumped together, it no longer works, causing cells to function abnormally as though there's no TDP-43 at all. TDP-43 only recognizes one particular class of cryptic exon, but other proteins can block many types of exons, so researchers next tested what would happen when they added one of these blocking proteins to directly target cryptic exons in cells missing TDP-43. Indeed, adding this protein allowed cells to block cryptic exons and remain disease-free. "What's thought provoking is that we may soon be able to fix this in patients who have lots of accumulated TDP-43."

Link: http://www.hopkinsmedicine.org/news/media/releases/scientists_report_explanation_for_protein_clumps_in_autopsy_brain_cells_of_als_patients_

At a recent conference appearance, scientist-advocate Aubrey de Grey of the SENS Research Foundation made a point that I think bears repeating. The mainstream approach to medical science is to screen for drug compounds that produce beneficial alterations in cellular mechanisms observed in late stage disease. This almost entirely focuses on proximate causes of harm in a diseased, dysfunctional metabolism, far removed from the root causes that created the medical condition in the first place. It thus produces therapies that do little good in the grand scheme of things since they don't address the real cause of disease. They are rather efforts to make a badly damaged system limp along a little longer with patches and compensations, which is always expensive and doomed to failure, whether we are talking about a mechanical device or a human being.

This strategy for medical research and development must change radically if we are to see meaningful progress towards prevention and cure of age-related disease. It must be replaced with something more like de Grey's SENS programs, in which carefully designed therapies repair specific forms of cell and tissue damage to achieve rejuvenation. The form of these therapies is already known in great detail; it is clear what must be built. Some are already under development, such as senescent cell clearance and allotopic expression of mitochondrial genes. This is the future of medicine, not continuing to mine the natural world in the hope of finding compounds that do marginally more good than harm, and can at best only slightly slow down the aging process.

de Grey attributed the gains in longevity over the last century to one primary factor - the reduction of infectious diseases. With infectious diseases largely gone in the developed world, he said we need to turn our attention to the main cause of death. "There's almost one thing that kills everybody now in the developed world. It's the accumulation of these various types of molecular and cellular damage that the body does to itself as a side effect of just being alive at all." According to his research and theories, that molecular and cellular damage can be repaired with new regenerative medicines, including stem cell therapies, gene therapies, drugs and vaccines.

de Grey challenged the wisdom of modern pharmaceutical research leading to really expensive drugs that delay diseases by very short periods of time. "We will not cure cancer this way. We will not cure Alzheimer's this way." The incentive structure for modern pharmaceuticals perpetuates this because "it can be done reasonably quickly, sold for a lot of money and because people are desperate for anything."

"I think it's really important to understand that the relationship between quality of life and quantity of life is not as most people think about it. Today most people think about those two things as some kind of trade off, and that makes sense today because there are many things we like doing that are not very good for us. But we are talking about a world in which quality will confer quantity, in which you will live longer because you are living better. That's the critical thing here."

Link: http://www.geekwire.com/2015/can-humans-live-forever-this-scientist-thinks-its-possible/

The mammalian heart regenerates very poorly, which is one of the reasons why cardiovascular disease kills so many of us. In the research noted below scientists investigate a possible reason as to why this is the case, uncovering what they believe to be a meaningful difference in the structure of heart cells when compared with those of non-mammalian species in which the heart is capable of regrowth. A cell structure known as the centrosome, important in cellular replication, is lost in heart cells early on in mammalian development, but retained in other species known for the regenerative prowess, such as salamanders and zebrafish.

You might consider this a sort of regenerative research, but quite different in focus from work on stem cells and signals intended to spur heart tissue to regenerate where it would not normally do so. In this case it is suggested that perhaps it might be possible alter heart cells to be more like other muscle cells, more capable of ongoing self-repair. This is of course much more speculative than stem cell therapies at this stage, but all new medicine must start somewhere.

Heart cells are generated early in life and there is little turnover or reconstruction following injury in comparison to other tissues. Looking at other species, the hearts of zebrafish and salamanders regenerate exceptionally well over the whole life span. Remove a whole chunk of heart tissue and it will grow back. Is this a matter of signal environments, as is presently thought to be the case, or is it differences in the complex relationship between the immune system and tissues in regulation of healing, which is looking likely based on salamander studies, or is it inherent in the internal state of the cells themselves? Or all of the above?

Why the human heart cannot regenerate

Heart failure is the most common cause of death worldwide. The main reason for this is that damage to the human heart causes cardiac muscle cells to die, which in turn leads to reduced heart function and death. However, this is not the case for zebrafish or amphibians. If their hearts become damaged and cardiac muscle cells die, their remaining cardiac muscle cells can reproduce, allowing the heart to regenerate. The ability of most cardiac muscle cells to reproduce disappears in humans and all other mammals shortly after birth. What remains unclear, however, is how this happens and whether it is possible to restore this ability and therefore to regenerate the heart.

'In our study we discovered that the centrosome in cardiac muscle cells undergoes a process of disassembly which is completed shortly after birth. This disassembly process proceeds by some proteins leaving the centrosome and relocating to the membrane of the cell nucleus in which the DNA is stored. This process causes the centrosome to break down into the two centrioles of which it is composed, and this causes the cell to lose its ability to reproduce.' The centrosome is an organelle found in almost every cell. In recent years, experiments have shown that if the centrosome is not intact, the cell can no longer reproduce. This raised the key question to what extent centrosome integrity could be manipulated - such as in cancer where cells reproduce at an uncontrolled rate. 'We were incredibly surprised to discover that the centrosome in the cardiac muscle cells of zebrafish and amphibians remains intact into adulthood. For the first time, we have discovered a significant difference between the cardiac muscle cells of mammals and those of zebrafish and amphibians that presents a possible explanation as to why the human heart cannot regenerate.'

Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes

Increasing evidence supports the requirement of a functional centrosome for cellular proliferative potential. Centrosome disassembly appears to be a very effective way to achieve a post-mitotic state. But why do cardiomyocytes disassemble their centrosomes? Upon birth, the neonatal heart, and the cardiomyocytes therein, undergo increased hemodynamic stress. Effective cardiomyocyte function in response to increased hemodynamic stress may require a cytoskeletal architecture more conducive to handling postnatal physical stresses. Thus, centrosome disassembly may be a result of cytoskeletal reorganization. In this scenario, proliferative potential might be sacrificed for postnatal function.

The ability of zebrafish and newts to regenerate their heart has gained extensive interest in recent years. One major question is what distinguishes mammalian cardiomyocytes from those of zebrafish and newts with regards to their proliferative potential. Our data demonstrate that the state of cellular differentiation of cardiomyocytes from various species is not evolutionary conserved. The fact that adult zebrafish and newt cardiomyocytes maintain their centrosome integrity indicates that factors promoting adult zebrafish cardiomyocyte proliferation might not necessarily induce adult mammalian cardiomyocyte proliferation.

Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart.

Researchers here investigate the mechanisms involved in thymic involution, the atrophy of the thymus that occurs early in adulthood. The scientists propose that this atrophy occurs because thymus tissue is deficient in natural antioxidant compounds, and is thus unable to resist even normal levels of oxidative stress in the body.

The thymus plays an essential role in the process of generating new immune cells to tackle threats such as viruses, bacteria, and rogue cells. In childhood this organ is very active, but in adult life the flow of new immune cells slows to a trickle as a result of atrophy of the thymus. This is one of the factors contributing to the age-related decline of the immune system, and a number of research groups are investigating ways to rejuvenate or replace the thymus so as to provide a larger supply of active, useful immune cells to adults. This research on the cause of thymic involution is probably less relevant to rejuvenation, as the damage is already done in those of us needing a new thymus, but it may be useful when it comes to the ongoing protection and maintenance of a rejuvenated or replaced thymus.

The development of interventions to slow the progression of thymus atrophy has been limited by the lack of knowledge about the underlying mechanisms. The prevailing theory suggests that sex hormones play a key role, but this explanation does not account for the accelerated speed at which the thymus diminishes in size in comparison to other tissues. Researchers developed a computational approach for analyzing the activity of genes in two major thymic cell types - stromal cells and lymphoid cells - in mouse tissues, which are very similar to human thymic tissues in terms of function and the properties of atrophy. They found that stromal cells were deficient in an antioxidant enzyme called catalase, resulting in the accumulation of free radical and metabolic damage.

To test whether catalase deficiency plays a causal role in thymus atrophy, the researchers performed genetic experiments to enhance catalase levels in mice. By 6 months of age, the size of the thymus of the genetically engineered mice was more than double that of normal mice. Moreover, mice that were treated with two common antioxidants from the time of weaning achieved nearly normal thymus size by 10 weeks of age. "Our studies show that, rather than an idiosyncratic relationship to sex steroids, thymic atrophy represents the widely recognized process of accumulated cellular damage resulting from lifelong exposure to the oxidative byproducts of aerobic metabolism."

Taken together, the findings provide support for the free-radical theory of aging, which proposes that reactive oxygen species such as hydrogen peroxide cause cellular damage that contributes to aging and a variety of age-related diseases. These toxic molecules, which form in cells as a natural byproduct of the metabolism of oxygen, have been linked to progressive atrophy in many organs and tissues as part of the normal aging process. However, these are generally slow, progressive processes that do not become apparent until late in life and often go mostly unnoticed.

Link: http://www.sciencedaily.com/releases/2015/08/150806133043.htm

Few serious efforts have been made to generate robust demographic models of a near future in which radical life extension is achieved through rejuvenation therapies such as those of the SENS research programs. There is a paper from 2010 and little prior to that. Here a more recent model adds consideration of economic factors; the purpose isn't to predict what will happen, but to try to explore the likely nature of relationships between therapies to treat aging and extend healthy life spans, demography, and economic line items such as energy use and retirement.

Since the model used only explicitly factors in progress in technology via increased productive life span and GDP, I suspect the authors overstate concerns regarding energy and food. Even so, within their model the situation is hardly the Malthusian disaster predicated by people who subscribe to the overpopulation myth. The same model run in the 1930s, well before the green revolution in agricultural output, would probably have indicated far worse issues for food supplies, and also for the environment given the state of power generation technologies back then. Technology is not static, and efforts to improve it in specific ways are carried out in reaction to perceived shortcomings and expenses.

There is near certainty that the world will experience rapid population aging throughout this century, thanks primarily to widespread and substantial reductions in fertility and, secondarily, to ongoing extensions of life expectancy. Even as debate persists on biological limits to life, a growing body of demographic evidence suggests that improvements in human longevity are not diminishing, and may even be accelerating at older ages. At the same time, new breakthroughs in regenerative medicine and anti-aging therapies point to the possibility of improvements in longevity that are dramatic rather than incremental, and that reduce morbidity along with mortality. Yet, forecasts produced by governmental and intergovernmental organizations continue to assume a fairly narrow range of upside longevity variation, amounting to at most 10 years of added life expectancy. In this study, we take the opposite approach, exploring a future of very rapidly expanding life expectancy coupled with very low senescence. Using International Futures, a large-scale, long-term, integrated forecasting system, we explore the demographic, socioeconomic and ecological consequences of, and necessary adaptations to, such a world.

The purpose of this paper, then, is to consider the issues raised by a future of very rapidly expanding life expectancy coupled with very low senescence. More specifically, we want to look at how the world might evolve were there to be, over a 20-year period beginning as early as 2020, a rapid development and deployment of technologies that nearly eliminated mortality and morbidity from disease as well as eliminating infecundity. We label this world that of a Negligible Senescence scenario. We juxtapose this world with a Base Case scenario of more slowly progressing extension of life expectancy, accompanied by delayed but not ultimately reduced senescence (a more common forecast than that of negligible senescence). Our goal is not to model a likely future world, but rather to frame our understanding of the potential consequences of negligible senescence by evaluating the effects of a rapid and universal transition to such a regime.

We find that a world of negligible senescence would pose a number of immense challenges that go well beyond increased population size. The most obvious and immediate challenge lies with disseminating and paying for the life-saving intervention set itself. We estimate that rollout of such an intervention on a widespread basis would be infeasible even in the wealthiest countries if the initial price were set at $10,000 per year of healthy life added. At the price of $5000 per added healthy-life-year that we assumed through much of this paper, the initial financial burdens would be manageable for wealthy countries and would, over time, yield considerable reductions in disease-related expenditures that would more than offset the cost of the intervention. Yet poor and also middle-income countries would struggle to finance such an intervention even if, as we assumed, up to 95% of the costs in the poorest countries were defrayed through price reductions of the sort that have recently been observed for high-impact antiretroviral treatments.

With these caveats in mind, a world of negligible senescence would likely yield a still growing population of 14.8 billion by the year 2100, a considerable increase over the 7 billion today or the 10.1 billion forecast in our Base Case in 2100. Uncertainty in fertility, arising from the potential pronatalist impact of increased fecund spans and, on the other hand, the public interest in reducing fertility to check population growth, could yield a population with as many as 20 billion or as few as 11.6 billion.

A revolutionary jump in human longevity would require a comparable revolution in the meaning and timing of retirement. We explore scenarios that would see the average age of retirement rising to 114 by 2100 if fertility remained moderate. Even these relatively aggressive increases in retirement age necessitated a rise in savings from 22% today to 29% and doubling public pensions as a share of GDP, from 6% to something more like 14%. These increases would seem to be at the absolute edge of feasibility, and thus our retirement age scenarios should probably constitute something of a lower bound. On a positive note, individuals would still be able to enjoy decades of post-retirement life if they so chose, or embark on new patterns of employment, education, and leisure that are less defined by imminent mortality than the current pattern.

The potential addition of billions of people would concern many, especially given that this population (in the absence of negative feedbacks from environmental constraints) would see a GDP per capita 30% above the already substantial economic growth built into our Base Case. Energy demand levels, even with quite optimistic assumptions about efficiency gains and renewable contributions, would drive atmospheric CO2 levels above 600 ppm and, if coal were more heavily drawn upon without carbon sequestration, to 800 ppm or above. In the absence of food production technologies that are currently not on the forecast horizon, it might become nearly impossible to reduce the portion of the world's population that is undernourished.

Link: http://dx.doi.org/10.1016/j.techfore.2015.06.031

There is a mountain of evidence to show that regular exercise and maintaining a state of fitness is good for health and longevity. That mountain continues to grow, new papers arriving on a weekly basis to reinforce these points: don't be sedentary and don't get fat, or you'll pay the price of greater medical expenses over a shorter, less healthy life. A few examples are linked below, spanning a range of topics including associations between fitness and age-related structural damage and decline in the brain, exercise and mortality in middle age, and exercise as a therapeutic option for the elderly.

Regular moderate exercise is among the safest of ways to influence health, and it produces an expected benefit to long-term health that is modest in the grand scheme of things, but for basically healthy individuals still larger than that provided by any other available methodology aside from the practice of calorie restriction. You can't exercise your way to living to 100, a target that less than 1% of the population will reach in the environment of today's medical science, and exercise only modestly improves your 20% odds of making it to 90 in the environment of today's medical science. If exercise required multi-billion-dollar research programs and decades before it could be safely used, then I would be just as dismissive of it as I am of efforts to develop drugs to slightly slow the aging process. But exercise is free, available now, reliable, and backed by an enormous weight of evidence, and that makes all the difference as to whether or not to take advantage.

It is true that the future of practical, low-cost rejuvenation therapies will render academic all questions of whether or not we would gain a year in health here or a year there due to a healthier lifestyle. We'll be gaining decades of healthy life, and losing the marks and damage of age, thanks to therapies that target the causes of degenerative aging and age-related disease. The big question for those of us who stand today at the cusp of age and opportunity, at the whim of small chances that will spiral out to speed or slow the timeline for future medical development, is whether or not we will live long enough to benefit from rejuvenation treatments. That is where the year here and the year there become far more important, especially as the pace of progress in all technologies continues to accelerate.

Cardiorespiratory fitness is associated with white matter integrity in aging

Age-related decline in cerebral macrostructure, such as reductions in gray and white matter volume, is well-documented. More recently, diffusion tensor imaging (DTI) has been used to assess in vivo cerebral white matter microstructure and to evaluate specific white matter fiber bundles that underpin information transmission between gray matter regions. Age-related reductions in white matter microstructure have been reported in healthy older adults (OA), and decreased white matter microstructure in OA has been linked to poorer performance on tasks tapping processing speed, executive functions, and episodic memory.

The pervasive evidence for neural decline in OA has led to substantial interest in individual difference factors that are associated with age-related reductions in cerebral integrity. One such factor is cardiorespiratory fitness (CRF), an indicator of the ability of one's circulatory and respiratory systems to supply oxygen to skeletal muscle during sustained moderate to vigorous physical activity.

Exercise during teen years linked to lowered risk of cancer death later

Women who exercised during their teen years were less likely to die from cancer and all other causes during middle-age and later in life, according to a new study. The investigators used data from the Shanghai Women's Health Study, a large ongoing prospective cohort study of 74,941 Chinese women between the ages of 40 and 70. The women enrolled in the study between 1996 and 2000. Each participant was interviewed at enrollment about exercise during adolescence, including participation in team sports, as well as other adolescent lifestyle factors. They were also asked about exercise during adulthood and other adult lifestyle factors and socioeconomic status, and participants were interviewed again every two to three years. Investigators found that participation in exercise both during adolescence and recently as an adult was significantly associated with a 20 percent reduced risk of death from all causes, 17 percent for cardiovascular disease and 13 percent for cancer.

A Cluster Randomized Controlled Trial of Nonpharmacological Interventions for Old-Old Subjects with a Clinical Dementia Rating of 0.5: The Kurihara Project

The boundary or transitional state between normal aging and dementia, which is defined in various ways such as mild cognitive impairment (MCI) or a Clinical Dementia Rating (CDR) of 0.5, is recognized as a state of being at high risk of dementia. Although it is a serious challenge to control the risk of dementia in these people, pharmacological interventions remain unsuccessful. Meanwhile, recent studies have suggested potential benefits of nonpharmacological interventions. Among a variety of nonpharmacological methodologies, most popular and potentially beneficial interventions to date include cognitive interventions (CI), physical activities (PA) and a group reminiscence approach with reality orientation (GRA).

Previous studies have suggested that exercise may be one of the promising strategies for improving cognitive functions. Resistance as well as aerobic trainings may positively impact cognitive functioning and result in functional plasticity in healthy older adults. Furthermore, exercise training may have cognitive benefits for seniors with MCI, especially improvements in selective attention and conflict resolution, processing speed and verbal fluency in senior women with amnestic MCI. Thus, many previous studies have emphasized the positive impact of PA on the executive functions of subjects in the boundary state between normal aging and dementia. Indeed, our results support these previous findings; however, they also show that the benefit for executive functions may be a nonspecific effect that may occur with CI or the GRA as well. Nevertheless, we cannot exclude the secondary benefit of PA on cognitive functions, because an improvement in physical ability may potentially ameliorate cognition in the course of subsequent daily life.

Physical Activity Is Linked to Greater Moment-To-Moment Variability in Spontaneous Brain Activity in Older Adults

Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age is associated with greater brain structural and functional integrity, and higher cognitive functioning. In this study we extend our understanding of the different and overlapping roles of CRF and PA in brain resting state function in healthy but low-active older adults. Depending on brain region and task, greater CRF is associated with either increased or decreased change in blood oxygenation level dependent (BOLD) signal, a proxy for neural activity. As a result, it is unclear whether high or low amplitudes of BOLD signal reflect optimal functional brain health. Here we employed a more general measure of neural function: moment-to-moment variability in the BOLD signal during spontaneous brain activity. Moment-to-moment variability in the BOLD signal (SDBOLD) is known to reflect the dynamic range of neural processing, such as the modulation of functional networks and is suggested to be a promising tool in mapping neural correlates of cognitive abilities in aging. Specifically, lower SDBOLD in certain brain regions is associated with older age, slower, and less consistent performance on a perceptual matching task.

In this study, we sought to determine how the level of physical fitness (measured as CRF) and PA (measured via accelerometer) are related to functional brain health measured as SDBOLD. To this end, we collected resting functional magnetic resonance BOLD data from 100 healthy older participants (60-80 years). Given that: 1) advancing age is associated with decreasing SDBOLD; and 2) greater CRF, PA, and lower sedentariness are associated with better cognitive and brain health outcomes in older adults, we predicted that greater SDBOLD in certain regions would reflect greater brain health and therefore positively correlate with CRF and PA, and negatively with sedentariness. We found that older adults who spend more time daily on light PA (LI-PA; housework, gardening, relaxed walking) and moderate-to-vigorous PA (MV-PA, e.g. jogging, walking stairs, biking) had greater SDBOLD in multiple brain regions, and this relationship was positively associated with white matter microstructure.

To follow on from yesterday's article on trials of blood transfusions from young to old, here is an open access review paper from some of the researchers involved. A range of tests and scientific programs have grown out from heterochronic parabiosis research in which the circulatory systems of an old and a young laboratory animal are joined. This produces benefits in the older animal and negatively impacts the younger animal. Researchers are now searching for the underlying mechanisms and signals that cause these reactions, so as to build therapies that might, for example, increase stem cell activity in the old.

In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain.

Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors.

The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.

Link: http://dx.doi.org/10.1001/jamaneurol.2015.1616

Researchers here demonstrate the merits of intermittently disrupting the senescence-associated secretory phenotype (SASP) in conjunction with standard cancer treatments. SASP is the name given to the tendency of senescent cells to release various signals and active molecules that change nearby cell behavior, promote inflammation, and harm the structure of tissue. Senescent cells accumulate with age, and although initially helpful in suppressing cancer risk by removing the most cancer-prone cells from the picture, eventually there are enough senescent cells for SASP to become very damaging and tip the balance back towards cancer promotion.

The researchers here are using rapamycin as a SASP-disrupting agent, but there are no doubt better methods awaiting discovery, designed drugs with fewer side-effects than those accompanying the use of this one. Rapamycin is known to extend life in mice, and there has been some debate over whether it does so by slowing aging or merely because it is good at reducing cancer incidence in that species.

While scientists have demonstrated benefits in this research, the better path forward is probably outright removal of senescent cells: don't try to engage in the long and expensive process of tinkering with cell behavior, just take the targeted cell-killing technologies under development in the cancer research community and turn them against cellular senescence. Senescent cells have a range of distinct chemical signatures, so this is a very plausible plan for near future development.

Intermittent dosing with rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence, a phenomena in which cells cease to divide in response to DNA damaging agents, including many chemotherapies. Researchers showed that rapamycin reduced the secretion of inflammatory cytokines from senescent cells in culture and in mice by suppressing the mTOR pathway, which promotes growth. The team gave rapamycin to mice with prostate cancer - after they had been treated with DNA-damaging chemotherapy that causes senescence, both to the tumor and its microenvironment. The tumor shrinks but the immediate tissue environment is inflamed. "We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse." Most importantly, the results may help explain why rapamycin has had mixed results as a treatment for cancer. "It's being given to patients as a way of stopping the growth of tumors. But we think that rapamycin may also be beneficial for those tumors that are driven by inflammation. It needs to be tested in a population most likely to benefit."

"Senescence-activated inflammation could be driving the increased incidence of cancer that we see with aging. While this study took place in mice, the work sets the scene to do early clinical trials in humans. Inflammation has a role in almost all tumor development and some cancers are more inflammatory than others. It would be interesting to see the effect that rapamycin has on those tumors and the surrounding tissue." The potential of intermittent dosing is based on the fact that it takes time for the inflammatory loop (fueled by the senescence-associated secretory phenotype or SASP) to form and time for it to re-establish itself after a brief treatment of rapamycin. Rapamycin blocks the production of a protein called IL-1alpha. This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process it takes longer for it to get started again. Treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing. "It's an elegant solution - imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out and it stayed out long enough to benefit the health of the animal."

Link: http://www.buckinstitute.org/buck-news/new-paradigm-treating-inflammaging-and-cancer

There is an ongoing debate in the research community over whether aging should be considered a disease, formally or colloquially. It has been running for a few years, but has picked up steam of late, and more of the discussion is in the form of open access papers these days. To pick a few examples from earlier this year you might take a look at a paper by David Gems or the thoughts of other European researchers associated with Heales. Here I'll point out a recent addition to the discussion in which the author opens with this summary:

The aging of the population represents one of the largest healthcare challenges facing the world today. The available scientific evidence shows that interventions are available now that can target fundamental "aging" processes or pathways. Sufficient economic evidence is available to argue convincingly that this approach will also save enormous sums of money which could then be deployed to solve other urgent global problems. However, as yet this scenario has barely entered the public consciousness and, far from being a point of vigorous debate, seems to be ignored by policy makers.

Understanding why this lethargy exists is important given the urgent need to deal with the challenge represented by population aging. In this paper I hypothesize that one major cause of inaction is a widely held, but flawed, conceptual framework concerning the relationship between aging and disease that categorizes the former as "natural" and the latter as "abnormal." This perspective is sufficient in itself to act as a disincentive to intervention by rendering those who hold it prone to the "naturalistic fallacy" but can give rise to active hostility to biogerontology if coupled with loose and/or blurred understanding of the goals and potential of the field.

One of the biggest puzzles of our time is why, given the obvious potential for biomedical research to treat the causes and progression of the aging process, is next to no-one interested in making this happen? We live in a culture in which it is taken for granted that treating cancer, heart disease, and Alzheimer's is the right thing to do. All of these are conditions caused by aging: they are not magically separate from the aging process. They arise from the same underlying forms of cell and tissue damage that cause all of the other manifestations of disability and frailty. Yet when asked about developing treatments for the underlying causes of aging, treatments that can be made more effective as therapies for age-related diseases than the present state of the art, there is a lack of interest and even outright hostility. Further, it isn't too hard to see that the same people who reflexively oppose the treatment of aging today would accept and use these treatments without question had they merely been born fifty years or a century from now. The whole situation seems very irrational.

I have been following this research and advocating for faster progress towards rejuvenation therapies like those of the SENS research programs for going on fifteen years now. Yet I still couldn't give you a good answer as to why the populations of the world are happy to walk towards a slow, crumbling suicide rather than support progress in medicine for aging. We all have our theories as to why things are the way they are, and no way to prove them: it is still too early on the path towards popular acceptance and support to draw any conclusions from the success of one message over another. The people in our community, who are choosing to make charitable donations to SENS and other research programs, are those who have had the big realization and have a better than average understanding of the research situation. We're not at the stage yet where SENS and other branches of aging research enjoy the support of a large fraction of the population in the same fashion as cancer research, donations given primarily for cultural rather than intellectual reasons.

Here are thoughts on the matter, some of which you might agree with, some of which you might not. As I said, everyone has their theories. Regardless of those, the small history lesson on changing views of aging and disease in the middle of this paper is interesting in and of itself:

Should we treat aging as a disease? The consequences and dangers of miscategorisation

The accusation that early gerontologists deliberately invented the distinction between ageing and disease because "by ring fencing their area of work intellectually, gerontologists hoped to ring-fence it financially" is unfounded and unfair. These early researchers were not making some cynical bid for a separate pot of grant money. Instead, they were echoing a medical tradition about the relationship between ageing and disease which predated not just the scientific method, but the English language.

Perhaps unfortunately for all concerned, this conceptual distinction between "natural" (and normal) aging and "unnatural" disease is ripe with the potential for fundamental philosophical error and "moral concern." At the inception of the field this was of limited importance because the potential for clinical intervention in later life problems was very limited. However, this has changed. In retrospect, the publication of Normal Human Aging in 1984 occurred at a gerontological watershed. The mid 1980s could be said to be a period in which something was known about why aging occurred, much was known about what changed as humans aged, but almost nothing about how this happened.

It is now clear that the finite capacity to replace lost cells plays a causal role in mammalian aging. Senescence is the permanent entry of individual cells into a viable, but non-dividing state, usually as the result of repeated cell division. The molecular pathways which trigger this process are complex but are now relatively well understood. Most recently it has been shown that interdiction of key nodes of the pro-survival gene expression networks upregulated in senescence (either pharmacologically or using siRNA) killed senescent cells, but not their proliferating or quiescent, counterparts. In vivo this resulted in extended healthspan. Since the production costs of these first generation "senolytics" are low such treatments are likely to be cost-effective.

Crucially, the same mechanisms of cellular senescence cause both age-related diseases, and features of aging considered in the past to be "natural changes" (e.g., the accumulation of senescent cells in the skin contributes to wrinkling, a "natural change" and to cardiovascular disease, an "age-related disease"). If the distinction between aging and age-related disease is false then the practical consequences of maintaining that such a distinction exists could be severe.

The proposition that aging and disease are distinct is easy to grasp, coherent and compelling. But it is important to recognize that it is essentially just an exercise in logic resting upon the definition of "disease" as abnormal function. Thinking about aging and disease like this raises surprising conceptual barriers to intervention. To illustrate this, imagine a land (let us call it "Nofruit") where everyone has scurvy. Following this logic, in Nofruit scurvy is considered by the population to be a "natural condition". Thinking like this is, in itself, a disincentive to research. In Nofruit the line of thinking would go: Diseases have "magic bullets" or cures. Most authorities think scurvy is not a disease so it cannot, by definition, have a cure. Thus, most Nofruit scientists wouldn't even try to find a cure for scurvy even though orange juice represents about as cheap and effective a "magic bullet" as can be imagined. The "problem" of scurvy would be tacitly ignored, much the way the possibility of successful intervention in aging is tacitly ignored in the real world.

It is important to recognize that the Nofruit arguments do not require aging and age-related disease to share causal mechanisms. Both may cause harm in different ways. However, in actuality the mechanisms which cause aging and age-related disease really do overlap very substantially. Thus distinguishing between "aging" and "age-related disease" probably represents an artificial distinction; human understanding has drawn an arbitrary line on the complex phenotype which is later life. Maintaining an artificial aging-disease distinction give rise to a contradiction. What is the ethical rationale for treating entities classified as "diseases" caused by senescent cells (like cardiovascular disease) but not treating entities classified as "natural changes" (like wrinkles) which are also caused by senescent cells? As yet this problem does not seem to have been fully recognized by bioethicists, probably because the science on which it is based is so new that it has not yet been disseminated. The little which has been said on the topic however, offers gerontologists little reassurance that our work will be well received.

However, research into public attitudes to gerontological research in the UK indicated a desire among the participants for a long and active life rather than to serve as object lessons in deliverance from suffering. It has been suggested that the concerns shown about extended lifespans by some participants in the Pew Research survey may result from their belief that these would be associated with the kind of morbidity seen in aging Americans today. If so this reinforces the key message that healthspan is the outcome most desired by our populations. The most effective way to facilitate this would be to significantly increase the funding available for research into the fundamental biology of aging and facilitate the rapid translation of its discoveries into the clinical arena.

This popular science article looks at some of the present outcomes of heterochronic parabiosis research, in which the circulatory systems of two animals are linked, one older, one younger. This produces beneficial effects in the older animal, in particular a reactivation of stem cell populations and greater tissue maintenance. While some research groups are chasing down the molecular signals responsible, others are attempting to see if blood transfusions from young donors to old recipients could recapture any of the effect.

Personally I'm not optimistic with regard to the direct approach of transfusions based on the null results obtained from experiments in mice carried out to date. It is quite possible that the useful factors are very short-lived, or that the beneficial processes involved in heterochronic parabiosis require some interaction between old tissue and young tissue, and in either case straightforward transfusions of young blood are not going to be useful. Even when a method of recapturing parabiosis benefits is produced, as I'm sure it will be sooner or later, this still only partially addresses one of the causes of degenerative aging. Researchers still need to clear out metabolic waste, address mitochondrial damage, and so forth - the rest of the slate of SENS rejuvenation therapies are required.

On an August morning in 2008, Tony Wyss-Coray sat in a conference room at the Veterans Affairs hospital in Palo Alto, California, waiting for his lab's weekly meeting to begin. Saul Villeda, an ebullient PhD student with slick black hair and a goatee, had spent the past year engrossed in research that called to mind the speculative medical science of the middle ages. He was investigating whether the old and frail could be rejuvenated by infusions of blood from the young. Villeda had conducted pilot studies with pairs of surgically conjoined mice that shared a blood supply for several weeks. Young mice received blood from older mice, and old mice received blood from younger ones.

Villeda got three hours' sleep that night. The next morning, he stood up at the lab meeting and revealed to his colleagues what young blood did to the ageing brain. "There was a palpable electricity in the room," Wyss-Coray recalled. "I remember seeing the images for the first time and saying, 'Wow.'" Old mice that received young blood experienced a burst of brain cell growth in the hippocampus. They had three to four times as many newborn neurons as their counterparts. But that was not all: old blood had the opposite effect on the brains of young mice, stalling the birth of new neurons and leaving them looking old before their time.

Since that meeting seven years ago, research on this topic has moved on dramatically. It has led some to speculate that in young blood might lie an antidote to the ravages of old age. But the apparent rejuvenating properties of young blood must be treated with healthy scepticism. The hopes they raise rest solely on mouse studies. No beneficial effects have ever been proven in humans. Then again, no one has ever looked. That is about to change. In October 2014, Wyss-Coray launched the first human trial of young blood. At Stanford School of Medicine, infusions of blood plasma from young people are being given to older people with Alzheimer's disease. The results are expected at the end of the year. It is the greatest test yet for the medical potential of young blood.

Big questions lie ahead. Even if none of the patients benefit from young plasma, the research is far from finished. The plasma for the trial comes from donors under 30, and it may not be potent enough. The patients on the trial have dementia already, and may be too far gone to rescue. Earlier this year, John Hardy of University College London, who is the most cited Alzheimer's researcher in Britain, saw Wyss-Coray's latest data at a meeting in London. "It's really interesting work," he told me. "It's woken everybody up." Nonetheless, Hardy is cautious; he suspects that young plasma will be less effective in people than in mice, because people live so much longer, and in far more varied environments. But, he said: "I would guess this will still point us towards pathways involved in ageing more generally."

Link: http://www.theguardian.com/science/2015/aug/04/can-we-reverse-ageing-process-young-blood-older-people

The immune cells known as macrophages are involved in the regulation of regeneration, mostly in a beneficial sense, though here researchers identify an activity that suppresses excessive regeneration in muscle tissue. Sometimes excessive regeneration is exactly what is desired for medical purposes, however:

By removing the protein CD163 from mice, scientists have boosted muscle repair and recovery of blood flow after ischemic injury (damage caused by restriction of blood flow). The findings point to a target for potential treatments aimed at enhancing muscle regeneration. CD163 was known to scientists, mostly as a molecule involved in scavenging excess hemoglobin from the body, but its role in regulating muscle repair was not. Mice lacking CD163 showed increased blood flow and muscle repair, compared with controls, after an injury coming from a restriction of blood flow in one leg. Examining the mice lacking CD163, researchers were surprised to find that blood vessels and muscle fibers also grew substantially (roughly 10 percent) in their uninjured legs. "We were astonished. Why would something we did, which caused an injury to one leg, help tissue in the other leg regenerate when it wasn't injured in the first place?"

Potentially, researchers could try to achieve the effect of removing CD163 in humans by giving patients an antibody against CD163, but more research is needed to know how this might work. CD163 levels have been found to increase in aging humans in multiple studies. Macrophages, which are a type of white blood cell, appear to release a soluble form of CD163 in response to injury. In the blood, CD163 soaks up and counteracts another protein called TWEAK, which stimulates muscle cells to multiply. In CD163's absence, TWEAK can have a greater effect, and can apparently stimulate muscle growth distant from the site of injury. When infused into normal mice, TWEAK does not have any effect on muscle growth, possibly because of circulating CD163.

Scientists that study muscle cells have been interested in TWEAK for several years, but some studies have suggested that TWEAK negatively regulates muscle regeneration - the opposite of what this team observed. To prove that TWEAK was needed for the extra repair seen in mice lacking CD163, the researchers showed that if they injected an antibody against TWEAK, thus removing it from the blood, it eliminated the extra repair activity. "I think our results show a specific mechanism by which muscle regeneration takes place. TWEAK can be a pro-regenerative factor, but its effects have to be transient and limited."

Link: http://www.eurekalert.org/pub_releases/2015-08/ehs-hwb080315.php

Aubrey de Grey of the SENS Research Foundation is an advocate and scientist focused on advancing the state of rejuvenation research, progress towards therapies capable of repairing the cell and tissue damage that causes degenerative aging. He put forward the Strategies for Engineered Negligible Senescence (SENS) research proposals some fifteen years ago, and since then has raised funding, organized research programs, cofounded the Methuselah Foundation and SENS Research Foundation, and traveled the world to speak at scientific conferences and meetings of supporters.

Back when this all began, members of the scientific community were very reluctant to speak openly about treating aging as a medical condition, the press treated the prospect of therapies for aging as a joke, and the public at large gave no attention to the topic. Yet the potential was there, with many disparate branches of research into age-related diseases demonstrating even then that scientists understood more than enough to get started on meaningful therapies to repair the damage of aging. The problem has always been cultural: that no-one cares, that funding is non-existent, that few are willing to step up and speak out on the issue, that the status quo of suffering and disease is accepted. With the help of people like de Grey and his allies the last decade has seen a real sea change in the research community and the media, however, as well as in the actuarial and the futurist communities, and the years ahead will see that change in attitudes spread to the population at large. If we keep working at this by the mid 2020s I expect the average individual in the street to think of aging in the same way as he or she thinks of cancer today: a fearsome medical condition that causes great suffering, researchers need to work harder at fixing it, and charities raising funds for research are a worthy cause.

Over at the Reddit /r/futurology community today de Grey was answering questions in an AMA (Ask Me Anything) event. It is worth remembering that every Reddit community of any size is a collection of widely divergent interests. Thus /r/futurology is a mix of folk who follow progress in computing technology, basic income advocates, popular science buffs, futurists of all stripes, both for and against longevity enhancement, and various other less categorizable groups. So the forum can host a respectful AMA for de Grey packed by people who look forward to progress in rejuvenation research just a day after a long discussion on a recent aging research paper in which most of those involved were opposed to human life extension. It is a big world, communication is making it smaller, and we're all rubbing shoulders these days.

Ask Aubrey de Grey anything!

Buck-Nasty: I'm curious about how the advent of CRISPR affects the development of SENS therapies?

Aubrey de Grey: It's huge. It will be central to the delivery of the many SENS components that involve somatic gene therapy.

Buck-Nasty: Does it speed up the development timeline at all?

Aubrey de Grey: A lot, yes.

Jay27: Kind of a shame, because it looks to me like deep learning algorithms will be plowing their way through a million genomes in 2020. You'd think they'd yield some valuable genemod insights which can then be applied with CRISPR.

Aubrey de Grey: We don't need insights right now - we need implementation of what we already know or are developing. That's why CRISPR is so important.

Senf71: Is it fair for me to be telling my friends and others I tell about this stuff, that considering the $25 a month I donate to SENS and the many dozens of people I have educated about SENS and curing aging in general, many quiet successfully educated, that I may have personally saved the lives of 100,000 people at this point? Along that line is this something it would be good for you and your people to really emphasize during talks? To tell people that they can feel good about them selves for going out and advocating and donating even a meager amount of money because doing so means they are very truthfully saving the lives or 10s or 100s of thousands of people?

Aubrey de Grey: This is by far the best question yet on this AMA. Thank you! First: I think you can say something like that (depending on how long it's been that you've been sending us $25). I believe that $1 billion right now would hasten the achievement of LEV by about 10 years; you can do the rest of the maths, but it comes out to about $2 per life - and of course "saving" means a great deal more in terms of extra years than it does for other ways of saving lives, so arguably it's more like a few cents per life. And yes, I think I should emphasise this more. I probably will.

Spats_Mgee: Several aspects of your SENS proposal are essentially destructive in nature (removing intra/extracellular junk, killing errant cells, etc). Your proposal to deal with these problems involves utilizing enzymes found in other species to break down these molecular structures. I'm curious if you've weighed the pros and cons of this (let's say "organic") approach to the "inorganic" approach of using gold nanoparticles for targeted photothermal ablation of these cellular/molecular structures.

Aubrey de Grey: We've looked at this approach and we haven't rejected it out of hand. A big issue is penetration: how does one irradiate deep within the body?

Lavio00: I watched a video from you back in 2013 where you commented the announcement from Larry Page about Calico. You mentioned that Calico - if they're focused on early stage research - might highly benefit the battle against aging. What is your comment regarding Calico's research now that a couple of years have passed? More/less excited about their potential?

Aubrey de Grey: Cautious. They are structured perfectly: they are doing a bunch of highly lucrative irrelevant short-term stuff that lets them get on with unlucrative critical long-term stuff without distraction. But the latter may be getting too curiosity-driven and insufficiently translational. We'll see. Here "highly lucrative irrelevant stuff" = drugs for specific diseases of aging, "unlucrative critical stuff" = work leading to actual longevity escape velocity.

SirT6: One thing that has always struck me about your vision for extending human lifespan is that you don't seem particularly interested in attempting to leverage the molecular genetics of aging. Numerous animal studies have implicated a number of genes which may serve as pharmacological targets for ameliorating aging and age-related pathologies. Studies of human centenarians have also validated the idea that modulation of these genes or their protein products may be a viable option for extending lifespan. And from an evolutionary perspective, this seems to make sense - many genes exhibit antagonistic pleiotropy (good when young, bad when old), so inhibiting these genes/proteins as people age is likely to reduce the burden of age-related disease. I suppose you could argue that this won't drastically increase human lifespan, but it seems to be a far more tractable approach in the near term (clear molecular targets, easier biomarkers, simplified drug development etc.). I would be curious to hear your thoughts on the issue. Thanks!

Aubrey de Grey: You put your finger on it - tractability versus magnitude of effect. As I think you know, I subscribe to the school of thought that CR-mimicking genetic or pharmacological manipulations cannot to much in long-lived species. I don't want to suppress such research, but I do think that the field has been immensely harmed over the past 20 years by overoptimism concerning the CR-mimicking approach and consequent lack of interest in alternatives. Antagonistic pleiotropy has very little to do with this.

akerenyi: I believe that the distinction you make between SENS-type of research focusing on damage from ageing and research on age-related diseases (ARDs) is purely arbitrary and misleading. For example you correctly claim that ageing and ARDs are pretty much the same thing, but than go on the criticize research on ARDs for not focusing on the right thing, while even further you plan to use therapeutics coming from this research, like Alzheimer's vaccines for rejuvenation (correctly so). I think the reality is that research on ARDs does involve more basic, mechanistic work as well as more later-stage, symptomatic approaches, compared to your engineering approach. However, I think the former gave and will give the targets for SENS, like beta-amyloid or tau, while the latter gave us drugs like levadopa, which while being crude and non-definitive, did improve the quality of life of millions of patients, while stem-cell therapy or gene therapy is being developed. Please clarify whether you still think such a distinction is desirable or meaningful.

Aubrey de Grey: The issue is relative funding. Illustration: it is absolutely accepted that atherosclerosis, the #1 killer in the western world, starts with the inactivation of macrophage lysosomes by oxidised cholesterol. Yet, about two labs in the world are focused on that step. I'm very satisfied indeed with the amyloid-beta vaccine results - they eliminate plaques. Same with gene therapy.

jimofoz: Can you give us any updates on the research towards allotopically expressing all 13 protein coding mitochondrial DNA genes?

Aubrey de Grey: It's going really well. We've made big breakthroughs this year and we'll be publishing something soon.

jimofoz: How pleased are you that Gensight is now taking the allotopic mtDNA expression technology whose development SENS partially funded into stage III clinical trials?

Aubrey de Grey: Overjoyed. We funded the Corral-Debrinski lab early on. Our work is leaning heavily on their early discoveries.

Rdapt85: I haven't heard any development in GlycoSENS since the discovery of synthesizing glucosepane in the lab 2 years ago. How is it going?

Aubrey de Grey: It's tough as hell but yes, we are plugging away. Watch this space.

Antagonistic pleiotropy is a term used to describe the results of a trait or mechanism that is beneficial in youth but then causes harm in later life. Evolutionary processes appear to select such traits due to their impact on early reproductive success, and that is one of the reasons why we age. Here, researchers illustrate this point while investigating one of the many roles played by free radicals in mammalian tissues:

When scientists bred mice that produced excess free radicals that damaged the mitochondria in their skin, they expected to see accelerated aging across the mouse lifespan - additional proof of the free radical theory of aging. Instead, they saw a surprising benefit in young animals: accelerated wound healing due to increased epidermal differentiation and re-epithelialization. Free radicals are especially reactive atoms or groups of atoms that have one or more unpaired electrons. They are produced in the body as a by-product of normal metabolism and can also be introduced from an outside source, such as tobacco smoke, or other toxins. Free radicals can damage cells, proteins and DNA by altering their chemical structure. Excessive amounts of free radicals are known to cause cellular damage that leads to aging, but in some mouse models and human studies lowering free radicals with antioxidants have not always conferred the expected benefits.

While increased free radical production showed benefit in younger animals, the mice paid a price over time. Mitochondrial damage from excess free radicals caused some of the skin cells to go into senescence - they stopped dividing and started accumulating. Over time the energy available to the epidermal stem cells was depleted - the stem cells simply became too scarce and the mice showed expected signs of aging, thin skin and poor wound healing. "In this case, we found unexpected pleotropic effects, mechanisms that benefit us when we're young cause problems as we age." Mitochondrial stress caused by the increase in free radicals also forced the skin cells in the younger animals to differentiate faster than normal, further depleting the pool of stem cells available to renew the skin over time. "This is not a simple process. It may be that nature used free radicals to optimize skin health, but because this process is not deleterious to the organism until later in life, past its reproductive age, there was no need to evolve ways to alter this mechanism." There could be one practical implication of the study: taking large amounts of anti-oxidants might have deleterious effects, at least in the skin.

Link: http://www.buckinstitute.org/buck-news/surprising-results-study-mitochondrial-dysfunction-skin-casts-light-free-radical-theory

The amyloid associated with Alzheimer's disease builds up with age, and much more so in people eventually diagnosed with Alzheimer's. Many lines of evidence indicate that the underlying problem is one of slowly failing clearance of amyloid proteins: various systems and mechanisms falter with age due the accumulation of cell and tissue damage. Until amyloid proteins gather in large enough numbers to form lasting clumps, their presence are fairly dynamic, created and cleared on a timescale of hours. Researchers here provide direct evidence of slower clearance rates in older people:

The greatest risk factor for Alzheimer's disease is advancing age. After 65, the risk doubles every five years, and 40 percent or more of people 85 and older are estimated to be living with the devastating condition. Researchers have identified some of the key changes in the aging brain that lead to the increased risk. The changes center on amyloid beta 42, a main ingredient of Alzheimer's brain plaques. The protein, a natural byproduct of brain activity, normally is cleared from the brain before it can clump together into plaques. Scientists long have suspected it is a primary driver of the disease. "We found that people in their 30s typically take about four hours to clear half the amyloid beta 42 from the brain. In this new study, we show that at over 80 years old, it takes more than 10 hours." The slowdown in clearance results in rising levels of amyloid beta 42 in the brain. Higher levels of the protein increase the chances that it will clump together to form Alzheimer's plaques.

For the study, the researchers tested 100 volunteers ages 60 to 87. Half had clinical signs of Alzheimer's disease, such as memory problems. Plaques had begun to form in the brains of 62 participants. The subjects were given detailed mental and physical evaluations, including brain scans to check for the presence of plaques. The researchers also studied participants' cerebrospinal fluids using a technology known as stable isotope-linked kinetics (SILK), which allowed the researchers to monitor the body's production and clearance of amyloid beta 42 and other proteins.

In patients with evidence of plaques, the researchers observed that amyloid beta 42 appears to be more likely to drop out of the fluid that bathes the brain and clump together into plaques. Reduced clearance rates of amyloid beta 42, such as those seen in older participants, were associated with clinical symptoms of Alzheimer's disease, such as memory loss, dementia and personality changes. Scientists believe the brain disposes of amyloid beta in four ways: by moving it into the spine, pushing it across the blood-brain barrier, breaking it down or absorbing it with other proteins, or depositing it into plaques. "Through additional studies like this, we're hoping to identify which of the first three channels for amyloid beta disposal are slowing down as the brain ages. That may help us in our efforts to develop new treatments."

Link: https://news.wustl.edu/news/Pages/Brains-ability-to-dispose-of-key-Alzheimers-protein-drops-dramatically-with-age.aspx

Researchers here argue for decreased cell spreading in old skin to be a cause of higher levels of mitochondrial DNA deletions in longer-lived skin cells. Their methodology leaves open the possibility of other possible causes for the data they have gathered, however. I don't believe that they have convincingly demonstrated causality at this point. Nonetheless worth reading, I think.

Why is this interesting? Because mitochondrial DNA damage is strongly implicated as a contributing cause of degenerative aging, but there is considerable debate over how and why this damage occurs and accumulates with age. The SENS rejuvenation research viewpoint is to skip the debate over causes and just repair the damage and measure the benefits that result, but this is not a popular viewpoint in the scientific community, where most participants are aiming for complete understanding at some indefinite future date rather than the production of useful therapies as soon as possible. So we are going to see much more research in the future exploring this aspect of biochemistry.

Mitochondria are the power plants of the cell, each cell containing a swarm of hundreds of these descendants of symbiotic bacteria, each of which contains at least one copy of the remnant DNA left over from that of their ancestors. Evolution has moved much of this DNA to the cell nucleus, or it has atrophied, leaving just a small number of genes that are passed from mother to child. Mitochondrial populations are very dynamic, constantly dividing and fusing, passing chunks of protein machinery between one another, and culled by cell quality control mechanisms when damaged. Damage occurs to cellular machinery all the time, and near all of it is repaired. Mitochondrial DNA (mtDNA) deletions can be a real problem, however: DNA encodes for the proteins needed for correct function, and there is a way in which a mitochondrion with just the right type of damage can fall into a malfunctioning state that provides it an advantage in replication and resistance to quality control. When that happens the whole cell is quickly taken over by the descendants of that dysfunctional mitochondrion. The cell itself becomes broken, exporting harmful reactive molecules into surrounding tissues. A small but influential population of cells are in this state by the time old age rolls around, and they cause significant harm.

Why does this DNA damage happen? Some researchers believe it is due to the proximity of mitochondrial DNA to the energetic processes by which mitochondria produce chemical energy stores, coupled with comparatively poor DNA repair processes available in the mitochondria. Other researchers consider that the damage happens during mitochondrial replication, and other changes taking place in cells over the course of aging might explain a rising level of errors that occur during this replication. There are other theories - in biochemistry there are always other theories - and the one described in the following open access paper is one such.

Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging

In human skin, dermal fibroblasts are responsible for collagen homeostasis. Consequently, impaired dermal fibroblast function is a major contributing factor in human skin connective tissue aging. We previously reported that a prominent characteristic of dermal fibroblasts in aged skin is reduced spreading and contact with collagen fibrils, causing cells to lose their typical elongated spindle-like morphology and become shorter with a rounded and collapsed morphology. In young healthy skin, dermal fibroblasts attach to intact collagen fibrils and achieve normal cell spreading and shape. However, in aged dermis the collagen fibrils are fragmented, which impairs fibroblast-collagen interactions. These alterations impair fibroblast spreading and function. While cell shape is known to regulate many cellular functions, the molecular basis of their impact on dermal fibroblast function and skin connective tissue aging are not well understood.

Although dermal fibroblasts are the major cell type responsible for the maintenance of dermal connective tissue homeostasis, little is known about the role of mtDNA common deletion in aging dermal fibroblasts. Dermal fibroblasts have a very low proliferative rate which would allow for an accumulation of mtDNA deletion. Additionally, the relationship between age-related reduced cell spreading, which is a prominent feature of aged dermal fibroblasts, and mtDNA common deletion has been virtually unexplored. Based on this information, we explored the possible connection between age-related reduced cell spreading and mtDNA common deletion in the dermis of human skin. We found that mtDNA common deletion is significantly increased in both naturally aged and photoaged human skin dermis in vivo, and that reduced fibroblast spreading induces the increase in mtDNA common deletion through increased endogenous reactive oxygen species (ROS).

We modulated the shape of dermal fibroblasts by disrupting the actin cytoskeleton with latrunculin-A (Lat-A), which rapidly blocks actin polymerization. As expected, disruption of the actin cytoskeleton impaired fibroblast spreading and resulted in a rounded shape. Reduced cell spreading was associated with a significant elevation of mtDNA common deletion. As mitochondrial morphology is crucial for normal mitochondrial function, we assessed mitochondrial morphology. These data indicated that the gross shape of mitochondria was similar between Lat-A treated cells and control cells. It has been reported that cellular damage from reactive oxygen species (ROS) likely plays an important role in mtDNA deletions as well as in the aging process. We therefore examined the relative oxidant levels in fibroblasts using redox-sensitive fluorescent dye. Normal well-spreading fibroblasts displayed a very low level of oxidant-generated fluorescence. In contrast, reduced-spreading fibroblasts displayed intense oxidant-generated fluorescence.

We next investigated whether boosting cellular antioxidant capacity could protect against mtDNA common deletion associated with reduced cell spreading. We chose N-acetyl-cysteine (NAC), which is an antioxidant and metabolic precursor of glutathione. Reduced cell spreading increased mtDNA common deletion in a time-dependent manner, and that the increase was significantly prevented by NAC treatment. These results indicate that the deleterious effects of endogenous oxidative exposure are responsible, at least in part, for reduced-cell-spreading-associated mtDNA common deletion.

I have to think that the conclusion to be drawn here is that messing with the cell cytoskeleton is a bad thing, not that lack of cell spreading is a bad thing (though it probably is, just not demonstrated to be via this methodology). An item that immediately springs to mind is that progeria involves disruption of cytoskeletal structure in cells, and I'm sure people with more experience than I could come up with other off the cuff examples of cytoskeleton dysfunction producing cellular dysfunction. So here I'd want to see a replication of the mitochondrial DNA deletion data using another completely distinct methodology of preventing cell spreading before giving this too much consideration. It is easy to break things in biochemistry and produce results that look somewhat like aging, since breakage causes damage, and aging is an accumulation of damage. It is, however, hard to prove that any given artificial breakage is relevant to normal aging, and most are not.

To finish up for today I'll again make the point that the research community could skip this painstaking investigative work in order to focus on producing methods of repairing mitochondrial DNA damage, or delivering the proteins via another method, such as the allotopic expression technology funded by the SENS Research Foundation and presently under active development by Gensight. Fix the damage and see what happens, and if the repair is good enough and frequent enough then it doesn't matter how the problem occurs. Then, with the luxury of time, back to the labs to figure out every last detail of what happens if you don't take the treatments. The present status quo seems back to front, given that we're all aging to death.

Researchers here outline recent discoveries relating to changes in the endoplasmic reticulum inside cells that occur over the course of aging. All cellular machinery falters with age due to accumulating damage, and the primary goal of the research community remains to catalog and fully understand these changes, with doing something about coming it a distant second where it is a focus at all. The endoplasmic reticulum is the site of protein synthesis, and since all cellular machinery is built out of proteins, it is not unreasonable to look for links between changes in the endoplasmic reticulum - and its many component parts - and the disruption of proteostasis in aging. In older tissues there are many more broken and misfolded proteins, and this may turn out to have as much to do with issues in production as with issues in quality control and damage repair.

Each cell consists of different compartments. One of them is the endoplasmic reticulum (ER). Here, proteins which are then secreted e.g. into the bloodstream, such as insulin or antibodies of the immune system, mature in an oxidative environment. A type of quality control, so-called redox homoeostasis, ensures that the oxidative milieu is maintained and disulphide bridges can form. Disulphide bridges form and stabilise the three-dimensional protein structure and are thus essential for a correct function of the secretory proteins, e.g. those migrating into the blood. Researchers have now shown that the ER loses its oxidative power in advanced age, which shifts the reducing/oxidising equilibrium - redox for short - in this compartment. This leads to a decline in the capacity to form the disulphide bridges that are so important for correct protein folding. As a consequence, many proteins can no longer mature properly and become unstable.

Although, it was already known that increased protein misfolding occurs with the progression of ageing, it was not known whether the redox equilibrium is affected. Likewise, it was not known that the loss of oxidative power in the ER also affects the equilibrium in another compartment of the cell: in reverse, namely, the otherwise protein-reducing cytosol becomes more oxidising during ageing, which leads to the known oxidative protein damage such those caused by the release of free radicals. "Up to now, it has been completely unclear what happens in the endoplasmic reticulum during the ageing process. We have now succeeded in answering this question." At the same time, the scientists were able to show that there is a strong correlation between protein homoeostasis and redox equilibrium. "This is absolutely new and helps us to understand why secretory proteins become unstable and lose their function in advanced age and after stress. This may explain why the immune response declines as we get older. We gained a lot of insight, but have also learned that ageing is much more complex than previously assumed." Thus, for example, the mechanism of the signal transduction of protein folding stress to the redox equilibrium - both within the cell from one compartment to another and also between two different tissues - remains completely unclear.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=155133&CultureCode=en

Entirely artificial medical nanorobots will one day exist to augment or greatly improve on functions presently carried out by cellular machinery. Long before then, however, we will see the widespread use of modified cells and bacteria, altered to form programmable tools such as drug manufactories that travel to where they are needed and take the appropriate actions in response to local circumstances.

A successful microbial diagnostic or therapeutic agent must to able to detect a particular signal with high fidelity, integrate this signal through precise intracellular circuitry, and respond to this signal at the appropriate level. Researchers have recently described genetic tools that allow the commensal bacterial species B. thetaiotaomicron to efficiently perform all three of these functions. Notably, they show that circuits integrating signal detection, genetic memory, and CRISPR interefence function as expected when engineered B. thetaiotaomicron is introduced into the gut microbiome of mice.

In the future, one can imagine the use of these mechanisms to tightly regulate the expression of different genes in a biosynthetic gene cluster for a small molecule therapeutic (e.g., an antibiotic), engineered in a microbiome-derived Bacteroides strain. The in vivo expression of this gene cluster could be controlled by the level of a carbohydrate administered in the diet, or preferably, by a specific small molecule produced by the target pathogen itself. Decoupling of the synthesis and secretion of the small molecule (e.g., to reach an effective local therapeutic dose) can be achieved by putting the export machinery under the control of an inducible circuit that responds only to high intracellular levels of the small molecule, or by engineering a time delay between the synthesis and secretion of the molecule. Once the therapeutic effect has been achieved (e.g., the elimination of a pathogen), CRISPR interference can be used to knock down residual expression of the therapeutic genes or to eliminate the chassis itself by targeting an essential gene. This final step could be triggered by a second signal administered in diet, or by the absence of the pathogen-derived small molecule. This entire series of events could be recorded on memory switches and read through analysis of the Bacteroides genome in host feces, providing timely snapshots of what is happening in vivo.

Although it is still early days for its approval, using engineered commensal microbes to produce therapeutic molecules may be preferred over using oral or systemic drugs for several reasons. First, commensals naturally occupy specific niches in the gastrointestinal tract, allowing drug delivery to a very defined site. Subsequently, the dosage needed to obtain a local therapeutic effect would be much lower than needed if orally administered, and many adverse effects could in turn be eliminated. Second, because the production of a therapeutic molecule can be precisely controlled in engineered bacteria, long-term control of diseases can be achieved using a single organism that produces the drug only when needed. Last, using an engineered bacterium to produce and deliver one or more therapeutic molecules could provide an economical alternative to the costly production, formulation, distribution, and storage of drugs. This is even more applicable in the cases where a drug is specially formulated or administered via intramuscular or subcutaneous injection to avoid degradation in the stomach.

Link: http://dx.doi.org/10.1016/j.cels.2015.07.003