Insight into the Machinations of Classifying Aging as a Disease
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The open access paper quoted here provides some insight into present attempts to change the regulatory classification of aging in the lab and the clinic: the prospect for meaningful progress in the science is real, but regulation is holding things back, which is why so many articles have appeared of late on whether or not aging is a disease.

The bureaucracy of what is and is not officially a disease is baroque and slow-moving, a many-faceted entity with areas of different importance depending on whether clinical medicine or research or translation or funding is being considered. There is considerable interest at the present time in doing something about that fact that aging is generally not accepted to be a treatable medical condition in most parts of the system that matter, which is to say those relating to the flow of money into early stage and translational research. That flow of money is tiny at this time; there is very little support for developing any of the clear paths towards treating aging as a medical condition, and this has a lot to do with regulatory barriers. If it is illegal to treat aging, none of the big for-profit concerns are going to go all in on building potential therapies, for example.

Aging is a complex continuous multifactorial process leading to loss of function and crystalizing into the many age-related diseases. Here, we explore the arguments for classifying aging as a disease in the context of the upcoming World Health Organization's (WHO)'s 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11), expected to be finalized in 2018. We hypothesize that classifying aging as a disease will result in new approaches and business models for addressing aging as a treatable condition, which will lead to both economic and healthcare benefits for all stakeholders. Classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. We propose forming a Task Force to interface the WHO in order to develop a multidisciplinary framework for classifying aging as a disease

The recognition of a condition or a chronic process as a disease is an important milestone for the pharmaceutical industry, academic community, healthcare and insurance companies, policy makers,and individual, as the presence of a condition in disease nomenclature and classification greatly impacts the way it is treated, researched and reimbursed. However, achieving a satisfactory definition of disease is challenging, primarily due to the vague definitions of the state of health and disease.

Despite the growing abundance of biomarkers of aging, classifying aging as a disease will be challenging due to the absence of the "ideal norm." Despite significant effort from the academic and industry communities, sarcopenia is still not classified as a disease despite clear clinical and molecular representation and similarity with premature musculoskeletal aging and myotonic disorders. One approach to address this challenge is to assume an "ideal" disease-free physiological state at a certain age, for example, 25 years of age, and develop a set of interventions to keep the patients as close to that state as possible. Considering the WHO definition of health, it may be possible to agree on the optimal set of biomarkers that would be characteristic to the "state of complete physical, mental and social well-being, not merely the absence of infirmity" and agree on the physiological threshold after which the net totality of deviation of these biomarkers from norm can be considered a disease.

Link: http://dx.doi.org/10.1101/024877

Dietary Glycemia Correlates with Visual Health in Aging
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Researchers here note a correlation between glycemic index, a measure of the impact of carbohydrate content of food on blood glucose, and risk of suffering age-related blindness. Given the comparatively large influence of calorie intake over all aspects of health and metabolism, and the composition of the typical modern diet, I think one has to consider the usual suspects of total overall calories consumed, visceral fat, and chronic inflammation before moving on to look at things like the contribution of diet to cross-links in the eye or lipofuscin formation in the retina.

Extending healthful life is a millennia-old dream and objective. During the intervening centuries a multitude of concoctions and remedies have been offered, usually with few substantiated results. During the last century it was demonstrated that limiting caloric intake is associated with extended life in many mammals, albeit results remain to be clarified in humans. A myriad of modeling studies have revealed signaling pathways that are associated with life extension and the last two decades have seen an interest in the types of dietary carbohydrates that might confer health advantage, and possibly longevity.

Loss of vision due to age-related cataracts or age-related macular degeneration is widely prevalent, affecting about 85% and 15% of the elderly respectively. With centenarians among the fastest growing segments of societies, and with loss of vision a very costly personal and societal burden, there is keen interest in extending vision - that is, delaying age-related macular degeneration and cataract - or diminishing risk for these debilities. Using extensive epidemiologic and nutritional information from the Nurses' Health Study and Age-Related Eye Disease Study (AREDS) we determined that measures of total carbohydrate, and even more so, glycemic index (GI), are associated with visual health. We also modeled this relationship in mice in order to elucidate etiologic relationships between dietary glycemia, visual health, and genetics.

Link: http://dx.doi.org/10.1016/j.mam.2015.08.005

October 1st is International Longevity Day: Events are Planned
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October 1st is the UN International Day of Older Persons, but our community would like it to also be Longevity Day, a time to remind the world that research into human rejuvenation is practical, that near-future therapies are plausible, and that all of this will move much faster with greater funding and support. This year, as last, grassroots advocates will hold events around the globe, many of which are coordinated through the International Longevity Alliance and related groups.

October 1st is also the launch date for this year's Fight Aging! matching fundraiser in support of the rejuvenation biotechnology programs coordinated by the SENS Research Foundation. This is a chance for all of us to do our part to help speed things along; the progress you see today in SENS technologies relevant to treating aging as a medical condition came about as the result of similar fundraising in past years. The matching fund for 2015 weighs in $125,000, and we'll be seeking to raise that much again, matching every $1 donated with $1 from the fund. This is a stretch goal for our community, and all offers of assistance in preparation and fundraising are greatly appreciated.

If you are interested in holding an event this year to mark Longevity Day, then contact the International Longevity Alliance: there is a month left in which to organize, and the Alliance has plenty of helpful materials and references. With regards to the Fight Aging! fundraiser, there are message posters that we'd love to see more widely distributed. Pass them around, show them off, or - even better - improve on them and share the results.

International Longevity Day - October 1, 2015

There has been emerging a tradition by longevity researchers and activists around the world to organize events dedicated to promotion of longevity research on or around October 1 - the UN International Day of Older Persons. This day is sometimes referred to in some parts of the longevity activists community as the "International Longevity Day". As this is the official UN Day of Older Persons, this provides the longevity research activists a perfect opportunity, perhaps even a perfect excuse, to emphasize the importance of aging and longevity research for the development of effective health care for the elderly, in the wide public as well as among decision makers.

Let us maintain and strengthen this tradition! Let us plan and organize a mutually reinforcing network of events worldwide. If you plan to organize an event for that day - either live meetings or on-line publications and promotions - please let us know. Together we can create an activism wave of strong impact.

The critical importance and the critical need to promote biological research of aging derives from the realization that tackling the degenerative processes and negative biological effects of human aging, at once and in an interrelated manner, can provide the best foundations to find holistic and effective ways for intervention and prevention against age-related ill health. Such an approach has been supported by scientific proofs of concept, involving the increase in healthy lifespan in animal models and the emerging technological capabilities to intervene into fundamental aging processes.

The focus on intervention into degenerative aging processes can provide solutions to a number of non-communicable, age-related diseases (such as cancer, heart disease, type 2 diabetes and neurodegenerative diseases), insofar as such diseases are strongly determined by degenerative aging processes (such as chronic inflammation, cross-linkage of macromolecules, somatic mutations, loss of stem cell populations, and others). This approach is likely to decrease susceptibility of the elderly also to communicable, infectious diseases due to improvements in immunity. The innovative, applied results of such research and development will lead to sustainable, economically viable solutions for a large array of age-related medical and social challenges, that may be globally applicable. Furthermore, such research and development should be supported on ethical grounds, to provide equal health care chances for the elderly as for the young.

Therefore it is the societal duty, especially of the professionals in biology, medicine, health care, economy and socio-political organizations, to strongly recommend greater investments, incentives and institutional support for the research and development dealing with the understanding of mechanisms associated with the human biological aging process and translating these insights into safe, affordable and universally available applied technologies and treatments. October 1 - the International Day of Older Persons - provides the researchers and advocates an opportunity to raise these points and make these demands.

The Critical Need to Promote Research of Aging Around the World

Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

The Tasks of Longevity Promotion: Science, Ethics and Public Policy - Potential presentation topics on longevity research

The task of healthy life extension, or healthy longevity extension, dictates a broad variety of questions and tasks, relating to science and technology, individual and communal ethics, and finally public policy, especially health and research policy. Despite the wide variety, the related questions may be classified into 3 groups.

The first group of questions concerns the feasibility of the accomplishment of life extension. Is it theoretically and technologically possible? What are our grounds for optimism? What are the means to ensure that the life extension will be healthy life extension?

The second group concerns the desirability of the accomplishment of life extension for the individual and the society, provided it will become some day possible through scientific intervention. How will then life extension affect the perception of personhood? How will it affect the availability of resources for the population?

Yet, the third and final group can be termed normative. What actions should we take? Assuming that life extension is scientifically possible and socially desirable, and that its implications are either demonstrably positive or, in case of a negative forecast, they are amenable - what practical implications should these determinations have for public policy, in particular health policy and research policy, in a democratic society? Should we pursue the goal of life extension? If yes, then how? How can we make it an individual and social priority?

Given the rapid population aging and the increasing incidence and burden of age-related diseases, on the pessimistic side, and the rapid development of medical technologies, on the optimistic side, these become vital questions of social responsibility.

A Study Shows Older People are Now Smarter but Less Fit
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Trends in technology and increasing wealth improve health due to greater access to better forms of medicine, but also tend to produce a fatter, less fit older population, a consequence of the broadening range of attractive and affordable transportation devices and calories. Gains from medicine compete in many people with the losses due to diminished personal fitness. This is very noticeable in countries like South Korea where the transition from poverty to wealth was rapid, taking place over just a handful of decades. Here researchers show similar trends in European populations:

People over age 50 are scoring increasingly better on tests of cognitive function, according to a new study. At the same time, however, the study showed that average physical health of the older population has declined. The study relied on representative survey data from Germany which measured cognitive processing speed, physical fitness, and mental health in 2006 and again in 2012. It found that cognitive test scores increased significantly within the 6-year period (for men and women and at all ages from 50 to 90 years), while physical functioning and mental health declined, especially for low-educated men aged 50-64. The survey data was representative of the non-institutionalized German population, mentally and physically able to participate in the tests.

Previous studies have found elderly people to be in increasingly good health - "younger" in many ways than previous generations at the same chronological age - with physical and cognitive measures all showing improvement over time. The new study is the first to show divergent trends over time between cognitive and physical function. "We think that these divergent results can be explained by changing lifestyles. Life has become cognitively more demanding, with increasing use of communication and information technology also by older people, and people working longer in intellectually demanding jobs. At the same time, we are seeing a decline in physical activity and rising levels of obesity."

A second study found similar results suggesting that older people have become smarter also in England. "On average, test scores of people aged 50+ today correspond to test scores from people 4-8 years younger and tested 6 years earlier." The studies both provide confirmation of the "Flynn effect" - a trend in rising performance in standard IQ tests from generation to generation. The studies show that changes in education levels in the population can explain part, but not all of the effect. "We show for the first time that although compositional changes of the older population in terms of education partly explain the Flynn effect, the increasing use of modern technology such as computers and mobile phones in the first decade of the 2000s also contributes considerably to its explanation."

Link: http://www.iiasa.ac.at/web/home/about/news/150831-pop-PLOSONE.html

Chimeric Antigen Receptor T-cells versus Solid Tumors
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The future of cancer research is targeting, meaning the ability to destroy cancer cells efficiently and with few to no side-effects on normal tissues. Chimeric antigen receptor (CAR) T-cells are a step forward in this regard, and have proven to be an effective treatment for leukemia in trials. Researchers are now attempting to adapt their use to other types of cancer. In this example, the T-cells are engineered to make them more discriminating when targeted at solid tumors:

Many solid cancers have high levels of certain proteins such as ErbB2 and EGFR, which make them suitable targets for anticancer therapies. However, such proteins are also present at low levels in normal cells. Because of this, CAR T cells that are developed to target one of these proteins on tumor cells also recognize and attack normal cells that have the protein, causing severe toxicity.

To develop CAR T cells that can distinguish between cancer and normal cells, researchers first constructed a panel of CARs with the single chain variable fragments (scFv) - the part of the CAR T cell that recognizes the tumor target - using sequences from mutated 4D5 antibodies that had varying affinities to ErbB2, a protein present at high levels in some solid tumors, including breast cancer. Next, they incorporated different scFvs into the CAR backbone or "construct," such that they resulted in a range of CAR T cells - from those that had high affinity to ErbB2 to those that had low affinity to ErbB2. The newly engineered CAR T cells varied in their affinity to ErbB2 by three orders of magnitude. The researchers then conducted a series of experiments to test the functionality of the affinity-tuned CAR T cells and found that high-affinity CAR T cells did not discriminate tumor cells from normal cells and attacked all of them, whereas low-affinity CAR T cells were sensitive to tumor cells that had high levels of ErbB2 and not to normal cells that had low levels of the protein.

Next, they tested the engineered CAR T cells in mice that bore human cells with high levels of ErbB2 on one side of their bodies and human cells with normal levels of ErbB2 on the other side of their bodies. Here again, low-affinity CAR T cells selectively eliminated cells that had high levels of ErbB2 but had no effect on cells that had normal levels of the protein. In order to prove that this technology can be extended to other solid tumor targets, the researchers developed low-affinity CAR T cells targeting EGFR, a protein present in high levels in some lung and colon cancers, among others, and preliminary preclinical results showed that these CAR T cells were able to discriminate between cancer cells and normal cells.

Link: http://www.eurekalert.org/pub_releases/2015-09/aafc-nec082815.php

Lifespan.io Officially Launches, Crowdfunding the Development of a Cure for Aging
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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.

Rejuvenation Biotechnology 2015 Wraps Up on a High Note
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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

Regular Stem Cell Transplants Extend Life in Normal Rats
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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

A Few Recent Papers on Alzheimer's Disease
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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.
A Recent Interview with Aubrey de Grey of the SENS Research Foundation
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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

Theorizing on Gene Network Stability and Aging
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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

More Life, Less Severe Illness, but More Years of Illness
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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.

Towards Cell Therapy as a Replacement for Liver Transplant
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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

Fatty Acids Correlate with Longevity in Bird Species
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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

An Audio Interview with Aubrey de Grey and Brian Kennedy
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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.