Fight Aging! Newsletter, October 9th 2017

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

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  • MouseAge Crowdfunding Project Gains a Matching Fund: Donations are Doubled
  • Considering Autophagy in the Context of Stem Cell Aging
  • Can Aging be Slowed by Shutting Off the Inflammatory Signaling of Senescent Cells?
  • Towards the Recognition of Aging as a Treatable Medical Condition
  • More Evidence for Hippo Pathway Blockade to be a Road to Enhanced Regeneration
  • TRF1 Gene Therapy Improves Health Span in Mice
  • Macrophages Promote Muscle Regeneration via Secretion of ADAMTS1
  • A Gene Therapy Restores Some Degree of Vision in Mice with Retinal Degeneration
  • Genetic Interaction with Temperature in Nematode Longevity
  • Delivery of Extracellular Vesicles for Regenerative Therapy in Bone Tissue
  • A Slowly Spreading Realization that Radical Change in Human Longevity Lies Ahead
  • An Interview with Greg Fahy on Thymus Rejuvenation
  • Crowdfunding a Portuguese Translation of Ending Aging
  • Using Historical Basketball Player Records to Investigate Height and Longevity
  • Excess Visceral Fat Tissue Raises Cancer Risk

MouseAge Crowdfunding Project Gains a Matching Fund: Donations are Doubled

Longevity Month is upon us once more, and this year it finds that the MouseAge crowfunding project has been running for a few weeks at The MouseAge developers are building a visual aging biomarker system, akin to past work on the assessment of human age from facial photographs, but carried out for mice instead of people. Such a system could in principle greatly reduce the cost of many kinds of exploratory study in mice, enabling rapid first passes at evaluating the effects of potential rejuvenation therapies. Currently this sort of work is an expensive and lengthy process of wait and see: a range of low-cost methods of immediate assessment of biological age are definitely needed to speed up progress towards therapies capable of treating the causes of aging, and the visual assessment approach is an intriguing one. With the start of Longevity Month, the volunteers have announced a matching fund for donations to the project - donate this month, and your contribution is doubled.

What is Longevity Month? Advocates for longevity science, those who call for faster progress and more investment into the development of working rejuvenation therapies, have settled upon October as a month for fundraising and outreach activities. This started a few years ago with the European volunteers of the International Longevity Alliance and Heales, as the United Nations designates October 1st as the International Day of Older Persons, and the European community has tended to hold events at this time of year, such as last year's Eurosymposium on Healthy Aging. Advocates mark October 1st as Longevity Day and the month of October as Longevity Month. Small beginnings and simple ideas like this can help to produce meaningful change as they grow and spread - consider the originally humble origins of many of the now widely known and celebrated theme days, commercial and otherwise. Someone thought that he or she would give it a try, and it worked. It never hurts to try, and it is certainly the case that advocacy for any cause is a matter of trying all of the plausible options until you find the one that works, the one that everyone will later tell you was strikingly obvious, and ask why you didn't just try that first of all? Successful strategies are always obvious in the hindsight of others, but sadly only there.

MouseAge Longevity Month Updates - Extension, Matching Funds and More!

To coincide with our initiatives for Longevity Month, we are happy to announce some exciting updates for the MouseAge campaign to create a visual biomarker for mouse aging and speed the pace of longevity-focused mouse trials. The A.I. engineers on the team , with the support of Youth Laboratories, have decided to volunteer their assistance, pledging to donate their time in developing the machine learning algorithm and software engineering components of this project. This will effectively allow all goals on the crowdfunding campaign to be reduced by 15,000, and the initial goal will now stand at 15,000.

Together with a coalition of generous supporters LEAF has built up a pool of matching funds to support the campaign. This means that all donations will be doubled up until the new initial goal of 15,000 is reached. 1,000 in matching funds will be released for every 1,000 donated, so together we can move very quickly to support this important project!

Longevity Month 2017 - Tell Us Your Story!

Over the past few years there has been a tradition of longevity researchers and activists around the world organizing events on or around October 1 - the UN International Day of Older Persons, or Longevity Day. This year we want to continue this tradition by doing something special, making a video to showcase you, our community, as it is only with your outstanding help that we have been able to accomplish so much in such a short period of time. So now it is your turn to tell us your story, and let the world know why you care about research to end the diseases of aging. We will be accepting videos all through the month of October, Longevity Month, and we are also extending the MouseAge campaign to match this timeline. With these videos we will create a compilation to be unveiled on Giving Tuesday , November 28, 2017.

Considering Autophagy in the Context of Stem Cell Aging

In the paper I'll point out today, the topic is autophagy and stem cell aging. You can't wander far in the libraries of research relating to aging without bumping into a discussion of autophagy. This is a collection of quality control processes for cellular structures and proteins, working to destroy those that have become damaged or dysfunctional in some way. Damage of any number of different types occurs constantly inside cells, and so does repair: any sort of of unwanted modification of a protein alters its behavior, making it unsuitable for its intended task. Unfortunately, proteins are fragile, and cells are full of reactive molecules and damaging reactions. The longer that damaged components remain in circulation, the more secondary harm they can produce, both within the cell, and beyond in the surrounding tissue. Given that, it is understandable that greater levels of autophagy should produce better function and longer-lasting biological structures at all levels. Indeed, more autophagy slows the aging process to some degree, as demonstrated in numerous studies of short-lived laboratory species. Aging is caused by an accumulation of certain forms of damage that arise from the normal operation of cellular metabolism, and thus processes relating to general damage control tend to have some impact.

Still, there are limits. Greatly increased autophagy only somewhat slows aging. The forms of damage that are important in the long term are not greatly hampered by the constant efforts to repair the far more numerous other forms of damage. It makes sense to consider that aging could really only result from forms of damage that autophagy isn't all that effective at preventing. Consider mitochondrial damage for example, well-studied in the context of aging: the processes of mitophagy break down dysfunctional mitochondria, but the specific mitochondrial damage that causes aging is resistant to mitophagy. The quality control mechanisms cannot efficiently recognize that specific damage and its consequent mitochondrial dysfunction as a signal to remove the problem structures.

Autophagy declines with age, just like every other cellular system, as the components required for recycling of structures become dysfunctional over time. To pick one example, the lysosomes in long-lived cells, responsible for breaking down proteins and other structures in the cell, become bloated by metabolic waste that is hard for them to deal with. This prevents them from carrying out their recycling tasks, and as a result the cell eventually breaks down in a garbage catastrophe. Aging itself might be thought of as a process that commences with a failure of repair: once the maintenance systems decline, everything else follows rapidly. As is the case for autophagy, the tissue maintenance activities of stem cells decline with age, and there are links between the failure of a cellular process and the failure of an entire cell population to carry out its duties.

Autophagy in stem cell aging

Proteostasis is necessary for most cellular functions, such as genetic replication, catalysis of metabolic reactions, and the immune response. Impairments in proteostasis can lead to toxic aggregations and accumulation of unwanted proteins resulting in cellular dysfunction. The maintenance of tissue homeostasis and the regenerative capacity after an injury depends on tissue-specific stem cells. The elucidation of the hallmarks of aging identified the impairment of protein homeostasis and stem cell exhaustion as major processes involved in the decline of the regenerative potential capacity linked to the accumulation of age-associated damage.

Autophagy is a highly conserved catabolic process, essential for this protein quality control, where intracellular components are delivered to lysosomes for self-degradation. There are three different types of autophagy depending on the signals that induce the pathway, and the mechanism by which the cargo reaches the lysosome: macro-autophagy (MA), micro-autophagy, and chaperone-mediated autophagy (CMA). In particular, MA is involved in recycling long-lived proteins and cytoplasmic organelles. This process implies the incorporation of proteins, organelles, and cytoplasm in a structure called the autophagosome, which once formed fuses with the lysosome to form autolysosomes and then releasing its content in the lysosomal lumen where it is degraded via acid hydrolases. Autophagy basal levels are very low under normal conditions, and they are activated in response to stress and extracellular cues.

Aging results from the accumulation of cellular damage promoted by chronic stresses of small magnitude. Therefore, being a sensor of stress, autophagy has been linked to aging. Several studies have described a decline in autophagy activity as well as expression of autophagy genes such as Atg1, Atg5, Atg6, Atg7, Atg8, and Atg12 in response to aging in several animal models and human tissues. The majority of these works have focused on MA, the most studied form of autophagic process, but there have also been studies showing a decline in CMA, particularly in the liver and the central nervous system, which have been linked to decreased function in these organs. Longevity studies with gain and loss of autophagy genes in animal models such as yeast, C. elegans, Drosophila and mice, support a direct role for autophagy in longevity, aging and development of age-associated pathologies. This has encouraged the scientific community to identify the precise role and molecular mechanisms of autophagy in aging, as targeting autophagy could be a novel therapy against aging and age-related diseases.

How autophagy decreases with age remains unclear and under intense investigation. Recent works carried on aged muscle stem cells (MSC) and hematopoietic stem cells (HSC) have revealed the impairment of MA in stem cell activity with aging. Moreover, these studies have confirmed that correct functioning of MA is necessary to maintain the appropriate blood system and muscle development and to allow adult stem cell to survive under metabolic stress. These studies suggest that MSC and HSC lose their regenerative abilities when they reach an advanced age and that autophagy is deficient in the old stem cell population. In a recent work, it was found that approximately 30% of aged HSCs exhibited high autophagy levels, maintaining a low metabolic state and strong long-term regeneration potential similar to young HSCs. However, the remaining population of aged HSCs showed loss of autophagy, which causes activated metabolic state, accelerated myeloid differentiation, and impaired HSCs self-renewal activity and regenerative potential.

These studies confirm that autophagy maintains stemness in MSC and HSCs; however, the maintenance of this feature seems to be different in each niche. Whether these results can be translated to other stem cell niches will be determined in the future. In addition, it will also be important to elucidate whether CMA or micro-autophagy play any role in stem cell aging. In summary, there is a requirement of correct autophagy activity for stem cell function, and the pharmacological restoration of autophagy is postulated as a novel strategy to boost stem cell activity for regenerative medicine and aging.

Can Aging be Slowed by Shutting Off the Inflammatory Signaling of Senescent Cells?

Today I'll point out an interesting paper in which researchers sabotage the ability of senescent cells to generate inflammation. Senescent cells are one of the root causes of aging. They are created constantly in all tissues, a normal part of the operation of cellular metabolism, but near all are destroyed shortly thereafter. Those that linger cause ever greater disruption and failure in tissues and organs because they secrete a variety of signals known as the senescence-associated secretory phenotype (SASP), useful in the short term and when localized, but outright destructive over the long term or in great volume. One of the characteristic outcomes of the presence of lingering senescent cells is a significant increase in chronic inflammation, and this in turn accelerates the progression of all of the common age-related conditions.

With regards to what to do about senescent cells, the research community seems fairly evenly split between groups working on ways to destroy them and groups working on ways to modulate their activities. I think the former approach will be far more beneficial in the near term: it bypasses the need to understand in detail all of the highly varied senescent cell signals and their effects, a task that will likely still be ongoing a decade from now. Further, modulating the signals of senescent cells without removing them will require continual medication, rather than the envisaged infrequent, once-every-few-years treatments that clear out senescent cells. I see this as one of many areas in which the rational incentives in academic research (find out more, map more of the system, better understand the whole picture) seem to lead inexorably towards the production of objectively worse solutions in medicine.

That to one side, and as today's research illustrates, researchers appear to be making some progress in linking existing knowledge on inflammatory signaling to the the quickly growing knowledge of the biochemistry of senescent cells in aging. I mentioned another paper on this same topic and mechanism a couple of months ago. Here, the authors have found a way to interfere in one of the primary pathways by which senescent cells communicate with the immune system, and demonstrated in mice that this can blunt some of the consequences of high levels of senescence that are artificially induced through techniques such as irradiation. Unfortunately this also prevents the beneficial short-term benefits arising from senescence-associated inflammation, such as in immune surveillance of cancer. It remains to be seen as to how much of an effect this sort of approach will have on the consequences of cellular senescence in normally aging mice. Not to mention humans: at this point we really have no idea what the impact of clearing senescent cells will turn out to be in our species, never mind any of the possible approaches to selectively reduce the impact of their signaling in very narrow ways.

Cell Stress Response Sheds Light on Treating Inflammation-related Cancer, Aging

Human cells have complicated ways to protect themselves from becoming cancerous. One way is to force "premature aging" via senescence, a process that induces cells to stop growing. Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues. This accumulation impairs healthy tissue by triggering hyper-inflammation. This overdrive eventually contributes to age-related diseases including cancer, heart disease, and neurodegeneration. The overall idea for future therapy is to make a small molecule that could stop the dark side of senescence to treat age-related diseases, especially those related to chronic inflammation.

"Chromatin - structures in the cell nucleus in which genes reside - is traditionally viewed as a cell component that stays put in the nucleus to regulate gene expression. We discovered misplaced chromatin fragments outside the nucleus that pinch off from the nuclei of senescent cells." This wayward chromatin activates a DNA-sensing pathway called cGAS-STING, a mechanism based outside the nucleus best known for restraining microbial infection, such as by bacteria or viruses. In the case of senescence and aging, the body's own chromatin leaking outside of the nucleus is read by cells as a "danger signal" akin to a microbial infection. The misplaced fragments and the cell's reaction to them eventually lead to inflammation. "While short-term inflammation can help stop cancer from starting, the problem is that long-term, chronic inflammation can lead to tissue destruction, aging, and even, paradoxically, can help cancer to grow and spread."

Mice without an active alarm pathway that have been exposed to a cancer-inducing stress do not call the immune-system for help. This causes problems because damaged cells give rise to tumors in the impaired mice. However, when normal mice are exposed to stressors that induce aging, the build-up of senescent cells stimulates a continual call for immune cells, leading to chronic inflammation, which ultimately causes tissue damage and premature aging. Months after receiving irradiation stress, normal mice with an active alarm system showed massive graying of their fur, a sign of aging in mammals, just like humans show grey hair in old age. By sharp contrast, mice without the alarm system still had their black fur after irradiation. The researchers believe that finding molecules to target the always-on inflammatory pathway may hold promise in treating chronic inflammation associated with numerous diseases, especially those of aging, such as arthritis, arteriosclerosis, neurodegeneration, obesity, and possibly even hair graying and loss.

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear.

Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice.

Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Towards the Recognition of Aging as a Treatable Medical Condition

In recent years numerous groups have made a start on the long road of changing the public view of aging, from considering it a normal state to considering it a pathological state. To have it recognized as a harmful medical condition that can in principle be treated - that medical technologies can be developed for this purpose soon enough to matter. This is a process of unofficial advocacy and persuasion on the one hand, to change minds and educate people, but on the other there is also a strong component of formalism, of working with regulatory definitions. Medical research and development is, sadly, heavily regulated. The structure of regulation shapes the ability to raise funding and carry out meaningful work on the creation of means to treat aging. The US FDA, for example, doesn't recognize aging as a condition that can or should be treated, though the first cracks in that position are taking shape in the form of the TAME metformin trial. Yet the current position still means that efforts to treat aging struggle to find the necessary resources to proceed.

Since most agencies base their regulation on the World Health Organization's (WHO's) International Statistical Classification of Diseases and Related Health Problems, with ICD-11 being the latest edition in the process of being finalized, some initiatives have focused on placing aging into that document as a formally defined disease. This would be in a definitive way, unlike the one or two present entries that might be interpreted as referring to aging, given the right light, but in practice are disregarded. Whether or not aging is called a disease is a matter of semantics, and in this the powers that be and the fellow in the street both seem quite willing to designate numerous specific aspects of aging as diseases, with fashion rather than logic dictating what is a portion of normal aging and what is a disease. But when it comes to the ICD, these semantics drive policy and regulation. That has material consequences, more is the pity. Things would move forward a lot more rapidly absent the heavy restrictions placed upon medical research and development, I feel. There are already ample laws covering fraud and harm in the conduct of any human action. Why all the rest layered on top? It feels like control for the sake of control, institutions perpetuating themselves simply because they can.

Ultimately, rules follow opinions, or at least those opinions prevalent among the rule-making class. They are swayed by the zeitgeist. So a shift of public opinion and awareness about aging - and about the advent of near-future rejuvenation therapies that actually work - is important. In the ideal world, the fellow in the street would think of aging in the same way as he thinks of cancer: that someone should do something about it, because it is a painful, undesirable thing, and it is both good and generous to help the laboratories and clinics and funding institutions to make progress on this front. As things stand, we're a fair way from that goal, unfortunately. It will be very interesting to watch how matters progress in public opinion should the first human trials of senolytics produce good data and proof of effectiveness. Meanwhile, there are people toiling in the maze of regulatory definition, trying to carve out a path, a way to adjust the present stifling system of rules and statements:

Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy

Given the rapid aging of the world population and the accompanying rise of aging-related diseases and disabilities, the task of increasing the healthy and productive period of life becomes an urgent global priority. It is becoming increasingly clear that in order to accomplish this purpose, there is an urgent need for effective therapies against degenerative aging processes underlying major aging related diseases, including heart disease, neurodegenerative diseases, type 2 diabetes, cancer, pulmonary obstructive diseases.

One facilitating possibility may be to recognize the degenerative aging process itself as a medical problem to be addressed. Such recognition may accelerate research, development and distribution in several aspects: 1) the general public will be encouraged to actively demand and intelligently apply aging-ameliorating, preventive therapies; 2) the pharmaceutical and medical technology industry will be encouraged to develop and bring effective aging-ameliorating therapies and technologies to the market; 3) health insurance, life insurance and healthcare systems will obtain a new area for reimbursement practices, which will encourage them and their subjects to promote healthy longevity; 4) regulators and policy makers will be encouraged to prioritize and increase investments of public funds into aging-related research and development; 5) scientists and students will be encouraged to tackle a scientifically exciting and practically vital problem of aging.

Yet, in order for the degenerative aging process to be recognized as a diagnosable and treatable medical condition and therefore an indication for research, development and treatment, a necessary condition appears to be the development of evidence-based diagnostic criteria and definitions for degenerative aging. Such commonly accepted criteria and definitions are currently lacking. Yet without such scientifically grounded and clinically applicable criteria, the discussions about "ameliorating" or even "curing" degenerative aging processes will be mere slogans. Such criteria are explicitly requested by major regulatory frameworks, such as the International Classification of Diseases (ICD), the Global Strategy and Action Plan on Ageing and Health (GSAP), the European Medicines Agency (EMA), the US Food and Drug Administration (FDA). Nonetheless, nobody has yet done the necessary work of devising such criteria.

"Senility," tantamount to degenerative aging, is already a part of the current ICD-10 listing. In the draft ICD-11 version (to be finalized by 2018), the code MJ43 refers to "Old age," synonymous with "senescence" and "senile debility." The nearly 40 associated index terms in the ICD-11 draft also include "ageing" itself, "senility," "senile degeneration," "senile decay," "frailty of old age," and others. Still, the current definitions, such as "senility," seem to be rather deficient in terms of their clinical utility. This may be the reason why "senility" has been commonly considered a garbage code, e.g. in the Global Burden of Disease (GBD) studies. The reason "senility" has been considered a garbage code is likely because there have been no reliable, clinically applicable and scientifically grounded criteria for diagnosis of "senility" or of "senile degeneration." Consequently, there could be no official case finding lists. Hence, in order to successfully use this code in practice, it appears to be necessary to be able to develop formal and measurable, biomarkers-based and function-based diagnostic criteria for "senility" or "senile degeneration," as well as measurable agreed means to test the effectiveness of interventions against this condition.

More Evidence for Hippo Pathway Blockade to be a Road to Enhanced Regeneration

In the research I'll point out today, scientists interfere with the Hippo signaling pathway in mouse heart tissue to spur greater regeneration following a heart attack. The pathway controls cell proliferation, making it the target of attention from the regenerative medicine research community. Today's paper is one of a number of approaches that target this pathway: a fair few groups are involved in work on enhanced regeneration that in some way touches upon Hippo activity. When looking back at a sampling of the past few years, there are studies using microRNAs to interdict one part of the pathway, others uncovering regulatory RNAs that adjust this complex machinery at a different point, work on mapping links between Hippo and other pathways known to be involved in regeneration, and a paper reporting that suppression of the Hippo pathway makes the liver more regenerative by allowing mature cells to dedifferentiate into progenitor cells.

It is not unreasonable to expect there to be manipulations that enhance regeneration. Evolution doesn't optimize for individual convenience. There are many fairly similar species with broadly different regenerative capacities that evolved from a common ancestor. Somewhere there must be changes of a comparatively modest scope that change the degree to which tissues maintain themselves. "Modest scope" in the context of cellular biochemistry may still be ferociously complex as an implementation project for medical technology, but the examples found to date are promising, even taking into account the potential risk that any specific approach to producing increased regenerative activities may significantly increase the risk of cancer.

Beyond stem cell therapies and the machinery surrounding the Hippo pathway, we can also point to adjustment of macrophage polarization and levels of cellular senescence as ways to improve baseline human regeneration or reverse some of the declines that take place with age. As an aside on that latter topic, one can draw links between cellular senescence and Hippo pathway activity, and given the recent understanding that senescent cells disrupt regeneration and are a significant cause of fibrosis, it is very interesting to see that the researchers here find that disabling Hippo pathway activity reduces fibrosis following injury in the heart. Researchers are also narrowing down some of the important differences between mammals that cannot regrow limbs and species such as salamanders and zebrafish that can. It is a little early to say where this will all end up a decade or two from now, but the advent of multiple methods of incrementally improving regenerative capacity for short period of time, so as to evade increased cancer risk, seems a safe prediction.

Scientists reverse advanced heart failure in an animal model

Researchers have discovered a previously unrecognized healing capacity of the heart. In a mouse model, they were able to reverse severe heart failure by silencing the activity of Hippo, a signaling pathway that can prevent the regeneration of heart muscle. During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart progressively weakens; most people who had a severe heart attack will develop heart failure.

"One of the interests of my lab is to develop ways to heal heart muscle by studying pathways involved in heart development and regeneration. In this study, we investigated the Hippo pathway, which is known from my lab's previous studies to prevent adult heart muscle cell proliferation and regeneration. When patients are in heart failure there is an increase in the activity of the Hippo pathway. This led us to think that if we could turn Hippo off, then we might be able to induce improvement in heart function."

"We designed a mouse model to mimic the human condition of advanced heart failure. Once we reproduced a severe stage of injury in the mouse heart, we inhibited the Hippo pathway. After six weeks we observed that the injured hearts had recovered their pumping function to the level of the control, healthy hearts." The researchers think the effect of turning Hippo off is two-fold. On one side, it induces heart muscle cells to proliferate and survive in the injured heart, and on the other side, it induces an alteration of the fibrosis. Further studies are going to be needed to elucidate the changes observed in fibrosis.

Hippo pathway deficiency reverses systolic heart failure after infarction

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls.

Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized capacity for repair involving more than cardiomyocyte renewal.

TRF1 Gene Therapy Improves Health Span in Mice

One of the research groups interested in telomerase gene therapy and its ability to lengthen mouse life span also works on a number of related items, such as the potential to shut down cancers by dramatically accelerating the erosion of telomeres in cancerous tissue, telomeres being the caps of repeated DNA sequences at the end of chromosomes. As is true elsewhere in biochemistry, here it is the case that a mechanism influential on aging is also important in cancer. Other approaches to cancer that involve telomeres include sabotaging the ability of telomerase to extend telomeres. This sort of thing can form the basis for a potential therapy that could in principle put a halt to all types of cancer. All cancers, without exception, depend on the abuse of either telomerase or alternative lengthening of telomeres (ALT) in order to keep telomeres long and thus keep replicating rampantly. Each cell division shortens telomeres a little, and when telomeres become too short, a cell self-destructs or becomes senescent, in either case ceasing to replicate. Thus without telomere lengthening, a cancer must inevitably wither away.

The method used to accelerate telomere length loss is a blockade of TRF1, a component of shelterin, which appears necessary to the operation of various processes that help to maintain telomere integrity. Given other work on telomeres and telomerase, it makes sense to ask whether turning this around to enhance levels of TRF1 and its activity will slow aging in mice, as is the case for the use of gene therapy to increase telomerase levels. Researchers here show that the enhanced TRF1 approach does extend the span of healthy life in mice, but doesn't have much of an effect on overall life span. I think that most of the commentary on telomerase gene therapies made in recent years probably also applies to this work, particularly with respect to whether or not the effect is mediated through increased stem cell activity, potential applications, expected degree of safety in humans, the sizable differences between mouse and human telomere dynamics, and so on.

Telomere shortening has been identified as one of the primary hallmarks of aging. Mammalian telomeres are structures at the end of linear chromosomes that consist of repeated DNA bound by an array of associated proteins known as shelterin, which prevent chromosome ends from being recognized as double-strand DNA breaks and from chromosome end-to-end fusions. Telomerase is a reverse transcriptase (TERT) that elongates telomeres de novo by adding telomeric repeats on chromosome ends using as template an RNA component (TERC), thus preventing telomere erosion. However, mammalian cells stop expressing telomerase in the majority of tissues after birth, leading to progressive telomere erosion throughout the lifespan of the organism. Telomere shortening has been demonstrated to be sufficient to trigger age-related pathologies and shorten lifespan in mice.

Telomerase reactivation has been envisioned as an strategy to maintain telomeres and therefore to increase the proliferative potential of tissues, both in the telomere syndromes and in age-related conditions. In addition to telomerase, the shelterin complex is also critical for the protection of telomeres. Shelterin consists of six proteins, of which TRF1 is one of the key components. In particular, deletion of TRF1 in mouse embryonic fibroblasts (MEFs) results in induction of senescence, as well as in chromosome fusions and multitelomeric signals (aberrant number of telomeric signals per chromosome end). Importantly, these effects of TRF1 abrogation are independent of telomere length, as TRF1 deletion uncaps telomeres independently of telomerase and cell division. In addition, conditional TRF1 abrogation in various mouse tissues has demonstrated the importance of TRF1 for tissue regeneration and tissue homeostasis. Indeed, high TRF1 levels mark stem cell compartments as well as pluripotent stem cells and are essential to induce and maintain pluripotency.

Given the importance of TRF1 for organismal viability and tissue homeostasis, here we set to address whether TRF1 levels vary with aging in vivo both in mouse and human tissues, as well as to study the potential therapeutic effects of TRF1 increased expression in delaying aging-associated pathologies in vivo. A previous work of our group showed that constitutive TRF1 overexpression acted as a negative regulator of telomere length, mediating telomere cleavage by XPF nuclease. To circumvent this undesired effect of TRF1 overexpression, here we induced moderate and transient TRF1 overexpression in adult (1 year of age) and old (2 years of age) mice using nonintegrative adeno-associated gene therapy vectors (AAV) that can transduce many different tissues but their expression is diluted as cells proliferate.

The results shown here demonstrate that TRF1 levels decrease with age both in mice and in humans. Furthermore, we demonstrate that transient TRF1 expression through the use of AAV9-TRF1 gene therapy in wild-type mice is able to improve mouse physiological health span as indicated by improvements in different markers of aging. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues.

Macrophages Promote Muscle Regeneration via Secretion of ADAMTS1

The immune cells known as macrophages play an important role in regenerative processes, as demonstrated by the fact that if they removed from the picture, the pace and quality of tissue healing deteriorates considerably. A number of studies suggest that macrophages have two characteristic behavior patterns, the first an inflammatory behavior associated with destruction of invading pathogens, and the second focused on coordination of regeneration. Both behaviors are in evidence at the site of a wound, and healing can be improved by adjusting their proportions away from inflammation and towards regeneration. Further, studies are beginning to show that differences in macrophage behavior appear to be part of the reason why species such as salamanders and zebrafish have such proficient regenerative capacities. This is evidently a promising area of research, and here scientists report on the identification of one of the specific signals involved in the macrophage influence on regeneration:

The progressive activation and differentiation of satellite cells is critical for proper skeletal muscle growth and muscle regeneration after injury. This cascade is initiated when satellite cells are activated to break quiescence, progress through differentiation, and fuse to nascent or injured muscle fibers. Therefore, elucidating the signals and pathways that regulate this cascade is central to understanding muscle physiology and could provide a foundation for developing novel therapies for the treatment of muscle disorders and regenerative medicine.

Activation of satellite cells occurs in response to a variety of chemical, physical and physiological cues to mediate muscle tissue homeostasis and regeneration. The specialized niche of satellite cells, which are located between the basal lamina and the myofiber, is a critical element in the regulation of satellite cell quiescence and activation. For example, activated Notch signaling, which is directly regulated by proximal extracellular signals, is a well-studied example of a potent pathway that plays an important role in maintaining satellite cell quiescence. In addition, ADAM10, an enzyme known to promote Notch signaling, was found to have a role in the maintenance of the quiescent state. Yet, in spite of the apparent canonical role of Notch signaling in the regulation of satellite cell activation, the extracellular triggers that inhibit Notch signaling and promote satellite cells to break quiescence and differentiate are largely unknown.

Here we describe our discovery that macrophages, which are enriched at the site of muscle injuries, secrete a protein called ADAMTS1 (A Disintegrin-Like And Metalloproteinase With Thrombospondin Type 1 Motif). ADAMTS1 contains two disintegrin loops and three C-terminal thrombospondin type-1 motifs. We established that ADAMTS1 functions as an extracellular signal to satellite cells that promotes activation. We also found that constitutive overexpression of Adamts1 in macrophages accelerates satellite cell activation and muscle regeneration in young mice. Our data indicate that the mechanism of this ADAMTS1 activity is by targeting NOTCH1 protein on the satellite cells. These findings significantly enrich our understanding of the extracellular signals that regulate satellite cell activation and identify a pathway that could potentially be targeted with therapeutics to enhance muscle regeneration.

A Gene Therapy Restores Some Degree of Vision in Mice with Retinal Degeneration

The paper I'll point out here is an excellent example of the glacial pace of many lines of research. Years can pass between studies that look very similar, and one wonders what has been taking place in between, if anything. It has been nearly ten years since I first pointed out a study demonstrating partial restoration of visual function - at least sensing of light and darkness in the visual field - in mice with retinal degeneration. A gene therapy was used to produce expression of the protein melanopsin in retinal cells where it is usually absent. This in turn allowed these cells to participate in the light-sensing activity of the retina, where usually they would not. In effect it was providing a sort of rudimentary backup to the photoreceptor cells that are lost in degenerative conditions affecting the retina.

This week, a new paper has arrived to document a recent study of melanopsin gene therapy in which the only real differences from the study conducted a decade ago are that the mice are followed for longer after the procedure, a year, a more modern method of gene therapy is employed, and the melanopsin is the human version rather than the mouse version. At this pace, the approach will be made obsolete by progress elsewhere in the field before any sort of clinical translation ever starts.

Even in end-stage retinal degeneration such as retinitis pigmentosa (RP), the remaining retinal layers and central visual projections remain structurally intact. Stimulation of these remaining cells is potentially sufficient to mimic visual responses and restore vision, and by this means the subretinal electronic implant has shown proof of principle for restoration of vision in patients after severe photoreceptor loss. An alternative gene therapy strategy involves the expression of transgenes encoding photosensitive proteins in remaining retinal cells, making them directly light sensitive in the absence of rods and cones.

A candidate protein for this purpose is melanopsin, the photopigment naturally present in a subset of ganglion cells that are intrinsically photosensitive - intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is particularly suited to this purpose since it is native to the human eye and therefore is less likely to be immunogenic. Melanopsin shows greater sensitivity to light than alternative microbial optogenetic tools, such as channelrhodopsin-2 or halorhodopsin.

Previous work used intravitreal delivery of an adeno-associated viral (AAV) vector to express mouse melanopsin in ganglion cells with restoration of visual responses. We investigated whether human melanopsin could be effectively delivered via an alternative subretinal approach, using a ubiquitous (CBA) promoter to drive expression in all remaining outer retinal cells for several reasons. Subretinal vector delivery is well established in human clinical trials but has not been assessed in combination with a CBA promoter as an optogenetic approach for vision restoration. Transduction of cells in the upstream retina maximizes the potential of retaining complex processing of the visual signal. Furthermore, increased availability of chromophore in the outer retina may be required for effective photon capture in the absence of specialized outer segment discs. Other studies have used AAV vectors containing an enhancer to target a melanopsin-mGluR6 chimera or rhodopsin via intravitreal injection. However, there is variation in anatomy between primates and mouse models, and this may render the intravitreal approach less effective in humans. The increased risks of an inflammatory response following intravitreal AAV injection may also limit the translational potential of this route of delivery.

We therefore assessed transduction after subretinal delivery of melanopsin and whether this could support long-term restoration of light sensitivity and visual function in a mouse model of end-stage RP. Ectopically expressed melanopsin mediated depolarization of outer retinal cells and ultimately ganglion cell action potential firing, resulting in long-term restoration of the pupil light reflex and behavioral light avoidance up to at least 13 mo following injection. Finally, subretinal melanopsin expression led to light-induced changes in visual cortex blood flow and provided long-term improvements in a visually guided behavioral task that requires image-forming vision. In combination, these results suggest that this approach may be clinically useful in vision restoration in patients with end-stage RP.

Genetic Interaction with Temperature in Nematode Longevity

Environmental temperature and longevity tend to be related in species that do not maintain their body temperature. You might look at research into the sizable differences between life spans of various mussel species and how that relates to the temperature of the waters in which they are found, for example. It is an interesting question as to how relevant this research is to mammals, which do regulate their body temperature. While there appears to be a relationship between regulated body temperature and longevity in mammalian species, it is far from clear that this has much in common with the environmental temperature and longevity relationships observed in species such as the nematode worms investigated here. In any case, this, like calorie restriction, is not the road to rejuvenation therapies that will radically alter the present course of aging. Rather, it is the path to a better understanding of how the natural state of aging tends to vary between individuals and species. This is interesting, but not transformative.

As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. In C. elegans, animals that develop and age at 15 °C ('low temperature') are long-lived compared to wild-type animals grown at 20 °C (room temperature), whereas wild-type worms that develop and age at 25 °C ('high temperature') are short-lived compared to wild-type worms grown at 15 °C or 20 °C. This 'temperature law' has been described as widely accepted, but not tested beyond limited number of strains.

While the 'temperature law' is observed among wild-type organisms, the interplay between genetics and temperature is not well understood. Multiple recent reports suggest that the effects of temperature on longevity are genetically controlled and that both heat and cold modify transcriptional pathways that effect lifespan. To better understand the interplay between temperature and longevity, we measured the lifespans of worms with genetic manipulations known to affect longevity at 15 °C, 20 °C, or 25 °C. We found six examples of how longevity can be impacted across temperatures, representing conditions that: robustly increase lifespan at all temperatures (daf-2 RNAi); robustly decrease lifespan at all temperatures (rhy-1(ok1402)); decrease lifespan at high but not low temperature (daf-16(mu86)); increase lifespan at high temperature but decrease lifespan at low temperature (rsks-1(ok1255)); increase lifespan at low temperature but not high temperature (cep-1(gk138)); and do not alter lifespan at any temperature (cah-4 RNAi).

Having established that relative longevity can vary across temperatures, we next asked whether this variability is common among conditions known to modify longevity. We tested nearly fifty genotypes and interventions previously reported to affect lifespan and found that relative longevity was consistently inconsistent across temperatures. However, there are consistent trends within longevity pathways, where strains/conditions known to have opposing effects are also affected by temperature oppositely. In summary, we find significant interaction between longevity interventions and environmental temperature in two-thirds of the cases examined, indicating that a temperature-independent effect on longevity is more the exception than the rule. This variation confirms that genetics play a substantive role in temperature-dependent longevity that cannot be explained solely by the rules of thermodynamics and chemical kinetics. The observed variation in relative longevity with temperature is consistent with the hypothesis that a distinct set of mechanisms determine nematode longevity at different temperatures.

It has been suggested that protein quality control and the heat stress response are of primary importance for determining nematode longevity at 25 °C. Our data support this model; we find interventions that limit heat stress response (e.g., daf-16(mu86)) are detrimental at high, but not low, temperature, while interventions that improve protein homeostasis, such as dietary restriction or reduced expression of translation machinery (e.g., rsks-1(ok1255), rpl-6 RNAi), show lifespan extension at high temperature. The relevant mechanisms affecting longevity at low temperature are less clear, particularly because relatively few aging studies are conducted at 15 °C compared to 20 °C or 25 °C. Our results demonstrate that the impact of temperature on relative lifespan is of greater importance than generally appreciated by the C. elegans aging field. The vast majority of published studies report the impact of different interventions on lifespan at a single temperature, usually either 20 °C or 25 °C. We suggest that studies reporting effects on lifespan should typically be performed at more than one temperature to understand the robustness of the effect and the interaction with temperature.

Delivery of Extracellular Vesicles for Regenerative Therapy in Bone Tissue

A sizable portion of signaling between cells is carried by vesicles, tiny packages of secreted molecules wrapped in a membrane. Investigations of the effects of early stem cell therapies have revealed that in many cases whatever benefits are realized must be produced by signals that induce behavioral changes in native cells, since the transplanted cells die quite quickly. Now researchers are beginning to look at harvesting or manufacturing suitable vesicles as a way to recreate some of the beneficial effects of cell transplantation, a path that bypasses the need to create patient-matched cells or otherwise deal with immune rejection issues. This part of the field is at a very early stage, but nonetheless examples such as the study here are emerging:

A recent paper describes a new approach to bone regeneration; stimulating cells to produce vesicles which can then be delivered to facilitate tissue regeneration. The researchers believe that the findings mark the first step in a new direction for tissue regeneration with the potential to help repair bone, teeth and cartilage. Current approaches have significant limitations; autologous grafts cannot meet demand and cause patient morbidity, allogeneic bone lacks bioactive factors, and growth factor-based approaches (e.g. BMP-2) may have serious side-effects and high costs. Consequently, there is a considerable need to devise new methods for the generation of large volumes of bone without associated patient morbidity.

In recent years, attention has been focused on cell-based approaches. However, translation is frequently prevented by insurmountable regulatory, ethical and economic issues. This novel solution delivers all the advantages of cell-based therapies but without using viable cells, by harnessing the regenerative capacity of nano-sized particles called extracellular vesicles that are naturally generated during bone formation. Excitingly, the team have shown in-vitro that if extracellular vesicles are applied in combination with a simple phosphate the therapy outperforms the current gold standard, BMP-2. "It is early days, but the potential is there for this to transform the way we approach tissue repair. We're now looking to produce these therapeutically valuable particles at scale and also examine their capacity to regenerate other tissues."

A Slowly Spreading Realization that Radical Change in Human Longevity Lies Ahead

The author of this piece appears quite disgruntled about the prospect of living longer in good health, given an expectation of severe upheaval in government programs of entitlements relating to medical services, pensions, and other wealth transfers that are currently (poorly) structured around the reality of a population expensively and painfully aging to death. Nonetheless, it is an example of the point that a realization is spreading regarding the plausibility of sizable near future changes in human longevity: as that occurs there will be - and must be - large changes in the flows of money associated with aging, from life insurance and annuities to the structure of public funds.

Many of these changes will be disruptive, and those who relied upon government planners and politicians to help them will be let down, as is always the case. A distant and largely unaccountable bureaucrat never has your best interests in mind. There are plenty of examples to survey from just the past decade of large-scale financial issues around the world. So prepare accordingly when considering the future - but why be disgruntled? Being alive and in good health, as opposed to the alternative, is a prize worthy of considerable effort. And if you are alive and in good health for decades longer than expected, then why think of retirement? Why not continue to participate in an active life and a career?

Is the rise in life expectancy in the West coming to an end? This year the Office for National Statistics (ONS) announced something depressing: a slight fall in life expectancy for pensioners - six months for women and four for men. Overall, life expectancy is still rising but at a much slower rate than everyone thought it would. There is no shortage of experts out there prepared to explain why life expectancy has stalled. Maybe it's a result of the financial crisis, a failure of elderly care linked to austerity? Maybe it's obesity, something that could even make today's young the first generation to live shorter lives than their parents? Or maybe it is just that we are already close to the outer limits of possibility when it comes to life expectancy?

Yet look a little closer and talk to longevity experts and healthcare investors and a different picture emerges. The slowdown in life expectancy actually comes at a time when the science of ageing is getting very exciting. Much of the rise in life expectancy of the past 50 years has been down to environmental effects: the near eradication of real poverty in the West; the rise of universal medical treatment; antibiotics; better air quality; improved working conditions. All these things should keep adding a little more to the numbers. They are also just the beginning. Next will come an enhanced understanding of what actually causes ageing and how it can be stalled, alongside the start of mass molecular fiddling.

The new book Juvenesence: Investing in the Age of Longevity forecasts that within the next 20 years average life expectancy in the developed world will rise to between 110 and 120. This makes the authors happy. Their book is full of soothing thoughts. That's going to sound lovely to most people. But you can bet there is a large group who find it totally terrifying: policymakers. Ageing populations are very expensive. Our systems aren't yet in any way equipped to cope with the odd half a million 90-year-olds the UK has already, let alone millions of 100-year olds. Our health and welfare systems were designed for a different era, and the unfunded liabilities of public and private pension funds are the kind of thing that never get addressed.

This should make individuals worry, too. Very few people have planned properly for their own retirements - and even if they have, extended longevity will mean that the assumptions on which they have based their calculations are entirely wrong. On top of this, almost no one will have planned for the fact that this will make governments that don't seriously reform - my guess is that's all of them - increasingly broke. Nor will they have planned for the obvious next step: that cash-strapped governments look to other people's capital for help. If we do enter a new age of the long-lived, it will probably be less an age of the happy rentier than the very heavily taxed rentier. If you don't want to spend your 11th decade wishing that longevity science had never become a thing, think of what you once thought you should save for your retirement and triple it. Golden years? Working years.

An Interview with Greg Fahy on Thymus Rejuvenation

Greg Fahy is currently wrapping up a trial of one of the simpler methods that might produce some degree of rejuvenation in the the thymus, turning back a little of the process of thymic involution, the withering of functional tissue in this organ. The thymus atrophies quite early in adult life, and further with later aging. As the thymus provides an environment for processes that are necessary in the creation of the immune cells called T cells, this decline limits the immune system. A faster pace of creation for T cells should help with some of the age-related deterioration of the immune system, which arises in part because too many of the existing cells become dysfunctional, and because the pace of replacement is too slow to keep up.

I think that this trial is unlikely to be enormously effective at addressing the problem, and will probably only produce modest effects, but the point of the exercise is to prove in humans that any degree of thymic restoration can produce a commensurate level of benefits. If that can be accomplished via this approach, then hopefully funds can be found to bring one of the more effective methods demonstrated in mice into human medicine: FOXN1 gene therapy, tissue engineering and transplant of replacement thymic tissue, some form of cell therapy to spur regeneration of new thymus tissue, and so forth.

So from around age 20 (or younger) the thymus begins to shrink and loses the ability to produce T cells, why does this happen?

Nobody knows why thymic atrophy, or involution, occurs, but it happens in all vertebrates, starting really at the age of puberty. Some have suggested that it happens to save energy, since the production of properly qualified T cells is very energy intensive and inefficient, and of course, at puberty, the body begins to devote more energy to reproduction, which might require a tradeoff against using energy for immune maintenance. This could be adaptive since, in nature, humans would not have lived long enough for immune system collapse to set in, even though today, the situation is different. Regardless of the evolutionary reason for it, the most immediate biochemical cause of involution seems to be mostly a drop in thymic FOXN1 expression, although some have pointed to a decline in intra-thymic IL-7 and the negative influence of circulating sex hormones, for example.

You recently ran a human clinical trial to regrow the thymus gland. Can you please tell us what is the main goal of the project and what is the progress?

The trial was conducted under an FDA-approved IND and with review from multiple scientific and ethics committees. It consisted of a 12-month treatment course for 9 men divided into two cohorts, with the first cohort starting in October of 2015 and the second ending in April of this year. Our goal was to gather preliminary evidence indicating that it is possible to safely regenerate the normal aging human thymus and restore its functions, essentially reversing the process of age-related immunological deterioration. We chose to work with healthy men in part because this was a small trial, which required a reasonably uniform population, and in part because more information was available for men than for women. We chose an age range of 50 to 65 years because this range extends from several years before to a few years after the threshold age at which the immune system tends to collapse. Success would therefore suggest the possibility of preventing or even reversing the early stages of immune collapse. In future trials, we intend to enroll both women and older men.

The outcome measures included MRI evaluation of thymic density before and after treatment, simple and sophisticated assessment of T cell population distributions, measurements of many serum factors related to immune system function and general health, lymphocyte telomere length distributions and telomerase activity, and biological age based on the Horvath epigenetic clock. Regarding our results, first of all, when you're working with human beings, safety has to be the top priority, so I'm glad to be able to say that we met or exceeded all of our safety targets. Regarding thymic imaging results, preliminary analyses indicate that there was a consistent and substantial increase in thymic density, which indicates replacement of thymic fat with more water-rich material, and in previous studies on human immunodeficiency patients, this coincided with improved thymic function. Superficial tests of immune system aging showed improvements in 8 out of 9 men, and we were able to identify a possible correctable reason for the failure of the 9th volunteer. Men of all ages were able to respond positively and to avoid side effects. However, the most definitive endpoints of our study are still being analyzed at four different locations around the world, so we won't really know the final results of our study for probably another month or two.

Are we going to see a publication anytime soon?

I'm not sure about soon, but certainly, as soon as we can. This will be a complicated paper with lots of authors and lots of data to present, but also with top-tier academic co-authors who can help us go through the scientific review process quickly. In any case, we certainly want to make sure that any novel results are shared with the broader medical and scientific communities.

Crowdfunding a Portuguese Translation of Ending Aging

Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime, written by Aubrey de Grey and Michael Rae of the SENS Research Foundation, has been translated into a number of languages since its first release nearly a decade ago, but Portuguese is not yet one of them. A couple of Brazilian members of our community are hoping to change that, and are currently crowdfunding the necessary resources to achieve this goal. Translating scientific texts is always a degree more challenging than the usual fare, but helping to further spread the SENS view of aging is a worthy cause: this is a detailed plan for the creation of rejuvenation therapies that work by repairing the damage that causes aging. Consider helping this endeavor. Note that the crowdfunding page is in Portuguese at the top, and you will need to scroll all the way down for the English version of the project explanation:

We are Nina Torres Zanvettor and Nicolas Chernavsky, professional translators from Campinas (Brazil). Nicolas graduated as a journalist in USP (University of São Paulo) and has 13 years of experience as a translator. Nina graduated in Chemistry in Unicamp (University of Campinas), has a master degree in Inorganic Chemistry by Unicamp as well and works as a translator and a English teacher. The translation project of Ending Aging into Portuguese was created after Aubrey de Grey came to Brazil for the first time, in February of 2017. In that occasion, we met Aubrey after his talk at Campus Party, in São Paulo. We talked about the possibility of helping SENS using our professional experience in English-Portuguese translation. The scientific specialization of Nina together with the linguistic knowledge of Nicolas, mixed with a great dose of passion for the end of aging, could result in a translated version that would bring the ideas of the book to Portuguese speakers.

When we get sick and need medical assistance, or take a medicine or even go through a surgery, we realize the importance of healthcare. However, nowadays, medical science has still a lot of limitations. Diseases like Parkinson's, Alzheimer's, cancer and cardiovascular diseases are still practically inescapable when we reach a certain age. That's why the modern medicine is realizing that in order to defeat these diseases, we will have to face something that is difficult to face: aging. Only by defeating aging we could defeat these diseases, because they are the final phase of aging itself, which, in physical terms, is the accumulation of damage throughout our life at the cellular and molecular level.

Thus, this new area of medicine, focused on the aging issue, can give more decades of life to everyone. One of the world's most important scientists in this area, the British biogerontologist Aubrey de Grey, proposes a pathway so that in a few decades, probably still during the lifetime of most of the people still alive, we could build therapies to repair the damage caused by aging. The pathway proposed by Aubrey de Grey is called SENS (Strategies for Engineered Negligible Senescence). He identified seven basic types of cellular and molecular damage which result on aging: the mutations of our chromosomes, the glycation, the formation of extracellular and intracellular aggregates, the cellular senescence, the reduction of stem cell reserves and mitochondrial mutations. For each one of these forms of damage, Aubrey de Grey proposes a repair therapy.

Supporting this project, you are helping to spread knowledge in the area and to accelerate scientific research, contributing to the end of aging. We need the help of everybody in this journey towards the end of aging, and in this context, it's important to notice that the Portuguese language is the sixth most spoken language in the world, spoke by 273 million of people. Besides, in order for these technologies to reach everybody, this knowledge needs to reach everybody as well, including the Portuguese speaking world.

Using Historical Basketball Player Records to Investigate Height and Longevity

Height is a matter of importance to observers of basketball, so the records of professional players from past decades can be used to investigate the effects of height on longevity. Evidence to date strongly supports an inverse relationship in humans: the taller you are, the shorter your life expectancy, though the size of this effect is unclear and debated. The underlying reasons are thought to involve cancer risk, as taller people have more cells and thus more chances for something to go wrong, as well as lung function, and the influence of growth hormone metabolism on the pace of aging. To what degree does all of this matter? The ultimate goal of rejuvenation research programs such as those of the SENS Research Foundation is to make all of these interesting variations in human health and longevity entirely irrelevant: when medicine can turn back the causes of aging to grant additional decades of life, it will not in fact matter that your genetic heritage adds or removes a few years of life expectancy.

The premise that larger body size leads to reduction in lifespan longevity has generally been substantiated through scientific research over the past 40 years. For example, research suggests smaller body size is generally better for one's health, and is supported by robust cross-cultural findings of average lifespan reduction with increasing height observed in groups such as deceased American male veterans, French males and females who died before the year 1861 and males born in Sardinia, Italy between 1866 and 1915. While the biological reason for the relationship between height and lifespan longevity in humans is not yet fully understood, it is difficult to ignore the potential profound effect of genetics on lifespan longevity. A study on 8,006 American men of Japanese ancestry found height was positively associated with mortality, and perhaps of more interest, was the first to conclusively link the "longevity gene" FOX03 to smaller body size and greater lifespan longevity in humans.

Although a sizeable amount of evidence suggests that larger body size independently reduces longevity, it also important to recognize confounders of this relationship that affect biological parameters independent of body size characteristics, such as differences in genotypes, socioeconomic status (SES), education, medical care, relative weight, hygienic practices, nutrition, and lifestyle choices such as engaging in regular exercise and avoiding smoking. Further, it has been suggested that height generally explains less than 10% of the proportion of variance regarding longevity, and researchers surmise that the lack of consensus on the degree to which height affects longevity is likely due to the impact of these extraneous variables.

If height indeed influences longevity independently, deceased professional basketball players represent a promising group to further investigate this phenomenon in given their general exceptional height and relative homogeneity of other confounders such as affluence (particularly in the more recent decades), where the higher SES/social status may result in less confounding by factors such as ethnicity. We hypothesized that when adjusting for birth decade, exceptionally taller players will have died at relatively younger ages. The population of this study was comprised of living and deceased players who played in the National Basketball Association (NBA), debut between 1946-2010, and/or the American Basketball Association (ABA), debut between 1967-1976.

Overall, 3,901 living and deceased players were identified and had a mean height of 197.78 cm, and of those, 787 former players were identified as deceased with a mean height of 193.88 cm. Descriptive findings indicated that the tallest players (top 5%) died younger than the shortest players (bottom 5%) in all but one birth decade (1941-1950). Similarly, survival analyses showed a significant relationship between height and lifespan longevity, where taller players had a significantly higher mortality risk compared to shorter players (hazard ratio: 1.30). As many players have superior height compared to the age- and sex-matched average height of the US general population, there appears to be a curvilinear relationship between height and longevity where the magnitude of mortality risk decreases past a certain threshold. However, smaller sample sizes in the younger players may have been driving this effect. From a general population perspective, it is unclear whether there is a threshold for the apparent longevity benefits from having smaller body size.

Excess Visceral Fat Tissue Raises Cancer Risk

One of the many detrimental consequences of carrying excess fat tissue is an increased risk of cancer. Visceral fat generates chronic inflammation in addition to other forms of metabolic disruption, and that inflammation speeds the development and progression of all of the common age-related conditions, cancer included. The epidemiological research noted here is one way of looking at the numbers behind this relationship. When considering the number of people who are harming their health by being overweight, it is interesting to note the fact that progress in medical technology is still keeping pace to reduce mortality in later life, even while using poor strategies that do not address the root causes of either aging or fat-associated metabolic dysfunction, but instead try to compensate for or tinker with the later disease state.

Being overweight or obese are associated with increased risk of 13 types of cancer. These cancers account for about 40 percent of all cancers diagnosed in the United States in 2014, according to the latest Vital Signs report by the Centers for Disease Control and Prevention (CDC). The Vital Signs report analyzed 2014 cancer incidence data from the United States Cancer Statistics report and reviewed data from 2005 to 2014 to determine trends. About 630,000 people in the U.S. were diagnosed with a cancer associated with being overweight or obese in 2014. About 2 in 3 occurred in adults 50- to 74-years-old. Cancers associated with being overweight or obese, excluding colorectal cancer, increased 7 percent between 2005-2014. Colorectal cancer decreased 23 percent, due in large part to screening. Cancers not associated with being overweight or obese decreased 13 percent.

In 2013-2014, about 2 out of 3 adults in the U.S. were overweight (defined as having a body mass index of 25-29.9 kg/m2) or had obesity (having a body mass index of 30 kg/m2 and higher). The body mass index (BMI) is a person's weight (in kilograms) divided by the square of the person's height (in meters). Many people are not aware that being overweight and having obesity are associated with some cancers. The International Agency for Research on Cancer (IARC) has identified 13 cancers associated with being overweight or obese: meningioma, multiple myeloma, adenocarcinoma of the esophagus, and cancers of the thyroid, postmenopausal breast, gallbladder, stomach, liver, pancreas, kidney, ovaries, uterus, colon and rectum (colorectal).


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