Fight Aging!

I think that in years to come, we'll consider 2015 to be the point at which things really started to move for SENS rejuvenation research. It has to be said that medical research moves slowly at the best of times. It takes a good long run-up to show results, and it took a decade for SENS to grow from an idea and a few interested researchers to its present state of a foundation, the support of leaders in the research community, a loose network of research groups, and a few newly formed startup companies. It is perhaps an appropriate year for the unveiling of the Methuselah 300 monument, listing the donors who provided the initial funds and support to start this ball rolling.

Senescent cell clearance as a treatment for degenerative is having its breakout year. The Methuselah Foundation and SENS Research Foundation provided seed funding to Oisin Biotechnology for work in mice on a method of clearing senescent cells. Meanwhile another research group spent 2015 uncovering tissue specific drug candidates that tip senescent cells into the mode of programmed cell death called apoptosis, demonstrating this in mice with a couple of different drugs, producing results good enough to prove that meaningful health benefits result from a single treatment in older animals. This work should once and for all settle that SENS advocates have been right for the last decade, and the rest of the research community should have listened years ago.

It has also been a breakout year for gene therapy, but in a much bigger way. CRISPR has reached critical mass, and we are going to see an avalanche of gene therapies taking place in the years ahead both in trials and outside the regulatory system. A demonstration of this point was made by the BioViva CEO, who used medical tourism and the connections of a biotech startup company to undergo telomerase and follistatin gene therapies. Five years from now, it won't take any connections - just look up a reputable clinic outside the US and take a trip. If you look back at the progression of stem cell therapies since the turn of the century, that is exactly what is going to happen for the first gene therapies. Very few of the plausible candidates are what I'd call rejuvenation therapies at this point, more compensatory approaches that can spur additional stem cell activity or muscle growth or the like, but the growth in expertise in gene therapy in the field as a whole is a good thing for the future of SENS treatments that do require gene therapy.

Glucosepane cross-links are an important contribution to aging in humans - they are a part of the reason that skin and blood vessels lose their elasticity. The former is unfortunate, the latter ultimately fatal. For some years now the SENS Research Foundation has been funding efforts to develop the tools needed to work with glucosepane in cells and tissues, and this year a first success was published in a prestigious journal: a reliable method of synthesizing glucosepane as needed, a very important part of the toolkit.

Another lengthy SENS research program now blossoming is the use of allotopic expression of mitochondrial genes. The researchers originally funded by the Methuselah Foundation and SENS Research Foundation formed a company, Gensight, that is now well on its way to clinical application of this technology for inherited mitochondrial disease. That foundation of practice and experience will hopefully create a much better basis to finish up the work for all mitochondrial genes and the treatment of aging in the years ahead.

The long-running efforts by SENS researchers to find bacterial enzymes capable of breaking down some of the waste chemicals that form lipofuscin, a mix of metabolic wastes that clogs up lysosomes in old cells, have reached the point of commercial development. Candidate drugs have been licensed out to newly formed Human Rejuvenation Technologies, Inc.. Now we wait and see how that goes, but in general you should consider these sorts of deals a way to bring in more money for later stage research - it's just less visible until it reaches its goals.

Even the cancer programs based on preventing the lengthening of telomeres at the SENS Research Foundation are getting more attention from publications, and are no longer alone in the research community. Other groups are striking out in their own attempts to suppress cancer by preventing cells from lengthening their telomeres.

Speaking of commercial development: this year's Rejuvenation Biotechnology conference was a success. The hand off from academia to industry doesn't just magically happen in any field, and longevity science is no exception to this rule. This conference series exists to build the relationships and awareness needed for a smooth transition of rejuvenation therapies from the laboratory to biotech startups and Big Pharma in the years ahead.

Amyloid clearance inside the Alzheimer's research community continues to be a long, slow, painful progress of advancement by small degrees. This is not the only sort of amyloid, however, and this year efforts to clear transthyretin amyloid - associated with heart disease in the old and heart failure in the very oldest individuals - met with success in a human trial. This is perhaps the most advanced of SENS repair therapies at this point in time, an actual honest to goodness narrow scope rejuvenation therapy with a successful trial behind it. Next up should be an sober assessment on how to jailbreak this advance out of the regulatory regime and into more general availability via medical tourism.

2015 saw continued and louder debate within and around the scientific community on the topic of whether or not aging should be officially defined as a disease. I expect this discussion to continue to grow, given the financial and regulatory incentives involved:

• From the 2014 International Conference on Aging and Disease
• Why Seek to Classify Aging as a Disease?
• Another Call to Classify Aging as a Disease
• Insight into the Machinations of Classifying Aging as a Disease
• Aging as the Greatest Disease of All
• Arguing that Public Reluctance to Treat Aging as a Medical Condition is at Root a Categorization Problem

Crowdfunding by the longevity science community continues apace. We're still not as good at fundraising as our nearest cultural neighbors, the strong AI philosophy of development typified by the Machine Intelligence Research Institute, but a little friendly competition never hurt anyone. That branch of the strong AI community, like SENS and much of the radical life extension advocacy community, arose from the transhumanist communities of the past few decades, and many of the same people have interests on both sides of the fence. It seems reasonable to think that we can do just as well as MIRI and related organizations when it comes to pulling in funds for our goals in healthy longevity. This year the Fight Aging! matching fundraising held in collaboration with the SENS Research Foundation raised $250,000 for rejuvenation research, and an earlier crowdfunding project at Lifespan.io raised $45,000. We're improving year over year, but there's much further to go yet.

What about the large investments in our space? Calico continues to make deals and be a mystery to anyone other than the insiders, but increasingly looks like something halfway between Big Pharma and the NIH, which is to say irrelevant to any meaningful progress towards human longevity in the near term. It will be sad if it ends up another Ellison Medical Foundation, but that may well be where things are heading. The principals at Human Longevity Inc. are much more vocal in talking up their position, but are definitely not doing anything that is of great relevance to life extension - it's more a personalized medicine company with great PR, nothing exceptional. You might look at a good interview with Aubrey de Grey and Brian Kennedy from earlier this year for more on these two initiatives. On a different and more positive note, philanthropist Peter Thiel has been talking more openly about his interest in longevity science this year: I think it is important the people who are backing the more important ventures speak out in this way.

Off in the research community interested in slowing aging, the population of people without large amounts of funding in other words, advocacy for change is continuing. A trial of metformin to treat aging is being used to change the way in which the FDA views aging and therapies - at least I hope that's the intended goal here, as I have no expectation that this will move the needle on human health and life span. The Longevity Dividend advocates have, meanwhile, set down their scientific evidence and vision for more NIA funding for therapies to gently slow the aging process in a new book.

Parabiosis research, linking together the circulatory systems of an old and a young individual to identify factors that may influence or be influenced by aging, is proceeding apace. It is being used to identify various potential drug targets, mostly with the expectation of increasing stem cell activity in old individuals. The debate over the validity of previous discoveries, such as GDF-11, also continues.

As usual there have been some novel or early and odd results here and there in the literature, things that stand out and make you wonder. We can never expect anything of relevance to emerge from any of these, but you never know. For one, researchers identified a marker for less fit cells, and by eliminating those cells made flies live longer - with a lot of subtlety in what exactly "less fit" and the presence of the marker actually means. In other news, a company is working on therapies using isotope replacement in water, based on evidence suggesting that this increases resistance to oxidative stress in proteins and slightly slows aging. Elsewhere, the quest to understand the suspiciously large gain in life expectancy resulting from bisphosphonate treatment for osteoarthritis in a study some years ago has progressed to a hunt for plausible mechanisms. I'd rather see an attempt to reproduce the initial results. Elsewhere again, researchers provided evidence to show that twins with different exercise levels do not have any longevity differences - which is hard to reconcile with what the data presently shows on exercise and its benefits.

On a completely different topic, a novel Alzheimer's theory is that accumulation of amyloid is due to a slow physical failure of drainage channels for cerebrospinal fluid near the nose. As a theory this has the attractive property that it is comparatively easy to prove or disprove, and the Methuselah Foundation funded a test this year - so we shall see. In other news, the types of age-related diabetes are multiplying again; the assignment of Alzheimer's disease as type 3 diabetes seems to be an ongoing unresolved debate, while researchers have recently produced a much more compelling set of data in support of a type 4 diabetes caused by a novel form of age-related immune dysfunction.

The cryonics community provided a demonstration of memory retained in vitrified and restored nematode worms, a great piece of evidence to support the hypothesis that present cryonics practices are sufficient to preserve the fine structure of the human brain. Other evidence continues to be presented in the Brain Preservation Foundation technology prize contest, and in a milestone the year James Bedford became the longest surviving human being to evade the final end of information-theoretic death. This year also saw the launch of a new research-focused cryonics collaboration in the UK.

Researchers investigating proficient regeneration in salamanders have uncovered an unsuspected link between harmful senescent cells and this regeneration: salamanders suddenly become very good at clearing senescent cells while they are regrowing a limb. In zebrafish, another regenerative species of interest, researchers used a human gene to turn off limb regeneration, a result that perhaps points out why this desirable feature doesn't exist in our biology. In other news, researchers using decellularization of donor organs as a tissue engineering strategy have advanced to the point of being able to decellularize and repopulate an entire rat limb and all of its structures. Other researchers have restored the immune system in mice with transplants of engineered thymus organoids, grown from cells. In another area of regenerative medicine, a team showed that converting nerve cells into photoreceptors could restore sight to mice with degenerative blindness - a possible alternative to more conventional visions of cell therapy.

Lastly, here are links to a few short commentaries that might be worth reading again, you never know. Certainly I'd forgotten that half of them existed:

• Is it Different this Time Around?
• The Scientific Institution is Biased Against Shortcuts to the Production of Practical Technology
• Disappointing Comments on Longevity Science From Bill Gates
• The Arcane
• The Immortals Among us
• The Relevance of SEC Changes to Crowdfunding Rules
• Existing Longevity Therapies that are Technically Feasible, but Difficult and Expensive to Obtain
• Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They?

This open access review looks over present work on the engineering of new bone tissue, created from a patient's own cells, and the state of progress towards clinical availability. For most people the greatest problem with bones is the loss of strength and resilience that occurs in later life. One can hope that work presently largely focused on regrowing bone lost to physical damage or surgery will lead to a much greater understanding of the relevant cellular biology along the way, which in turn will uncover ways to restore strength to bone tissue in the old.

Medical advances have led to a welcome increase in life expectancy. However, accompanying longevity introduces new challenges: increases in age-related diseases and associated reductions in quality of life. The loss of skeletal tissue that can accompany trauma, injury, disease or advancing years can result in significant morbidity and significant socio-economic cost and emphasise the need for new, more reliable skeletal regeneration strategies. Current approaches to replace or restore significant quantities of lost skeletal tissue come with substantial limitations and inherent disadvantages that may be harmful. Tissue engineering and regenerative medicine have come to the fore in recent years with new approaches for de novo skeletal tissue formation in an attempt to address the unmet need for bone augmentation and skeletal repair. These approaches seek to harness stem cells, innovative scaffolds and biological factors to create, ideally, robust, reproducible and enhanced bone formation strategies to improve the quality of life for an ageing population.

A wealth of in vitro data over the last four decades has elucidated invaluable information on the molecular and cellular mechanisms involved in osteogenic repair, and the more recent development of complex, multicellular, three-dimensional models has significantly enhanced our understanding of osteogenesis and bone healing. However, these techniques remain unable to mimic the cellular, molecular, physiological and biomechanical intricacies present at the whole organism level. Critical aspects in bone repair such as the presence of a vascular network and biomechanical stimulation have proven difficult to reproduce outside of the living organism.

To date, stem cell therapy is hampered predominantly by our limited understanding of skeletal stem cells. There is a need for facile, safe and efficacious protocols of stem cell isolation and expansion together with enhanced bioinformatics knowledge on the phenotypic 'fingerprint' of the skeletal stem cell at a single-cell resolution and the generation of skeletal cells from pluripotent stem cell sources. It is likely new cell approaches and the development of 'smart' hydrogels, able to temporally and spatially control growth factor release to render safe and efficacious growth factor use in stimulation of fracture healing and arthrodesis, are areas that will see significant development. The next 5 to 10 years will see intense interest in the potential of additive manufacture to produce synthetic multiphasic scaffolds in which the internal architecture and topography are analysed for cartilage and bone regeneration requirements.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654432/

Chemical reactions leading to modification of long-lived proteins in tissues, such as those making up the extracellular matrix or that occupy important positions in nerve cells, are a source of damage and dysfunction. Proteins can only perform correctly when they possess the right structure: modify that structure and problems arise. Degenerative aging is, at root, nothing more than an accumulation of damage, but there remains a lot of room to debate which specific types of damage might be more or less important than others over the present span of human life. One of the better known classes of damaging modification to proteins is produced by reactions with sugar compounds, particularly advanced glycation end-products (AGEs) such as glucosepane, but this is far from the only type of modification that occurs in the complex biology of a living individual. In the research noted here, for example, the authors add data to what is know about carbamylation of proteins.

Definitively establishing the relative degrees of significance of different forms of protein modification will probably require a means of clearing out and reversing each of these chemical reactions: given that technology, run the test and see what happens. This is somewhat complicated by the fact that species with different life spans tend to have radically different relationships with the various types of damaging protein modification. This has been amply demonstrated over the past twenty years of work on AGEs: those relevant to long-term health in mice and rats are not particular relevant in humans, and vice versa, a unfortunate circumstance that led to failure for the first efforts to produce treatments capable of clearing AGEs.

Chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging.

To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.

Link: http://dx.doi.org/10.1073/pnas.1517096113

A few weeks ago researchers announced the discovery of a potential new class of drug capable of some degree of clearance of senescent cells in old tissues. As an approach to treating aging and its associated medical conditions this has long been advocated by the SENS Research Foundation, and is now coming to be known as a senolytic therapy. The paper is published in Nature Medicine, but is unfortunately not open access. The researchers there referred to the most effective drug candidate by its development code name, ABT-263. Another collaborating research group, those involved in identifying dasatinib and quercetin as senolytic drugs in research announced earlier this year, published their own paper on the ABT-263 discovery yesterday in Aging Cell. There they use ABT-263's generic name navitoclax, and this latest paper is open access, so you'll find more of the details laid out and easily accessible.

Cells become senescent as a result of damage, toxins, and stress, ceasing to divide and secreting a range of signals. This is most likely an evolutionary adaptation of processes involved in embryonic development and wound healing that have also come to suppress cancer risk in early old age, shutting down the ability to replicate in those cells most at risk. Senescent cells are destroyed by their own programmed cell death mechanisms or by the immune system, but some evade these fates and linger. The immune system becomes damaged and ineffective itself in later life, and that no doubt doesn't help matters. As senescent cells accumulate in ever greater numbers over the years, the combined effects of their secreted signals become damaging to surrounding tissues, generating inflammation, remodeling important structures, and eventually encouraging the generation of cancer rather than suppressing it. The presence of senescent cells contributes to the progression of near all of the common age-related diseases.

Selective destruction of cells is a major theme in cancer research and other areas of medicine, and destruction of senescent cells looks to be the shortest path to removing this contribution to degenerative aging. A good means of clearing these cells means that we don't have to stop to fully understand how and why cellular senescence causes damage - we can just test removal in the laboratory and look for a beneficial outcome. So far, that is exactly the outcome seen in animal studies. Early this year the first senolytic drug combination of dasatinib and quercetin was tested in mice with mediocre results in terms of percentage of cells cleared and a level of removal that varied widely by tissue type. Nonetheless it produced measurable, significant benefits after just a single treatment. This is a form of narrow, selective rejuvenation, the restoration of some parameters of biology in a living individual to the state they were in earlier life.

The focus of the research and drug screening that identified navitoclax is the inhibition of Bcl-2 and related proteins. These proteins are involved in the regulation of apoptosis, a programmed cell death mechanism. In theory senescent cells should already be predisposed to that fate, so nudging more of them over the line to trigger apoptosis is a plausible approach.

Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors

Senescent cells contribute to age-related diseases. Much like cancer cells, senescent cells are resistant to apoptosis, potentially protecting them from their own pro-inflammatory secretions, reactive metabolites, and activated DNA damage response. They are instead eliminated by the immune system. We therefore hypothesized that senescent cells depend upon anti-apoptotic defenses similarly to cancer cells. Indeed, our analysis of the transcriptome of senescent human preadipocytes identified pro-survival pathway up-regulation.

Here, we tested if the Bcl-2 family inhibitors, navitoclax and TW-37, are senolytic. Like the combination of dasatinib and quercetin, navitoclax is senolytic in some, but not all types of senescent cells: it reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, TW-37 had little senolytic activity. Navitoclax targets Bcl-2, Bcl-xl, and Bcl-w, while TW-37 targets Bcl-2, Bcl-xl, and Mcl-1. The combination of Bcl-2, Bcl-xl, and Bcl-w siRNA's was senolytic in HUVECs and IMR90 cells, while combining Bcl-2, Bcl-xl, and Mcl-1 siRNA's was not. Susceptibility to navitoclax correlated with patterns of Bcl-2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to navitoclax. Thus, navitoclax is senolytic and acts in a potentially predictable cell type-restricted manner.

Senolytics could be valuable in treating disorders related to senescent cell accumulation, e.g., atherosclerosis, chronic obstructive lung disease, idiopathic pulmonary fibrosis, osteoarthritis, diabetes, kidney dysfunction, dementias, and neurodegenerative diseases. It appears that the senolytics described so far are limited in the senescent cell types they can target, underscoring the value of testing each cell type involved in particular diseases of interest as part of the senolytic drug development process. We speculate that it may be possible to base selection of senolytic drugs for a particular disease indication on the molecular profiles of the types of senescent cells that underlie that disease. Furthermore, combination treatments for certain indications involving multiple senescent cell types may be optimal in some cases. Overall, our findings support the feasibility of using our hypothesis-driven, bioinformatics-based strategy to develop more, perhaps better senolytic agents. Furthermore, it appears feasible to develop senolytic agents that target senescent cells of a particular type, in a particular tissue, or for a particular indication.

The challenge in tissue engineering lies in recreating the precise structure of the extracellular matrix observed in natural cartilage. Without that correct structure all that results is a sloppy gel of cartilage cells rather than a useful load-bearing tissue, and that sloppy gel was the only outcome of early attempts to grow cartilage. In recent years progress has been made towards getting the structure right, either through better approaches to growing cartilage cells or through decellularization of existing donor cartilage. In recent news, researchers have claimed sufficient progress in growing cartilage from a patient's own cells to move forward into human trials:

Cartilage injuries and diseases are very common. About 40 percent of adults over 65 years old have osteoarthritis. Cartilage has no nerves and so does not cause pain until the cartilage is gone and the bone underneath starts to be affected. Cartilage also has no blood vessels and therefore cannot heal on its own once injured. In the worst case, the knee joint has to be replaced by an artificial joint. Currently, the clinical gold standard for repairing cartilage is a surgical procedure known as osteochondral autograft transplantation. It involves harvesting a graft from one part of the joint and transplanting it to replace the damaged cartilage. However, this procedure leaves the autograft donor sites injured and may lead to chronic pain and degeneration. An alternative is to use the patients' own cells such as stem cells and grow them into a three dimensional tissue-like structure until it becomes at least partially functional, before replacing the defective tissue.

Over the last eight years, researchers have developed several technologies enabling the growth of complex tissues consisting of multiple tissue components. The core technology is to grow cartilage tissues complete with underlying bone tissues in vitro using the patient's own stem cells isolated from clinically accessible sources such as bone marrow. This 'complex tissue plug' mimics the structural organization of native cartilage-bone tissues. Animal studies in rabbits have shown that replacing defects in knee joint cartilage with these tissue engineered cartilage-bone tissue plugs gives rapid and sustained regeneration of high quality cartilage with structure, composition and mechanical properties comparable to that of the clinical gold standard autografts. The use of these regenerative complex tissue plugs allows surgeons to use the same autograft surgical procedure to repair cartilage damage without the need to hurt the patients' own cartilage. Currently, by working with orthopaedic surgeons, the research team is preparing to translate this technology for human applications.

Link: http://www.asianscientist.com/2015/12/in-the-lab/hku-biomedical-engineers-develop-cartilage-regeneration-technology-grow-cartilage-ones-cells-cartilage-repairs/

This popular press article takes a look at the Russian cryonics provider KrioRus and the long-standing US provider Alcor. As for many such articles it is perhaps too ready to selectively quote skeptical scientists while ignoring the vocal support of many other scientists. The small cryonics industry provides low-temperature storage of the body and brain on death, using vitrification for avoidance of ice formation and the best possible preservation of fine structure that stores the data of the mind. This is the only possibility at a longer life in the future for those who will age to death prior to the advent of rejuvenation biotechnology, and it is a tragedy that so few people are interested in cryopreservation as an alternative to oblivion and the grave. In a better world, near everyone would be preserved for a future of medical molecular nanotechnology capable of restoring vitrified tissue and regenerative medicine capable of rebuilding a body, and no-one would think it normal to embrace self-destruction rather than hope at the end of life.

In both countries, the cryopreservation process is largely the same. Once a patient is pronounced legally dead, the body must be cooled within the next few hours to start bringing down the body temperature. Most cryonics companies work with standby services whose main purpose is to get the body out of the hospital or morgue as soon as possible to begin the process. Over several hours, the patient's blood is replaced with a cryoprotectant, essentially a chemical anti-freeze that shields tissue from freezing damage. Then the patient is cooled to -196C over the course of several days using nitrogen gas.

Those who elect to sign up seem to fall into two categories. The first consists of people who consider themselves pioneers and would be quite content to come back in the future, knowing no one and nothing of the current culture. The second is of people scared both by the prospect of death and by the finality that comes with saying goodbye to a loved one for ever, a feeling most sceptics would find hard not to empathise with.

Of those two categories, Gary Abramson and Maria Entraigues-Abramson probably fall into the former. A photogenic couple who live in Los Angeles, the two met at a conference devoted to life extension and married not long after. "I had this curiosity since I was a little girl about ageing. I always felt it was something that was not right," Entraigues-Abramson told me. "If you're frozen, you're locked in time," Abramson chimed in. "If you wait 100 years or 1,000 years or however much time it takes for the technology to develop, it doesn't matter. I'm sure it's a split second for your experience. It may be a one in one thousand chance. But the alternative is a 100 per cent guarantee annihilation of your existence." "And if you don't like it in the future, you can always die again if you want to," Entraigues-Abramson said. "You can take a peek and say, 'I like it' or 'I don't. I'd rather be dead. People think cryonics is freaky but lying in the ground and decomposing isn't? What's the difference?"

Link: http://www.ft.com/intl/cms/s/2/d634e198-a435-11e5-873f-68411a84f346.html

In the paper I'll point out today, researchers demonstrate one of the many ways in which insulin signaling and its surrounding mechanisms can be manipulated to slow specific measures of aging. In this case the focus is on the aging of heart tissue, and the methodology is genetic engineering to delete the gene encoding IGF-1R, the receptor for insulin-like growth factor 1 (IGF-1), a method already demonstrated to enhance longevity in mice.

A great deal of the aging research community restricts itself to cataloging the molecular biology of aging: firstly assessing which mechanisms are more or less important in the relationship between metabolism and aging, and secondly manipulating the operation of metabolism in order to produce new states with a modestly altered pace of aging. For most of these researchers therapies are not the goal, but rather only information. Where therapies do become the goal, the standard practice of developing drugs to alter metabolism so as to slow aging has so far demonstrated itself to be an expensive way to produce little but knowledge. Consider the hundreds of millions spent on sirtuin research, all the hype that accompanied that investment, and how little there is to show for it today. That is par of the course.

In the list of influential mechanisms linking cellular biochemistry with aging, insulin metabolism is perhaps the most studied and cataloged to date. It is of central importance in the behavior of cells, and as such this topic touches on numerous others: the role of growth hormone, diabetes, inflammation, regulation of cellular housekeeping activities, cellular senescence, and calorie restriction, as well as species life span and variations in aging, all areas of interest for diverse research groups in the life sciences. The researchers here deleted IGF-1R in heart tissue and observed the benefits in mice as they aged, looking for links to mechanisms known to be important in aging, such as inflammation and cellular senescence. The full text of this open access paper is only available in PDF format, I'm afraid, but here are some of the relevant portions:

Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

The prevalence of cardiovascular disease increases with advancing age. In addition to long-term exposure to risk factors for heart disease, the aged heart exhibits intrinsic structural remodeling which reduces cardiac functional reserve and predisposes the heart to hemodynamic stress. Senescent remodeling includes left ventricular (LV) hypertrophy, diastolic dysfunction, interstitial fibrosis, and reduction in maximal heart rate.

Prior studies report that reduction of insulin/insulinlike growth factor (IGF)-1 signaling leads to longevity in a number of species. Notably, IGF-1R heterozygous knockout mice live on average 33% longer than their wild type controls without differences in food intake, physical activity or metabolic rate. However, it is not known if decreasing IGF-1R signaling in the heart can retard cardiac aging. We sought to test the hypothesis that long-term inactivation of IGF-1R in cardiomyocytes delays the development of aging-associated myocardial pathologies using very old cardiomyocyte-specific IGF-1R knockout mice.

The present study demonstrates that deletion of IGF-1R in cardiomyocytes attenuated aging-related cardiac pathologies, including ventricular hypertrophy, interstitial fibrosis, and inflammation. Mechanistically, we showed that IGF-IGF-1R-Akt signaling may be an essential regulator of cardiomyocyte senescence. IGF-1 is primarily produced in the liver following stimulation by growth hormone (GH) and acts by binding to IGF-1Rs to promote organ growth. The mRNA expression of GH in the pituitary declines with age in mice, as they do in humans. In parallel, serum IGF-1 levels decline progressively in healthy people from early adulthood to older age.

Our data provide novel evidence that physiological IGF-1R signaling promotes cardiomyocyte senescence and that long-term deletion of IGF-1R in cardiomyocytes prevents structural deterioration in aged hearts. It seems paradoxical that IGF-1R expression increased in aged hearts given that local IGF-1 or IGF-1R levels may decline with aging in mice. For example, in cerebral vasculature, expression of IGF-1 significantly decreases with age. Although the underlying mechanism is not understood, we speculate that induction of IGF-1R but not IGF-1 in aging hearts could represent a compensatory mechanism that promotes aging-associated cardiac remodeling. Thus, it could be anticipated that the very old IGF-1R knockout mice would display blunted cardiac hypertrophy under natural aging circumstances. Furthermore, aging related fibrosis was diminished in IGF-1R knockout mice hearts. The decreased fibrosis could be associated with an increased ability to adapt to hemodynamic stress. The capacity for adaptation to hemodynamic stress and ischemia is diminished in aged myocardium.

The heart produces proinflammatory cytokines such as TNF, IL-1, IL-6, and RANKL in pathological states, and these cytokines may promote cardiac remodeling by facilitating hypertrophy and fibrosis. Moreover, chronic inflammation is a characteristic of aging and senescent cells secrete components of the SASP, the senescence-associated secretory phenotype, including proinflammatory cytokines, chemokines, and proteases. Although the role of SASP in aging phenotypes has been extensively investigated, the association of cardiac inflammation with aging is not clearly defined. One of the salient features of our findings is that aging induces proinflammatory cytokines in the heart mediated by, at least in part, the IGF-1R system.

In this post, someone much more enthusiastic than I about the use of traditional drug development to slightly slow the progression of aging makes the point that next to nothing is known about how the present collection of candidates interact. This is of interest from a pure science perspective, but not - to my eyes - from a getting things done perspective. The expected outcome for this sort of drug development, largely meaning reuse of existing drugs, as measured in terms of how much additional healthy life we would expect to obtain, and how much that progress would cost, is just not worth it in comparison to focusing on the establishment of SENS-like rejuvenation therapies based on damage repair. That doesn't stop the science of drug interactions from being interesting, but it does mean we should be looking elsewhere for meaningful progress towards healthy life extension.

I take about a dozen different pills for longevity. There is some evidence behind each of them, but what we really don't know is how they interact. It would be nice to think that their benefits simply add, so that if one pill produces a 10% average increase in life span, then 10 pills increase life span 100%. Fat chance. Some of them are ineffectual, of course. But for the ones that offer a benefit, most of the benefits are probably redundant. (When different treatments work via the same pathway, we can't expect that two together work any better than either one of them separately). A few may mutually interfere. But there also may be a few magic combinations that synergize positively. If they work via pathways that are substantially independent, we might hope that the life extension from the two together might be equal or even greater than the sum of the benefits separately. Most of the life extension drugs that we have target a single pathway: they work through the insulin metabolism. The remainder work to suppress inflammation, or re-energize mitochondria, or lengthen telomeres, or reduce TOR signaling.

Almost no work has been done with combinations of longevity treatments. In 2013, Steve Spindler's lab published a study based on eight different commercial formulas of vitamins and supplements. Their data were beautiful - and the survival curves for each of the eight fell exactly along the survival curve of the control group. I have heard that the NIA's Interventions Testing Program (ITP) has tested rapamycin in combination with metformin, with successful results (to be published next year). In a rational world, some of the billions of dollars that go into "me too" drug development and chemotherapy trials by Big Pharma would be diverted to test all of the above compounds, alone and in combination. But in the branch of the multiverse where you and I live, this will not happen in 2016. Hence "quick and dirty" (meaning cheap) alternatives look attractive.

This is a research proposal, the germ of an academic publication that I have been working on in recent months: the plan is to screen for combinations of drugs that offer dramatic life extension in mice, using the minimum number of mice to test the maximum number of combinations. Standard practice is to use 30-80 mice for each test in order to get a clean survival curve. The innovation I am offering is to use just a few mice for each combination of treatments so that more combinations can be tested, albeit less precisely. How many mice do we really need to be reasonably sure of not missing an outstanding combination of treatments? I have been modeling the situation with computer-generated data, testing different statistical methods to see which works best, and how many mice are needed in order to be reasonably certain of not missing a great combination. My definition of a great combination is that it extends life span in excess of 50%. The test I propose will not be capable of distinguishing "which is better" among the rank-and-file of many treatments and combinations. However, there will be enough statistical power to identify the really hot performers, which are of most interest to us.

I believe that using about 1400 mice in an experiment lasting about 3 years, we should be able to evaluate all combinations of 15 separate life extension treatments, and narrow the field to 6 candidate triples that show offer life extension in excess of 50%, and thus show promise for further testing. The program I have outlined could be undertaken for less than the cost of testing the 15 separate treatments using traditional methodology, and I think what we would learn from the combinations protocol could be a great deal more useful. The total cost might be $1 to $3 million, depending mostly on where the work is done. The biggest risk is that the high-benefit "magical" synergistic combinations that this program is designed to look for simply don't exist. If they do exist and can be found, the public health impact is likely to be enormous.

I would wager on these synergies not existing, but of course you don't know for sure if you don't look - again pure science versus getting things done. Everything is a trade-off. However, even if such synergies do exist, note that growth hormone receptor knockout (GHRKO) mice, the current record holders for mouse longevity, live more than 60% longer than their unaltered peers. Yet the small human population with the hereditary condition of Laron-type dwarfism, caused by a dysfunctional growth hormone receptor, doesn't appear to enjoy any meaningful extension of healthy life span, though it is possible they are modestly more resistant to diabetes and cancer.

Link: http://joshmitteldorf.scienceblog.com/2015/12/22/we-know-nothing-about-longevity-drug-interactions/

Myostatin is a part of the system of regulation that controls muscle growth. Linked here you'll find recent news of a clinical trial of myostatin inhibition as a treatment for age-related loss of muscle mass, though note that the atrophy of tissue is only one of the reasons for loss of strength. There are also issues within the biochemistry and structure of muscles caused by aging and which must be understood and repaired. Nonetheless, removing the myostatin gene entirely does dramatically increases muscle mass, as demonstrated in natural and engineered mutant lineages in a number of mammalian species. There are even a few rare natural myostatin loss of function human mutants, as muscled as you might expect even at very young ages, and at least one human recipient of gene therapy intended to enhance muscle growth through the same system of regulation. An alternative to one-time, permanent gene therapy is an ongoing treatment with antibodies tailored to block the action of myostatin, as is this case in this clinical trial. The degree of effect is likely to be lower, but from the point of view of the researchers involved the ability to stop the treatment is more important than optimizing performance at this stage:

A proof-of-concept, phase 2 trial by an international research team has found promising results for a myostatin antibody in treating the decline in muscle mass and power associated with aging. "Myostatin is a natural protein produced within the body that inhibits muscle growth. It has been hypothesized for some time that inhibition of myostatin may allow muscle to grow, resulting in improved muscle mass and physical performance. The current study confirms these beliefs."

In the study, injections of a myostatin antibody over a 24-week period resulted in an increase in lean (muscle) mass and improved performance on tasks requiring muscle power in patients older than 75 with low muscle strength, low muscle performance and a history of falling. "This is the first study to show that myostatin antibody treatment improves performance on activities requiring muscle power. 'Muscle power' refers to the ability to generate muscle force quickly. During aging, it is lost more rapidly than muscle strength, contributing to disability, falls, reduced quality of life and, in some instances, death. Myostatin antibody treatment improved muscle power in the elderly, as indicated by improvements in the ability to climb stairs, walk briskly and rise repetitively from a chair. Treatment particularly benefited those who were most frail at baseline, a population who may not be receptive to conventional intervention such as resistance exercise."

Link: http://news.iupui.edu/releases/2015/12/myostatin-warden-muscle-growth.shtml

At the present time it is technically possible to benefit from a small range of therapies that we can reasonably expect to at least modestly slow or reverse specific narrow aspects of aging. I'm not talking about the pills and potions of the supplement sellers here, which are worthless, nor the efforts to repackage a few existing drugs as calorie restriction mimetics, as that is little better. If you want to do something about your long-term health and life expectancy that doesn't require any more effort than a trip to the store, then focus on exercise and calorie restriction - nothing else at that same level of easy availability is anywhere near as effective or as proven. What I have in mind here is instead the first gene therapies, stem cell transplants, and glimmerings of SENS-like repair therapies capable of removing some of the metabolic wastes associated with age-related diseases.

In order to actually undergo one of these new therapies, you would have to undertake some combination of the following: (a) spend money at early adopter levels, high in comparison to the cost a customer would pay for a final product years down the line, (b) network for connections to find access to the necessary services and other items, (c) persuade the small number of current developers to depart from their current practice of adhering to regulation and provide you access, (d) break (the unjust and largely horrible) laws related to provision of medical services, (e) travel to a less restrictive jurisdiction as a medical tourist, and (f) accept a fair degree of risk of failure - that even if everything else goes well, and all involved do their jobs, the present implementation of the treatment just doesn't work, or the present understanding of the science and data provides a false and inflated impression of what the treatment can achieve.

A good example of a combination of most of the above is the BioViva CEO's gene therapy from earlier this year: money and networking are the currency of a startup, and the existence of that startup was required to bring together all the necessary players to get the job done. That and medical tourism to a country where provision of the treatment is legal, as it would be everywhere in a just world. Sadly, in our world, there are entire branches of government in the wealthier nations staffed by those who, day in and day out, toil to block access to potential therapies for people who can make the educated decision to take the risk. This is one of many reasons why medical progress is inordinately slow and expensive. Early adoption plays an important part in the process of development for any technology, and medicine is no different.

Here are a few pointers based on the work of recent years, in no particular order, and with no attempt to be comprehensive. There are others I could list, many of which would fall under the heading of gene therapies in some implementations.

Gene therapies:

With the advent of CRISPR, the technical feasibility of gene therapy is now leaps and bounds ahead of where it was just a few years ago. The remaining challenge in delivery is obtaining reliable tissue coverage in adults; the results in terms of proportion of cells affected is very variable in animal studies, and understanding why these variations occur is an ongoing process. So you can undergo gene therapy and come out with too low a percentage of altered cells to make any meaningful difference.

That to one side, there are any number of gene therapies that are now technically feasible in humans. They span the spectrum of risk. In the most favorable camp are alterations already undertaken in animals for years, that researchers are practiced in, and which appear to be wholly beneficial, such as myostatin gene therapy to spur muscle growth and resist age-related muscle loss. In the least favorable camp there are alterations that could absolutely be set up quickly with CRISPR and a small lab, but have only been carried out in rodents a few times, and with limited long-term observation, such as adding extra lysosomal receptors to maintain youthful measures of liver function in old age via increased cellular garbage collection.

Stem cell therapies:

If you are 60 years old in the US, with a typical level of wealth for that age group, and a typical level of creakiness in the joints, then why wouldn't you spend $10-20,000 on first generation stem cell therapies that have a good expectation value in terms of delivering relief from pain, control of inflammation, improved function, and so forth? The only reason people aren't doing this in droves is that it is still something that you have to know about, to pester the right doctors, to do some legwork on clinics and hospitals. For these very simple treatments you don't even have to leave the country anymore, since the FDA finally relented a few years back, but if you want to save money then heading to Canada or Mexico is very feasible.

If you are younger and your joints are not at that point of constantly reminding you of their damage, the cost-benefit analysis is much less clear. Will a healthy person in their 30s or 40s gain any meaningful benefit - short term or long term - from today's simple stem cell therapies? "No" seems like a very plausible answer to that question, there will be no useful data to help pin down the bounds of the possible for decades yet, and by that time it'll probably be irrelevant.

Enhancing native stem cell activities:

Parabiosis research is uncovering signals in the blood that govern stem cell activities, such as GDF-11. Augmenting or reducing levels of these signals so as to spur greater stem cell repair and maintenance of tissues can be achieved via gene therapies of various sorts, as well as by targeted drugs. This is all still new enough that getting access to treatments would be a case of persuading one or more of a small circle of respected researchers to do this for you, and that just isn't going to happen outside of the context of licensing their intellectual property and funding their development process - things that look a lot like starting a company and building a technology. The risk here is also an unknown; will this spur cancer, or cause other interesting problems? There is too little work in rodents to even be certain of the present safety for laboratory animals.

Thymus restoration:

The loss of much of the thymus in early adulthood slows the supply of new immune cells to a trickle. Expanding that supply would be one way to reverse some of the age-related decline of the immune system. It is possible to grow thymic tissue from cells and transplant it, for example: both things have been done for humans, just not together in one patient. That is a very plausible near-term goal for a clinic outside the US that already has experience in cell therapies or tissue engineering. It is also possible to conduct gene therapy for FOXN1 to restore thymic activity - one of the many riskier options that CRISPR now makes possible should anyone be willing to do it for you.

Immune cell infusions:

Researchers and many clinics are perfectly capable of generating immune cells to order, and in large numbers. It just isn't present practice to make a therapy out of this by delivering those immune cells to patients. It would be a matter of money and organization rather than new science to put together such a treatment given a clinic with the ability to carry out existing stem cell therapies. Provided regularly, such a therapy may well augment the aging immune system with large numbers of new immune cells capable of defending against pathogens and eliminating unwanted cells.

Clearance of transthyretin amyloid:

Earlier this year, promising trial results were announced for clearance of transthyretin amyloid, a form of metabolic waste associated with mortality in the oldest of old people, as well as with heart disease in younger old people. The therapy is one of the first successful implementations of a SENS approach to aging, meaning repair of damage and clearance of wastes, but since it is being developed within the regulatory system it is being used to treat a specific age-related disease rather than as a therapy for a general form of damage that underpins many aspects of age-related degeneration.

This is another great example of a treatment that is technically feasible, has a reasonable expectation to produce some level of long-term benefits to everyone, but the only way to obtain access for the foreseeable future is to have the funds and connections to start a development collaboration with the small group of researchers involved: they are not going to step beyond the bounds of the system. The picture changes somewhat when this becomes a generally available clinical therapy, at which point things come back to medical tourism, but that is still years away for this particular approach to amyloid clearance given the slow pace of regulatory processes in medicine.

Bisphosphonates:

Bisphosophonates were shown to grant a sizable five year increase in life expectancy in a study population of a little more than a hundred osteoarthritis patients. Obtaining and using drugs of this nature without a prescription - which you won't get unless you have osteoarthritis or one of the other conditions that bisphosophonates are used to treat - is of course going to be illegal in highly regulated nations like the US. The primary risk is that the data is incorrect, however; an effect of this size should not just appear out of the blue for a class of medicine that has been used for a long time. While researchers are investigating potential mechanisms that might explain these results, this seems a case of data that needs replication and confirmation rather than unquestioning acceptance.

Television viewing time is available in some large epidemiological data sets, and is a useful proxy for time spent sedentary rather than active. Past studies have demonstrated an association between higher television viewing time and higher mortality rates, and this much larger study shows the same:

Television viewing is a highly prevalent sedentary behavior among older adults, yet the mortality risks associated with hours of daily viewing over many years and whether increasing or decreasing viewing time affects mortality is unclear. This study examined: 1) the long-term association between mortality and daily viewing time; 2) the influence of reducing and increasing in television viewing time on longevity and 3) combined effects of television viewing and moderate-to-vigorous physical activity (MVPA) on longevity. Participants included 165,087 adults in the NIH-AARP Diet and Health Study (aged 50-71 yrs) who completed questionnaires at two-time-points (Time 1: 1994-1996, and Time 2: 2004-2006) and were followed until death or December 31, 2011.

Over 6.6 years of follow-up, there were 20,104 deaths. Compared to adults who watched less than 3 h/day of television at both time points, mortality risk was 28% greater in those who watched 5+ h/day at both time-points. Decreasing television viewing from 5 + h/day to 3-4 h/d was associated with a 15% reduction in mortality risk and decreasing to lest than 3 h/day resulted in an 12% lower risk. Conversely, adults who increased their viewing time to 3-4 h/day had an 17% greater mortality risk and those who increased to 5+ h/day had a 45% greater risk, compared to those who consistently watched less than 3 h/day. The lowest mortality risk was observed in those who were consistently active and watched less than 3 h/day of television.

We confirm that prolonged television viewing time was associated with greater mortality in older adults and demonstrate for the first time that individuals who reduced the amount of time they spent watching television had lower mortality. Our findings provide new evidence to support behavioral interventions that seek to reduce sedentary television viewing in favor of more physically active pursuits, preferably MVPA. Given the high prevalence of physical inactivity and prolonged television viewing in older adults, favorable changes in these two modifiable behaviors could have substantial public health impact.

Link: http://dx.doi.org/10.1186/s12966-015-0315-0

A number of research groups in different areas of regenerative medicine are working on ways to wrap individual stem cells in supporting materials that enable the cells to both survive and behave as desired for long enough to produce results following transplantation. In this case, the focus is on hair regeneration:

The dermal papilla cell (DPC) is a type of highly specialized mesenchymal cells located in hair follicles (HF). Due to the primary role in the epithelial-mesenchymal interaction that enables hair-follicle morphogenesis and hair cycling, DPC has become an attractive cell source for hair regeneration to treat alopecia patients. However, DPCs tend to lose their function during in vitro culture. Hence, there exists a clear need to develop a microenvironment that can recapitulate the interactions within the native milieu of DPCs.

Layer-by-layer (LBL) nano-coating with biocompatible materials on the cell surface displays the versatility with tunable loading and release properties, which can provide a remodeled microenvironment for regulating cell function. Here, we developed a LBL self-assembly technique for single DPCs to create a nano-scale ultrathin extracellular matrix (ECM). We showed that the single cell-based LBL-encapsulation would not impact the viability, morphology, proliferation and intrinsic properties of DPCs. We then included fibroblast growth factor-2 (FGF-2) into the LBL nano-structure to regulate the DPC function. Finally, we performed in vivo hair reconstitution assays using LBL-encapsulated DPCs combined with freshly isolated epidermal cells (EPCs) and found this strategy can treat hair loss. Tests on nude mice showed that the implanted encapsulated cells caused abundant hair growth with the hair follicle organisation showing mature characteristics.

Link: http://dx.doi.org/10.1039/C5TB02265G

This has been a great year for SENS rejuvenation research, both in progress in the lab and in fundraising from the growing community of supporters. The work needed to build the first therapies capable of repairing the root causes of aging, and thereby preventing and turning back age-related disease and disability, is moving forward. New allies are arriving, and more attention by industry, public, press is being given to this critical area of medical research. The year ends a little under a week from now, and there is still more than $25,000 left in the final matching fund put up a week ago by the Foster Foundation. All charitable donations made to the SENS Research Foundation before the end of 2015 will be matched from this fund - so it isn't too late to make a difference this year.

We are pleased to announce that the Foster Foundation, a longtime supporter of SENS Research Foundation, has offered us a final year end challenge. They will match dollar for dollar up to $50,000 raised from December 14th to 31st. Formerly the Rose and Winslow Foster Family Foundation, the Foundation has provided over $150,000 in donations to SRF this year. We thank them for their amazing support of our mission. Help us secure this challenge grant by donating today and helping enable SRF's critical work to end age-related disease.

Earlier this year, the SENS Research Foundation crowdfunded more than $45,000 for mitochondrial DNA repair research via Lifespan.io. This year also saw progress in the for-profit world towards the first practical single-gene implementation of this same technology for the treatment of inherited mitochondrial disease, an important part of building a robust clinical technology platform to prevent the contribution of mitochondrial DNA damage to degenerative aging. Our 2015 Fight Aging! matching fundraiser, held in collaboration with the SENS Research Foundation, was also a success and raised $250,000 for research into the effective treatment of aging over the last few months.

Going on for 600 people donated to this year's SENS fundraisers, or at least to those where I can count the totals. The more attention we can create, the more discussion, the more modest donations made in the same spirit as people donate to cancer research, the better off we will all be. It is the hum and chatter and spirited donations from the grassroots that draw the attention of high net worth philanthropists and conservative traditional funding sources. The only way to see six and seven figure checks in the mail is to first have thousands of people cheering you on. Those with deep pockets rarely lead the crowd: they put their support to organizations with backing. Early stage research in the life science is very cheap these days - that $45,000 for mitochondrial repair research will enable six months of highly productive work at the cutting edge by people who know more about the particular approach taken by the SENS Research Foundation than near anyone else in the world. Our donations are not of token value, and enable real and meaningful progress. Nonetheless, in the long term the greater value we provide to the future of humanity is to shine a light, to be a beacon pointing out the worth of SENS research - and the value of the treatment of aging as a goal - to those who can fund causes with millions and more.

This is an important, transformative time in the shift from the old approach to age-related disease towards the new approach of medicine to treat aging itself. The avalanche is starting, and what we do today will shape the direction and pace of progress for years to come. So back the causes you believe in.

Over the last twenty years researchers have undertaken a great many rodent studies of calorie restriction, also known as dietary restriction, and its ability to improve health, slow aging, and extend longevity. As this paper goes to show there is much left to learn, however. In particular, the relationships between degrees of calorie restriction, enhanced longevity, and benefits to particular narrow aspects of health are complex. One of the unexpected outcomes here is that mild calorie restriction has a very similar outcome in terms of life expectancy as that of more rigorous calorie restriction - at least in one particular commonly used laboratory rat lineage. That qualification is necessary, as results have varied over a selection of various lineages.

Given that short-lived species such as mice and rats have far more plastic life spans than long-lived species such as humans, the long-term characteristics of the calorie restriction response when it comes to aging and disease are likely to be quite different for us in many of the important details. Certainly it doesn't extend human life by up to 40% as it does in mice, as that outcome would have been noticed centuries ago at the very least. This is the case even though many of the short-term measures of changing metabolism in response to calorie restriction are similar for all mammals, and it has been shown to result in notable health benefits for human practitioners.

Dietary restriction (DR) has become the gold standard to which manipulations that increase life span and appear to retard aging are compared. DR has been shown to increase life span and reduce or delay the increase in age-related pathologies and the decline in most physiological functions in numerous genotypes of laboratory rodents. DR increases the life span of a wide variety of other organisms. These data have led to the view that the effect of DR on longevity and aging is universal, a view that was reinforced in 2009 with the first data showing that DR significantly decreased the incidence of age-related deaths and delayed the onset of age-related pathologies in rhesus monkeys. The universality of the effect of DR on longevity was called into question in 2010 when researchers reported the effect of DR on approximately 40 different recombinant inbred lines of male and female mice. Surprisingly, approximately one-third of the mice showed a decrease in life span on the DR diet; one-third showed no effect of DR on life span; and only one-third showed the expected increase in life span.

One possible explanation for the recent contradictory data on DR is that the level of DR required to increase life span is genotype dependent, and because the previous studies used only one, relatively high, level of DR, which might have had a negative effect (instead, lower levels of DR might increase life span). The standard DR diet that is usually used in DR rodent studies one in which rodents are fed 60% of the diet consumed by animals fed ad libitum (AL) (i.e., 40% DR). This is the level of restriction used by the National Institute on Aging (NIA) for their aged rodent colonies, which have been available to investigators studying aging. It is generally believed that the increase in life span is directly related to the level of DR, that is, increasing the level of restriction leads to a greater increase in life span up to a certain point (e.g., around 60% DR) where further restriction is harmful. However, there are only limited data to support this view.

The purpose of this study was to determine whether a modest level of DR (10% DR) could increase the life span of male F344 rats and compare its effects on life span and pathology to the effects of 40% DR. We found that 10% DR significantly increased mean life span, and surprisingly, the increase in mean life span obtained by 10% DR was similar to that observed with 40% DR. However, we observed differences in the effects of 10% and 40% DR on the incidence of fatal neoplasia; 40% DR resulted in a significant reduction in fatal neoplastic diseases, especially leukemia, which was the most common neoplastic disease in the rats.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/nyas.12982/

Researchers have recently suggested that the practice of calorie restriction requires elements of the circadian clock to be present and functional in order to extend life, implying that adjustment of these mechanisms is a part of the way in which calorie restriction works to slow aging. There has been an increased interest in the circadian clock in aging research of late, a system of regulation that governs changes in cellular metabolism and tissue function over the course of a day. Elements of the clock become dysregulated with advancing age, though as for most of the catalog of known age-related changes in cellular behavior it is unclear as to where this failure sits in the grand chain of cause and consequence in aging. This chain spans the processes that lead from fundamental molecular damage through complex and poorly understood interactions all the way to the end stage of age-related disease and death. Is disarray of the circadian clock closer to the damage end, and thus produces many detrimental consequences in and of itself, or is it closer to being a final consequence, with little further damage done as a result? In this context research of the sort linked here is interesting:

Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock - transcriptional factor BMAL1 - results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR.

The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on an ad libitum (AL) diet but failed to increase life span of Bmal1−/− mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CR vs. AL by 50-70% in WT mice at several daily time points tested, while in Bmal1−/− the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1−/− induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression of Bmal1 (by 150%) and its downstream target genes Periods (by 470% for Per1 and by 130% for Per2).

We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.

Link: http://dx.doi.org/10.1096/fj.15-282475

A few weeks ago I pointed out recent study data from a German population on cytomegalovirus (CMV) and its role in immune aging. Today I'll note a companion study of a different population of older people that focuses more on the relationship between CMV and mortality. It is the story you might expect if you've been reading on this topic for any great length of time, as testing positive for CMV infection is here found to be associated with a significantly greater rate of age-related disease and mortality. Cytomegalovirus (CMV) is a pervasive herpesvirus that, like its peers, cannot be effectively cleared from the body by the immune system. Unlike its peers CMV has no obvious and immediate effect on health for anyone with a normally functioning immune system. You probably have it already, you never noticed your initial infection, and the overwhelming majority of people test positive for CMV infection by the time they are old. A growing body of evidence implicates long-term CMV infection in the development of immunosenescence, the processes that result in declining effectiveness and growing dysfunction of the immune system in aging.

The immune system is one of the more intricate cellular systems in the body, and it is far from fully understood at the detail level. Most of the ways in which it can fall into persistent dysfunction, as is the case in autoimmune disease and aging, are similarly at best currently understood only in outline. Yet the immune system is very important in the progression of degenerative aging. It has numerous roles that go beyond defending against invading pathogens, such as the elimination of potentially cancerous or senescent cells, both of which can be a source of harm. Further, a dysfunctional, aged immune system generates ever greater levels of chronic inflammation, and this inflammation contributes to the development of all of the common, ultimately fatal age-related conditions.

The immune system in adults has a very slow rate of generation of new immune cells, and this and other factors give it many of the characteristics of a system that is limited by space. Present thinking on CMV is that its constant presence causes the immune system to devote ever more of this limited space to cells that are specialized for CMV and useless for everything else. Further, constant immune activity, such as when battling pathogens like CMV that cannot be cleared, tends to force more immune cells into an exhausted, senescent state - this is a well studied phenomenon for HIV and AIDS, for example. This is no doubt an incomplete sketch of a complicated and nuanced collection of destructive processes, but what can be done about it? A way to clear CMV won't fix the damage done to date, and infection doesn't appear to do any harm beyond this slow immune destruction, so targeting CMV is probably not the best of approaches - more of a nice to have for the long term. Delivering lots of new immune cells on a regular basis to circumvent natural limits, such as via cell therapies or rejuvenation of the thymus will be more effective for the elderly. The other side of the coin is targeted destruction of CMV-specialized and useless immune cells, which should spur replacement with unspecialized and useful cells. As the paper quoted below demonstrates, something effective must be done:

CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

Human cytomegalovirus (CMV) is a ubiquitous herpes virus and shares a high prevalence in developed countries. A growing body of evidence suggests an important role of CMV during aging. Seropositivity for CMV is one of the parameters in the immune risk profile (IRP), associated with increased mortality in longitudinal studies in octo- and nonagenarians. While the IRP was present in only 20% of the 85-year-olds, CMV seropositivity is present in approximately 80-90% of octogenarians. CD8 T-cell responses in CMV-seropositive elderly are characterized by an accumulation of dysfunctional T cells with short telomeres and low proliferation potential, often considered as replicative senescent. Clinically, CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies. It has been proposed that CMV-driven cardiovascular mortality might be the main cause for the observed increase in mortality in CMV-seropositive people over the age of 65 years.

The goal of our study was to evaluate whether in octogenarians CMV seropositivity and T-cell senescence are independent predictors of all-cause and especially cardiovascular and CHD-mediated mortality. we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65-month follow-up (47.3% survival rate). CMV-seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%) compared to CMV-seronegative participants together with lower CD4/CD8 ratio and higher frequencies of senescent-like CD4 memory cells and senescent-like CD8 memory cells. CMV seropositivity was also associated with increased six-year cardiovascular mortality (hazard ratio 1.75) or death from myocardial infarction and stroke (hazard ratio 1.89). Analysis revealed that low percentages of senescent-like CD4 T cells and near-senescent CD8 T cells reduced the risk of cardiovascular death. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T-cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.

Nrf2 regulates a range of proteins associated with cellular repair and stress resistance, and is considered a longevity-assurance gene. There is more of it and its activities in some long-lived species, and also as a result of some of the interventions known to modestly slow aging in laboratory species. Levels of Nrf2 decline significantly with aging, however, and the balance of evidence suggests that we'd be modestly better off if that didn't happen. Researchers are slowly tracing back down the chain of cause and consequence to better understand the proximate causes of this loss:

Nrf2 is both a monitor and a messenger. It's constantly on the lookout for problems with cells that may be caused by the many metabolic insults of life - oxidative stress, toxins, pollutants, and other metabolic dysfunction. When it finds a problem, Nrf2 essentially goes back to the cellular nucleus and rings the alarm bell, where it can "turn on" up to 200 genes that are responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other actions. "At least one important part of what we call aging appears to be a breakdown in genetic communication, in which a regulator of stress resistance declines with age. As people age and their metabolic problems increase, the levels of this regulator, Nrf2, should be increasing, but in fact they are declining."

Nrf2 is so important that it's found in many life forms, not just humans, and it's constantly manufactured by cells throughout the body. About half of it is used up every 20 minutes as it performs its life-protective functions. Metabolic insults routinely increase with age, and if things were working properly, the amount of Nrf2 that goes back into the nucleus should also increase to help deal with those insults. Instead, the level of nuclear Nrf2 declines. "The levels of Nrf2, and the functions associated with it, are routinely about 30-40 percent lower in older laboratory animals. We've been able to show for the first time what we believe is the cause."

The reason for this decline is increasing levels of a microRNA called miRNA-146a. MicroRNAs were once thought to be "junk DNA" because researchers could see them but they had no apparent biological role. They are now understood to be anything but junk - they help play a major role in genetic signaling, controlling what genes are expressed, or turned on and off to perform their function. In humans, miRNA-146a can turn on the inflammation processes that, in something like a wound, help prevent infection and begin the healing process. But with aging, this study now shows that miRNA-146a expression doesn't shut down properly, and it can significantly reduce the levels of Nrf2. This can cause part of the chronic, low-grade inflammation that is associated with the degenerative diseases that now kill most people in the developed world, including heart disease, cancer, diabetes and neurological disease. "The action of miRNA-146a in older people appears to turn from a good to a bad influence. It may be causing our detoxification processes to decline just when we need them the most."

Link: http://oregonstate.edu/ua/ncs/archives/2015/dec/research-identifies-key-genetic-link-biology-aging

The German parliament has a formal petition system that does actually seem to result in dialog with politicians, unlike the comparable setup in the US that is for show and little else. This is one of many examples showing why single issue political parties are more of a viable approach to advocacy in European countries, and why you see more of that type of initiative in Europe. The German parliament started using an internet version of their petition system some years ago, and here is an example of the longevity science advocates of the German Party for Health Research supporting a petition to increase funding for research aimed at the treatment of aging. They are looking to obtain 50,000 signatures from German citizens to get to the point of consideration:

The German Party for Health Research is supporting the petition, directed to the German parliament (Bundestag), for more research against age-related diseases. Please help to reach the quorum of 50,000 signatures. If you are a German or live in Germany, sign the petition and spread the link. Only if enough people hear about the petition, the quorum can be reached. If you can, also try to inform the media. You can also donate to the German Party for Health Research, with reference "petition" - we would have more options to promote the petition (e.g., via Facebook ads). The petition translated into English is follows:

The German Parliament should decide that additional 2% of the federal budget is invested into research against age-related diseases such as cancer, cardiovascular diseases, Alzheimer's and type 2 diabetes. Age-related diseases cause most of the suffering in Germany and worldwide and contribute considerably to health costs. Using today's biotechnologies we have now the opportunity to develop therapies against all age-related diseases. The fact that even big companies such as Google already invest large amounts of money into the development of such therapies reveals that this isn't just an utopian endeavor anymore.

Damage and waste products are caused by normal metabolism inside and outside of cells, which accumulate during the lifespan and give rise to age-related diseases as soon as a certain amount is reached. By repairing the damage and getting rid of the waste products at a molecular and cellular level, it will in future be possible to cure and prevent age-related diseases. The more research in this area is done, the greater the chance that such therapies are developed sooner. The additional money should be used to establish new research institutes and educate more scientists in relevant areas. This implies the expansion of concerned faculties at the universities. Not only would the development of these therapies be a humanitarian act, but Germany would also greatly benefit economically in the long term. Since most people will eventually be hit by age-related diseases, each individual would benefit. To finance it, one can subtract 2% from every other budget area, for example.

Link: http://parteifuergesundheitsforschung.de/petition-to-the-german-parliament-for-more-research-against-age-related-diseases/

The news for today is that the Major Mouse Testing Program has launched. This is an initiative set up by advocates and researchers associated with the non-profit International Longevity Alliance, and is intended to speed up testing and replication of promising potential treatments for aging in mice - though of course there are considerable differences by scientific faction as to just what is considered a promising potential treatment. The Major Mouse folk will be crowdfunding their efforts, building on the growing experience in the community in raising funds for research this way in recent years.

Within the SENS portfolio of repair biotechnologies there are actually few options presently at the point of viable interventions that are both low cost and worth trying: senescent cell clearance has a number of potential approaches, mitochondrial DNA repair is getting close, though not on the cost front due to the reagents needed, there have been demonstrations of improved lysosomal function in old animals leading to functional rejuvenation of tissues, and so on. We can argue about which portions of the very broad field of stem cell medicine might be considered rejuvenation biotechnology at this point. Even in this comparatively small present portfolio of practical options there is far too little work taking place in mice, however. There should be dozens of studies running for senescent cell clearance alone given the potential it shows. This is just considering SENS, however. For people who are more interested in the mainstream approach of trying drugs to slow aging, such as the development of calorie restriction mimetics, autophagy enhancers, and the like, for all that this is likely an expensive way to produce marginal benefits, there is an enormous array of things to test that are not being tested.

A lot of compounds and drugs have been tested in mice (and other laboratory species) in the past few decades. Most of these results have to be thrown out, especially those showing modest extension of lifespan, as few of those studies controlled adequately for inadvertent calorie restriction or were otherwise robust enough to pass muster. Calorie restriction has a large effect on aging and lifespan in short-lived animals, larger than almost any other intervention tested to date: if a compound makes animals nauseous, they will eat less and live longer, but there are many other ways to accidentally create incorrect data. The National Institute on Aging runs the Interventions Testing Program (ITP), which conducts very robust life span studies in mice. The most important output of this program, to my mind, is that it has demonstrated that most currently available interventions have tiny positive effects at best. Hopefully it has served to convince more people that developing drugs to alter metabolism with the aim of slowing aging is a road to nowhere, and that a different approach - i.e. SENS-like therapies that repair the damage that causes aging - is needed.

The Major Mouse Testing Program exists because the ITP is slow, and very few groups outside the ITP are doing anything of this nature. The ITP staff test only a few options in any given year, and adventurous tests such as "let's combine everything shown to extend life so far and see what happens," or "let's try something related to SENS" are never going to be on the agenda at the NIA, or at least not for the foreseeable future. The Major Mouse folk are not so constrained, however.

Major Mouse Testing Program

We live in exciting times - for the first time in human history extending healthy human lifespan is rapidly becoming a realistic prospect. Scientific breakthroughs in research mean we could soon be living healthy, active lives for much longer than people do now. Some drugs tested have been found to increase mouse lifespan such as Metformin and Rapamycin for example and are considered for human testing. Many more substances have never been tested and we do not know if they might extend healthy lifespan. More studies are needed before we can move onto human tests - and ultimately medicines that people can use. What happens next depends on how much more quality research is being done by scientists - and that research needs funding. We are launching an ambitious international project, called the Major Mouse Testing Programme (MMTP) via a crowdfunding campaign to support this important work.

Right now very few high impact studies investigating lifespan are initiated each year - and with around one in ten promising substances tested so far found to actually make mice live longer, this is painfully slow progress. We are working to redress this situation and with an international team of dedicated lead researchers, three high quality laboratories and a dedicated team, we are hoping to make a real contribution to the field of regenerative medicine. The Major Mouse Testing Programme is a project that aims to speed up the pace of progress up by rapidly testing longevity interventions - meaning research which would have taken 100 years at today's rate can be done in five. It is also plausible that some interventions, when combined could have a synergy where the effects are greater than the individual compounds, this has certainly been the case for senescent cell clearance with Dasatinib and Quercetin. It is likely there are more synergies to be discovered and this is where the MMTP plans to push forward, not only testing single interventions but also combinations to seek out these powerful combinations.

We have opted to test with mice partly due to the costs involved and mouse studies are also considerably easier to organize and are the usual starting point prior to moving into higher animals such as rabbits, dogs and ultimately humans. Organisations such as the FDA for example also usually require substantial animal data prior to approving any clinical trials involving people so this is another reason for choosing to begin here. The initial phase of the project has a limited number of substances to be tested, but importantly it will demonstrate that the team is able to conduct the large scale intervention studies testing more complicated and expensive interventions demand. As part of the current project we are planning to test at least two substances. One which is known to increase mouse lifespan (Rapamycin) to show that the labs can generate the same consistently high quality data. This will serve as our positive control group to ensure all three labs are operating to the same rigorous high standards and are producing the same data.

You can see the first set of interventions the team plans to test in their research portfolio, along with explanations as to why these drugs have been chosen. You'll see that the senolytic drug combination to clear senescence cells reported earlier this year is on the list. Running a replication study there is a useful thing to do, I'd say, given that the original researchers don't seem all that interested in following up on their work with a life span study.

Researchers recently reported the development of a system to generate a form of damage to nuclear DNA in a sizable number of discrete locations in a controlled, isolated way, and use it to test a limited hypotheses regarding the contribution of DNA damage to age-related epigenetic changes. This is a small step forward towards determining whether or not nuclear DNA damage is a meaningful cause of aging. This damage occurs constantly and randomly, most of it repaired, but the few mutations that slip through accumulate in tissues across a lifespan. You have more of this damage if you are old, and this is one of the reasons that cancer is an age-related disease: the more mutations, the more likely it is that the right combination to spark a cancer occurs. But beyond cancer, is this random nuclear DNA damage, different in every cell, a significant cause of aging over the present human life span? The consensus is yes, and the thinking is that these mutations cause enough dysregulation of cellular activities to be harmful, but this consensus is disputed.

What is needed is a way to either create or repair random nuclear DNA damage in isolation of other cellular processes. There are plenty of interventions to slow aging in laboratory animals that happen to slow the rate at which nuclear DNA damage occurs, but these interventions also alter vast swathes of the operating details of cellular metabolism. There is no way to pin down the relevance of nuclear DNA damage on its own in that situation. The methodology reported in the open access paper linked here is a small step towards the sort of biotechnology needed to reproduce random nuclear DNA damage in much the same way as it occurs naturally, and thus run a study on whether or not it is a cause of aging. There is still a way to go towards that end result, however:

The accumulation of DNA damage is a conserved hallmark of cancer and aging. Of all DNA lesions, DNA double-strand breaks (DSBs) are arguably the most harmful. Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes. Consistent with the latter, DSB induction was found to be sufficient to promote a subset of age-related pathologies in mice. In addition to the often detrimental effects of mutations and chromosomal abnormalities, DSBs cause significant changes in the chromatin environment both at and beyond the break site, raising the intriguing possibility that DSB repair contributes to (persistent) epigenetic defects that may eventually alter cell function. It is of note that epigenetic dysfunction in a small subset of cells may be sufficient to affect entire tissues, and possibly organismal aging.

The distinction between cell-intrinsic and systemic consequences of DSB induction is, thus, critical to advance our understanding of the role of DSBs in age-associated functional decline. However, despite numerous cell-based reporter systems for DSB induction, there is a scarcity of tools to follow the consequences of DSBs for cell and tissue function in higher organisms. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.

Link: http://dx.doi.org/10.1093/nar/gkv1482

The oldest of active athletes retain greater muscle power than the average older person, though there is always the question of cause and effect: to what degree is this a consequence of the choice to continue as an athlete, accompanied by all that exercise, versus being a situation in which an individual can only continue to be an athlete because he or she happens to be more resilient. As this study demonstrates, the resistance to age-related loss of overall muscle power in these individuals is not due to suffering a lower level of the shared fundamental degeneration of capabilities in muscle fibers:

Elite runners do not experience the muscle weakening associated with aging as non-athletes do. Movement and strength come from the muscle fibers that make up a muscle group contracting and generating tension. Muscle weakening happens when the fibers contract slower and with less force. Muscle fiber samples were taken from the quadriceps of older elite runners and non-athlete adults in the same age range. "These are individuals in their 80s and 90s who actively compete in the world masters track and field championships. In the study, we had seven world champions, and everyone placed in the top four of their respective events."

The fibers' contraction speed and force were compared to fibers from 23-year-old non-athlete adults. Muscle fibers from older non-athletes contracted considerably slower and weaker than fibers from young non-athletes. To the researchers' surprise, the muscle fibers of masters athletes contracted at a speed and force similar to those of older non-athlete adults, not the young adults. Success in high-performance sports in old age does not appear to be due to maintained contraction capability of the fibers. This study suggests that aging is associated with decreased muscle quality regardless of physical activity status. However, other studies have shown that muscle fibers can be arranged in a variety of ways to optimize strength, speed and power of the whole muscle, so there are many structural ways to compensate for the reduced performance at the fiber level to maintain performance at the whole muscle level.

Link: http://www.the-aps.org/mm/hp/Audiences/Public-Press/2015/70.html

Today I'll point out a couple of recent publications on the topic of longevity-associated genetic variants in humans. The research community devotes a lot of effort to the identification and confirmation of human genetic variants associated with greater longevity. The cost of obtaining genetic data continues to fall rapidly, and a few years from now will become small in comparison to the other costs of running a study. Ever more researchers are joining in as genetic studies fall within their budgets. In the world of pure scientific endeavor, the quest for knowledge, this is all good. There are few realms as large as that of genetics and cellular biochemistry, and the floodgates of data are opening as never before. Decades of work lie ahead to map even a sizable fraction of the intersection of aging and cellular metabolism at the detail level of molecular biology. In the long term, this is all useful: no data goes to waste, and whatever sort of comprehensive molecular nanotechnology that comes after medicine as we understand it today will require the complete map of human biochemistry as a starting point. That is a long way away, however.

From a practical point of view, in the context of producing ways to treat aging soon enough to matter, establishing the reasons why some people tend to live somewhat longer than others is a sideshow, however. It has little to no relevance to meaningfully extending the healthy human life span for everyone. For one, it is clear from work to date that (a) there are many, many contributing factors to the relationship between genetics and aging, (b) any single factor has a tiny, sometimes almost indistinguishable statistical effect on mortality, and (c) the vast majority of those factors are different for every study population. You can fill a book with the associations found to date and never replicated, while there are only a few genetic variants that hold up in multiple studies, such as APOE. Secondly, given drugs or other therapies that accurately alter genes and protein levels in a human to mimic those of a centenarian, what does that get you? A very small boost to your chances of living more years in a state of advanced aging and increasing frailty. The vast majority of those with the same genetic variants as long-lived study populations die on much the same schedule as the rest of us. If the research community is going to invest time and effort on treatments for aging, then they should at least be treatments with a large expectation value in terms of mortality reduction and healthy life extension.

These studies are representative of the range of work presently taking place: initial identification of possible associations with longevity; confirmation studies discarding the majority of associations found elsewhere; and studies outlining ways to improve the process of identifying genetic associations with longevity.

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

Longevity is a complex phenotype, and few genetic variants that affect lifespan have been identified. However, aging and disease are closely related, and a great deal is known about the genetic basis of disease risk. Here, we show using genome-wide association studies (GWAS) of longevity and disease that there is an overlap between loci involved in longevity and loci involved in several diseases, such as Alzheimer's disease and coronary artery disease. We then develop a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from 14 large studies of disease and disease-related traits in order to narrow the search for SNPs associated with longevity. Using iGWAS, we found eight SNPs that are significant in our discovery cohorts, and we were able to validate four of these in replication studies of long-lived subjects. Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits. Beyond the study of human longevity, iGWAS can be applied to boost statistical power in any GWAS of a target phenotype by using larger GWAS of genetically-related conditions.

In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40). With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease).

Association study of polymorphisms in FOXO3, AKT1 and IGF-2R genes with human longevity in a Han Chinese population

FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study. The other eleven SNPs were not significantly associated with human longevity in Han Chinese population.

Serum BPIFB4 levels classify health status in long-living individuals

People that reach extreme ages (Long-Living Individuals, LLIs) are object of intense investigation for increase/decrease of genetic variant frequencies, genetic methylation levels, protein abundance in serum and tissues. The aim of these studies is the discovery of the mechanisms behind LLIs extreme longevity and the identification of markers of well-being. Our recent multi-step genetic analysis of Italian (the screening set), and US and German LLIs (replication sets) and relative control populations, identified a variant in BPIFB4, down-regulated during aging and high in CD34+ of LLIs, and the codified protein (LAV-BPIFB4) to be a powerful boost for endothelial vasorelaxation and revascularization, two functions lost during aging and cause of human frailty.

Here is a demonstration of splitting tissue engineered teeth early in their development process so as to multiply the number of teeth produced. Researchers have for years now been able to grow functional teeth from cells in rodents, either by implanting suitable cells into the jaw, or more recently growing entire teeth outside the body. Work on refining the techniques involved continues apace, and one might well ask what is taking so long in moving these advances to human medicine. Dentistry is usually one of the more rapid areas of progress in clinical medicine, and it is getting on for near a decade now since the first demonstrations of teeth grown from cells in mice:

Researchers have found a way to - literally - multiply teeth. In mice, they were able to extract teeth germs, groups of cells formed early in life that later develop into teeth, split them into two, and then implant the teeth into the mice's jaws, where they developed into two fully functional teeth. Teeth are a major target of regenerative medicine. Approximately 10 percent of people are born with some missing teeth, and in addition, virtually all people lose some teeth to either accidents or disease as they age. Remedies such as implants and bridges are available, but they do not restore the full functionality of the teeth. Growing new teeth would be beneficial, but unfortunately humans only develop a limited number of teeth germs, the rudimentary cell groups from which teeth grow.

"We wondered about whether we might be able to make more teeth from a single germ." To demonstrate that it might be feasible, the group focused on the fact that teeth development takes place through a wavelike pattern of gene expression involving Lef1, an activator, and Ectodin, an inhibitor. To manipulate the process, they removed teeth germs from mice and grew them in culture. At an appropriate point in the development process, which turned out from their experiments to be 14.5 days, they nearly sliced the germs into two with nylon thread, leaving just a small portion attached, and continued to culture them. The hope was that signaling centers - which control the wave of molecules that regulate the development of the tooth - would arise in each part, and indeed this turned out to be true. The ligated germs developed naturally into two teeth, which the team transplanted into holes drilled into the jaws of the mice.

The teeth ended up being fully functional, allowing the mice to chew and feel stimulus, though they were only half the size of normal teeth, with half the number of crowns - a result that could be expected given that the researchers were using already developed germs. Significantly, they were able to manipulate the teeth using orthodontic methods, equivalent to braces, and the bone properly remodeled to accommodate the movement of the teeth.

Link: http://www.riken.jp/en/pr/press/2015/20151218_4/

Researchers here demonstrate some of the benefits of enhanced cellular housekeeping in mice, the latest work on a general class of therapies to slow the progression of aging based on producing a state of more diligent cellular maintenance. Maintenance processes of interest include the various systems of autophagy responsible for recycling damaged cellular components, as well as the activities of proteasomes responsible for breaking down damaged or otherwise undesirable proteins. These processes are known to be more active in many of the interventions that extend life and slow aging in animals. Despite interest in this approach there has been little concrete progress beyond the laboratory over the past decade; the research here is similar to a number of past animal studies that have gone little further.

A study of mice shows how proteasomes, a cell's waste disposal system, may break down during Alzheimer's disease, creating a cycle in which increased levels of damaged proteins become toxic, clog proteasomes, and kill neurons. The study suggests that enhancing proteasome activity with drugs during the early stages of Alzheimer's may prevent dementia and reduce damage to the brain.

The proteasome is a hollow, cylindrical structure which chews up defective proteins into smaller, pieces that can be recycled into new proteins needed by a cell. To understand how neurodegenerative disorders affect proteasomes, researchers focused on tau, a structural protein that accumulates into clumps called tangles in the brain cells of patients with Alzheimer's disease and several other neurodegenerative disorders known as tauopathies. Using a genetically engineered mouse model of tauopathy, as well as looking at cells in a dish, the scientists discovered that as levels of abnormal tau increased, the proteasome activity slowed down.

Treating the mice at the early stages of tauopathy with the drug rolipram increased proteasome activity, decreased tau accumulations and prevented memory problems. They found that the drug worked exclusively during the early stages degeneration, which began around four months of age. It helped four-month old tauopathy mice remember the location of hidden swimming platforms as well as control mice, and better than tauopathy mice that received placebos. Treating mice at later stages of the disease was not effective. "These results show, for the first time, that you can activate the proteasome in the brain using a drug and effectively slow down the disease, or prevent it from taking a hold."

Rolipram was initially developed as an antidepressant but is not used clinically due to its side effects. It increases the levels of cyclic AMP, a compound that triggers many reactions inside brain cells. Rolipram works by blocking cyclic AMP phosphodiesterase four (PDE4), an enzyme that degrades cyclic AMP. The scientists found that cyclic AMP levels are critical for controlling proteasome activity. Treating brain slices from tauopathy mice with rolipram, or a version of cyclic AMP that PDE4 cannot degrade, reduced the accumulation of tau and sped proteasome activity.

Link: http://www.nih.gov/news-events/news-releases/speeding-brains-waste-disposal-may-slow-down-neurodegenerative-diseases

An interesting open access paper on exercise in identical and non-identical twin pairs was recently published, the data suggesting that long-term differences in physical activity between identical twins don't result in any significant difference in longevity, even though other differences in health outcomes are observed. We might draw parallels between this and similar results observed in a mouse study from a few years back, in which the exercising mice had better health but no increase in maximum life span. The researchers here theorize that the well-known epidemiological association between exercise and increased life expectancy is perhaps as much a matter of genetics as of choice.

For any observed statistical relationship in humans there are always questions of causation. This is especially true in the web of associations related to aging and mortality in population data, in which life expectancy, wealth, social status, intelligence, education, exercise, diet, and culture all have ties to one another. That we pay great attention to these relationships is a function of having no good way to treat aging, I've long thought: we care about trivial differences in life expectancy of a few years here and a few years there because this is all that is in our power to change right now, and that will continue until the development of rejuvenation therapies. Life expectancy and exercise are linked robustly in many data sets, and even more so now that accelerometers are so cheap and ubiquitous that even large studies can use them to obtain actual rather than self-reported data on physical activity. There are studies to demonstrate longer life expectancy in athletes, longer life expectancy in those who exercise modestly versus those who are sedentary, and so forth. What are these studies measuring, however? For example, what if people who are more robust and would live longer regardless of exercise tend to exercise more? Or perhaps exercise levels are a good proxy for lower levels of visceral fat tissue and consequent chronic inflammation - themselves linked to greater risk of age-related disease and mortality.

The results of this study definitely muddy the waters in the search for causation and mechanism in exercise and mortality reduction, providing evidence to support a state of considerable complexity in the relationship between exercise, genetics, and outcomes in health. Nothing in biology is ever as simple as we'd like it to be, so this should perhaps be expected. Regardless he data presented below should be added to the many past studies on exercise and mortality, and its weight balanced accordingly - never take any single set of data and interpretations as gospel in science. This doesn't change the consensus, which is that you should exercise, and that you are expected to obtain benefits by doing so. It does add subtlety to the picture, however.

Lifespan - genetic background and physical activity

Animal studies have already shown that a strong link exists between genetic background and physical activity level. The purpose of our study was to investigate the associations between genetic background, physical activity level, and lifespan. We studied also both identical and non-identical same sex twin pairs of which one was physically active and his/hers co-twin was inactive. We looked for the association between physical activity level and lifespan by following the mortality of the twins for 23 years.

High physical activity level was associated with longer lifespan when looking at non-identical twins that differ for their genetic background. However, in identical twins, that share the same genetic background, in pairwise analyses comparing physically active members of a twin pair with their inactive co-twin, there was no difference in lifespan. Our results are consistent with previous findings, that animals that have high aerobic capacity are physically more active compared to animals with low aerobic capacity. The findings in human twins were in agreement with this: discordance in physical activity level was clearly more common among non-identical twins than in identical twins showing an effect of genetic background on physical activity level.

Vigorous physical activity in adulthood did not increase lifespan in human twins, even though physical activity is well-known to have various positive effects on health, physical fitness, and physical function. Based on our findings, we propose that genetic factors might partly explain the frequently observed associations between high physical activity level and later reduced mortality in humans. Our finding covers vigorous physical activity started at adulthood, hence physical activity started during childhood may have different effects. Thus, it will be critical to determine whether physical activity has a positive effect on lifespan when commenced early in life.

Physical activity in adulthood: genes and mortality

Observational studies report a strong inverse relationship between leisure-time physical activity and all-cause mortality. Despite suggestive evidence from population-based associations, scientists have not been able to show a beneficial effect of physical activity on the risk of death in controlled intervention studies among individuals who have been healthy at baseline. On the other hand, high cardiorespiratory fitness is known to be a strong predictor of reduced mortality, even more robust than physical activity level itself. Here, in both animals and/or human twins, we show that the same genetic factors influence physical activity levels, cardiorespiratory fitness, and risk of death. Based on both our animal and human findings, we propose that genetic pleiotropy might partly explain the frequently observed associations between high baseline physical activity and later reduced mortality in humans.

The prospective Finnish Twin Cohort includes all same-sex twin pairs born in Finland before 1958. Physical activity was measured with a structured questionnaire. We used persistence and changes in vigorous physical activity during the years 1975, 1981, and 1990 as baseline predictors of mortality. Altogether, 11,325 twin individuals (4190 complete twin pairs) answered the required physical activity questions for all three baseline time points. Of the 4190 same-sex twin pairs, we identified 179 persistently discordant for participation in vigorous physical activity.

Taken together, our results are consistent with previous data on rodents and humans, which indicated that genetic predisposition plays a significant role in exercise participation. These results are also consistent with our previous suggestion that genetic pleiotropy may partly explain the associations observed between high physical activity and mortality in our past epidemiological studies, which called for high quality intervention studies to analyse the true effects of physical activity on morbidity and mortality among initially healthy individuals. Our results also support the notion that inherited aerobic capacity is a predictor of longevity, but further study in both animals and humans is required to determine whether this is true for the portion of aerobic capacity enhanced by vigorous physical activity. Our findings are also consistent with previous studies that show positive effects of physical activity on glucose metabolism in rodents and human twins. However, vigorous physical activity does not improve longevity in twins or rodents, particularly when commenced in maturity. It is to note that randomized controlled trials show that vigorous physical activity has other health benefits.

Researchers here demonstrate that a biomarker of aging presently under development shows a lower measure of age in the children of long-lived individuals. A number of research groups are involved in trying to create a standard measure of biological age based on patterns of DNA methylation, a type of epigenetic modification that regulates the production of specific proteins from their genetic blueprints. Cells react to circumstances, and one of those circumstances is the accumulation of molecular damage that causes aging. These forms of damage are the same in all of us, and so we should expect to find patterns in the epigenetic changes that accompany aging: some are individual, a matter of circumstances and environment, but others are shared and reflect the level of age-related cell and tissue damage suffered over the years.

Ageing researchers and the general public have long been intrigued by centenarians. We find it useful to further distinguish centenarians from semi-supercentenarians (i.e. subjects that reach the age of 105 years, 105+) and supercentenarians (subjects that reach the age of 110 years, 110+) because subjects in these latter categories are extremely rare. As of January 1, 2015, in the 60,795,612 living individuals in Italy, 100+ are 19,095, 105+ are 872, and 110+, which constitute an even smaller subgroup, are 27, according to the data base from the Italian National Institute of Statistics. On the whole, 105+ and 110+ subjects have to be considered very rare cohorts of particular interest for the study of both the ageing phenotype and the healthy ageing determinants. This means that 105+ and 110+ are most informative for ageing research, even if it is not yet known whether 105+ reach the last decades of their life according to a molecular trajectory which progresses at a normal rate of change or whether the attainment of this remarkable age results from a slower molecular ageing rate.

Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6), 63 semi-supercentenarians' offspring (mean age: 71.8), and 47 age-matched controls (mean age: 69.8). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference of 5.1 years) and that centenarians are younger (8.6 years) than expected based on their chronological age. Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.

Link: http://www.impactaging.com/papers/v7/n12/full/100861.html

As a companion to the recently published book Aging: The Longevity Dividend, you might take a look at this paper on the economics of even marginal success in slowing aging. The gains examined are very small in the grand scheme of things, a few additional years of health via some form of drug-based therapy to adjust the operation of cellular metabolism, such as calorie restriction mimetics, or other approaches such as enhancing autophagy. Drugs based on recapturing the well-studied calorie restriction response have been promised for years, but have yet to arrive in any meaningful way, despite a large research investment in time and money.

Biomedicine has made enormous progress in the last half century in treating common diseases. However, we are becoming victims of our own success. Causes of death strongly associated with biological aging, such as heart disease, cancer, Alzheimer's disease, and stroke, cluster within individuals as they grow older. These conditions increase frailty and limit the benefits of continued, disease-specific improvements.

Here, we show that a "delayed-aging" scenario, modeled on the biological benefits observed in the most promising animal models, could solve this problem of competing risks. The economic value of delayed aging is estimated to be $7.1 trillion over 50 years. Total government costs, including Social Security, rise substantially with delayed aging - mainly caused by longevity increases - but we show that these can be offset by modest policy changes. Expanded biomedical research to delay aging appears to be a highly efficient way to forestall disease and extend healthy life.

$7.1 trillion over 50 years is ~$140 billion a year, which is about half of the present yearly direct costs of chronic disease in the US. The opportunity costs of aging and disease, in the form of people unable to work and support themselves, are much higher. Delayed aging is not solved aging, of course. If we want an end to aging, and an end to the costs of age-related disease, then rejuvenation research should be the primary approach, meaning efforts to repair the causes of aging rather than only trying to slowing them down. It isn't any harder to achieve this goal, so why aim for the worse outcome?

Link: http://dx.doi.org/10.1101/cshperspect.a025072

Some of the researchers involved in the Longevity Dividend initiative have taken the sensible approach of distilling into a new book their view on aging research, the existing evidence, the bounds of the possible in the near future of longevity science, and what should be done to treat aging. They should have done this years ago; it might have greatly helped efforts to lobby for greater funding of favored programs on aging and longevity in the National Institutes of Health. Certainly, the creation of Ending Aging was a very important foundation for the growth of support for SENS research; a well-assembled book is a solid point of reference that keeps on providing worth to those involved in advocacy for the cause it details.

So that said, the Longevity Dividend view is one of aiming for marginal, unambitious gains. It is an outgrowth of the mainstream position in aging research that sees the only viable path ahead as being a slow, expensive process of tinkering with the operation of metabolism so as to slightly slow the aging process - to slightly slow down the accumulation of cell and tissue damage that causes aging. This, of course, will be of little use to the people who are already old, heavily damaged, when the first treatments eventually emerge, and of not that much greater benefit to everyone else. Adding a couple of years to life expectancy doesn't change the big picture all that much at all. Further, the Longevity Dividend typifies the very conservative mindset of Big Government science: change must be small, everything is infused with politics and lobbying of formal hierarchies, and the pace of progress in persuasion is slow and expensive.

So while it is great that there are more researchers out there working to propagate the view that aging can and should be treated - there is still a long way to go yet to persuade the rest of the world to agree with that scientific consensus - in all of this the Longevity Dividend is really the antithesis of the SENS advocacy and rejuvenation research that I see as the most promising way forward. SENS comes as an outside influence on the present funding establishment and its rigid limitations, using philanthropic donations to create radical change, and engineer effective progress towards ways to repair the damage and end aging: to bring aging under medical control and prevent and reverse all age-related disease, not just slow it down a little. In any case, that is my opinion. You can see what you think now that the Longevity Dividend argument is laid out in a coherent fashion and at length:

New book on Aging: The Longevity Dividend from Cold Spring Harbor Laboratory Press

Aging is one of the greatest challenges currently facing society. People are living longer than ever, but many of the later years are fraught with frailty and disease, placing an enormous burden on health-care systems. Understanding the biological changes that occur during aging and developing strategies to address them are therefore urgently needed.

Written and edited by experts in the field, Aging: The Longevity Dividend from the Cold Spring Harbor Perspectives in Medicine collection, examines the biological basis of aging, strategies that may extend health span, and the societal implications of delayed aging. Contributors discuss genetic variants that accelerate or protect against aging, biochemical pathways that modulate longevity (e.g., mTOR), biological consequences of aging (e.g., decline in stem cell function), and various animal models used to study aging processes. They emphasize that age-delaying interventions will yield greater health and vitality than disease-specific treatments. Drugs that may promote health span or longevity (e.g., metformin) and efforts to prevent and treat frailty (e.g., through exercise) are explored.

Aging: The Longevity Dividend, Excerpt from the Foreword (PDF)

With the general realization that the population of our planet is rapidly becoming older, economists, population health experts, epidemiologists, policy planners, physicians, scientists, and others have started considering implications of this "silver tsunami" for the society. At the level of physiological functioning and health maintenance in old age, it became apparent that this increase in longevity will be accompanied by multiple comorbidities in a significant proportion of the older population.

Therefore, developing strategies to maintain optimal health in an increasingly aging population is becoming a global strategic imperative. This book represents the latest concerted and broad effort to shine a light on the potential of biology of aging research to implement what could be a revolutionary change in improving the health span of older adults. It is a culmination of more than 25 years of effort by the editors of this volume to draw broader attention to this issue. Specifically, beginning in 1990, S. Jay Olshansky and colleagues, many of them coauthors of this volume, started to make a powerful case for why and how research into life-span and health-span extension, as part of the larger field of biology of aging, may have a unique potential to provide broad and far-reaching benefits to the aging human population. The effort, aptly named the Longevity Dividend Initiative, has already made substantial headway in the larger community of researchers and is beginning to extend to policy makers and society overall. This book is part of a groundswell of recent activities to help scientists and public advocates of science reach the tipping point and bring about a coherent, conceptually innovative, scientifically based, and publicly as well as industry-supported and sponsored strategy to deal with health issues central to older adults from a revolutionary standpoint.

The argument for the Longevity Dividend is that the payback to society and individuals from extending health span via fundamental interventions based on knowledge of biology of aging will be considerable and broad. This argument, in its entirety, seems intuitively appealing to the point of being a "no-brainer": The current approaches to treating age-related diseases that produce the highest morbidity and mortality in the older adult population are only incrementally effective at increasing life span and minimally effective in increasing health span, defined as the fraction of life span spent in good health and prosperity. In fact, curing all cancers, for example, although desirable, merely replaces cancer with other chronic morbidities such as Alzheimer's, cardiovascular diseases, metabolic diseases, and so on. By contrast, in numerous laboratory animal models, including some studies in nonhuman primates and humans, interventions based on manipulations of nutrient sensing and cellular metabolism have shown not only longevity extension but also significant postponement of multiple age-related diseases (including cancer, Alzheimer's, cardiovascular, and metabolic diseases). This, therefore, is close to, or achieves, health-span extension.

The promise of translating these interventions to human subjects, then, starkly contrasts with current, disease-specific research and treatment approach. Simply put, the choice would come down to the two extremes: (1) the current health-care approach, with most individuals enjoying a relatively long life span but reduced health span with multiple comorbidities and increased, ballooning health-care costs; or (2) the biology-of-aging-based health-span extension, which, if successfully translated to humans, would provide increased health span at a fraction of today's health-care cost, with a vigorous and engaged older adult population and even a potentially productive older workforce.

At present, two key issues stand in the way of broad application of health-span extension to humans. First, we are still not at the point of having applications that are distribution-ready. Second, serious additional roadblocks exist to implementation, including the omnipresent lack of funding for research and, even more so, advanced-stage clinical testing. There also remain ingrained views in society that aging is immutable and/or that intervening in the aging process will produce deleterious and unwanted consequences such as further overpopulation and shortages of resources. Yet the increase in human longevity during the last century was one of humanity's most remarkable medical and technological accomplishments. As valuable as oil, gold, diamonds, fresh water, and clean air may seem, life itself is likely to be our most precious commodity - and we managed to manufacture more of it during the last 150 years than during all of humanity's existence prior to the 19th century.

You may recall a study a few years back that showed a surprisingly large reduction in mortality and consequent extension of life expectancy for a group of more than a hundred older people taking bisphosphonates, a class of treatment for osteoarthritis. The size of the effect was five years or so, which is on the same order as exercise or calorie restriction in humans, meaning that it is large enough to be suspicious of such a result turning up out of the blue for any existing drug treatment. I would be looking for artifacts in the study data and to want to see both confirmation by other teams and a larger study population. Researchers here are looking at possible mechanisms for this reduced mortality, focusing on zoledronate, one particular bisphosphonate drug:

Researchers have discovered the drug zoledronate is able to extend the lifespan of mesenchymal stem cells by reducing DNA damage. DNA damage is one of the most important mechanisms of ageing where stem cells lose their ability to maintain and repair the tissues in which they live and keep it working correctly. "The drug enhances the repair of the damage in DNA occurring with age in stem cells in the bone. It is also likely to work in other stem cells too. This drug has been shown to delay mortality in patients affected by osteoporosis but until now we didn't know why. These findings provide an explanation as to why it may help people to live longer. Now we want to understand whether the drug can be used to delay or revert the ageing in stem cells in older people and improve the maintenance of tissues such as the heart, the muscle and immune cells, keeping them healthier for longer. We want to understand whether it improves the ability of stem cells to repair those tissues after injury, such as when older patients with cancer undergo radiotherapy."

Approximately 50 per cent of over 75 year-olds have three or more diseases at the same time such as cardiovascular disease, infections, muscle weakness and osteoporosis. In the future it is hoped this drug could be used to treat, prevent or delay the onset of such diseases rather than using a mixture of drugs. "We are hopeful that this research will pave the way for a better cure for cancer patients and keeping older people healthier for longer by reducing the risk of developing multiple age-related diseases."

Link: http://www.sheffield.ac.uk/news/nr/bone-drug-protects-stem-cells-from-ageing-1.535075

Here I'll point out a aging research crowdfunding project at Experiment, focused on carrying out a small project in developing functional metrics of age to help evaluate treatments that might affect the pace or state of aging. The longevity science community has undertaken a growing number of crowdfunding efforts, and I think that this trend is important in the bigger picture of how to make crowdfunding work for scientific research on all scales and for all fields. That part of the community I'm involved with hasn't made much use of Experiment as a platform because it is focused on supporting very small projects, well under $10,000, while we tend to aim to raise much more than that per fundraiser, each supporting a larger discrete project. So it is good to see some inroads here.

In a better world than ours, a stronger scientific community would see every laboratory pulling in additional funds via crowdfunding. In doing so researchers would develop a community of supporters and a better relationship with the broader public, creating a greater understanding of what it is they do in their investigations and the potential of their work. Today next to no-one thinks about or cares about medical research until it is too late, and that has a lot to do with the sparse nature of funding for progress in medicine, I'd say. Changing this state of affairs would bring great benefits. There is also this: traditional philanthropy occupies a very important role in the modern institution of science, as other sources of funding almost never put resources towards the high-risk, early stage, radical new approaches that actually create discoveries. They are only willing to devote funds after the prototypes and proofs exist - which somewhat misses the point of what science is all about and how progress in science and technology happens at the sharp end. Nonetheless, it is what it is, and philanthropic funding is the engine that creates discovery. Opening that up to the public at large can only help.

Harvard Medical School has reported successful aging reversal using genetic and biochemical methods in the labs of Dr. George Church and Dr. David Sinclair. The Church Lab has encouraged us to build a new updated functional test of age. The test will measure functional biomarkers of the lab's subjects compared to their sequenced genomes and of clinical trial subjects elsewhere, estimating the age at which a person physically functions, enabling researchers to validate measurements from genetic and biochemical aging interventions and reliably compare results across subjects, studies and approaches. Our research will determine which biomarkers provide reliable indications of aging level and which test technologies can reliably measure the biomarkers at reasonable cost.

Now that institutions have succeeded in genetically reversing aging in laboratory samples of human cells and biochemically in live mice, we are developing a new system for measuring functional age in order to validate those results in people. Already, there are people whose genetics or lifestyle cause them to age more slowly or faster. Therefore, we already have experience measuring differences in levels of aging, for example tests taken using the H-SCAN function age test developed in 1990. We are developing a successor to that test. We will determine suitable functional age biomarkers and test technology via research and expert advice from Church, Sinclair and others. We will compare that data to the H-SCAN Test's 12 biomarkers and hardware.

Our goal is preparation of a device requirements document that an engineer can use to create a design for the test prototype. The document will contain a list of the functional aging biomarkers to be tested, the range of values to be tested, how each biomarker declines with age, why each biomarker was selected, specifications and sources of testing instruments for each biomarker, integration of the instruments in the device, sequence of tests, and requirements for user interface, software calculations, regulatory agencies, exterior design, connectivity, data security, and installation.

Link: https://experiment.com/agemetrics

The Methuselah Foundation has a record of seed funding early stage biotech and medical companies that are undertaking novel work that is (a) relevant to aging or tissue repair and (b) not already in progress to any meaningful degree elsewhere. Funding startups is one way to push forward the state of the art, providing support for research that is almost at or just past the point of initial technology demonstrations in the laboratory. The list of companies funded by the Methuselah Foundation includes the bioprinting company Organovo, an investment that has paid off handsomely in all senses of the phrase, and more recently Oisin Biotechnology, a new initiative focused on senescence cell clearance. The latest investment, announced a few days ago, is focused on getting to an answer on a novel approach to therapies for Alzheimer's disease:

Could a New Approach to Alzheimer's Move Us Closer to a Cure?

Leucadia Therapeutics LLC, a biotechnology company focused on treating and preventing Alzheimer's disease, using patent-pending technology to correct the cause of the disease rather than its effects, and Methuselah Foundation, a public charity incentivizing innovation in regenerative medicine, today announced a joint partnership to develop a novel therapeutic strategy to treat Alzheimer's disease. The company will use this investment to accelerate development of novel therapy with the goal of beginning clinical trials in 2018.

Leucadia Therapeutics Chief Scientific Officer, Douglas Ethell, Ph.D., said, "This is an exciting event for LT as it frees us from fundraising and allows us to focus our efforts on getting into the clinic as soon as possible." Under this agreement, the Methuselah Foundation has made an equity investment in Leucadia Therapeutics LLC. Over the next 3-5 years, Leucadia will develop and test a novel therapeutic device to treat the underlying cause of Alzheimer's disease.

As you can see the release provides no scientific details, but that's fine - information is available elsewhere. The scientist leading this effort, Douglas Ethell, has a background in dementia and stem cell research, and gave a talk on the underpinnings of his new approach at Rejuvenation Biotechnology 2015 entitled "CSF Hydrodynamics at the Cribform Plate: Has the Cause of Alzheimer's Disease Been Under or Over Our Noses All Along?" Unfortunately the video and abstract for this presentation are not yet published online, but we can instead look at a 2014 paper in which Ethell outlines the evidence for his hypothesis that Alzheimer's is caused by an age-dependent decline in drainage of cerebrospinal fluid through narrow passages in the head, a process that may normally assist in removal of unwanted metabolic waste - such as the amyloid associated with Alzheimer's disease.

Disruption of Cerebrospinal Fluid Flow through the Olfactory System May Contribute to Alzheimer's Disease Pathogenesis

Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa.

Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk.

I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL.

Ethell is not the only researcher providing evidence for this sort of idea, that the failure of drainage channels for cerebrospinal fluid is important in the development of dementia, and that these failures are essentially mechanical and structural issues in the same way as, say, stiffening of blood vessels is a mechanical and structural issue. Underlying cellular problems that involve the accumulation of forms of biochemical damage are what give rise to these mechanical and structural failures, but then the proximate issue that causes disease is that the system of tissues no longer pumps or flexes or drains fluid correctly. There are similar hypotheses for the declining integrity of the choroid plexus, a filtration system for cerebrospinal fluid, to be a proximate cause of Alzheimer's disease. It is certainly the case that amyloid levels in the brain appear to be dynamic on a short timescale; there is a lot of support for the view of Alzheimer's disease as the result of a slow failure of a constant, ongoing clearance of metabolic wastes rather than a slow accumulation of metabolic wastes with little clearance.

One of the good points about the failing drainage hypothesis is that it is comparatively cheap to test, and that test is what the Methuselah Foundation is buying here. Any way to restore the declining mechanisms involved, even if forcing the situation without repairing the underlying causes, will suffice for that test. If it the resulting treatment leads to reduced levels of metabolic waste in the brain, which should happen fairly rapidly if those waste levels are dynamic on a short time scale, then the hypothesis is correct. If it doesn't, then it is probably incorrect. This is medical science at its best and most practical.

Ghrelin is secreted in the body as a part of the process of hunger, and increased amounts in circulation have a range of sweeping effects on the operation of metabolism. It has been proposed that some portion of the long-term health benefits of calorie restriction and intermittent fasting arise because there are longer periods of hunger and thus longer periods in which there is more circulating ghrelin. For example, ghrelin has been shown to reduce inflammation and promote the development of new immune cells, among many other changes. So read this research in the broader context; I note it because it should be of interest to those who practice dietary restriction of one form or another, not because I believe that the approach here is necessarily going to result in a useful form of therapy:

A new study by a team of researchers suggests that the appetite-regulating hormone ghrelin could be used clinically for the early treatment of critical limb ischemia (CLI), an advanced form of peripheral artery disease. CLI is the severe obstruction of blood flow to the extremities that often requires major amputations and in half of all cases leads to death within five years. Its leading risk factors are diabetes, obesity and age. Using a mouse model of CLI, researchers showed that administering ghrelin daily over two weeks markedly improved blood flow in affected limbs. They found that ghrelin promoted growth of new structurally and functionally normal blood vessels, improved cell survival, and decreased tissue fibrosis.

The findings are exciting as currently there are no drugs treatments for CLI and other techniques are effective in only half of the cases. "Our team has previously shown that ghrelin showed promise for treating the presently incurable lung disease known as pulmonary hypertension, which is caused by blood vessels becoming progressively blocked. This prompted us to investigate whether ghrelin might have a similar effect in CLI." The researchers also studied ghrelin's action at the molecular level in tissue with restricted blood supply and identified that the hormone modulated downstream signalling cascades involved in new blood vessel growth and cell survival.

Link: http://www.otago.ac.nz/news/news/otago412601.html

Researchers here propose enhancing the cellular operation of the immune cells called macrophages in order to slow the progression of atherosclerosis, a condition in which blood vessel walls become inflamed and damaged, and dangerous fatty plaques grow inside the blood vessels. A number of processes contribute to the progression of atherosclerosis once any initial damage to blood vessel walls exists, and one of the important ones is the behavior of macrophages at the site of damage. These cells are drawn by the presence of oxidatively damaged cholesterol and lipids, ingest them and break them down. Some are overwhelmed by the volume of these damaged molecules, however, becoming what are called foam cells. Many die and their debris contributes to inflammation, and the growth of plaques that narrow blood vessels. This attracts further macrophages in a vicious cycle that ends in disaster when a plaque breaks free and blocks a blood vessel to cause a stroke or heart attack. This research is focused on enhancing the ability of macrophages to deal with cholesterol:

Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways.

In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1α, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe−/− mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans.

This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.

Link: http://dx.doi.org/10.1161/CIRCRESAHA.117.305624

It has been a great year for SENS rejuvenation biotechnology, both for funding and for results delivered by ongoing research programs. The 2015 fundraising continues apace, with yet another organization taking up the baton to offer a matching fund. Following on from our successful $250,000 Fight Aging! 2015 fundraiser to support the work of the SENS Research Foundation, the Foster Foundation has announced a matching fund of their own. They have put up a $50,000 fund to match all donations to the SENS Research Foundation made between now and the end of the year, just two weeks away. From the latest SENS Research Foundation newsletter:

We are pleased to announce that the Foster Foundation, a longtime supporter of SENS Research Foundation, has offered us a final year end challenge. They will match dollar for dollar up to $50,000 raised from December 14th to 31st. Formerly the Rose and Winslow Foster Family Foundation, the Foundation has provided over $150,000 in donations to SRF this year. We thank them for their amazing support of our mission. Help us secure this challenge grant by donating today and helping enable SRF's critical work to end age-related disease. So far we have received $8,402.61 towards this challenge.

The rejuvenation research programs running under the auspices of the SENS Research Foundation, and related efforts conducted by a few other organizations, represent the best of current approaches to the treatment of aging. Aging is caused by forms of cell and tissue damage, and therefore the fastest approach to building effective therapies, medical technologies capable of preventing and reversing aging, is to repair this root cause damage. Sadly all too little of modern medical research is focused on this goal, and the mainstream research community has so far only broadly undertaken work for cancer, stem cell therapies, and amyloid clearance, the latter mostly in the course of efforts to treat Alzheimer's disease. These are just three slices of the seven or more broad categories of repair technology needed, and much of the present mainstream work in these fields is either not directed at the treatment of aging, or is not likely to produce meaningful outcomes in terms of repair. This is why non-profit initiatives like the SENS Research Foundation are vital to the future of our health and longevity. Non-profits undertake the work that is overlooked, unprofitable, or unpopular in the existing funding ecosystem, and as a result can unblock logjams and enable progress and adoption of specific lines of research in the broader scientific community.

The SENS Research Foundation can point to success as a patron of mitochondrial repair research over the past eight years or so, helping to build the foundation for allotopic expression - placing backups of mitochondrial genes in the cell nucleus - to the point at which Gensight is now devoting tens of millions of dollars to development of the technology. The SENS Research Foundation has also recently funded the startup Oisin Biotechnology to proof and develop a method of senescent cell clearance, and transferred some of the promising results of their lysosomal aggregate clearance research to another startup, Human Rejuvenation Technologies, for the development of treatments for atherosclerosis. They are also in the process of unblocking work on clearance of glucosepane cross-links in humans, funding the development of the tools needed for effective research and development in that area.

These are all programs with concrete results that aim at repair of causes of degenerative aging and age-related disease. Few other organizations can claim to be doing as much with such a modest yearly budget. The more that we can help the SENS Research Foundation to grow, the faster we will see real, working rejuvenation treatments. The clock is ticking and none of us are getting any younger yet - a lot of work is left to accomplish before that starts to happen, and here is the chance to help make it happen.

A number of the large FOX family of proteins, in particular the FOXO proteins, appear to play roles in the complex interaction between metabolism and aging. They are thus targets for investigation and potential intervention in that part of the research community interested in trying to slightly slow aging via pharmacology. The plan there is to alter the operation of cellular metabolism in ways that boost existing mechanisms of repair and maintenance, or slow the pace at which the damage that causes aging is generated. The response to calorie restriction is the best understood of such altered states of metabolism, and investigations of the mechanisms involved in calorie restriction have determined much of the present focus on specific genes and proteins for those interested in developing drugs to modestly slow aging. The past decade suggests that attempting to do this is both hard and expensive; at least a billion spent on sirtuin research, for example, produced no useful results in terms of therapies. Even if further billions produce useful drug candidates, they will still be at best as effective as calorie restriction, and while calorie restricted individuals enjoy health benefits they still age and die on much the same schedule as their unrestricted peers. This isn't the road to rejuvenation.

An exciting research area on FOXO transcription factors' impacting on longevity has arisen in recent years. Studies have been conducted to address their upstream regulation, their downstream effectors, and respective signaling pathways in various animal models. Consequently, how these FOXO-mediated programs affect cellular or tissue function and whether there is an effect at an organismal level, has also been scrutinized. Several lines of evidence suggest that FOXOs affect longevity in a pleiotropic fashion, influencing several cell-regulated activities such as stress resistance, metabolism, cell cycle arrest, and apoptosis.

A myriad of future work can be envisioned at this time. The induction of FOXO-mediated programs in tissues with distinct metabolic potential such as brain, muscle, or adipose tissue and with different stages of differentiation or metabolic conditions (nutrition, oxidative stress) will enlarge our knowledge of how FOXO factors affect cellular/organismal lifespan. To further comprehend how FOXOs affect longevity, it is of high importance to understand how human FOXO sequence variants (namely FOXO3A) affect protein expression, its structure, or transcriptional activity. In order to see how these variants translate into physiological profiles, future investigations should address how these variants affect the level of FOXO proteins and their downstream effectors in serum. This approach has been used successfully in patients with vitiligo, in which FOXO3A levels were shown to be decreased when compared with the control group.

Compression of morbidity relates to both extended lifespan and delayed onset of age-related diseases, such as cancer and cardiovascular disorders. The development of molecules targeting aging mechanisms that underlie a number of age-related diseases is an exciting field that is nowadays in its first steps. It is noteworthy that clinical trials to test lifespan extension in humans would be challenging and require markers that can detect difference in aging rate across a short time frame. But given the potential of FOXO proteins to impact on numerous disorders such as cancer, diabetes, neurodegeneration, or immune system dysfunction, novel therapeutic modalities based on FOXOs will most likely take place in the near future.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12427/

Some of the chemical factories and filters in our bodies could be replaced by any device that performs the same function, and that device doesn't have to look anything like the structures they replace. However, the easiest way to recapitulate the original tissue function is still to use actual tissue, either donor or engineered. Researchers here report that decellularization, removing the cells from donor tissue and replacing them with the recipient's cells, is potentially a way to use discarded donor tissue as the basis for bioartificial organs:

The pancreas is a large gland near the stomach that secretes insulin to regulate the metabolism of glucose and other nutrients. Researchers have been working for years to develop an artificial pancreas in the lab to help the millions of people with type 1 diabetes. But what if the answer is to "recycle" the more than 300 human pancreata from organ donors that aren't currently being used? Researchers now report on the potential to use human pancreata as the "hardware" of a new-generation, bio-artificial pancreas. Currently, about 25 percent of the approximately 1,300 pancreata recovered for transplant cannot be used due to defects and other reasons. "We see these unused organs as potential 'hardware." The 'software' would be the patient's own cells, so that there would be no issues with rejection. We believe this research represents the first critical step toward a fully human-derived artificial pancreas."

The goal of the research was to test the suitability of pancreata from organ donors as a platform for building a new bio-artificial pancreas. First, the discarded organs were washed in a mild detergent to remove all cells, a process that is known as decellularization. A similar procedure is being used by regenerative medicine researchers in efforts to engineer human kidneys, livers and intestine. For the study, 25 human pancreata were processed to remove cells. The researchers found that the framework of blood vessels remained intact after the washing process. In addition, the researchers are the first to report that numerous growth factors were retained in the structures. Some of these proteins are essential in blood vessel formation, cell proliferation and glucose metabolism.

In theory, these organ structures could be re-populated with a patient's own cells. Insulin-producing cells could be generated from the patient's skin cells or could come from the patient's pancreas. Cells to line the organ's blood vessels (endothelial cells) could also come from the patient's pancreas. To test the compatibility of the decellularized structures and new cells, the researchers placed both insulin-producing and endothelial cells on the decellularized structures. In both cases, the organs structures were cell-friendly and allowed the cells to attach, function and maintain their original cell type. Next, to test the ability of the structures to grow new blood vessels, small samples of the cell-coated pancreata structures were implanted in chicken eggs. The structures integrated well with the developing environment of the chicken egg and generated capillaries.

Link: http://www.wakehealth.edu/News-Releases/2015/Researchers_Report_Possibility_of_Using__Unused_Human_Pancreata_to_Build_New_Organs.htm

Effective clearance of senescent cells in humans is arguably the form of SENS-style rejuvenation treatment based on repair of cell and tissue damage that is closest to practical implementation. A therapy capable of safely clearing even half of the senescent cells present in all tissues should prove very beneficial - and it is something that can be applied multiple times, as needed, repeatedly turning back this contribution to degenerative aging. As is always the case in these matters, however, only a few research groups are actively working on the problem, and funding is a desert in comparison to other areas of far less interesting research. This is why the research materials I'll point out here, news of a new potential class of senescent cell clearing drugs, still in the early stages of investigation, is worthy of attention rather than being buried by a score of similar announcements. In populous and comparatively well-funded fields such as the treatment of heart disease or arthritis there are far too many potential new drugs under study at an early stage in laboratories and noted in research papers to remark upon each of them. Few of these promising starts in cell cultures will ever get much further than that; there are many possible reasons why good results in cells don't translate to good results in animals. Similarly many of the promising results in animal studies fail on the next stage beyond that. So temper your enthusiasm.

Cells become senescent in response to damage, toxic environments, or as an alternative to self-destruction when they reach the end of their replicative life span. Some are destroyed by the immune system, but enough remain and linger that many tissues are made up of a sizable proportion of senescent cells by late life. These cells behave badly, secreting compounds that alter surrounding cellular activities, spur chronic inflammation, and degrade the extracellular matrix that is fundamental to tissue properties such as elasticity or load-bearing strength. Even partial and uneven clearance of senescent cells has been demonstrated in animal studies to provide lasting benefits to health following a single treatment. Better and more comprehensive clearance should produce greater benefits. That, of course, requires the development of improved methods of clearance.

The research materials quoted below can be taken as a representative sample of the sort of work that should be taking place in many more laboratories, an exploration in search of ever more effective ways to eliminate senescent cells from the body. Inevitably there will be dead ends, surprises, and much more failure than success. That is always the way in research. The way to make progress is to take many chances, invest in many diverse approaches to increase the overall odds of at least one useful result. Perhaps the most useful outcome here is that these results provide another solid demonstration that senescent cell clearance produces meaningful health benefits in aging mice. It is worth remembering that SENS rejuvenation research advocates have been calling for investment in this approach to the treatment of aging for more than a decade now, providing detailed research and development plans along with that advocacy, and were initially mocked for it in many quarters. Only in the last couple of years has the research community directed even a modicum of funding towards senescent cell clearance. There are lessons to be learned here, and one of them is that we could be closer to the defeat of aging than we are today had more people listened back then.

The first broad spectrum drug that can potently kill senescent cells in culture

Researchers are reporting the discovery of the first broad spectrum drug that can potently kill senescent (or aging) cells in culture and effectively clear the cells in animals by specifically targeting a pathway that is critical for the survival of senescent cells. Because senescent cells are believed to play a role in the late effects of radiation on normal tissues and certain age-related diseases, this study has broad implications for future therapies targeting the common biological mechanism that contributes to late tissue injury caused by radiation and aging. Cellular senescence, the loss of cells' ability to divide, normally functions as a tumor suppressive mechanism; however, senescent cells become "toxic" as they accumulate after exposure to radiation and with age. This is because they cause stem cell aging that reduces the ability of tissue regeneration and repair and drive chronic inflammation and oxidative stress. Since chronic inflammation and oxidative stress are thought to be the root cause of some late effects of radiation and many age-related diseases, including radiation-induced long-term bone marrow injury and age-related osteoarthritis and atherosclerosis, eliminating senescent cells has the potential to mitigate radiation-induced late tissue injury and treat many age-related diseases.

In the current study, ABT-263, a molecule initially developed as an anti-cancer therapy, was given orally to either normally aged mice or irradiated mice to induce premature aging of the hematopoietic system, the organs and tissues involved in production of blood. ABT-263 effectively depleted senescent cells, including senescent "stem cells" of the bone marrow and muscle. Depletion of the senescent cells appeared to reduce premature aging of the bone marrow caused by irradiation, and even rejuvenated the function of stem cells in normally aged mice. "Our results demonstrate that clearance of senescent cells by a pharmacological agent is beneficial in part by rejuvenating aged tissue stem cells. Because a decline in tissue stem cell function is associated with exposure to radiation and aging, we believe clearing senescent cells and rejuvenation of tissue stem cells could have a major impact on mitigation of radiation injury and treatment of diseases of aging. ABT-263 was originally developed as an anti-cancer agent. It has toxic side effects that make it inappropriate for development as an agent for diseases of aging. We are investigating next-generation small-molecule drugs that are optimized to clear senescent cells without drug-induced toxicity."

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug.

We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.

Researchers here link age-related issues with the body clock to the development of osteoarthritis, a degenerative condition of joints. The body clock controls changes in cell and organ activities according to the time of day. This overall system has its reflections in the biochemistry of all types of cells, and, as for many other aspects of cellular biology, the mechanisms involved in clock-related regulation become disarrayed with age. The proximate causes of this disarray are only partially cataloged and explored, long lists of changing protein levels and relationships mapped one by one. The root cause is most likely the well-known forms of cell and tissue damage that cause aging, but - as ever - drawing a line between that damage, through largely unmapped, complicated chains of cause and consequence, to link up with any one specific end result of aging is a challenging, expensive, and time-consuming process. It would be faster to fix the damage and see what happens, a path that would also provide a much greater chance of meaningful therapies resulting from research work.

Researchers have for the first time established that the painful and debilitating symptoms endured by osteoarthritis sufferers are intrinsically linked to the human body clock. Body clocks within cartilage cells - or chondrocytes - control thousands of genes which segregate different biological activities at different times of the day. The body clock, researchers realised, controls the equilibrium between when chondrocyte cells are repaired during rest and when they are worn down through activity. But the research revealed that as we age, our cartilage cell body clocks deteriorate, making the repair function insufficient, which could contribute to osteoarthritis.

The team examined three types of human cartilage under the microscope : normal, mildly affected by osteoarthritis and severely affected. As the osteoarthritis became more severe, the number of cells that express BMAL1 - a protein which controls the body clock - became less and less. And in terms of aging, he found similar reduction of BMAL1 in chondrocytes, which coincided with the reduced 'amplitude' of the body clock (up to 40% weaker in older mice), supporting the theory that aging, at least partially through dysregulation of the chondrocyte clocks, is a major risk factor for osteoarthritis.

Link: http://www.manchester.ac.uk/discover/news/body-clock-study-unlocks-prospect-of-treatment-for-osteoarthritis/

The gene p53 is an important tumor suppressor. A loss of function in p53 is involved in many cancers, permitting uncontrolled replication of cells. Here researchers make progress in understanding how this works under the hood, finding links that may help to provide a detail view of how rapamycin and a few other drugs act to reduce cancer risk.

The gene p53 has been described as the "guardian of the genome" due to its prominent role in preventing genetic mutations. More than half of all cancers are thought to originate from p53 mutations or loss of function. New research describes how mutations and or loss of function of the p53 gene activate a protein complex known as mammalian target of rapamycin complex 1 (mTORC1), which helps regulate the energy resources needed for cell proliferation.

mTORC1 is made up of several dozen proteins, and cells use the intracellular membranes of their lysosome as a scaffold to bring all of these proteins together. In response to the need of a normal cell, the p53 gene helps maintain proper levels of a protein known as tuberous sclerosis complex 2 (TSC2) in the lysosome. When p53 is not functioning properly, TCS2 levels in the lysosome drop, and a small protein known as RHEB takes its place. It is this accumulation of RHEB that activates mTORC1 and leads to the abnormal control of cell proliferation. "We have uncovered for the first time the signaling process that leads to excessive growth of cancer when p53 is lost. These protein interactions are like individual links in the chain of events leading to the development of cancer."

Link: http://www.eurekalert.org/pub_releases/2015-12/vcu-msu121415.php

I'm pleased to announce that the 2015 Fight Aging! matching fundraiser to benefit the SENS Research Foundation has hit the funding goal. Three months ago Fight Aging!, Josh Triplett, Christophe and Dominique Cornuejols, Michael Greve of forever-healthy.org, and Stefan Richter collaborated to create a $125,000 matching fund for SENS donations. We challenged the community to meet that amount by the end of this year: every dollar donated to SENS rejuvenation research before December 31st would pull in a matching dollar from the fund. With that total hit here in the middle of December, we have collectively managed to channel $250,000 to the best and most promising research aimed at treating the causes of aging. A quarter of a million dollars can buy a fair amount of early stage research in the life sciences these days. The cost of the tools is falling even as their capabilities grow, and so this is a great time to support medical research. We can make a real difference.

It is important work that we fund with our donations. SENS research programs represent the best chance at significant progress towards rejuvenation therapies in our lifetimes, leading to a range of treatments that work by repairing or clearing the forms of fundamental cell and tissue damage that cause aging and age-related disease. In many cases, SENS-funded research is near the only meaningful work on such therapies, and in those areas SENS Research Foundation programs exist to remove roadblocks and thus enable broader participation and interest in the research community. SENS rejuvenation research has been funded at a low level for a little more than a decade now, long enough for the first results to be visible. In the past couple of years concrete progress has occurred in many of the relevant fields, the fruits of past philanthropic donations.

Most recently, this year saw an important piece of infrastructure technology produced in efforts to clear glucosepane cross-links, for example. In 2014 and 2015 researchers produced technology demonstrations for senescent cell clearance treatments, showing benefits to health in normal aged laboratory mice. A startup company was funded based on one of these technologies. In 2015 another startup, Human Rejuvenation Technologies, received a technology transfer from the SENS Research Foundation with the aim of producing a therapy for atherosclerosis based on programs for clearance of intracellular aggregates. In addition, the first promising trial results in human patients arrived for a treatment that clears transthyretin amyloid from old tissues. Further, methods of repairing mitochondrial DNA damage funded in part by the SENS Research Foundation have moved beyond the laboratory and have been under commercial development since 2013.

The SENS supporters of past years have good reason to be pleased with what has been achieved with their charitable donations, a significant increase in progress towards the tools needed to bring aging under medical control. The SENS Research Foundation and its allies have achieved more than just technological progress, however. Moving forward in the production of medical technology to treat aging has always been as much about persuasion as about research, a matter of having to convince the world that yes, this is possible, plausible, and necessary. People are largely blind when it comes to the costs and suffering caused by aging, and even as recently as a decade ago the medical research community was a hostile environment for anyone who thought to talk openly about treating the causes of aging - to do so was to risk funding and career. This has changed in large part thanks to the efforts of advocates such as the SENS Research Foundation staff, past and present. The present culture of aging research is one in which people debate openly over how best to treat aging; this is a very big deal, and another reason for long-time supporters of the SENS Research Foundation to be pleased at how much has been achieved to date.

A fraction of the characteristic age-related decline and disarray of the immune system is due to long-term cytomegalovirus (CMV) infection. This herpesvirus is near ubiquitous in the population by the end of life, but for most people there are no immediate or obvious symptoms, or at least not beyond the slow corrosion of the immune system. CMV cannot be cleared from the body, but the immune system appears to devote ever more of its limited resources to this futile battle at the cost of its overall effectiveness. In the research paper noted below, researchers catalog more of the details of this process.

A robust therapy to clear CMV, were one developed, wouldn't fix the damage to the immune system created during the period of infection. One possibly alternative approach is to use targeted cell killing treatments to remove the specialized immune cells and free up space for their replacement, something that has been demonstrated to various degrees in the laboratory, but there is sadly little ongoing work here - the usual story for anything that might make a real difference in aging.

Aging and latent infection with cytomegalovirus (CMV) are thought to be major factors driving the immune system towards immunosenescence, primarily characterized by reduced amounts of naïve T-cells and increased memory T-cells, potentially associated with higher morbidity and mortality. The composition of both major compartments, γδ as well as αβ T-cells, is altered by age and CMV, but detailed knowledge of changes to the γδ subset is currently limited. Here, we have surveyed a population of 73 younger (23-35 years) and 144 older (62-85 years) individuals drawn from the Berlin Aging Study II, investigating the distribution of detailed differentiation phenotypes of both γδ and αβ T-cells.

This study presents a uniquely detailed analysis of the γδ T-cells, in younger and older people with a carefully characterized background. In the same subjects, we also assessed αβ T-cells, and found strong associations of CD8+ αβ T-cells, Vδ1+, other (Vδ1-Vδ2-) with age and also with CMV-seropositivity. The CD4:CD8 ratios were lower in old CMV-seropositive than in seronegative individuals. We found increased Vδ1:Vδ2-ratios associated with CMV in the old, similar to what is reported in cancer, supporting the theory of dual reactivity of γδ T-cells. It remains to be determined whether the increased Vδ1+ compartment in CMV-seropositive individuals might have similar detrimental impact as reported for the survival of melanoma patients. The memory differentiation patterns in the Vδ1+ compartment are similar to the CD8+ αβ T-cells markedly changed by age and amplified by the presence of CMV, suggesting an increased memory compartment of acquired immunity over the life-time and in particular in association with CMV. More functional and longitudinal studies are needed to better understand age-associated immune exhaustion and the role, if any, that a latent CMV infection plays therein due the major investment of immune system resources to maintain control of latent CMV.

Link: http://dx.doi.org/10.1186/s12979-015-0052-x

This open access review covers, in some detail, the state of development for stem cell therapies aimed at tendon regeneration. This is one of numerous tissues in the human body with normally limited regenerative capacity, and for which stem cell treatments offer the potential for complete healing. Progress towards that goal is, as ever, not as rapid as we'd like, however. Note that the full paper is PDF format only for the moment:

Tendon injuries are a common cause of physical disability. They present a clinical challenge to orthopedic surgeons because injured tendons respond poorly to current treatments without tissue regeneration and the time required for rehabilitation is long. New treatment options are required. Due to its relatively low cellularity and vascularity as well as the change in the tissue microenvironment after injury, tendons form scar tissue and ectopic bone after injury without regenerating the original tendon structure.

Tissue engineering with stem cells offers the potential to replace the injured/damaged tissues with healthy and functional ones. The use of stem cells for tendon tissue engineering is advantageous compared to terminally differentiated cells as stem cells are pluripotent or multipotent, highly proliferative and synthetic, and can provide the appropriate signals to promote tendon regeneration compared to terminally differentiated cells. Moreover, stem cells can also be used as a vehicle for gene therapy and sustained delivery of bioactive factors for tendon repair.

While the application of stem cells for the promotion of tendon healing is promising in small animal models, there have been few well-controlled large animal studies and clinical trials. The follow-up duration in animal studies was usually short (usually 4-12 weeks). Further research on the efficacy and safety of stem cell-based therapy for tendon repair in well-designed large animal models with extended follow-up time and randomized controlled clinical trials is needed.

Link: http://dx.doi.org/10.2147/SCCAA.S60832

Researchers have discovered a new form of cellular senescence, created by engineering mitochondrial dysfunction in cell cultures and genetically altered mice. This is quite interesting in that both growing numbers of senescent cells and rising levels of mitochondrial damage are recognized as distinct contributions to degenerative aging, fundamental forms of tissue damage that occur as a side-effect of the normal operation of metabolism.

We shouldn't be at all surprised to find forms of aging-associate damage interacting with one another or spurring one another along. While there is an excellent catalog of fundamental damage, the enumerated differences between old tissue and young tissue, and there is a less comprehensive but still very good catalog of the ways in which we humans fall apart when we are old, linking these two catalogs together with detailed chains of cause and effect is a massive undertaking. The complex interactions that happen in between initial damage and final disease state are at present more a matter of blank space on the map than a matter of filled lines and connections. There are exceptions: the contribution of lipofusin accumulation to age-related retinal disease is fairly direct, for example. Most of the picture is far less clear, and looks like the situation for mitochondrial damage and cellular senescence, however: numerous conflicting sketches of what is thought to happen, chains of cause and consequence have many steps, and there is a lot of room for debate and discovery. The way in which aging progresses at the detail level is enormously complex, and a full understanding of aging in this sense would require a full understanding of the molecular biology of the cell in all of its states. This is a work in progress that researchers expect to remain in progress for decades yet.

What this means to many scientists is that those decades of work must take place before any real impact on the aging process can be produced. Full understanding before action is the mantra. There are other approaches, however: it would be much faster to start in on repairing forms of age-associated damage in laboratory animals and see what happens. That is a rapid path to both answers and the possibility of rejuvenation therapies, skipping over the expensive and time-consuming need to understand the huge blank spaces on the map. Getting to rejuvenation therapies more rapidly is the entire point of the SENS approach to aging, based on damage repair, and where SENS or SENS-like work has reached the stage of technology demonstrations in laboratory animals, as is the case for senescent cell clearance, it is pretty clear that meaningful health benefits are the outcome.

Returning to cellular senescence created by mitochondrial damage, the real question here is whether or not this exact situation is something that happens in the course of normal aging. It is very possible to create cell states in the laboratory that do not occur in a normal aged organism, or do occur but not to a significant degree. Fortunately for the knowledge-seekers among us this form of senescence is distinctive, so an answer to that question lies somewhere in the near future. That said, this is arguably one of the complexities buried in the progression of aging that can be skipped over on the way to human rejuvenation; if therapies are deployed to both repair mitochondrial damage and clear senescent cells, then does it matter how these two forms of damage build on one another? Not all that much. This is the power of the repair approach to treating aging. It side-steps an enormous amount of investigative work that would be required by other forms of research and development.

Signaling from dysfunctional mitochondria induces cellular senescence with a distinct secretory phenotype

Researchers need to stop thinking of cellular senescence, now accepted as an important driver of aging, as a single phenotype that stems from genotoxic stress. Research now reveals that cellular senescence, a process whereby cells permanently lose the ability to divide, is also induced by signaling from dysfunctional mitochondria - and that the arrested cells secrete a distinctly different "stew" of biologically active factors in a process unrelated to the damaging free radicals that are created in mitochondria as part of oxygen metabolism. "We don't yet know how much this process contributes to natural aging. But we do think the findings are important in addressing mitochondrial diseases, and those age-related diseases, such as some forms of Parkinson's, which involve mitochondrial dysfunction."

The discovery was unexpected and was made by eliminating sirtuins, a class of proteins long linked to longevity, one by one in human cell cultures. "The senescent phenotype only occurred when we eliminated the mitochondrial sirtuins." In addition, the senescent cells secreted a different IL-1-dependent inflammatory arm - a major factor in the more familiar form of SASP. The authors dubbed this new phenomenon MiDAS - mitochondrial dysfunction-associated senescence. "For any disease that has a mitochondrial component this research adds a potential explanation for the real driver of the dysfunction - and it's not free radicals, which we ruled out in our study. Our finding suggest a new role for mitochondria when it comes to affecting physiology."

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mitochondrial DNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

In recent news, researchers have found methylene blue to be a promising drug candidate for the treatment of progeria. This is one of the oldest of modern synthetic medical compounds, as it is getting on for 140 years since it was first created by chemists. Nearly a decade ago it was shown to delay cellular senescence and enhance mitochondrial activity in cell cultures. The results for progeria to date look very good in much the same sort of cell studies, but the important qualifying next stage of animal studies has yet to happen.

Progeria is often called an accelerated aging condition. It is not accelerated aging, however, but a form of genetic damage to lamin-A, a protein central to the correct operation of cells. This global dysfunction results in degenerative conditions that have many similarities to those of the later stages of aging, and which are fatal over the course of ten to twenty years. Few patients live past their teens. It is thought that the same damage as runs rampant in progeria is present to a much lesser degree in normal aging, though it is an open question as to whether there is enough of it to have any meaningful impact in comparison to the contribution of other forms of cell and tissue damage. Still, this small shared commonality is why it is worth paying attention to progress towards therapies for progeria, as you'll sometimes see results like these:

Research suggests that a common, inexpensive and safe chemical called methylene blue could be used to treat progeria - and possibly the symptoms of normal aging as well. A new study shows for the first time that small doses of methylene blue can almost completely repair defects in cells afflicted with progeria, and can also repair age-related damage to healthy cells. "We tried very hard to examine the effect of methylene blue on all known progeria symptoms within the cell. It seems that methylene blue rescues every affected structure within the cell. When we looked at the treated cells, it was hard to tell that they were progeria cells at all. It's like magic."

Progeria results from a defect in a single gene. This gene produces a protein called lamin A, which sits just inside the cell's nucleus, under the nuclear membrane. Healthy cells snip off a small piece of each new lamin A molecule - a small edit that is necessary for lamin A to work properly. Cells with progeria, however, skip this important editing step. The defective lamin A interferes with the nuclear membrane, causing the nucleus to form bulges and deformations that make normal functioning impossible. Cells with progeria also have misshapen and defective mitochondria, which are the small organelles that produce energy for the cell. Although previous studies suggested damage to mitochondria in progeria cells, the current study is the first to document the nature and extent of this damage in detail. A majority of the mitochondria in progeria cells become swollen and fragmented, making it impossible for the defective mitochondria to function.

The team found that methylene blue reverses the damages to both the nucleus and mitochondria in progeria cells remarkably well. The precise mechanism is still unclear, but treating the cells with the chemical effectively improved every defect, causing progeria cells to be almost indistinguishable from normal cells. The researchers also tested methylene blue in healthy cells allowed to age normally. The normal aging process degrades mitochondria over time, causing these older mitochondria to resemble the mitochondria seen in progeria cells. Once again, methylene blue repaired these damages. "So far, we have done all of our work in stem cell lines. It is critical to see whether the effect extends to whole animals. We also want to see if methylene blue can repair specific effects of progeria in various cell types, such as bone, skin, cardiovascular cells and others. Further down the line, other groups might begin human clinical trials. It's very exciting."

Link: http://cmns.umd.edu/news-events/features/3352

This open access paper describes detrimental age-related changes in the lymphatic system that involve disruption of the extracellular matrix and inflammation-associated biochemistry, something that suggests the involvement of senescent cells. Like old blood vessels, lymph vessels become leaky and less capable with age:

The lymphatic system comprises blunt-ended lymphatic capillaries, collecting lymphatic vessels, lymph nodes, and the thoracic duct. The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Our ultrastructural and proteomic analysis indicated a loss of the basal membrane and the extracellular matrix supporting the lymphatic endothelial cells as well as the proteins related to GAP junction formation. Functionally, the aged lymphatic vessels were impaired in their ability to actively support lymph flow. Significant reduction in pumping indices, including amplitude, frequency, and fractional pump flow, were observed. Under resting conditions these changes can generate low level of tissue edema, particularly when associated with increased vessel permeability as also observed in this study. However, in pathological conditions, such as acute and chronic inflammation, the increased volumetric loads imposed on the lymphatic collectors could further enhance their impaired ability to support the lymph flow.

A reduced thickness in the glycocalyx, with increased protein glycation and oxidation, was also observed. These modifications help explain the increased permeability observed in the aged collectors. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Microvascular dysfunction with hyperpermeability was also previously observed in aged blood vessels and was attributed to oxidative stress, inflammation, and activation of apoptotic signaling. Likely, the same mechanism contributes to the hyperpermeability observed in the aged lymphatic collectors. Indeed, analysis confirmed the presence of posttranslational modifications associated with oxidative stress. These modifications can alter proteins half-life, increase protein degradation, and decrease cellular functionality. Indeed, several of the collagen proteins as well as cadherins and GAP junction proteins were decreased in aging collectors. Disruption of these proteins was previously observed to be associated with paracellular permeability in blood capillaries. Similarly, we observed endothelial cells barrier dysfunction and increased permeability in aged lymphatic collectors. Functionally, the ability of pathogens to more readily escape the aged lymphatic collectors would contribute to the decreased ability of the immune system to control infections in aging. Indeed, decreased lymph transport to the lymph nodes is associated with an increase in the number of tissue colony-forming units.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531072/

To go along with Nature Medicine's latest focus issue on aging and the prospects for producing therapies to treat aging, I see that Science Magazine's December 4th special issue covers much the same topic. It is interesting to see this example of a convergence of discussion in respected publications, representative of a greater willingness by the scientific community to earnestly consider and plan a path towards the medical control of aging.

I used the occasion of the Nature Medicine issue to complain about the present mainstream research focus; when it comes to aging, the majority of scientists involved in the field undertake research programs that cannot possible produce meaningful results in terms of additional years of healthy life. Meanwhile approaches that can in principle produce real, actual rejuvenation in old people, and prevent aging in the young, are neglected in comparison. Today I'll instead focus on the more positive side of things, which is that the treatment of aging is now a serious, accepted, legitimate field of research within the broader scientific community. It took twenty years of persuasion and slow bootstrapping of research results to get to this point, but now here we are.

Ten or fifteen years ago for scientists to talk in public about extending healthy human life spans was to risk funding and career, which certainly stunted the pace of progress. There has been a sea change in the last few years as the results of advocacy flourished - things couldn't be more different now. Within the extended research community the important arguments today are over how aging should be treated, not whether or not it is plausible, useful, or desirable. The common sense position has finally won out among scientists: aging should be treated because it is the cause of age-related disease, and it is a given that we should work towards curing and preventing age-related disease because it is a source of suffering, pain, and death. If you think that suffering, pain, and death are bad things, then you should be all for working as hard as possible to end degenerative aging. It is the greatest single cause of suffering, pain, and death in the world by a very broad margin: more than 100,000 lives lost every day, and hundreds of millions of others in various states of pain, frailty, and disability.

Toward Healthy Aging, Putting Off the Inevitable

The dream of cheating death has evolved into a scientific quest to extend healthy life span. Scientists and doctors are looking for ways to maximize the number of years that we live free of chronic diseases, cancer, and cognitive decline. But before we can intervene, we have to understand the cellular and molecular mechanisms that drive aging and senescence. Some clues reside in our telomeres, the tips of our chromosomes that shrink with age. Others lie in our stem cells, which can only go on for so long repairing our tissues. Our mitochondria, too, the so-called powerhouses of the cell, may hold some answers to prolonging youthfulness. Other research points to changes in the gut microbiota associated with frailty in the aged. At a mechanistic level, the modulation of coenzyme NAD+ usage or production can prolong both health span and life span. Current geroscience initiatives aim to harness basic insights in aging research to promote general advances in healthy aging.

Questions remain throughout the aging field. By tweaking everything from genes to diets to environmental temperature and mating, scientists have created Methuselah flies and other remarkably long-lived animals while garnering fundamental insights into the biology of aging. Still, researchers puzzle over the most basic questions, such as what determines the life spans of animals. Meanwhile, a handful of molecular biologists are searching for ways to measure a person's biological, as opposed to chronological, age, but that quest, too, has proved elusive. An ever-growing literature addresses both theoretical and pragmatic approaches to the challenge of aging. In this special issue, we have focused mainly on the cellular aspects of mammalian aging, with the goal of spurring future developments in promoting health span, if not life span.

Death-defying experiments

The longest lived laboratory animals shed light on the forces that lead some to any early grave and others to beat the odds and see many more birthdays than the norm. Experiments with mice, flies, and worms have won that manipulating genes, restricting calorie intake, and giving animals drugs can extend life span - by as much as 10-fold. Researchers also have elucidated several biochemical pathways that lead to longevity. And one lab animal, the hydra, appears to have found a fountain of youth of sorts: Unless it sexually reproduces, it appears immortal.

Stem cells and healthy aging

Research into stem cells and aging aims to understand how stem cells maintain tissue health, what mechanisms ultimately lead to decline in stem cell function with age, and how the regenerative capacity of somatic stem cells can be enhanced to promote healthy aging. Here, we explore the effects of aging on stem cells in different tissues. Recent research has focused on the ways that genetic mutations, epigenetic changes, and the extrinsic environmental milieu influence stem cell functionality over time. We describe each of these three factors, the ways in which they interact, and how these interactions decrease stem cell health over time. We are optimistic that a better understanding of these changes will uncover potential strategies to enhance stem cell function and increase tissue resiliency into old age.

Healthy aging: The ultimate preventative medicine

Age is the greatest risk factor for nearly every major cause of mortality in developed nations. Despite this, most biomedical research focuses on individual disease processes without much consideration for the relationships between aging and disease. Recent discoveries in the field of geroscience, which aims to explain biological mechanisms of aging, have provided insights into molecular processes that underlie biological aging and, perhaps more importantly, potential interventions to delay aging and promote healthy longevity. Here we describe some of these advances, along with efforts to move geroscience from the bench to the clinic. We also propose that greater emphasis should be placed on research into basic aging processes, because interventions that slow aging will have a greater effect on quality of life compared with disease-specific approaches.

The mortality data for 2014 was recently published by the CDC. The popular press has been making a big deal of the fact that the statistical measure of life expectancy at birth has remained much the same these past few years. This is something that epidemiologist S. Jay Olshansky has suggested might happen as a result of the consequences of greater obesity temporarily outweighing progress in medicine, but a few years is too short a period of time to confirm any departure from the long slow upward trend in life expectancy established over past decades. Meanwhile we should bear in mind that present trends are the outcome of a period of development in which researchers were making no efforts to treat the causes of aging; gains in life expectancy were incidental. That is now changing, and future trends will reflect a research community increasingly involved in building therapies that target the mechanisms of aging. The past will not reflect the future, and this is a time of transition.

This report presents 2014 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population. Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, the 10 leading causes of death, and the 10 leading causes of infant death were analyzed by comparing 2014 final data with 2013 final data.

Life expectancy at birth represents the average number of years that a group of infants would live if the group was to experience, throughout life, the age-specific death rates present in the year of birth. In 2014, life expectancy at birth was 78.8 years for the total U.S. population - 81.2 years for females and 76.4 years for males, the same as in 2013. Life expectancy for females was consistently higher than life expectancy for males. In 2014, the difference in life expectancy between females and males was 4.8 years, the same as in 2013. Life expectancy at age 65 for the total population was 19.3 years, the same as in 2013. Life expectancy at age 65 was 20.5 years for females, unchanged from 2013, and 18.0 years for males, a 0.1-year increase from 2013. The difference in life expectancy at age 65 between females and males decreased 0.1 year, to 2.5 years in 2014 from 2.6 years in 2013.

In 2014, the 10 leading causes of death - heart disease, cancer, chronic lower respiratory diseases, unintentional injuries, stroke, Alzheimer's disease, diabetes, influenza and pneumonia, kidney disease, and suicide - remained the same as in 2013. The 10 leading causes accounted for 73.8% of all deaths in the United States in 2014. From 2013 to 2014, age-adjusted death rates significantly decreased for 5 of the 10 leading causes of death and significantly increased for 4 leading causes. The rate decreased by 1.6% for heart disease, 1.2% for cancer, 3.8% for chronic lower respiratory diseases, 1.4% for diabetes, and 5.0% for influenza and pneumonia. The rate increased by 2.8% for unintentional injuries, 0.8% for stroke, 8.1% for Alzheimer's disease, and 3.2% for suicide. The rate for kidney disease in 2014 remained the same as in 2013.

Link: http://www.cdc.gov/nchs/data/databriefs/db229.htm

Researchers are working on the use of red blood cells engineered to act as drug manufactories, a way to deliver sustained doses of a therapy to patients while circumventing some of the challenges inherent in other delivery methods:

The new technology draws on recent advances in the ability to genetically modify and grow human red blood cells from stem cells in culture. Using established molecular biology techniques, scientists can engineer progenitor cells taken from human bone marrow and grow blood cells that produce specific therapeutic proteins on their surface or inside the cell. Before they become fully mature, mammalian red blood cells eject their genetic material, so as a therapy they are easier to control and less risky than other stem cell and gene therapies, which can lead to abnormal cell growth and tumors. Human red blood cells circulate for as long as four months, meaning they could potentially form the basis of long-term therapies. The cells can get anywhere in the body through the bloodstream and can protect the therapeutic agent from the immune system.

The first drug will be for phenylketonuria, or PKU, a devastating genetic disorder that renders people with the disease unable to digest the amino acid phenylalanine, which is found in most high-protein foods. Researchers have so far tested the PKU drug in animals and in human blood in the lab, and it aims to begin clinical testing next year. Researchers have identified enzymes that can break down phenylalanine, "but you can't just inject an enzyme into the bloodstream," because the body will clear it quickly, and it could induce an immune reaction that would render future treatments with the same enzyme useless. Engineering red blood cells to produce the desired enzyme "answers both problems."

Animal tests suggest that engineered red blood cells can be a "very potent" therapy for a range of diseases. Not-yet-published work has shown that cells modified to produce an antibody to a specific bacterial toxin render mice resistant to many times the lethal dose of that toxin. It takes only a few weeks to grow cells that produce a new protein of interest, and the potential for new drugs based on red blood cells is "only limited by your imagination."

Link: http://www.technologyreview.com/news/544281/turning-red-blood-cells-into-versatile-drug-carriers/

The Nature Medicine journal's December 2015 issue is focused on aging and the present mainstream view of the road ahead towards treatments. Sadly, to my eyes at least, the mainstream view is still very much focused on investigating the mechanisms that cause variations between individuals in the outcomes and pace of aging - the scientific impulse towards generating full understanding at work. Genetics are at the forefront of this investigation, alongside prosaic environmental factors such as diet and lifestyle choices. This is, of course, absolutely the proven, correct path for the scientific method, and in the very long term all knowledge is useful. The mapping of the molecular biology of all observed states of human metabolism should continue, and in a better world it and all other scientific investigation would have a hundred times the funding it does at present.

To think this approach is the sum of the possible misses a very important aspect of our situation today, however. We stand at a point at which the research community might, given the right choices in funding research and development, bypass the need for the full understanding of the progression of aging and eliminate that progression by repairing its causes. The causes of aging are forms of cell and tissue damage that are comparatively well understood; there is consensus, good mapping of the basics of the biochemistry involved, little in the way of new additions to the list in the past twenty years, and where there is bickering, it is over which of these things is more or less important than the others, or over the big unexplored gulf of interlinked chains of cause and effect that lies between these well-understood causes and the complex mess they create given decades of aging. So we should skip the mess and fund the research to fix them all; the fastest and cheapest way to figure out relevance is to repair the damage in mice and see what happens. Well planned research programs and proposed treatments exist for all of these forms of damage, at varying stages of progress and funding, with the aim of producing novel forms of regenerative medicine capable of rejuvenation, turning back aging by removing its root causes.

There isn't yet much enthusiasm for this path from the mainstream. These researchers are focused on genetic variance, obesity, diet, calorie restriction mimetics, and a hundred other similar things that can swallow billions and decades to produce only knowledge and marginal gains in health and life span. It is a great pity, but at least there are some signs of progress towards better approaches. The Alzheimer's research community is working on clearance of amyloid, which is a form of repair technology that is much needed. Senescent cell clearance has gained more attention over the past few years after technology demonstrations proving the point that removal of these cells - which are themselves a form of damage when they gather in numbers - produces significant benefits when tried. Selling the damage repair approach as a coherent philosophy of action for the treatment of aging is still an uphill battle despite these gains. The zeitgeist of today is longevity-related genes and expensive programs proposing to use drugs to make the metabolisms of some people more like those of some other people who have a marginally greater - but still tiny - chance of living to extreme old age in a state of frailty. Seems a waste when we could spend the same resources to implement SENS rejuvenation treatments with a good expectation of the ability to turn back aging as a result.

Aging: toward avoiding the inevitable

Although many would say that aging is a normal part of human biology, age is also the greatest risk factor for a wide variety of chronic disease. Whereas the passing of time cannot be stopped, a growing body of research in model organisms suggests that it may be possible to delay the concurrent decline in health. Preclinical data support a 'unifying aging hypothesis,' that a common pathway or pathways regulate the aging process and its associated disease indications. Examples of these pathways are covered in the two reviews in this issue on senescence, and metabolism, and in a perspective on proteostasis. However, a recurring theme is the heterogeneity of human aging. As noted in a recent report from the World Health Organization, we do not all age at the same rate with the same prevalence of age-related diseases. Understanding the genetic and/or environmental factors accounting for this heterogeneity, faithfully modeling them in preclinical studies and controlling for them in clinical studies are perhaps the biggest challenges facing the field.

With regard to understanding the genetic underpinnings of aging, inbred model organisms will take us only so far. Interrogating the diversity of the human genome and correlating it with aging phenotypes will be essential. Thanks in part to ever-improving next-generation sequencing technology, these efforts are well under way. In 2007 the Scripps Translational Science Institute launched the Wellderly Study, starting by sequencing a panel of candidate genes associated with aging in cohorts of people and working towards whole-genome coverage. The Longevity Genes Project, which was initiated at Albert Einstein College of Medicine in 2008, also aims to find genes associated with longevity by using a cohort of centenarians, their offspring, and age-matched individuals unrelated to these offspring. More recently, Human Longevity, Inc., a company founded by J. Craig Venter, declared that it is "building the world's most comprehensive database on human genotypes and phenotypes to tackle the diseases associated with aging-related human biological decline." These data sets, which are increasing in terms of their numbers of patients and coverage of the genome, will be invaluable to researchers seeking to unravel the genetic factors that influence human aging.

In terms of clinical studies of therapies aimed at extending healthspan, there are several the challenges unique to this field. But all indications suggest that therapies will be coming. They may be established agents repurposed for treating aging, such as the rapamycin analogs used by Novartis in a proof-of concept trial to boost immune function in the elderly. They might also be new agents dedicated to 'drugging' aging. In addition to profiling the genomic and phenotypic aspects of human aging, Human Longevity, Inc. is developing cell therapies aimed at regenerating human tissues. Calico - a company launched by Google - has partnered with the Buck Institute for Research on Aging and the Broad Institute of Massachusetts Institute of Technology to identify therapeutic targets, and with AbbVie to develop drugs to hit these targets. Even with candidate drugs in hand, testing them in clinical trials will require innovation and collaboration with regulatory agencies. The Targeting Aging with Metformin (TAME) study is paving the way toward having healthspan recognized as an indication by regulatory bodies. The challenges ahead in dissecting the factors that contribute to aging and age-related disease loom large. With technology, collaboration and innovation, the aging research community will overcome them.

But not by using calorie restriction mimetics or by mapping and mimicking the differences between people slightly more likely to live to 100 and people slightly less likely to live to 100. Aging is caused by damage, and that root cause damage is the same in everyone. Repair the damage - in the same way in everyone, using mass-produced therapies - and you don't have to care in the slightest about understanding the vast complexity and genetic diversity inherent in the way in which a heavily damaged human biology fails in one way or another. Trying to nurse along a failing machine in its heavily damaged state with the hope that it will fall apart a little later than it would otherwise have done is a fool's game: expensive, hard, and with little to show for it at the end. The meaningful approach is to instead repair the machine, replace its parts, remove the rust and damage and dysfunction. That is the right path to extending or restoring a functional, healthy life span.

This is one example of a number of lines of research aimed at interfering in the process of fibrosis, the generation of harmful scar tissue that can cause severe dysfunction in organs once underway:

Chronic damage to the liver eventually creates a wound that never heals. This condition, called fibrosis, gradually replaces normal liver cells - which detoxify the food and liquid we consume - with more and more scar tissue until the organ no longer works. Scientists have identified a drug that halts this unchecked accumulation of scar tissue in the liver. The small molecule, called JQ1, prevented as well as reversed fibrosis in animals and could help the millions of people worldwide affected by liver fibrosis and cirrhosis. "After too much damage in the liver, the scar tissue itself causes more scar tissue. We can actually reverse liver fibrosis in animals and are now exploring potential therapeutic applications for humans."

When the liver is damaged, small collections of hepatic stellate cells that specialize in storing vitamin A are called upon to tend to the wound. These activated stellate cells shed their vitamin A, travel to the site of injury and create thick, fibrous scar tissue to wall off and repair the damage. However, with prolonged organ stress, healthy liver cells become replaced by scar tissue, eventually leading to organ failure. "Traditional therapies targeting inflammation don't work because these cells have multiple ways to bypass the drug. In contrast, our strategy was to stop the fibrotic response at the genome level where these pathways converge."

The search for the critical genome pathway struck gold, uncovering a regulatory protein, called BRD4, that is a master regulator of liver fibrosis. With this new knowledge in hand, the team found JQ1 successfully inhibited BRD4 and halted the transformation of hepatic stellate cells into fiber-producing cells. This is good news, as JQ1 is a prototype of a new class of drugs currently being tested in human clinical trials for various cancers. "JQ1 doesn't just protect against the wound response, but also reverses the fibrotic response in mice. Our results indicate that BRD4 is a driver of chronic fibrosis and a promising therapeutic target for treating liver disease. We think this discovery may also treat fibrosis in other organs, like the lung, pancreas and kidney."

Link: http://www.eurekalert.org/pub_releases/2015-12/si-flf120815.php

It has long been suspected that hydra, small freshwater animals, are immortal in that they do not suffer degenerative aging. In practice this means that no changes in mortality rate, reproduction rate, and measures of cellular metabolism are observed over time. This is a highly regenerative species, with individuals capable of rebuilding themselves from fragments, and it may be the case that their constant regeneration is the source of their agelessness. Regarding that agelessness, the challenge for researchers is that verifying the lack of aging in a species is a slow statistical business of wait and see, and one can always suspect at the end of any given study that the authors did not check rigorously enough for signs of aging. Perhaps it is there, just too slow to show up over the time allotted. Certainly there has been some back and forth debate over the last twenty years regarding what the data does or does not support. This latest research provides a set of much more robust evidence in support of hydra agelessness:

The common perception that the bodies of all living beings age, is wrong. This has now been proved by a long-term experiment with the freshwater polyp Hydra, a microscopic animal. Observing many hundreds of them for almost ten years, they calculated that Hydra's mortality permanently stays constant and extremely low. For most species, including humans, the probability of dying within a specific year rises with age. Scientists regard this as an indicator of the decay of the aging body. For Hydra, evolution seems to have found a way to escape the mechanisms of the physical deterioration of getting older. For humans the probability of dying within one year is reaching levels as high as 50 percent for advanced ages. For Hydra, however, it remains constant at a low 0.6 percent. Humans only experience such small values when they are between 20 and 30 years old. Additionally, Hydra's reproduction rate did not diminish with age, instead the small animals continued to breed. In this sense the Hydra stayed forever young.

In a unique long-term experiment researchers created artificial conditions for the tiny water animals with their flimsy tentacles, which were free of fatal natural threats like predators. For almost ten years they have cared for of about 1,800 of the Hydras. Overall, the team has counted 3.9 million observation days of individual Hydra. The number of natural deaths per year, however, can be counted on one hand. On average there have been only five. When a Hydra passed away it was mostly due to laboratory accidents, such as a polyp sticking to the lid of its bowl and then drying up or simply having been dropped on the floor. From of the few natural deaths that remained researchers calculated Hydra's mortality. It is so low that even several lifetimes of researchers would not suffice to observe the end of the lifecycle of the polyps. Even after 500 years five percent of a cohort will still be alive. For two out of twelve of the Hydra cohorts under investigation, the risk of death was actually so small, that it will take 3,000 years until only five percent of the polyps remained.

"Hydra apparently manages to keep its body young because it does not senesce by accumulating damages and mutations, as most other living beings do. Hydra are probably able to follow a special self-preservation strategy, as its body and cellular processes are rather simple." For instance, Hydra are capable of completely replacing parts of the body that are damaged or are somehow lost. It can even fully regenerate if its body is destroyed almost completely thanks to a high number of stem cells. Stem cells are capable of developing into any part of the body at any time. Additionally, as Hydra replaces all of their cells within only four weeks, it regularly and quickly expels all cells that have been changed genetically by mutations. Thus, damages have little chance to accumulate.

Link: http://www.demogr.mpg.de/en/news_press/press_releases_1916/forever_young_4396.htm

As we age skin and blood vessels lose their elasticity. People care too much about the skin and too little about the blood vessels, but that is always the way of it. Appearance first and substance later, if at all. Yet you can live inside an aged skin; beyond the raised risk of skin cancer its damaged state arguably only makes life less pleasant, and the present state of medical science can ensure that the numerous age-related dermatological dysfunctions can be kept to a state of minor inconvenience. Loss of blood vessel elasticity, on the other hand, will steadily destroy your health and then kill you. Arterial stiffening causes remodeling of the cardiovascular system and hypertension. The biological systems that regulate blood pressure become dysfunctional as blood vessels depart from ideal youthful behavior, creating a downward spiral of increasing blood pressure and reactions to that increase. Small blood vessels fail under the strain in ever larger numbers, damaging surrounding tissue. In the brain this damage contributes to age-related cognitive decline by creating countless tiny, unnoticed strokes. Ultimately this process leads to dementia. More important parts of the cardiovascular system are likely to fail first, however, perhaps causing a stroke, or a heart attack, or the slower decline of congestive heart failure.

From what is known today, it is reasonable to propose that the two main culprits driving loss of tissue elasticity are sugary cross-links generated as a byproduct of the normal operation of cellular metabolism and growing numbers of senescent cells. Elasticity is a property of the extracellular matrix, an intricate structure of collagens and other proteins created by cells. Different arrangements of these molecules produce very different structures, ranging from load-bearing tissues such as bone and cartilage to elastic tissues such as skin and blood vessel walls. Disrupting the arrangement and interaction of molecules in the extracellular matrix also disrupts its properties. Persistent cross-links achieve this by linking proteins together and restricting their normal range of motion. Senescent cells, on the other hand, secrete a range of proteins capable of breaking down or remodeling portions of the surrounding extracellular matrix, and altering the behavior of nearby cells for the worse.

The most important cross-linking compound in humans is glucosepane. Our biochemistry cannot break down glucosepane cross-links, and as a result it accounts for more than 99% of cross-links in our tissues. This isn't a big secret. Given this you might expect to find researchers working flat out in scores of laboratories to find a viable way to break it down. After all here we have one single target molecule, and any drug candidate capable of clearing even half of existing cross-links would provide a treatment that can both reverse skin aging and vascular aging to a much greater degree than any presently available therapy. The size of the resulting market is every human being, the potential for profit staggering. Yet search on PubMed, and this is all of relevance that you will see published on the topic in the past few years:

• Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
• Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes.
• Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.
• Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications.
• The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.

This is a tiny output of work. The research and development world is not beating a path here as it should. The thesis is that this lack of enthusiasm exists because the state of tools and processes needed to work with glucosepane has long been somewhere between underdeveloped and nonexistent. No group will choose to work in an area in which they have to build the tools first when there are so many other choices available. This sort of chicken and egg situation exists in numerous places in every field of science and technology, small fields where a great deal might be achieved, but no-one does anything because the short-term rational choice is to do something else in an area where the tooling already exists. This is why we need advocacy and philanthropy, to fix problems of this nature. In recent years the SENS Research Foundation has been funding development of the tools needed for research groups to work with glucosepane in living tissues, and just this year we have seen the first published results: a simple, cheap, efficient method of creating as much glucosepane as needed for ongoing cell and tissue studies. There is now no roadblock standing in the way of any researcher wanting to run up batches of glucosepane, create small sections of engineered skin and blood vessel tissue, generate cross-links in that tissue, and then carry out assessments of drug candidates for clearing those cross-links.

The tools are a big deal, I think. Glucosepane clearance is a very narrow, very small pharmacological problem with a huge pot of gold on the other side. Pharmaceutical companies and established laboratories should be packed with staff running, not walking, to work on this. It is crazy that anyone has to be out there banging the drum to draw attention.

This paper notes that long-lived humans show lower levels of nuclear DNA damage and better preservation of mechanisms that repair and prevent that damage - which is as one would expect given that interventions that slow aging in laboratory species tend to produce much the same comparative outcomes in DNA integrity over a life span. Damage to nuclear DNA occurs constantly, but is repaired very efficiently. Nonetheless, mutational damage accumulates randomly in an individual's cells, a change here, a change there. The level of this damage correlates with age, and is lowered in individuals of the same chronological age as a result of interventions that slow aging, such as calorie restriction. Rising levels of nuclear DNA damage are definitely a cause of the increased cancer risk in aging, but it is the general consensus in the research community that, going beyond cancer, this damage also contributes to degenerative aging in other ways, such as by producing increasing disarray in cellular activities. This consensus doesn't have the robust demonstrations in animal studies needed to back it up at the present time, however, and has been challenged. It is difficult to split apart this aspect of aging from all others in a living organism so as to produce a study in which just the effects of DNA damage can be isolated.

Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases, and the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society.

Available data indicate improved DNA repair and antioxidant defense mechanisms in "super old" humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in "successful agers". There is also compelling evidence suggesting that life-style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching "super old" age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans.

More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere shortening.

Link: http://dx.doi.org/10.1016/j.mrrev.2015.08.001

Many researchers are involved in the study of aging in different species with varied life spans, with the aim of identifying important factors in the molecular biology of aging. What drives these differences in life span? Researchers are interested in finding answers from both the evolutionary and cell biology perspectives. This article focuses on the relationships between species life span, predation, and size:

Aristotle's observation that bigger animals tend to live longer has lasted. Indeed, it's the only trend today's scientists agree on. "All of the other hypotheses have fallen apart," says Steven Austad, a biogerontologist at the University of Alabama, Birmingham. One of the most popular ideas of the past 100 years has been that animals with higher metabolic rates live shorter lives because they run out their body clock faster. But "it hasn't held up," Austad says. Parrot hearts can beat up to 600 times per minute, for example, but they outlive by decades many creatures with slower tickers. Other assumptions, for example that short-lived animals generate more tissue-damaging free radicals or have cells that stop dividing sooner, also lack strong evidence. "A lot of simple stories have vanished."

By the mid-1980s, Austad was observing opossum behavior in Venezuela as a postdoc when he began to notice how quickly the marsupials aged. "They'd go from being in great shape to having cataracts and muscle wasting in 3 months." Austad also noticed something even more intriguing: Opossums on a nearby island free from predators seemed to age slower - and live longer - than their mainland counterparts. The observation helped explain why Aristotle's key insight continues to hold true. Large animals tend to live longer, says Austad, because they face fewer dangers. It's not a simple question of survival, he says, but rather the result of millions of years of evolutionary pressure. Whales and elephants can afford to take their time growing because no one is going to attack them, he explains. And that means they can invest resources in robust bodies that will allow them to sire many rounds of offspring. Mice and other heavily preyed-on small animals, on the other hand, live life in fast-forward: They need to put their energy into growing and reproducing quickly, not into developing hardy immune systems.

When it comes to our pets, the bigger-is-better theory gets flipped on its ear. Cats live an average of 15 years, compared with about 12 years for dogs, despite generally being smaller. And small dogs can live twice as long as large ones. Yet the lesson of Austad's opossums may still apply. Gray wolves, the ancestors of dogs, live a maximum of 11 or 12 years in the wild, whereas wildcats can live up to 16 years. This suggests that the two species face different evolutionary pressures, Austad says. Wolves are more social than cats and thus more likely to spread infectious disease, he says; wildcats, on the other hand, keep to themselves, reducing the spread of disease, and are adept at defending against predators. "Cats are so incredibly well-armed, they're like porcupines" - an animal that notably also has a long life span for its size, more than 20 years. Indeed, two other small animals that are good at avoiding danger, naked mole rats and bats, can live 30 and 40 years, respectively. (Mole rats spend most of their time underground, whereas bats can simply fly away.)

Despite the differences between cats and dogs, both pets are living longer than ever before. Dog life expectancy has doubled in the past 4 decades, and housecats now live twice as long as their feral counterparts. The reasons can largely be chalked up to better health care and better diet. Americans will spend $60 billion on their pets this year, with a large chunk of that going to humanlike health care (think annual physicals and open-heart surgery) and premium food. "The same things that allow us to live longer also apply to our pets."

Link: http://news.sciencemag.org/health/2015/12/feature-dog-lives-300-years-solving-mysteries-aging-our-pets

There is a growing interest in the delivery of additional telomerase to tissues, usually via gene therapy, as a method to either partly reverse the progression of some specific symptoms of aging, or to slow the progression of aging in general. The open access research linked below is an example of the type, with the authors focused on measures relating to cellular senescence and atherosclerosis in the vascular system.

Delivery of telomerase to tissues is one of many potential approaches to generating increased stem cell activity. Everything from stem cell transplants through to exercise may produce at least some of its effects by either slowing or temporarily reversing the characteristic decline in a patient's stem cell activity with age. Stem cells are responsible for maintaining tissues, delivering a supply of new cells to replace those come to the end of their useful life spans. The loss of stem cell activity over the course of a lifetime, most likely regulated by epigenetic changes that are themselves a reaction to rising levels of cell and tissue damage, is thought to be an evolved balance between death by cancer (too much stem cell activity in age-damaged tissues) and death by organ failure (too little stem cell activity in age-damaged tissues). One of the most interesting developments in the growing scientific industry of stem cell manipulation is that treatments, experimental and clinical, have so far produced less cancer than feared at the outset. There may be a fair amount of wiggle room in the evolved balance to make things better via increased stem cell activity.

Stem cell activity isn't really the goal of the researchers here, however. They want to activate telomerase in all cells in the vascular system, not just stem cells, aiming to reduce the number that become senescent and suppress the harmful activities of those that are senescent. Senescent cells accumulate in tissues with age, and when present in greater numbers they cause significant harm, generating chronic inflammation, degrading tissue structure, and altering the behavior of surrounding cells for the worse as well. The goals of the researchers here are more akin to the goals of early efforts to produce treatments based on telomerase, building on its primary function of lengthening telomeres. Telomeres cap the ends of chromosomes and are a part of a counter mechanism that determines cell life span: each cell division results in the loss of a little telomere length, and when they become too short the cell self-destructs or becomes senescent. In human somatic cells, the vast majority of any tissue, there is no telomerase activity, and the counter only counts down. The stem cells supporting that tissue use telomerase to maintain their cell lines indefinitely, however, retaining the ability to deliver new cells with long telomeres to replace those that have reached the end of their replicative life span. Thus average telomere length in tissue is some function of how fast cells replicate and how fast new cells are delivered. This average seems to decline with aging, but is fairly dynamic on shorter timeframes, given transient illness and other changing circumstances.

This whole baroque system probably evolved due to the constraints imposed by cancer. Limiting unfettered replication to only a tiny proportion of cells must be in some way absolutely necessary to produce large, complex animals. Delivering telomerase to somatic cells obviously puts a large thumb on one side of the balance here, and this is where the concerns about cancer continue to appear pressing enough for caution. Still, we have telomerase gene therapy in mice producing extended healthy life spans and being used to treat heart attacks. It seems certain based on the evidence to date and the breadth of interest that this is going to be tried in human medicine by more than just the adventurous startups at the head of the pack.

For my part, this all looks like work that isn't quite aligned with the goals of damage repair after the SENS model. If it produces benefits over and above the present state of medicine, then great. But if we think that aging is caused by damage, then overriding either stem cell decline or the senescent state still needs to be coupled with repair of cell and tissue damage: mitochondrial DNA, amyloids, lipofusin, cross-links, and so forth. It is arguably the case that dealing with those forms of damage would in and of itself restore stem cell activity and reduce the development of cellular senescence, returning the tissue microenvironment to a more youthful appearance, and in doing so reduce or remove these reactions to damage. That, of course, remains to be tested. But as for senescent cells, it seems more effective to destroy them than to try to modulate their behavior.

Telomerase Therapy to Reverse Cardiovascular Senescence

Aging of the vascular system is considered a major contributor in the development of atherosclerotic lesions. The structural and functional integrity of the arterial wall progressively declines with aging, as manifested by endothelial and vascular smooth muscle cell dysfunction, reduced regenerative capacity, and a decline in circulating and tissue resident progenitor cells. Cellular aging and associated cellular dysfunction is caused by multiple factors, such as accumulation of DNA damage, misfolded proteins, and telomere attrition. In some cells, telomere length may be restored by activity of the enzyme telomerase reverse transcriptase (TERT) together with its RNA component (TERC). The ability of embryonic or induced pluripotent stem cells to replicate indefinitely is due to the expression by these cells of functional TERT and TERC. Notably, TERT and TERC are reactivated in about 90% of malignancies, accounting for their transformation into essentially immortalized cells. Accordingly, one potential therapeutic approach to treating some malignancies would be to antagonize the activity of telomerase in cancer stem cell. On the other hand, a transient restoration of telomerase activity to somatic cells could have therapeutic effects. Evidence suggests that inducing telomerase activity in somatic cells and thereby restoring telomere length may reverse cell senescence and restore a functional phenotype.

Cellular senescence of endothelial cells, vascular smooth muscle cells, tissue resident cells, and circulating progenitor cells plays an important role in the early stages of a developing vascular lesion that ultimately leads to an atherosclerotic plaque. Aged endothelial cells manifest increased expression of proinflammatory surface markers, a decrease in nitric oxide (NO) production, and a change of structural phenotype that compromises the barrier function of the endothelial monolayer of arterial vessel walls. Additionally, the decrease in circulating endothelial progenitors fails to compensate for micro-injuries of the arterial vessel wall, in turn exposing the subendothelial vessel structures to circulating factors that further promote lesion formation. Preclinical studies suggest that activation of telomerase can delay or even reverse the senescent phenotype of aged vascular cells.

With aging, phenotypic changes occur within endothelial cells as they switch to an activated state, expressing inflammatory surface markers such as VCAM-1 and ICAM-1 and secreting proinflammatory cytokines. The chronic activation of the immune system and leukocyte recruitment to the dysfunctional regions of endothelial cell layers further accelerates the aging process. Aging of the endothelium is accelerated at sites of disturbed flow such as the iliac artery bifurcation, where the telomeres of human endothelial cells are demonstrably shorter and analysis reveals an increased number of senescent endothelial cells. This accelerated aging at vascular bifurcations may be due in part to the hemodynamic activation of an inflammatory phenotype by low and oscillating shear stress at these sites. Thus, a pathologic cycle of inflammation and aging occurs at the very sites (bends, branches, and bifurcations) where the most severe atherosclerotic lesions typically occur.

This pathologic cycle could potentially be reversed by therapeutic extension of telomeres. Previously, we have shown that aged human aortic endothelial cells manifest many attributes of a senescent vasculature, including reduced ability to proliferate and respond normally to shear stress, to generate nitric oxide, and to resist adhesion of leukocytes. When we transfected these endothelial cells using a lentiviral vector to overexpress telomerase, these senescent properties were reversed. Telomerase transfected endothelial cells made more nitric oxide, manifested fewer adhesion molecules, were less adhesive for mononuclear cells, and had greater replicative capacity. Such changes would be expected to reduce the progression of atherosclerosis if vascular regeneration by telomere extension could be achieved in patients.

Some rare few individuals do not feel pain, and are consequently a danger to themselves, often dying young. Unfortunately little headway has been made in manipulating the mechanisms thought to cause this condition, not just as a matter of treatment, but also as a way to create much safer and more sophisticated methods to temporarily switch off pain in the rest of us. Now, researchers have succeeded in reversing painlessness in an afflicted individual, better characterized the central mechanism of this condition, and this should directly result in a new methodology for efficient pain suppression. While this research is not directly relevant to aging, pain is an important consideration everywhere in medicine, especially in chronic disease, and this has the look of a profound step forward:

People born with a rare genetic mutation are unable to feel pain, but previous attempts to recreate this effect with drugs have had surprisingly little success. Using mice modified to carry the same mutation, researchers have now discovered the recipe for painlessness. 'Channels' that allow messages to pass along nerve cell membranes are vital for electrical signalling in the nervous system. In 2006, it was shown that sodium channel Nav1.7 is particularly important for signalling in pain pathways and people born with non-functioning Nav1.7 do not feel pain. Drugs that block Nav1.7 have since been developed but they had disappointingly weak effects.

The new study reveals that mice and people who lack Nav1.7 also produce higher than normal levels of natural opioid peptides. To examine if opioids were important for painlessness, the researchers gave naloxone, an opioid blocker, to mice lacking Nav1.7 and found that they became able to feel pain. They then gave naloxone to a 39-year-old woman with the rare mutation and she felt pain for the first time in her life. "After a decade of rather disappointing drug trials, we now have confirmation that Nav1.7 really is a key element in human pain. The secret ingredient turned out to be good old-fashioned opioid peptides, and we have now filed a patent for combining low dose opioids with Nav1.7 blockers. This should replicate the painlessness experienced by people with rare mutations, and we have already successfully tested this approach in unmodified mice."

Broad-spectrum sodium channel blockers are used as local anaesthetics, but they are not suitable for long-term pain management as they cause complete numbness and can have serious side-effects over time. By contrast, people born without working Nav1.7 still feel non-painful touch normally and the only known side-effect is the inability to smell. Opioid painkillers such as morphine are highly effective at reducing pain, but long-term use can lead to dependence and tolerance. As the body becomes used to the drug it becomes less effective so higher doses are needed for the same effect, side effects become more severe, and eventually it stops working altogether. "Used in combination with Nav1.7 blockers, the dose of opioid needed to prevent pain is very low. People with non-functioning Nav1.7 produce low levels of opioids throughout their lives without developing tolerance or experiencing unpleasant side-effects. We hope to see our approach tested in human trials by 2017 and we can then start looking into drug combinations to help the millions of chronic pain patients around the world."

Link: http://www.ucl.ac.uk/news/news-articles/1215/041215-transgenic-mice-painless-life

I think you'll find this open access work on a potential biomarker of aging to be interesting; the researchers use it to assess the results of different lifestyle choices, finding that some of those known to shorten life expectancy produce a higher measure of biological age in their biomarker. This seems a small step closer to validating the usefulness of such biomarkers. A number of research groups are presently developing biomarkers of aging based on characteristic patterns of epigenetic modifications or altered protein levels. We should expect to find common patterns because the cell and tissue damage that causes aging, and the evolved reactions to that damage, are the same in everyone. The challenge lies in identifying these common patterns amidst the complex, varied alterations that occur due to individual circumstances and environment, but solid progress has being made in recent years.

Human ageing is associated with a number of changes in how the body and its organs function. On the molecular level, ageing is associated with numerous processes, such as telomere length reduction, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. In addition to chronological time, lifestyle factors such as smoking or stress can affect both the pattern of DNA-methylation and telomere length and thereby the aging of an individual. Ageing and lifestyle are the strongest known risk factors for many common non-communicable diseases, hence, various predictor models have been developed using measures of facial morphology, physical fitness and physiology, telomere length and methylation pattern to predict ones chronological age.

Comparisons of the actual chronological age with the predicted age, sometimes denoted the biological age, can be used as an indicator of health status, monitor the effect of lifestyle changes and even aid in the decision on treatment strategies. To date, no current models have explored the potential of using the plasma protein profile for age prediction. We have previously characterized abundance levels of 144 circulating plasma proteins and have found over 40% of investigated proteins to be significantly correlated with one or more of the following factors, age, weight, length and hip circumference. We therefore reasoned that the plasma protein profile might also be predictive of these traits. Here we demonstrate for the first time that the profile of circulating plasma proteins can be used to accurately predict chronological age, as well as anthropometrical measures such as height, weight and hip circumference. Moreover, we used the plasma protein-based model to identify lifestyle choices that accelerate or decelerate the predicted age.

Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating proteins accurately predicts chronological age, as well as anthropometrical measurements such as weight, height and hip circumference. The plasma protein profile described herein is highly accurate in predicting chronologic age. The plasma protein profile can also be used to identify lifestyle factors that accelerate and decelerate ageing. We found smoking, high BMI and consumption of sugar-sweetened beverages to increase the predicted chronological age by 2-6 years, while consumption of fatty fish, drinking moderate amounts of coffee and exercising reduced the predicted age by approximately the same amount.

Link: http://dx.doi.org/10.1038/srep17282

That old people will go into orbit to escape the rigors of gravity and thus live longer in their declining years was a staple of golden age and later science fiction. These works were written at a time in which our knowledge of human biochemistry - and the application of that knowledge to medicine - was crude in comparison to today. It is fascinating that we can say that for such a short span of years, a mere short lifetime past, but the differences between the medicine of the 1950s and the medicine of today are profound indeed. The writers of that time largely envisaged a future incorporating great gains in energy generation, and a consequent diaspora from Earth, while computation, medicine and the human condition remained much unchanged; older spacemen in the outer reaches struggling with heart disease in their fifties. Instead we found that expanding the generation, storage, transmission, and application of energy is very hard, and the largely unanticipated information revolution occurred instead. We lost the near future of cheap heavy lift to orbit and the solar system at our beck and call, but gained Moore's Law, biotechnology, nanotechnology, a pervasive internet, and medical progress that is in the early stages of conquering heart disease and may yet save us from all of degenerative aging.

As it turns out, retreating from the rigors of gravity may well have the opposite effect to that imagined by the authors of the last century. Among the alterations produced by orbital habitation in zero gravity are those that appear, at least superficially, much like accelerated aging of the cardiovascular system. The root causes have yet to be pinned down, since very few people are actually researching this topic, but since the onset of these symptoms is fairly rapid, I'd guess at the cause being more a matter of regulatory dysfunction than increased tissue damage, such as the presence of cross-links related to arterial stiffening in aging. Here I'll point out a few links to the work of one research group on this topic in recent years:

Waterloo to lead new experiment aboard International Space Station

The experiment will link changes in astronauts' hearts and blood vessels with specific molecules in the blood to determine why astronauts experience conditions that mimic aging-related problems and chronic diseases on earth. The findings will help identify important indicators for chronic disease and assist with the development of early interventions for people on earth. "We know that astronauts return from space with stiffer arteries and resistance to insulin, conditions affecting many adults as they age. For the first time, we will be able to track exactly how - and why - the body's blood vessels change, and use these findings to potentially improve quality of life and the burden of chronic disease."

"In space, astronauts' bodies show aging-like changes much faster than on Earth. The International Space Station provides a unique platform to study aging-related conditions providing insights that can be used to help understand some of the biggest health issues affecting society. Our research to date suggests that even though astronauts exercise every day, the actual physical demands of tasks of daily living are greatly reduced due to the lack of gravity. This lifestyle seems to cause changes in the vascular system and in the body's ability to regulate blood glucose that would normally take years to develop on earth."

U.Waterloo - Vascular Aging and Space Research Program

We study factors related to cardiovascular health with aging. One focus is on blood pressure regulation and its impact on brain blood flow to help us understand some of the factors that could contribute to falls in the elderly, especially those that occur on rising from bed. Another focus is on aging blood vessels. We have reported a strong link between peripheral arterial stiffness and a reduction in brain blood flow. Our space research program is very active. We recently completed the study Cardiovascular and Cerebrovascular Control on Return from the International Space Station (CCISS). We are currently collecting data for the project Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular).

Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular)

Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular) investigates the impact of long-duration space flight on the blood vessels of astronauts. Space flight accelerates the aging process, and it is important to understand this process to develop specific countermeasures. Data is collected before, during, and after space flight to assess inflammation of the artery walls, changes in blood vessel properties, and cardiovascular fitness.

Spaceflight can cause stiffening of the arteries, affecting the body's ability to control blood pressure. This investigation assessed the blood vessels of astronauts and found decreased flexibility of the carotid artery during flight. Researchers found no relationship between the level of physical fitness and this decrease. The experiment also provided data on the mechanisms behind increased arterial stiffness from spaceflight. Further research is needed to establish effective ways to counter the cardiovascular consequences of spaceflight and ultimately help treat increased arterial stiffness from aging on Earth, which can cause high blood pressure and organ damage.

Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired carbon dioxide. Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day or the morning 1 or 2 days after return to Earth. The results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular carbon dioxide reactivity.

Recent findings in cardiovascular physiology with space travel

The cardiovascular system undergoes major changes in stress with space flight primarily related to the elimination of the head-to-foot gravitational force. A major observation has been that the central venous pressure is not elevated early in space flight yet stroke volume is increased at least early in flight. Recent observations demonstrate that heart rate remains lower during the normal daily activities of space flight compared to Earth-based conditions. Structural and functional adaptations occur in the vascular system that could result in impaired response with demands of physical exertion and return to Earth. Cardiac muscle mass is reduced after flight and contractile function may be altered. Regular and specific countermeasures are essential to maintain cardiovascular health during long-duration space flight.

I'm pleased to note that more than 130 people donated a total of more than $27,000 to SENS rejuvenation research on Giving Tuesday. We are now just a few thousand short of hitting the $125,000 goal for this year's Fight Aging! SENS fundraiser. Thank you all for your support! With the additional $125,000 from the matching fund, together we'll soon have directed a total of $250,000 to speed progress towards regenerative therapies capable of repairing the cell and tissue damage that causes aging.

The SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease, received $27,317 on December 1, Giving Tuesday - more than double what the foundation raised on Giving Tuesday 2014. Funds received this year came from nine countries, including Australia, Canada, Czech Republic, Denmark, Norway and the United Kingdom, as well as the USA. In addition to the donations, SENS Research Foundation will receive two $5,000 dollar for dollar challenge grants and a dollar for dollar match for all the funds raised.

Giving Tuesday is a global day of giving that harnesses the collective power of individuals, communities and organizations to encourage philanthropy and celebrate generosity worldwide. The event is held annually on the Tuesday after Thanksgiving in the U.S. to kick-off the holiday giving season and inspire people to collaborate in improving their local communities and to give back in impactful ways to the charities and causes they support.

SENS Research Foundation's goal at the outset was $20,000 with the help of contributors who pledged to match each dollar raised up to the first $5,000. The Croeni Foundation, a philanthropic organization dedicated to giving, the environment and health, matched the first $5,000 raised dollar for dollar. The foundation gave SRF an unrestricted $5,000 earlier this year, as well. Aubrey de Grey, CSO of SENS Research Foundation, will also match $5,000, and Fight Aging! is matching every dollar up to $125,000 raised from October 1 to December 31, 2015. "We are thrilled to have exceeded our goal for this year's Giving Tuesday. We extend our sincere appreciation to all those who contributed funds including Jan Croeni and the Croeni Foundation, Aubrey de Grey, and Fight Aging! for their support. These funds will help us continue our research into the damage repair approach to the diseases and disabilities of aging."

Link: http://sens.org/outreach/press-releases/givingtuesday-2015-success

Researchers have in recent years made inroads into the infrastructure and knowledge needed to investigate the molecular biology of aging in killifish. The various species of killifish occupy a good compromise position between short length of life and the degree to which their biochemistry is relevant to human aging. As an added bonus, there is a fair degree of variation in life span between different killifish species, allowing for comparative investigations of their genetics and cellular biology. Short-lived animals mean faster studies, more research conducted for any given amount of funding, but the further removed from humans the species is, the more likely it is that the output of any given study provides no useful insight to direct the study of aging in mammals. As in all things, there are trade-offs involved.

A favourite of fish hobbyists since the 1970s, killifish are gaining popularity among scientists who study ageing, and dozens of labs now house them. Elderly killifish - a couple of months old - show hallmarks of ageing. Their bright scales fade and their cognition wavers; many develop tumours. Lifespan-altering experiments that take years in mice and decades in primates can be over in months in killifish, which are also more closely related to humans than are fruit flies, nematodes and other short-lived lab organisms popular in ageing research. "It turns out to be the shortest-lived vertebrate that can be raised in captivity."

The turquoise killifish genome contains several clues to its peculiar, fleeting life. Valenzano and his colleagues found that variations in genes involved in nutrient sensing, DNA repair and ageing have been selected for during its evolutionary history. Such genes might prove instructive for ageing in longer-lived animals. One such is IGF1R, which has been linked to extreme longevity in bowhead whales, naked mole-rats and Brandt's bat. Genes linked to IGF1R vary between an extremely short-lived killifish lab strain and a wild variety that can live for twice as long. A similar difference between short-lived and longer-lived strains was also seen in a gene that has been linked to dementia in humans. "Maybe these genes are central hubs for regulating survival. In some species they can accelerate ageing, and in some they can slow it down."

Genetic-engineering experiments - such as creating knock-out fish that lack particular genes - are needed to confirm whether the genes pinpointed in these studies truly influence ageing. These tests are already under way. Earlier this year a team used CRISPR-Cas9 genome editing in 'proof-of-principle' experiments to alter several ageing-related genes in killifish. "We are excited at trying to make it live longer." The team is also screening drugs in killifish to see if any lengthen its lifespan or slow tissue degeneration.

Link: http://www.nature.com/news/short-lived-fish-may-hold-clues-to-human-ageing-1.18945

Here I'll point out interesting research, suggesting that excess fat in the pancreas, and really nowhere else, is the cause of type 2 diabetes. Of course the only way to gain that pancreatic fat is the standard method of eating enough to put on a lot of excess visceral fat tissue and other fat tissue throughout the body, a path that shortens life expectancy, raises the risk of all of the common age-related conditions, and increases lifetime medical expenses. Visceral fat is metabolically active and causes increased chronic inflammation, among other issues, and inflammation contributes to the progression of degenerative aging. The important point to take away from this backdrop is that developing type 2 diabetes is a lifestyle choice, and so is the maintenance of the condition; even after pushing through metabolic syndrome into full-blown diabetes, a patient can choose to turn back by losing weight. It is frankly amazing that so few do, given the harms, pains, inconvenience, and cost of suffering this condition.

There are other types of diabetes that are not choices. Type 1 diabetes is an autoimmune condition that rarely emerges in later life. It is an unfortunate happenstance that, like all forms of autoimmunity, is still comparatively poorly understand. There is only a collection of theories regarding its origins rather than anything more concrete at this time. The immune system is enormously complex and incompletely mapped, as are its failure modes. Of late researchers have proposed a type 4 age-related diabetes produced by a different sort of immune system dysregulation, quite capable of arising in older people without excess fat tissue. Again this may well be happenstance, the result of a lifetime of cell and tissue damage producing disarray in complex bodily systems.

Returning to type 2 diabetes and this recent research, if the cause lies specifically in pancreatic fat, then this might go some way towards explaining the differing susceptibility across the population of people who have chosen to gain excess fat tissue. Some fraction becomes diabetic, the rest do not. If there is significant variation in the degree to which becoming overweight leads to fat in the pancreas, based on genetics or environmental factors such as level of physical activity for example, then that would be enough to produce the observed outcome.

Type 2 diabetes reversed by losing fat from pancreas

Type 2 diabetes is caused by fat accumulating in the pancreas - and that losing less than one gram of fat through weight loss reverses the diabetes, researchers have shown. In a trial, 18 people with Type 2 diabetes and 9 people who did not have diabetes were measured for weight, fat levels in the pancreas and insulin response before and after bariatric surgery. The patients with Type 2 diabetes had been diagnosed for an average of 6.9 years, and all for less than 15 years. The people with Type 2 diabetes were found to have increased levels of fat in the pancreas.

The participants in the study had all been selected to have gastric bypass surgery for obesity and were measured before the operation then again eight weeks later. After the operation, those with Type 2 diabetes were immediately taken off their medication. Both groups lost the same amount of weight, around 13% of their initial body weight. Critically, the pool of fat in the pancreas did not change in the non-diabetics but decreased to a normal level in those with Type 2 diabetes.

"For people with Type 2 diabetes, losing weight allows them to drain excess fat out of the pancreas and allows function to return to normal. So if you ask how much weight you need to lose to make your diabetes go away, the answer is one gram! But that gram needs to be fat from the pancreas. At present the only way we have to achieve this is by calorie restriction by any means - whether by diet or an operation."

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified.

Weight loss after surgery was similar, as was the change in fat mass. Pancreatic triacylglycerol did not change in NGT but decreased in the group with T2DM. First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT but normalized in T2DM. We conclude that the fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Another day, another method of slowing aging in a laboratory species. The diversity of techniques is increasing every year, and many slip by without comment, as there are simply too many now to remark on every one of them. This particular method has the look of working via hormesis - allowing an accumulation of molecules that cells react to as damage, and thus increase repair and maintenance activities, but which is not harmful enough in and of itself to outweigh the benefits of that increased cellular housekeeping.

One of the reasons for such a wealth of ways to slow aging in short-lived species is that there are countless possible methods by which researchers can provoke a hormetic response, and the same is true for the other underlying mechanisms that might work to modestly slow aging if manipulated. Everything in cellular biochemistry is connected, so a core mechanism of interest might be tweaked by altering any one of dozens of genes or levels of circulating proteins. Indeed, part of the challenge inherent in this situation is that it is very hard to determine the identity of the core mechanism when there are so many actions that produce benefits, and every change cascades throughout cellular biochemistry. Another thing to bear in mind while reading these sorts of research results is that all of the methods of slowing aging in short-lived animals for which we also have data in humans show that in our species the result on life span is small at best, even when the result on health is worth chasing, as is the case for calorie restriction and exercise:

Researchers used statistical models to establish an intersection of genes that were regulated in the same manner in the worms, fish and mice. This showed that the three organisms have only 30 genes in common that significantly influence the ageing process. By conducting experiments in which the mRNA of the corresponding genes were selectively blocked, the researchers pinpointed their effect on the ageing process in nematodes. With a dozen of these genes, blocking them extended the lifespan by at least five percent. One of these genes proved to be particularly influential: the bcat-1 gene. "When we blocked the effect of this gene, it significantly extended the mean lifespan of the nematode by up to 25 percent."

The researchers were also able to explain how this gene works: the bcat-1 gene carries the code for the enzyme of the same name, which degrades so-called branched-chain amino acids. Naturally occurring in food protein building blocks, these include the amino acids L-leucine, L-isoleucine and L-valine. When the researchers inhibited the gene activity of bcat-1, the branched-chain amino acids accumulated in the tissue, triggering a molecular signalling cascade that increased longevity in the nematodes. Moreover, the timespan during which the worms remained healthy was extended. As a measure of vitality, the researchers measured the accumulation of ageing pigments, the speed at which the creatures moved, and how often the nematodes successfully reproduced. All of these parameters improved when the scientists inhibited the activity of the bcat-1 gene.

The scientists also achieved a life-extending effect when they mixed the three branched-chain amino acids into the nematodes' food. However, the effect was generally less pronounced because the bcat-1 gene was still active, which meant that the amino acids continued to be degraded and their life-extending effects could not develop as effectively.

Link: https://www.ethz.ch/en/news-and-events/eth-news/news/2015/12/genes-for-longer-healthier-life-found.html

Here is an open access commentary on recent research into the damaged biochemistry of extremely old individuals, in which the authors pull together the strands of chronic inflammation, senescent cell accumulation, and erosion of telomere length, all associated with mortality and the progression of degenerative aging, though much more robustly for the first two in that short list:

Human aging is accompanied by a chronic low-grade inflammation, called "inflammaging", a phenomenon associated with frailty, morbidity, and mortality in elderly people. This condition is related to the accumulation of senescent cells in aged tissues through the senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines among its key constituents. A well-known trigger of cellular senescence, closely related to inflammaging, is telomere length shortening. However, while considerable evidence shows that circulating inflammatory markers are predictors of mortality in community-living elderly individuals, there are conflicting results on the role of telomere length.

It was recently demonstrated with a cross-sectional approach that telomere length, measured in the DNA extracted from whole blood of centenarian offspring, centenarians and (semi-)supercentenarians displays a superior maintenance compared to the one measured in community-living elderly subjects. Indeed, telomere length of centenarian offspring is maintained for more than 20 years at a length corresponding to 60 years of age in the general population. Interestingly, the authors observed that while long telomeres might be a prerequisite for exceptional lifespan in humans, they did not predict mortality. Conversely, they confirmed that a multibiomarker score of systemic inflammation, which included anti-cytomegalovirus IgG, IL-6, TNF-α and C-reactive protein levels, was associated with an increased risk of mortality, loss of cognitive function and physical function decline, in normal aging and at extreme old age (up to 110 years).

These data demonstrate that a multiple biomarker index may represent a more powerful predictor of mortality in older adults than a single inflammatory mediator, as also recently shown through a combined measure of interleukin 6 (IL-6) and soluble TNF receptor 1 (sTNFR1). Therefore, the development of reliable measures of inflammatory status is of great interest in clinical practice both as risk assessment tools of age-related chronic diseases, and to monitor clinical progression or as a powerful surrogate biomarker in the research of new anti-inflammatory therapeutics.

Hence, given that inflammation is a consolidated predictor of mortality, it is also important to investigate the sources of this phenomenon and their relative contribution. While it is known that cell senescence and inflammation can drive each other thus causing accelerated aging, these results suggest that blood telomere length might not reflect the phenomenon of accumulation of senescent cells in various tissues and organs. This could be particularly true if accumulating senescent cells will be confirmed as a major source of circulating inflammatory markers in aging. In this context, the development of strategies to remove senescent cells could represent an emerging tool for the suppression of chronic inflammation and to ameliorate human healthy lifespan.

Link: http://www.ebiomedicine.com/article/S2352-3964(15)30135-3/fulltext

George Church is an important figure in the development of modern genomics and genetic engineering. Like a number of luminaries in the medical life sciences, in recent years he has become much more openly supportive of efforts to treat the causes of aging and extend healthy human life spans. You might recall the keynote he gave at the SENS6 rejuvenation research conference, and note that Church is a member of the SENS Research Foundation advisory board. With that context, I'll point you to recent remarks made to a journalist:

A Harvard professor says he can cure aging, but is that a good idea?

I mentioned to Church that CRISPR is the kind of work for which Nobels are awarded. He quickly responded that there are more important things in the balance than prizes. There are cures for human diseases, he said. Church thinks that one of the ailments he can cure is aging. When I met him early this year, in his laboratory at Harvard Medical School, where he is professor of genetics, he expressed confidence that in just five or six years he will be able to reverse the aging process in human beings.

"A scenario is, everyone takes gene therapy - not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging," he said. He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200. "One of our biggest economic disasters right now is our aging population. If we eliminate retirement, then it buys us a couple of decades to straighten out the economies of the world. If all those gray hairs could go back to work and feel healthy and young, then we've averted one of the greatest economic disasters in history. Someone younger at heart should replace you, and that should be you. I'm willing to. I'm willing to become younger. I try to reinvent myself every few years anyway."

So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes - and that it's already happening in mice in the laboratory. The best way to predict the future, he said, is to predict things that have already happened.

This is filtered through a layperson with mixed feelings about the whole business of trying to treat aging, so necessary context is lost. Church is big on the application of genetic tools to many present problems, no surprise given his background, and it is true that an entire class of solutions in medicine and other fields can be constructed atop robust, reliable gene therapy of the sort enabled by CRISPR. However, many types of genomic research into aging and longevity are presently taking place, and there are many types of intervention, existing and proposed, that can employ genetic engineering. Sadly, those gathering the greatest attention at the current time are also the least likely to produce meaningful results. Let me divide things up into a couple of categories:

Firstly, we have the search for longevity genes and the idea that we can use drugs, gene therapies, and other tools in the toolkit to adjust metabolism to look more like that of people with specific genetic or epigenetic traits that are linked to longer healthy lives. This covers a broad range of approaches, from calorie restriction and exercise mimetics to analysis of centenarian genomes in search of common factors. This is slow and expensive work, and so far has produced little more than knowledge. There is also the problem that in principle even complete success means tiny gains. What does it mean to have the full set of characteristic differences present in a centenarian's metabolism? It means you have perhaps a 1.5% chance of living to 100 rather than a 1% chance, to pull some numbers out of the air - the real numbers are along these lines. Identified genetic associations with longevity are a matter of a tiny increase in a tiny chance of survival, and if you get there you're still decrepit and age-damaged. The same goes for calorie restriction and exercise mimetics; even if completely recapturing the real thing, that gains a few years of additional life expectancy. You still age, you still die, and the schedule is much the same. This is not a goal worth spending billions and decades on, but it is nonetheless what most researchers are involved in.

Secondly we have classes of compensatory alteration to the genome, or equivalent therapies that change protein levels without changing genes. These are in principle capable of providing benefits that will have greater impact than any presently available option - such as calorie restriction - but they don't directly repair the damage that causes aging, and thus cannot on their own do more than delay the inevitable. In this category you'll find things such as follistatin or myostatin gene therapy to force greater maintenance of muscle mass, increased catalase production in mitochondria to slow their contribution to aging, attempts to mine regenerative and long-lived species for mechanisms that might be ported over to humans one day, and a range of gene and other therapies that spur old stem cells into action, overriding their response to cell and tissue damage, and restoring at least some of the tissue maintenance that falls off with age. The jury is still out on the degree to which these stem cell approaches raise the risk of cancer due to higher levels of damaged stem cell activity in damaged tissues, but so far it is less than expected. The bulk of researchers not involved in the first category above are working on something in the second, and this includes Church. I take his remarks quoted above to refer to the range of rodent studies from past years demonstrating a modest slowing of aging or partial restoration of some narrow set of measures relating to aging via gene therapies and the like.

Thirdly we have the role of gene therapies and genetics in repair therapies after the SENS model, addressing the causes of aging and thus in principle capable of producing indefinite healthy life spans if the repair is good enough and frequent enough. The SENS approach to mitochondrial DNA damage, currently in initial commercial development for inherited mitochondrial disease by Gensight, is a gene therapy, copying altered mitochondrial genes into the cell nucleus as a backup. Similarly forms of clearance of various forms of accumulated gunk - amyloid, lipofuscin, cross-links - that degrade cell and tissue function could well take the form of gene therapies to deliver additional tools needed for the job to cells, though it is more likely we'll see other forms of therapy at first. The SENS vision for preventing cancer may also be a gene therapy in its most complete form, acting to suppress the activity of all mechanisms capable of lengthening telomeres throughout the body. Here again, I suspect other less radical telomere extension blocking approaches will arise at first.

The point here is that genetic engineering and genomics covers a wide range of ground. A lot of it is pointless with respect to aging, at least from any perspective other than the scientific goal of full and complete knowledge of how the decay of the unmodified human machine progresses. Of the rest there are very definite classes of degree for the potential benefit that can be achieved. Not all approaches are the same, and in advance of trying them we can make reasonable predictions of the best possible benefit that could be achieved. We live in an age of rapid, radical progress in biotechnology. We should not be aiming low. I don't believe that slowing aging is good enough, and I don't believe that to be the best possible outcome achievable in the next few decades, were people to support the right lines of research. The weight of scientific evidence backing SENS rejuvenation approaches is compelling, and should be compelling enough to draw anyone away from tinkering with calorie restriction mimetic drugs or longevity-associated genes, lines of research with very limited best possible outcomes when it comes to translation to therapies for aging. Yet it is not, still, and this is why we continue to need advocacy and fundraising to advance the SENS cause, to produce more evidence, and persuade more support, and speed progress towards an end to aging.

Researchers continue to expand the application of decellarization to engineer more types of patient-matched tissues from more types of donor organ. Here is news of a proof of concept carried out in rats, in which a donor diaphragm is decellularized and transplanted successfully:

An international collaboration between scientists has resulted in the successful engineering of new diaphragm tissue in rats using a mixture of stem cells and a 3D scaffold. When transplanted, it has regrown with the same complex mechanical properties of diaphragm muscle. The diaphragm is a sheet of muscle that has to contract and relax constantly to allow breathing. It is also important in swallowing, and acts as a barrier between the chest cavity and the abdomen. The success of this study also offers hope for the possibility of regenerating heart tissue, which undergoes similar pressure as it contracts and relaxes with every beat. "So far, attempts to grow and transplant such new tissues have been conducted in the relatively simple organs of the bladder, windpipe and esophagus. The diaphragm, with its need for constant muscle contraction and relaxation puts complex demands on any 3D scaffold; until now, no one knew whether it would be possible to engineer. This bioengineered muscle tissue is a truly exciting step in our journey towards regenerating whole and complex organs. You can see the muscle contracting and doing its job as well as any naturally-grown tissue - there can be no argument that these replacements are truly regenerated."

In the current study, the researchers took diaphragm tissue from donor rats and removed all the living cells from it using a series of chemical treatments. This process removes anything that might cause an immune response in the recipient animals, while keeping all the connective tissue - or extracellular matrix - which gives tissues their structure and mechanical properties. When tested in vitro, these diaphragm scaffolds at first appeared to have lost their important rubber-like ability to be continually stretched and contracted for long periods of time. However, once seeded with bone marrow derived alloegenic stem cells and then transplanted into the animals, the diaphragm scaffolds began to function as well as undamaged organs. The method must now be tested on larger animals before it can be tried in humans, but the hope is that tissue-engineered repairs will be at least as effective as current surgical options.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=158969&CultureCode=en

Carbon buckyballs, C60, have been a topic of interest to the longevity advocacy community since a study a few years ago claimed significant life extension in rats. I remain very skeptical: it was a small number of animals, carried out by people outside the aging research community, published in a journal that doesn't normally cover this topic, and the claimed effect was double that achieved by the mainstream community via other methods in rats. It just doesn't pass muster. Nonetheless, people are interested, and crowdfunded attempts to replicate the result are ongoing.

There is better, albeit still thin, support for C60 to be a beneficial adjuvant treatment or delivery method for chemotherapy in cancer therapies. Ichor Therapeutics has been looking to raise funds for some of their early stage work on this topic of late. The Methuselah Foundation stepped in to fund this research earlier in the year, and here is an update on this topic. This will no doubt be of interest to those who consider it worthwhile following up on claims of life extension via C60 in normal mice:

Ichor Therapeutics, Inc., is a pre-clinical biotechnology company that develops technologies to target age-related pathology. The company received $79,775 in grant funding from Methuselah Foundation in July, 2015, to develop a C60-based therapy for acute myeloid leukemia (AML). AML is a lethal blood cancer with only a 24% five-year survival rate. Ichor reports that short-term biodistribution studies have been completed, and long-term studies are ongoing. These studies track the accumulation and reduction of C60 in the blood and various organs over time, and are essential for establishing a safety profile during pre-clinical studies. The company has also initiated a large scale repeat of its pilot efficacy study, which led to a doubling of median lifespan in a mouse model of AML.

"We are eagerly awaiting the results of our efficacy study. Our current data supports the hypothesis that C60 may be a safe and effective therapeutic candidate for several age-related diseases, including cancer. Quality assurance is a critically important part of manufacturing, yet is often ignored in the context of research grade products. Methuselah Foundation supported early development of quality assurance measures in preparation for our studies. We were surprised to discover that when we evaluated multiple sources of C60, there were large disparities between what is reported by vendors, and what is actually contained within their products." While a promising therapeutic compound, C60 is not approved for use as a drug or supplement. Its manufacturing is currently unregulated.

"Methuselah and Ichor will be exploring appropriate solutions to the problem of unreliable formulations. Ichor is actively adopting cGLP and cGMP standards. Once in place, we can begin FDA compliant manufacturing and pre-clinical safety and toxicity testing. We think C60 could have immense potential to treat disease, but it is important to take a measured approach as we move towards the clinic. Any new compound should be rigorously investigated before human use, especially for safety." The company expects its studies to conclude by March, 2016, and intends to publish the results in an open access peer-reviewed journal.

Link: http://ichortherapeutics.com/ichor-awarded-80000-grant-for-oncology-research/

Today I'll point out one representative example of the many ongoing research programs investigating the details of gene expression changes that occur with aging. Gene expression is the name given to the collection of processes that, step by step, act to manufacture proteins from their DNA blueprints, the genes. The pace of protein production changes in accordance with epigenetic modifications to DNA, and varying levels of proteins lead to alterations in cellular operation, which in turn feed back into further epigenetic modification processes. A living cell is a collection of countless feedback loops between its machinery, the pace of protein production, epigenetic decorations on DNA, and the surrounding environment. This cellular metabolism is enormously complex, and the ways in which it reacts to the changing environment and growing levels of cell and tissue damage over a lifetime are similarly complex. That damage, the root cause of degenerative aging, is the same for every individual, however, and so there are characteristic patterns to be found in epigenetic changes in aging.

Some research groups are presently gathering data on these patterns to try to build robust biomarkers of biological age, useful measures that might help speed up progress in longevity science by allowing fast validation or rejection of potential strategies, as well as an on-the-spot assessment of their estimated effect on life span. That remains a work in progress. Beyond this unified approach, I think we will also see a lot more in the way of ad-hoc measures of epigenetic changes adopted by single research groups or even for single studies. The paper quoted below is an example of the type; the researchers use measures of gene expression to support their particular interpretation of what a life-extending intervention is actually doing under the hood in the nematode worms used in the study. Beyond this, I should say, this is just another modest slowing of aging in a short-lived species, something that can now be achieved in scores of ways, and is of little relevance to human rejuvenation research. Drug interventions with large effects on longevity in short-lived species have very small or no effects in longer-lived species, and adjusting the operation of metabolism through drugs and the like is a dead end for meaningful human life extension. Next to nothing will come of it; the only viable path ahead towards radical healthy life extension of decades and more in the foreseeable future is that of damage repair, such as the SENS research programs.

That said, it doesn't make this research uninteresting; a great deal of the work that takes place in the aging research community, and which will do little for human longevity, is nonetheless both fascinating and enlightening. This research is an example of the way in which epigenetics is becoming a useful, necessary part of a wide range of research into aging, improving the output of the scientific community.

Scientists discover how to make youth last longer - in worms

Tests showed that a drug capable of prolonging life in nematodes by more than 30% worked by expanding only young adulthood, and had no effects on later life stages. The scientists made their discovery while testing a long list of compounds for any that might prolong the short lives of the short worms. When early hints suggested that the antidepressant mianserin extended their lifespan, the scientists set about testing it more thoroughly.

The group found that as normal, water-fed worms aged, their gene activity changed from being precisely coordinated to ever more disorganised. Genes that were involved in the same bodily function, and which usually worked together, began working against one another. The researchers call this loss of genetic orchestration "transcriptional drift" and after examining data from mice and from 32 brains of humans aged 26 to 106 found that the same process occurs in both. The scientists went on to develop a test that used genetic disorder as a measure of the age-related changes that happen from youth until old age. When they ran the test on worms fed on mianserin, they found that the drug suppressed transcriptional drift, but only when it was given early enough. "Based on their gene expression pattern, 10 day old worms looked seven days younger. What happens is the period of young adulthood is made longer, whilst all the rest that comes later stays the same. The life extension comes only from increasing the young period of life, and then when this period is over, the compound doesn't do anything any more."

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality

We classified gene expression changes for groups of genes into two types. Type I changes describe whether the overall expression across an entire functional group/pathway increases or decreases i.e. whether the pathway is up or down regulated with age. Type II changes describe the relative changes in gene expression among genes within functional groups with respect to each other. We named the type II change transcriptional drift. As animals age, genes within functional groups change expression levels in opposing directions resulting in the disruption of the co-expression patterns seen in young adults.

In this study, we have analyzed the dynamics of aging C. elegans transcriptomes and how these dynamics are affected by mianserin treatment. In C. elegans, transcriptional drift continuously increases with age across the transcriptome, substantially altering stoichiometric balances observed in young animals. Longevity mechanisms induced by either pharmacologically blocking serotonergic signaling or by blocking insulin signaling by daf-2 RNAi attenuate transcriptional drift. Abolishing lifespan extension by these mechanisms by either blocking serotonergic signaling too late (mianserin, day 5) or by addition of daf-16 RNAi (daf-2) abolished the attenuation of transcriptional drift.

Using transcriptome-wide transcriptional drift values as a metric for age showed that mianserin treatment attenuated the age-associated increase of transcriptional drift, thereby preserving the characteristics of a much younger (~3 days-old) transcriptome up to chronological day 10. These results showed that mianserin caused a 7-8 days delay in age-associated transcriptional change and suggested that the physiological changes leading to a lifespan extension were already completed by day 10. Measuring mortality levels supported this conclusion. By day 12, the entire mortality curve was shifted parallel by 7-8 days showing that the physiological delay leading to a lifespan extension was already completed. Experiments in which animals were exposed to mianserin for limited periods of time confirmed that mianserin exposure for the first 5-10 days of adulthood was necessary and sufficient to fully extend lifespan. The most parsimonious explanation that accounts for all these results is that mianserin treatment slows degenerative processes specifically between day 1 and 10, extending the duration of the period of young adulthood thereby postponing the onset of major mortality around mid-life.

Giving Tuesday is a once a year charitable event to encourage donations, awareness, and advocacy for all causes - and today is the day. Donations made today to the SENS Research Foundation to help fund rejuvenation research programs aimed at effective treatment of the root causes of age-related disease will be matched three times over.

(And if SENS research isn't your cup of tea, then allow me to point out that the scientist behind DRACO anti-viral technology, capable of controlling near all viral infections including many that currently lack effective therapies, is presently raising funds for ongoing research and development at IndieGoGo. Regardless of views on the best way forward for aging research, I would hope we can all agree that the work to date on DRACO is very promising, the world will be a better place with fewer viral infections, and that helping this project is also a worthy cause).

The SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease, has joined #GivingTuesday, a global day of giving that harnesses the collective power of individuals, communities and organizations to encourage philanthropy and celebrate generosity worldwide. Every dollar donated to SRF up to the first $5,000 will be quadrupled, making every dollar raised turn into $20,000.

SENS Research Foundation is aiming to reach a goal of $20,000 with the help of contributors who have pledged to match each dollar raised up to the first $5,000. The Croeni Foundation, a philanthropic organization dedicated to giving, the environment and health, has pledged to match the first $5,000 raised dollar for dollar. The foundation gave SRF an unrestricted $5,000 earlier this year, as well. Aubrey de Grey, CSO of SENS Research Foundation, has offered a dollar for dollar matching challenge up to $5,000. And Fight Aging! will match every dollar up to $125,000 through December 31, 2015.

"Today's cost for the treatment and care of chronic diseases of aging costs around $40,000 per second and will only continue to go up, as we spend more money per patient, while the number of patients is increasing. As a society, we need to change our ways and start treating age-related diseases more intelligently. The funds we raise on #GivingTuesday will help facilitate our efforts to do just that, as we work to continue learning how to prevent or reverse age-related diseases."

Link: http://sens.org/outreach/press-releases/givingtuesday-2015

Loss of elasticity in blood vessels is an important aspect of aging, as it creates hypertension and cardiovascular remodeling that ultimately leads to heart disease and death, along the way increasing the damage done by blood vessel failure in the brain as well as raising the risk for many other age-related conditions. Arterial stiffening is thought to be caused by cross-links and calcification, alterations in the extracellular matrix that degrade its structural properties. It is worth assuming that nothing in biology ever has one cause or a simple set of contributing mechanisms, however. Researchers here provide evidence for increased levels of the enzyme matrix metalloproteinase-12 (MMP12) to be significantly involved in arterial stiffening, though the underlying root cause of that increase remains an open question:

Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that MMP12, a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age.

In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans.

Link: http://dx.doi.org/10.1038/srep17189