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Fight Aging! Newsletter, December 19th 2016

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

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Contents

  • In the Last Three Weeks of the SENS Rejuvenation Research Fundraiser, Donations are Tripled by Matching Until the End of the Year
  • Can Cellular Senescence be Reversed in the Near Future, and is Reversal Desirable?
  • Looking Back and Ahead in the Use of Pluripotent Stem Cells in Medicine
  • Temporarily Applying Pluripotency Reprogramming Factors to Adult Mice
  • Testing the Quality of Brain Preservation by Exercising Neurotransmitter Functions
  • Latest Headlines from Fight Aging!
    • Proposing Cross-Linking in the Extracellular Matrix to Contribute to Immunosenescence
    • Evidence for Exercise to Improve Mitochondrial DNA Repair via p53 Activity
    • Initial Results Reported from a Phase 1 Safety Trial of a Tau Vaccine
    • A Summary of the NIA Interventions Testing Program
    • More Evidence for the Importance of BACE1 in Alzheimer's Disease
    • A Method to Partially Compensate for Failing Wound Healing in Skin
    • An Example of Reducing or Altering Cellular Senescence
    • A Discussion of Calico Labs
    • Arguing for Some Clonal Expansion of T Cells in the Aging Immune System to be a Beneficial Adaptation
    • MicroRNA Differences Across the Course of Aging Correlate with Life Span

In the Last Three Weeks of the SENS Rejuvenation Research Fundraiser, Donations are Tripled by Matching Until the End of the Year
https://www.fightaging.org/archives/2016/12/in-the-last-three-weeks-of-the-sens-rejuvenation-research-fundraiser-donations-are-tripled-by-matching-until-the-end-of-the-year/

This year's SENS rejuvenation research fundraiser has three weeks to go, and there are now two challenge funds with money left to match your charitable donations: the 150,000 fund established by Michael Greve's Forever Healthy Foundation, and today Josh Triplett has added another 20,000 above and beyond his generous donations earlier in the year. Thus donations to the SENS Research Foundation made now will be matched twice. Give 100 and a total of 300 will go towards expanding the SENS research programs aimed at bringing an end to age-related disease, frailty, and mortality, an end to the suffering and pain that accompanies aging today. In addition there are still matching funds left to encourage people to become SENS Patrons. Sign up as a monthly donor to the SENS Research Foundation before December 31st, and Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! will match the next year of your donations. If you know someone who hasn't yet decided on the charity he or she will support this year, then point out the good work of the SENS Research Foundation.

As 2016 winds to a close, drawing a line under a tremendous amount of progress towards the first viable rejuvenation therapies based on clearance of senescent cells, I encourage you to reread the SENS materials and the overview of the research programs that the SENS Research Foundation has organized and funded using years of donations from people like you and I. Consider for a moment how fortunate we are to live in an age in which we have the opportunity to help make the end of aging a reality. That there is a good enough understanding of the biochemistry of old tissues to identify the metabolic wastes, the cross-links in the extracellular matrix, the damage to mitochondrial DNA, the senescent cells, and other causes of aging. Further, that biotechnology is moving rapidly enough for the therapies repair and reverse these root causes of aging to be plausible and achievable. That observers such as I can assemble forecasts based on present ongoing work in the scientific and biotechnology communities and order the likely near future clinical availability of various approaches to human rejuvenation. All that remains is to persuade people and to raise the funds needed to make it happen, and in that we are so very much further ahead than we were even a decade ago.

Yet there is so very much left to accomplish! From here it might seem a mountain of work, to go from a world in which next to nothing can be done about aging to a world in which aging is controlled and defeated, but in reality small differences today are all that lie between (a) a future in which aging is, by increments, brought under medical control soon enough to save our lives and those of our children and (b) a future in which aging continues to destroy the lives of everyone. These small differences are the choices made by a handful of people today, choices that will snowball in the years ahead to create significant change: the choices made by researchers, advocates, and everyday philanthropists. If you are one of the modest community whose members read Fight Aging! from time to time, then you are one of those people, knowing enough and seeing far enough ahead to understand that the world can be changed for the better. That aging is not set in stone, and its causes can be repaired. All great and sweeping change starts small, with a few small decisions: the decision to tell a friend about the SENS Research Foundation and the likely prospects for the future; the decision to donate as you can to help the research take place; the decision to learn more about the underlying science.

A golden future lies ahead of us, if we just reach for it. So donate to the SENS Research Foundation, an organization doing a great deal to create that future, removing roadblocks from research and development, and giving rise to serious commercial efforts to produce cost-effective, widely available rejuvenation therapies.

Can Cellular Senescence be Reversed in the Near Future, and is Reversal Desirable?
https://www.fightaging.org/archives/2016/12/can-cellular-senescence-be-reversed-in-the-near-future-and-is-reversal-desirable/

Cellular senescence is one of the causes of degenerative aging. Normal somatic cells in adults become senescent at the end of their replicative life span, when they reach the Hayflick limit on cell divisions, or in response to damage or a toxic environment. Most such cells self-destruct or are destroyed by the immune system, but some linger to cause problems, ever more of them over the years. A senescent cell generates a mix of signals known as the senescence-associated secretory phenotype (SASP) that promotes inflammation, damages surrounding tissue structures, and alters the behavior of nearby cells for the worse. Senescence isn't all bad, however: in limited doses, it helps to lower the risk of cancer by shutting down those cells most at risk. It also occurs during wound healing and embryonic development, and plays necessary roles in both of those processes. Nonetheless, cellular senescence helps to kill us as we age, and as more of these cells accumulate in tissues, their presence speeds the progression of many age-related diseases.

Researchers are taking two broad approaches to cellular senescence at the present time. The first is to build therapies that can selectively destroy senescent cells, following the SENS rejuvenation model of periodic removal of damage. If the number of senescent cells is managed so as to keep that count low, then they will not cause further harm. This has the advantage of being straightforward and requiring little further research to put into practice. A range of demonstrated treatments and potential treatments already exist - gene therapies, immunotherapies, senolytic drugs, and so forth - and companies such as Oisin Biotechnologies and UNITY Biotechnology are bringing some of these technologies to the clinic. The second approach is nowhere near as far along, and involves altering the behavior of senescent cells to make the SASP less harmful. There is a long way to go yet in order to produce a decent therapy on this front, and it isn't clear how much potential there is in the present avenues of investigation, or how much more research is required to make meaningful progress. Such a therapy wouldn't remove senescent cells, and therefore would have to be a continual rather than periodic treatment.

There is a third potential approach, however, which is to revert senescent cells back to a normal state of operation. In the ordinary course of events, senescence is thought to be an irreversible state, though there is a substantial grey area here, as nothing is black and white in biochemistry. There may well be different degrees and types of senescence, similar outcomes produced by different balances of the same varied collection of processes and triggers. I think it highly unlikely that the switch for senescence boils down to one controlling protein and one configuration. That said, cells are state machines and substantial reprogramming of that state has already been demonstrated, such as for induced pluripotency. Given sufficient understanding of the machinery and the signals involved, it should be possible to turn a senescent cell into a perfectly normal cell. There is the caveat that it will probably just turn right back again if the stimulus or damage that provoked the change in the first place is still around, however. Thus any practical approach to revert senescence is likely only useful if accompanied by other forms of repair or alteration, such as lengthening of telomeres to push the cell back from the Hayflick limit. It is an open question as to whether or not this sort of approach would cause further problems by putting damaged and older cells back into circulation, but to a certain extent that question is in the process of being answered by work on telomerase gene therapies and first generation stem cell therapies, both of which appear to produce that outcome to some degree. This is all highly speculative, however - there is a lot of work left to be accomplished to turn arguments and evidence into solid facts.

From my point of view none of this is really worth the effort for therapeutic development given that senescent cells can be destroyed to produce benefits, and anything other than destroying them is going to be much harder to achieve. It is of course useful from a pure science perspective; it adds to the map of metabolism and the way in which cellular biochemistry interacts with aging. With that in mind, the paper linked below is an example of researchers investigating some of the machinery that forms the switches and triggers that determine whether or not a cell adopts a senescent state. At this point the cutting edge of cellular biochemistry has moved well past simpler considerations of genes and proteins and is delving into the highly complex interactions that take place inside the processes of gene expression, wherein the genetic blueprint is converted into one or more proteins. This has numerous stages, and at every stage there is a dance of various regulatory molecules also produced from DNA. The closer that researchers look, the more there is to be mapped.

Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1

Cellular senescence is a state of indefinite growth arrest triggered by exposure of a cell to stress-causing stimuli. When the stress signal arises from successive rounds of replication causing gradual shortening of telomeres, which exposes telomeric DNA and triggers a DNA damage response, the ensuing program is named replicative senescence. When the stress signal comes from other sources of damage, such as oxidants, radiation, heat, activated oncogenes, or toxins, the ensuing program is named stress-induced senescence. Senescence is characterized by increased activity of the tumor suppressor TP53, higher levels of its transcriptional target p21/CDKN1 and the CDK inhibitor p16/INK4A, and activation of the p16 target retinoblastoma (pRB). Senescent cells have a complex impact on human physiology and pathology. Some effects of senescent cells are beneficial, such as tissue remodeling, wound repair, and growth suppression of potentially oncogenic cells. However, many effects of senescent cells are believed to be detrimental. Besides causing tissue dysfunction, senescent cells exhibit a senescence-associated secretory phenotype (SASP), whereby they produce and secrete inflammatory cytokines and chemokines, matrix metalloproteases, and growth and angiogenic factors. The accumulation of senescent cells has been associated with disease processes such as sarcopenia, arthritis, cancer, diabetes, and neurodegeneration.

MicroRNAs (miRNAs) are ∼22-nucleotide long noncoding (nc)RNAs that form part of the RNA-induced silencing complex (RISC), within which the RNA-binding protein (RBP) AGO2 binds microRNAs directly. MicroRNA-RISC complexes influence protein expression patterns through the interaction of the microRNA with subsets of mRNAs via partial complementarity, generally leading to reduced stability and/or reduced translation of the mRNA. By influencing protein expression patterns, microRNAs have been implicated in key cellular processes, including numerous pathways that control senescence. Indeed, many microRNAs show altered expression levels during senescence. A notable class of microRNAs implicated in growth arrest and senescence is the human let-7 family. Given that let-7 members are expressed from genomic regions that are deleted in tumors and that they suppress expression of oncogenes and proteins that enhance cell proliferation, the let-7 family has been implicated in tumor suppression. Conversely, let-7 members have been proposed to promote senescence, as their levels rise during cell senescence and let-7 suppresses the production of proteins that promote proliferation and inhibit senescence.

Circular RNAs (circRNAs) are ncRNAs that form covalently closed circles. Initially, they were considered byproducts of splicing, but recent work has revealed that a vast number of circRNAs exist in mammalian cells and that some of them are abundant and stable, suggesting that they may have regulatory functions in the cell. A substantial fraction of spliced transcripts gives rise to circRNAs, but the repertoire of transcripts from which circRNAs are derived is cell type-specific, supporting the notion that circRNA biogenesis and function may be highly regulated. CircRNAs are believed to influence several cellular processes. CircRNAs have been known for more than two decades but did not draw much attention until recently, when their high abundance was revealed by transcriptome-wide RNA-sequencing and several circRNAs have been characterized as inhibitors of microRNAs and thus regulators of gene expression.

Here, we used high-throughput RNA sequencing (RNA-Seq) to survey senescence-associated circRNAs (which we termed 'SAC-RNAs') differentially expressed in proliferating and in senescent human fibroblasts. Among the circRNAs selectively reduced in senescent cells, we focused on CircPVT1, as silencing CircPVT1 in proliferating cells triggered senescence. Although several microRNAs were predicted to bind CircPVT1, only let-7 was found enriched after pulldown of endogenous CircPVT1, suggesting that CircPVT1 might selectively modulate let-7 activity and hence expression of let-7-regulated mRNAs. Reporter analysis revealed that CircPVT1 decreased the cellular pool of available let-7, and antagonizing endogenous let-7 triggered cell proliferation. Importantly, silencing CircPVT1 promoted cell senescence and reversed the proliferative phenotype observed after let-7 function was impaired. Consequently, the levels of several proliferative proteins that prevent senescence, such as IGF2BP1, KRAS and HMGA2, encoded by let-7 target mRNAs, were reduced by silencing CircPVT1. Our findings indicate that the SAC-RNA CircPVT1, elevated in dividing cells and reduced in senescent cells, sequesters let-7 to enable a proliferative phenotype.

Looking Back and Ahead in the Use of Pluripotent Stem Cells in Medicine
https://www.fightaging.org/archives/2016/12/looking-back-and-ahead-in-the-use-of-pluripotent-stem-cells-in-medicine/

There are a few papers and commentaries that you might find interesting in the latest issue of Regenerative Medicine. The one I'll point out here offers a retrospective and a forecast for the use of pluripotent stem cells in medicine. It is authored by one of the more outspoken figures from the last decade of research and development, but is worth reading regardless of that point. All industries tend to follow what has come to be known as a hype cycle as they reach critical mass and transition into broad adoption and large scale development. Stem cell medicine as a whole had its initial peak of attention and overhyped expectations, followed by a consequent period of disillusionment as people realized that it wasn't a silver bullet for everything, and that, yes, there was actually going to be quite a lot of work involved in turning the new knowledge of stem cell biology and promising early results in transplant therapies into the bigger, better next generation of medicine. All of that largely took place almost decade ago. As is always the case, it is after the initial hype and crash is out of the way that the real work begins in earnest, and at a far greater scale. The ongoing development of cell therapies is now well into this quieter, more productive period of growth; the engineering of reliable treatments that improve upon the prior state of the art.

Not all cell therapies are relevant to aging and rejuvenation, but since it is the case that comparatively simple forms of stem cell transplant can produce a number of benefits in age-damaged tissues, and are an incremental improvement over existing therapies for a number of conditions, a large fraction of the development initiatives in this industry are focused on age-related disease. So far the most reliable benefits are produced by classes of therapy in which stem cells provide signaling that reduces inflammation and spurs greater regenerative activity in native cell populations. In most cases the transplanted cells don't integrate or stick around for the long term, however. Stem cell treatments for the sort of inflammatory joint issues prevalent in the old are an example of the type, as are most treatments involving mesenchymal stem cells. Regeneration of internal organ damage and effective treatment of age-related disease has proven to be a more elusive goal, however. Benefits are observed, but reliability is a real challenge. A great deal of the data is hidden from view, given that most patients are treated via medical tourism and formal trials are an expensive and slow business.

Given all of this, it is fair to say that a large fraction of the effort and funding in stem cell medicine has little to do with addressing aging directly. The therapies are compensatory in nature, and do not target the causes of degenerative aging relevant to the space of cell therapies. Insofar as aging is in part a problem of cell loss on the one hand and a mix of damage and declining activity in stem cell populations on the other, we would want to see cell therapies that can replace lost cells (such as muscle cells in order to reduce frailty) and deliver fresh new stem cell populations that will integrate into tissues and take up the work of their predecessors. The latter is the preferable approach, as new stem cells that work as they did when youthful should solve the problem of lost cells and weakened tissues as a matter of course. The challenge here is that it appears that much of the problem of stem cell decline in aging is driven by changes in signaling in tissue, which in turns results from the varied forms of cell and tissue damage that cause aging. Stem cell decline is a reaction to damage, possibly an evolved response that serves to balance death by cancer on the one hand and death by failing organs on the other. Replacing stem cell populations with new, pristine cells is certainly needed, but will probably be of only limited benefit without inroads into other forms of rejuvenation therapy that can lift the burden of damage and thus revert the signaling environment to a more youthful state.

Pluripotent stem cells: the last 10 years

Pluripotent stem cells (PSCs) can differentiate into virtually any cell type in the body, making them attractive for both regenerative medicine and drug discovery. Over the past 10 years, technological advances and innovative platforms have yielded first-in-man PSC-based clinical trials and opened up new approaches for disease modeling and drug development. Induced PSCs have become the foremost alternative to embryonic stem cells and accelerated the development of disease-in-a-dish models. Over the years and with each new discovery, PSCs have proven to be extremely versatile.

In 2006, it had been 8 years since the initial isolation of human embryonic stem cells (hESCs) and incremental scientific progress was being made. However, ethical dilemmas regarding the use and/or destruction of human embryos as well as legislative barriers in several countries hindered hESC research endeavors. Moreover, the need to source several hundred embryos for the creation of hESC lines to cover the diversity of human leukocyte antigen (HLA) phenotypes made clinical translation of embryonic stem cell (ESC) based therapies seem difficult. This situation precipitated major initiatives to find alternatives. Single blastomere technology is one such alternative; it was developed in 2006 as a nondestructive ESC derivation method and was first demonstrated for mouse ESCs, then adapted for human ESCs in the same year. With this technique, a single cell or 'blastomere' is isolated from a morula (8-cell) stage embryo and, after culture and expansion, can give rise to an ESC line.

Somatic cell nuclear transfer (SCNT) is another alternative for generating hESCs without the destruction of naturally made embryos. This technique has been used successfully in other species such as calves, pigs and mice since the late 1990s and early 2000s, yet for various reasons including the availability of federal funding, institutional review board (IRB) requirements and public sentiment, it took until 2013 for it to be successfully applied to humans. In SCNT, the nucleus of an unfertilized egg is removed and replaced with the nucleus from a somatic cell. Precise culture conditions coupled with maternal factors within the egg promote the reprogramming of the somatic cell nucleus back to a pluripotent state and can give rise to an ESC line. Despite these successes, SCNT has not been widely used for ESC derivation due to the need for high-quality eggs and precise microsurgical techniques. Moreover, the requirement for egg donation is a significant barrier to its widespread use.

Arguably the most important alternative to conventional methods for hESC generation was the invention of induced PSC (iPSC) technology in 2006 and its application to human cells in 2007. iPSC technology avoids the use and destruction of human eggs and/or embryos altogether, thereby largely circumventing ethical controversy. iPSCs are generated through the reprogramming of somatic cells back to an embryonic-like state; the addition of exogenous reprogramming factors triggers this reprogramming process. iPSC technology revolutionized the field of PSC research. Today, generating iPSCs takes many shapes and forms, with different reprogramming factors, different methods for introducing factors to cells, different starting cell types, among others. The technology has undergone a fascinating evolution from its first report in 2006 to the present day and it will continue to evolve in years to come. In 2009-2011, right around the same time that various second-generation reprogramming methods were being developed, reports were starting to emerge that iPSCs were not equivalent to ESCs and that differentiation potential of iPSCs was either impaired or skewed based on the starting somatic cell type. Differences in the somatic cell type used for reprogramming, the specific reprogramming method employed, as well as the extent of culturing are thought to influence the degree of disparity between various iPSC lines and/or ESCs. Yet, in some instances, epigenetic memory can be reduced or even eliminated through subsequent passaging of iPSC clones, or alternatively by differentiation and secondary reprogramming, whereas errors that arise during reprogramming may be corrected through the use of chromatin modifying drugs. Improvements and modifications made to reprogramming methods over the past decade have helped improve the safety and quality of iPSCs such that the development of iPSC-based therapies is moving forward rapidly. In years to come, the development of iPSC-based therapies may overtake conventional hESC-based ones since their generation does not involve the destruction of embryos or even the use of any unfertilized eggs. This is particularly appealing for the long-discussed generation of banks of HLA-matched PSCs to cover patient diversity on a larger scale and reduce or avoid the need for concomitant immunosuppression.

PSCs may be useful for treating a wide variety of diseases given their ability to differentiate, theoretically, into every cell type in the body. The last 5-6 years have seen the PSC field begin to deliver on this promise, with a handful of clinical trials being approved in spinal cord injury, macular degeneration (AMD), diabetes and heart disease. Starting it off in 2009, Geron received investigational new drug (IND) approval to begin testing its hESC-derived oligodendrocyte precursors, GRNOPC1 in a Phase I trial for spinal cord injury. In 2010, a few months before Geron transplanted GRNOPC1 into its first patient, Advanced Cell Technology received IND approval to begin testing hESC-derived retinal pigment epithelium (RPE) for age-related macular degeneration. Around the same time that ACT's 2014 safety data were being published, Japan's RIKEN Institute successfully transplanted the world's first iPSC-derived therapy into humans. They too chose the eye and (wet) AMD as a first indication but decided to transplant autologous iPSC-derived RPE into patients instead of using an off-the-shelf allogeneic cellular product. Given the risks of first-in-human PSC-based therapies, the eye is considered a logical place to begin developing therapies. First, the eye is a locally contained environment, providing a natural barrier to any potentially deleterious cells spreading systemically. Second, its immune-privileged nature may make it more accepting of transplanted allogeneic cells in the long-term. Third, the lens provides a way to noninvasively image the transplantation site over time and functional readouts such as visual acuity are easy to obtain. Indeed, numerous groups have active trials listed. More than a decade of PSC research and development has also led to clinical trials for PSC-derived therapies in other disease areas. In 2014, Viacyte received IND approval to begin a Phase I/II trial to treat Type 1 diabetes. In addition to the above trials, a PSC-derived therapy was approved for an ischemic heart disease Phase I clinical trial in 2013.

The last decade has also seen incredible progress on the development of other PSC-based therapies, some very close to beginning clinical trials. Several groups have made great progress in generating PSC-derived dopaminergic (DA) neurons for the treatment of Parkinson's disease (PD). A long-standing goal for PSC research has been the in vitro generation of glucose-responsive, insulin-producing mature pancreatic β cells to treat diabetes. In 2014, a new protocol was finally able to overcome this challenge and resulted in the in vitro generation of β cells expressing mature pancreatic β cell markers. PSCs are being developed for therapeutic use in various other diseases as well. For example, autologous iPSCs are being generated for patients with the blistering skin disorder, epidermolysis bullosa as part of a cell replacement strategy. In the eye, retinal progenitors are being developed from both ESCs and iPSCs to use as a cell replacement therapy for retinal degenerative diseases, such as retinitis pigmentosa (RP), whereby transplantation of the progenitors would lead to in vivo differentiation and functional engraftment by mature photoreceptors. PSCs are also being developed to maintain the health of endogenous cells at risk for degeneration in various diseases. For example, iPSC-derived macrophages are being manipulated for therapeutic use in Alzheimer's disease (AD) patients. These macrophages have been engineered to express high levels of the β-amyloid-degrading enzyme, neprilysin 2, in an effort to reduce the burden of disease-associated plaques and spare the health of existing neurons in AD. Similarly, in amyotrophic lateral sclerosis (ALS), iPSC-derived neural stem cells may provide therapeutically useful support to endogenous neurons.

Gene editing technologies have been developed to correct disease-causing genetic mutations, functionally replace and/or knock-out expression of dysfunctional genes. Regardless of the editing system employed, the objectives of PSC-based gene editing endeavors fall into two major categories: improving disease models and drug screening systems through the creation of isogenic controls, and gene editing for cell-based therapies. Proof of principle studies includes a report where Crispr/Cas gene editing was used to correct the mutation of the β-globin gene in iPSCs from a β-thalassemia patient. These corrected iPSCs displayed improved differentiation capacity into various types of hematopoietic progenitors and may be one day used as a source of autologous hematopoietic stem cells for transplantation and repopulation of the hematopoietic system. Similarly, Crispr/Cas9 was used to correct a mutation in the gene encoding the RP GTPase regulator in iPSCs derived from a patient with X-linked RP. These corrected cells could in principle be differentiated into photoreceptors or their progenitors and used in cell replacement strategies for RP patients.

The dramatic progress made over the past decade will almost certainly translate into exciting new advancements in decades to come. First-in-man PSC-based clinical trials have thus far shown that PSC-derivatives are safe to use in humans, and provide the impetus for continued clinical trial testing. To date, trials have almost exclusively employed hESCs, yet that is likely to change in the future. Improvements in iPSC quality should enable these ethically sound alternatives to hESCs to catch up or even pass hESC usage in clinical trials. As differentiation procedures and 3D technologies improve, PSCs will become ever more integral to drug screening efforts and disease modeling, although it is unlikely they will ever fully replace the use of in vivo disease models. Another major advancement that will likely drive PSC research in years to come involves the marriage of gene editing technology with PSCs. The ability to precisely correct disease-causing mutations, create isogenic controls and potentially eliminate immunogenicity of PSC derivatives make gene editing in PSCs an incredibly important endeavor. The PSC field will likely produce additional exciting breakthroughs in the coming decade - advancements that could one day make incurable diseases curable.

Temporarily Applying Pluripotency Reprogramming Factors to Adult Mice
https://www.fightaging.org/archives/2016/12/temporarily-applying-pluripotency-reprogramming-factors-to-adult-mice/

Today's interesting news, doing the rounds in the popular press and being gleefully misinterpreted along the way, is that, working in mice, researchers have induced temporarily increased levels of the proteins used to reprogram normal cells into pluripotent stem cells. This produced a number of short term benefits to regeneration and metabolism, though the long-term results on life span remain to be assessed. Cancer and regeneration are two sides of the same coin, and it is thought that the characteristic decline in stem cell activity with age is part of an evolved balance between risk of cancer and risk of tissue failure. Many of the methods of globally spurring greater regeneration either definitely or theoretically carry the risk of cancer. Stem cell therapies and telomerase gene therapies fall into this categories, though on the whole the cancer risk in practice has so far turned out to be lower than the cancer risk in theory. The reasons for this remain to be fully explored. Nonetheless, the whole complex system of a few stem cells with unlimited replication supporting a tissue of many somatic cells with tightly limited replication that exists in near all species came into being in the evolutionary context of cancer. We depend upon biological structures that are self-repairing and resilient in many ways, but that are very vulnerable to cellular malfunctions of uncontrolled growth that distort the structure and disrupt correct function. So where we are less self-repairing and resilient than we might be, cancer is the first and most obvious culprit when considering the evolutionary history that created us.

It has been a decade since researchers first figured out how to reprogram normal adult cells into induced pluripotent stem cells, capable of forming any cell, but likely to do who knows what if put into the context of living tissue. Reprogramming occurs in a cell culture, using a cell sample, not in a living organism. This reprogramming actually involves surprisingly few changes, dialing up the gene expression of a few specific proteins, with the first attempts using Oct4, Sox2, cMyc, and Klf4. The use of induced pluripotent stem cells in medicine is a matter of developing a methodology that will differentiate the pluripotent cells into the desired type of stem or progenitor cell appropriate to the tissue in question, using the patient's own cells as a starting point so that the resulting therapeutic cells are matched perfectly. That is fairly safe, given suitable testing, and will eventually provide a cost-effective source of all the cells needed for the next generation of regenerative medicine and tissue engineering. The cells put in place match those already present in the tissue, and should pick up on the same environment of signals and undertake the appropriate work of regeneration. Delivering pluripotent stem cells as-is, on the other hand, is just asking for cancer: it is more or less the same thing as putting precancerous cells into the patient. There is no control or guidance, and what happens next is up to the hand of fate.

Given this, one would think that taking the next step and using gene therapy to upregulate the reprogramming proteins in a living individual would be even worse. In addition to a whole bunch of newly pluripotent cells, you have newly pluripotent cells appearing in random locations and changed from random cells with random levels of preexisting damage. None of this sounds particularly safe. In fact, that experiment has been carried out in mice, and as you might expect the result is the development of cancers. The newly created pluripotent cells start building whatever springs to mind, wherever they happen to be. However, there are several examples we can point to in which dialing up protein production permanently is disastrous, but turning it up intermittently is quite beneficial. One good example is the tumor suppressor gene p53, which if producing proteins all the time will, in addition to even more effectively reducing cancer risk, accelerate aging by suppressing processes that are also necessary to regeneration and tissue maintenance. Cancer and regeneration use the same mechanisms - one is simply more regulated than the other. Most of the tumor suppression genes that have been cataloged target these shared mechanisms. Yet producing additional p53 only when regulatory processes determine it is needed, suppresses cancer more effectively without accelerating aging.

In this context the researchers here use a methodology of temporarily increasing expression of the pluripotency genes Oct4, Sox2, cMyc, and Klf4 in mice. They do this in cell cultures, then in mice with an accelerated aging disorder - actually a dysfunction of the cellular structure akin to that in human progeria - and then in normal aged adult mice. I think it a good idea to ignore the first two of these. Cell cultures are not living animals, and we should usually pay little attention to studies on accelerated aging models for the same reason we should pay little attention to studies in poisoned mice. Progeria and poisoning are both conditions that have little relevance to normal aging, being an accumulation of cell damage that doesn't occur to any large degree in normal aging, so it is often very hard to determine whether or not the results are in any way useful. If you produce a lot of damage and then help work around that damage, but none of the above actually happens in the course of ordinary aging, what does that say? The answer depends on details specific to each case that most of us are not knowledgeable enough to assess.

Fortunately here the researchers did undertake a study in normal mice. Unfortunately it was only a short-term study, so considerations of life span and longer term outcomes, such as cancer rate, will have to wait. Still, as an additional data point in the larger picture of what can be done to enhance regeneration in mammals, it is interesting. We can consider all sorts of plausible candidate mechanisms that have been explored in past years and likely overlap with those involved in the outcomes produced by stem cell transplants and telomerase gene therapies. That said, this upregulation of pluripotency factors is certainly something that I'd put in the "very unwise" bucket, should you find yourself in the position to undergo such a gene therapy in the years ahead. It is much more risky than telomerase gene therapy, and that in and of itself looks like something to skip until more data on the outcomes in larger mammals arrives.

Turning back time: Salk scientists reverse signs of aging

As people in modern societies live longer, their risk of developing age-related diseases goes up. In fact, data shows that the biggest risk factor for heart disease, cancer and neurodegenerative disorders is simply age. One clue to halting or reversing aging lies in the study of cellular reprogramming, a process in which the expression of four genes known as the Yamanaka factors allows scientists to convert any cell into induced pluripotent stem cells (iPSCs). Like embryonic stem calls, iPSCs are capable of dividing indefinitely and becoming any cell type present in our body. "What we and other stem-cell labs have observed is that when you induce cellular reprogramming, cells look younger. The next question was whether we could induce this rejuvenation process in a live animal."

While cellular rejuvenation certainly sounds desirable, a process that works for laboratory cells is not necessarily a good idea for an entire organism. For one thing, although rapid cell division is critical in growing embryos, in adults such growth is one of the hallmarks of cancer. For another, having large numbers of cells revert back to embryonic status in an adult could result in organ failure, ultimately leading to death. For these reasons, the team wondered whether they could avoid cancer and improve aging characteristics by inducing the Yamanaka factors for a short period of time. To find out, the team turned to a rare genetic disease called progeria. Both mice and humans with progeria show many signs of aging including DNA damage, organ dysfunction and dramatically shortened lifespan. Moreover, the chemical marks on DNA responsible for the regulation of genes and protection of our genome, known as epigenetic marks, are prematurely dysregulated in progeria mice and humans. Importantly, epigenetic marks are modified during cellular reprogramming.

Using skin cells from mice with progeria, the team induced the Yamanaka factors for a short duration. When they examined the cells using standard laboratory methods, the cells showed reversal of multiple aging hallmarks without losing their skin-cell identity. Encouraged by this result, the team used the same short reprogramming method during cyclic periods in live mice with progeria. The results were striking: Compared to untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved and - most surprising of all - they lived 30 percent longer, yet did not develop cancer. Lastly, the scientists turned their efforts to normal, aged mice. In these animals, the cyclic induction of the Yamanaka factors led to improvement in the regeneration capacity of pancreas and muscle. In this case, injured pancreas and muscle healed faster in aged mice that were reprogrammed, indicating a clear improvement in the quality of life by cellular reprogramming.

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

The last decade of scientific research has dramatically improved our understanding of the aging process. The notion that cells undergo a unidirectional differentiation process during development was proved wrong by the experimental demonstration that a terminally differentiated cell can be reprogrammed into a pluripotent embryonic-like state. Cellular reprogramming to pluripotency by forced expression of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc [OSKM]) occurs through the global remodeling of epigenetic marks.

Although in vitro studies have been informative, the physiological complexity of the aging process demands an in vivo approach to better understand how reprogramming may affect cellular and organismal aging. Breakthrough studies have shown that cellular reprogramming to pluripotency, although associated with tumor development (e.g., teratoma formation), can be achieved in vivo in mice by the forced expression of the Yamanaka factors. In addition, we and other groups have demonstrated that partial reprogramming in vitro by transient expression of OSKM can induce a dedifferentiated progenitor-like state. Together, these observations suggest that cellular reprogramming may be used to promote tissue regeneration and led us to hypothesize that in vivo partial reprogramming could slow or reverse the aging process and extend organismal lifespan. Here, we report that cyclic in vivo induction of OSKM in a mouse model of premature aging improves age-associated phenotypes and extends lifespan. In addition, we demonstrate the amelioration of cellular phenotypes associated with aging by short-term induction of the Yamanaka factors in mouse and human cells. Finally, we show that short-term expression of OSKM alleviates pancreatic and muscle injury in older wild-type (WT) mice.

Our observations may reinforce the potential role of epigenetic changes as drivers of aging and highlight the plasticity of the aging process, which might be altered by cellular reprogramming in vivo. In addition, our results suggest that aged cells undergo a process of molecular rejuvenation during the initial stages of cellular reprogramming to pluripotency. Failure to erase critical hallmarks of aging may lead to refractory populations of cells and cellular senescence. Due to the complexity of the reprogramming and aging processes, future studies will be necessary to investigate whether partial reprogramming can ameliorate aging hallmarks during physiological aging and to better understand the molecular mechanisms behind this phenomenon. This information will be necessary if we are to develop accurate and efficient epigenetic remodeling strategies toward maximizing the beneficial effects of in vivo reprogramming while avoiding potential risks associated with the in vivo expression of the Yamanaka factors.

Reading the whole of the analysis in the paper, I have to say that I think these researchers have a lot of the picture back to front. Putting epigenetic changes front and center as a primary mechanism in aging, as opposed to a reaction to rising levels of cell and tissue damage, is the cart in front of the horse. Sure, those epigenetic changes cause further problems, but focusing on targeting them won't remove the primary damage that causes aging. It only forces the damaged engine to work harder. Maybe that produces benefits, as it seems to in stem cell therapies that work via signaling to put existing cells back to work, but it isn't solving the real problem.

Testing the Quality of Brain Preservation by Exercising Neurotransmitter Functions
https://www.fightaging.org/archives/2016/12/testing-the-quality-of-brain-preservation-by-exercising-neurotransmitter-functions/

You, your self, consists of the slowly shifting structural pattern of matter that holds the data of the mind. That structure is thought to reside in the synapses that connect neurons in the brain, though there is some debate on this topic and final confirmation still lies somewhere in the future. Survival after cold water drowning, in which the brain ceases all activity for a time but nonetheless carries on after rescue, adequately demonstrates that the basis of the mind is physical, not ephemeral, however, no matter where exactly it is to be found in the fine structure of brain tissue. This is important, because it means that an individual is only finally, absolutely dead and gone when that structure is destroyed. A person can be minutes past present definitions of clinical death, but still exist, still be dying in the sense that the structures of the mind are being destroyed by ischemia. Past that span of minutes it gets far more sketchy and unknown as how much of the self remains. That is a hard question to answer absent a definitive location for that data. What if the destruction can be halted, the brain preserved, however?

Preservation of the brain, the self, is the point of the cryonics industry. As soon as possible following death, the brain is cooled by stages and perfused with cryoprotectant. The result is vitrification with minimal ice crystal formation, a method demonstrated to preserve the fine structure of brain tissue, assuming a sufficiently comprehensive perfusion was achieved. There are examples of vitrified and thawed nematode worms retaining memory, and the cryobiology field is working towards reversible vitrification of organs to improve the logistics of organ transplantation and tissue engineering. When a patient is cryopreserved by a cryonics provider, the vitrified body and brain is stored in liquid nitrogen, awaiting a future with sufficiently advanced technology to undertake restoration. The individual is clinically dead, but not gone. The mind still exists, paused, and while that remains true we can envisage future combinations of molecular nanotechnology and regenerative medicine that could achieve a restoration to active life. Will that come to pass? Hopefully so, but nothing is certain. You roll the dice and look for the best odds, just as in any other decision. The odds following cryopreservation are infinitely better than those following burial or cremation. No-one comes back from oblivion.

A potential alternative to cryonics is plastination. This uses chemical fixation at room temperature instead of low-temperature vitrification, halting all biological processes by binding them up in fixative molecules while preserving the original molecular structure of the tissues. The technology needed to restore plastinated tissue is likely to be much more advanced than that needed to restore a vitrified brain: there are many more chemical reactions that need to be undone, molecule by molecule, and at the same time as kick-starting the normal cellular processes. At the present time there is no plastination industry akin to the cryonics industry that preserves people following death, but this may be nothing more than a historical accident. If the founders of the cryonics movement in the 1960s and 1970s had the chemistry background to settle on plastination, then we'd be looking back at decades of increasing experience in that technology instead. As the Brain Preservation Technology Prize contest of recent years illustrated, there isn't any great difference between the two approaches in terms of preservation of fine structure in brain tissue. Both can achieve the goal given a good methodology and absence of complications - and in both cases the burden and the challenge of restoration is placed upon future researchers. Which is fine; preserved patients can wait it out for as long as the preservation organizations continue.

How do we assess the quality of a preservation method, however? The primary methodology at the moment is the use of electron microscopy to assess the small-scale structure of neurons and synapses. It is possible to raise objections to this as a measure of success, but it is a good starting point. If significant disruption is seen here, then there is little point in looking any closer until we have a much better idea as to exactly which structures encode data. Another possible approach is to work with studies in lower species that can be preserved and restored, and assess their cognitive function after the process. That isn't possible for plastination, but has been done for vitrified nematode worms, as I mentioned above. Beyond this, what else can be attempted? In the research linked below, a novel approach is assessed in one of the common forms of plastinated brain tissue. The researchers manage to exercise some of the functionality of the preserved brain cells despite the chemical fixation process. If it can be replicated, this strikes me as a very compelling demonstration, and one that should certainly be expanded upon. I would be most interested to learn whether or not this sort of approach could be attempted in vitrified brain tissue at liquid nitrogen temperature - unfortunately I know far too little about this area of science to even guess at how one would go about such a task, or the degree to which it is possible at that temperature.

When Is the Brain Dead? Living-Like Electrophysiological Responses and Photon Emissions from Applications of Neurotransmitters in Fixed Post-Mortem Human Brains

The fundamental principle that integrates anatomy and physiology can be effectively summarized as "structure dictates function". This means the functional capacities of biological substrata are determined by the chemical composition, geometry, and spatial orientation of structural subcomponents. As the heterogeneity of structure increases within a given organ, so does the functional heterogeneity. Nowhere is this more evident than in the human brain. It can be described as a collection of partially-isolated networks which function in concert to produce consciousness, cognition, and behaviour. It also responds to its multivariate, diversely energetic environment by producing non-isotropic reflections within its micrometer and nanometer spaces. The specific spatial aggregates of these dendritic alterations result in processes that have been collectively described as memory: the representation of experience.

When structures of the brain undergo changes sufficient to terminally disrupt these functional processes and the individual is ultimately observed to lose the capacity to respond to stimuli, the brain is said to be clinically dead. This state has been assumed to be largely irreversible. It should be noted that the specific criteria which must be achieved in order to ascribe death to an individual are not universal and exhibit a significant degree of non-consensus. The precise point beyond which the brain is no longer "living", a threshold which remains unidentified, is perhaps less definite than has been historically assumed. Without life support systems, either endogenously in the form a cardiovascular network or exogenously in the form of mechanical aids, the brain degenerates progressively until full decomposition and dissolution. Complete loss of structure is strongly correlated with the complete loss of function. When the brain is dead and the tissue has lost its structural integrity, the individual is assumed to no longer be represented within what remains of the organ.

If, however, the brain is immersed within certain chemical solutions before degeneration and decomposition, the intricate and multiform structures of the human brain can be preserved for decades or perhaps centuries. The gyri and sulci which define the convex and concave landscapes of the brain's outer surface as well as the cytoarchitectural features of the cerebral cortex remain structurally distinct. The deep nuclei and surrounding tract systems remain fixed in space, unchanging in time. Though structurally intact, the functions of the brain are, however, still considered to be absent. It has been assumed that the chemical microenvironment (e.g., pH, nutrient content, ionic gradients, charge disparities, etc.) of both cells and tissues within the preserved brain must be altered to such a degree to prevent degradation that these spaces no longer represent those which underlie the cellular processes which give rise to normal human cognition and behaviour.

The principle of anatomy and physiology which describes the relationship between structure and function would hold that in the presence of structural integrity so too must there be a functional integrity. If the structure-function relationship is a physical determinant, functional capacities should scale with structural loss and vice versa. Therefore the maintenance of structure subsequent to clinical death by chemical fixation could potentially regain some basic function of the tissue to the extent to which structure and function are intimately related. Here we present lines of evidence that indicate brains preserved and maintained over 20 years in ethanol-formalin-acetic acid (EFA), a chemical fixative, retain basic functions as inferred by microvolt fluctuations and paired photon emissions within the tissue. They are both reliably induced and systematically controlled by the display of electrical and chemical probes which include the basic inhibitory and excitatory neurotransmitters or their precursors. Each of these profiles exhibit dosage-dependence and magnitude dependences that are very similar to those displayed by the living human brain. As neuroscientists we have been taught or have assumed that the fixed human brain is an unresponsive mass of organic residual that has replaced what was once a vital, complex structure that served as the physical substrate for thought, consciousness, and awareness. The results of the present experiments strongly suggest we should at least re-appraise the total validity of that assumption.

Latest Headlines from Fight Aging!

Proposing Cross-Linking in the Extracellular Matrix to Contribute to Immunosenescence
https://www.fightaging.org/archives/2016/12/proposing-cross-linking-in-the-extracellular-matrix-to-contribute-to-immunosenescence/

In this interesting open access paper, the authors propose that too little attention has been given to immune cell behavior in tissues rather than in blood, and that means that researchers have overlooked the possibility that age-related changes in the extracellular matrix structures that support tissues might be a significant cause of the growing immune dysfunction that takes place in later life. One of the more important of these changes in the extracellular matrix is the growing presence of cross-links, persistent sugary compounds produced as a byproduct of normal metabolic operations that chain together the large molecules of the extracellular matrix. In doing so these cross-links change the chemical and structural properties of the matrix and the tissue as a whole, producing results such as loss of elasticity in skin and blood vessels, which in turn contribute to a variety of age-related diseases. If cross-linking does indeed contribute to immunosenescence, the decline of the immune system with age, then that only increases the importance of ongoing research funded by the SENS Research Foundation aimed at safely breaking down this unwanted form of metabolic waste. In humans near all persistent cross-links appear to involve a single class of compound, glucosepane. So in theory there is only a single target here, needing just one drug development program to make a large difference to long-term health and longevity.

Immunosenescence is defined as age-related changes in the immune system. It is associated with a progressive deterioration of the ability to mount immune responses and with a higher mortality rate in the elderly. Immunosenescence is currently thought to depend on lifelong antigen load, leading to the senescence of cells in the immune compartment, with a prominent role attributed to the chronic anti-cytomegalovirus (anti-CMV) response. There seems to be an increasing use of immune resources allocated to the anti-CMV response with aging, a process that ultimately leads to exhaustion. The cause remains unclear and in humans the few studies examining the presence of viral reactivation in the blood, found it negative. More data are therefore needed in the field of human aging in order to conclude on this point. The role of CMV in immunosenescence is clearly important, but, rather than being directly causal, can also be interpreted as a consequence of more general age-related changes in the three-dimensional microenvironment in which most immune cells are mobile and operate, the extracellular matrix (ECM). Immunologists have neglected the implications of such changes, partly because most of the studies carried out on immunosenescence, at least until very recently, focused on blood because it is the most accessible source of cells and biological fluid in humans. Although of value, these data, lead to an overestimated qualitative and quantitative importance of this compartment in the understanding of the immune system physiology. The recent discovery of resident memory T cells, or TRM, showed immune surveillance to be largely local and, therefore, not readily accessible through studies on blood.

Here, we argue that efforts to decipher immunosenescence must consider both blood and the ECM. The TRM are located in the ECM, and the known biochemical and biophysical modifications to this medium associated with aging consequently hampers local immune surveillance by these cells. ECM proteins and proteoglycans have well-documented roles in scaffolding, but they also have a profound effect on cell behavior, through interactions with secreted ligands or cell-transmembrane receptors, in particular integrins. We suggest that the progressive and irreversible age-related changes in the extracellular matrix may actually provide a unifying framework explaining all the molecular and cellular features of immunosenescence. The key point is that for the immune cells to be functional, they must be free to recirculate, navigate and rest within the extracellular matrix, in tissues and organs. This point is instrumental in tissue surveillance and protection even in the absence of peripheral lymphocytes. We will consider immunosenescence within this framework, focusing on the adaptive immune system and T cells in particular, even though these cells are neither the only ones to be affected during aging nor the only ones concerned with mobility.

We argue that the mobility of immune cells in non-lymphoid tissues is a necessary element for effective immunity. A lack of immune cell mobility, either intrinsic, as in hereditary defects affecting actin remodeling for example, or extrinsic, as in aging, results in an impairment of immune responses. No three-dimensional (3D) model of deregulated cell mobility has ever been proposed or explored in the context of immunosenescence. We hope that this hypothesis which is based on reviews of fields that have not hitherto be connected together will promote future studies, in silico and in vitro, to validate this theory experimentally. The 3D model can reconcile many features of aging, such as the altered responses to vaccination, which is in essence both a memory and a local process, and dysfunctions of peripheral tolerance (autoimmunity). The chronic process of T cell death due to mechanical stress within the cross-linked mesh of the aged ECM may also account for activation of the inflammasome, leading to inflammaging, and to a state of immune deficiency typical of aged subjects. In conclusion, we propose an update of the theoretical framework of immunosenescence, based on a novel hypothesis: the increasing stiffness and cross-linking of the senescent ECM lead to a progressive immunodeficiency due to an age-related decrease in T cell mobility and eventually the death of these cells. A key element of this mechanism is the mechanical stress to which the cell cytoplasm and nucleus are subjected during passage through the ECM.

Evidence for Exercise to Improve Mitochondrial DNA Repair via p53 Activity
https://www.fightaging.org/archives/2016/12/evidence-for-exercise-to-improve-mitochondrial-dna-repair-via-p53-activity/

To add to the list of possible mechanisms by which exercise improves long-term health, researchers here offer evidence for exercise to enhance repair of damage to mitochondrial DNA. Note that they are using mice with a DNA repair deficiency that exhibit accelerated development of age-related disease, and this is often a path to results that have little bearing on normal aging, but in this case I don't think that greatly impacts the principal finding of a evidence for a novel mitochondrial DNA repair mechanism triggered by exercise. The herd of hundreds of mitochondria found in every cell are the remnants of symbiotic bacteria, with many important roles in cellular biochemistry. They still replicate like bacteria and carry their own DNA. Unfortunately that DNA is more prone to damage and less readily repaired than the DNA in the cell nucleus. Some forms of damage, such as deletions that impair the mitochondrial processes that produce the energy store molecule ATP, lead to mitochondria that are both dysfunctional and able to replicate more effectively than their peers. Cells become taken over by these broken mitochondria and fall into a state in which they export harmful, reactive molecules into the surrounding tissues. This process contributes to degenerative aging. Therefore any mechanism that improves mitochondrial DNA repair is likely to slow the impact of aging, and we might expect to find such mechanisms involved in at least some of the known methods of modestly slowing aging in laboratory species.

Molecular investigations of age-related pathologies implicate mitochondrial DNA (mtDNA) mutations as one of the primary instigators driving multisystem degeneration, stress intolerance, and energy deficits. It is intuitive to assume that the de novo mtDNA mutations observed during aging are due to accumulated, unrepaired oxidative damage, but some evidence actually suggests that mtDNA replication errors may be the more important culprit. The demonstration that multiple aspects of aging are accelerated in mutator mice harboring error-prone mitochondrial polymerase gamma (POLG1) provides support for the causal role of mtDNA replication errors in instigating mammalian aging.

The epidemic emergence of modern chronic diseases largely stems from the adoption of a sedentary lifestyle and excess energy intake. There is incontrovertible evidence that endurance exercise extends life expectancy and reduces the risk of chronic diseases in both rodents and humans. We have previously shown that endurance exercise effectively rescued progeroid aging in mutator mice concomitant with a reduction in mtDNA mutations, despite an inherent defect in POLG1 proofreading function. Exercise has also been shown to increase telomerase activity and reduce senescence markers. These findings suggest a link between exercise-mediated metabolic adaptations and genomic (nuclear and mitochondrial) stability; however, the identity of this metabolic link remains unknown. In this study, we have utilized PolG mice to investigate the mitochondrial-telomere dysfunction axis in the context of progeroid aging, and to elucidate how exercise counteracts mitochondrial dysfunction and mtDNA mutation burden through mitochondrial localization of the tumor suppressor protein p53.

Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient POLG1. We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality. Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.

Initial Results Reported from a Phase 1 Safety Trial of a Tau Vaccine
https://www.fightaging.org/archives/2016/12/initial-results-reported-from-a-phase-1-safety-trial-of-a-tau-vaccine/

Alzheimer's disease is both an amyloidosis and a tauopathy; its symptoms are produced by some combination of the presence of solid deposits of misfolded amyloid-β and tau protein, though there is much debate over which is more important and how they interact with one another and brain cells in order to produce pathology. Effective treatment will probably involve removing both amyloid-β and tau aggregates from brain tissue and cerebrospinal fluid. So far the best class of approach, and the one with the most funding behind it at the present, is immunotherapy, engineering the immune system to attack and remove the unwanted waste. Even that has proven to be much harder than expected, however, and the field is littered with failed trials and promising implementations that did not translate from animal studies to human biochemistry. Only recently have human trials produced meaningful results in amyloid clearance, and earnest efforts to remove tau from the brain started later and have less funding. Still, there is progress towards immunotherapies that can clear tau, as noted here:

So far, many of the antibody drugs proposed to treat Alzheimer's disease target only the amyloid plaques. Despite the latest clinical trial that is hailed as our best chance in the quest for treating Alzheimer's, all later phase trials have failed with many causing severe side effects in the patients, such as abnormal accumulation of fluid and inflammation in the brain. One of the reasons for side effects, many speculate, is due to the antibody directing a reaction towards normal amyloid present in blood vessels or simply releasing beta-amyloid caught in the vessel wall.

The authors of the study have developed a vaccine that stimulates the production of an antibody that specifically targets pathological tau, discovering its "Achilles' heel". It is able to do this because healthy tau undergoes a series of changes to its structure forming a new region that the antibody attacks. This new region (the "Achilles' heel"), while not present in healthy tau, is present in diseased tau early on. Therefore, the antibody tackles all the different varieties of pathological tau. In addition to this important specificity, the antibody is coupled to a carrier molecule that generates a considerable immune response with the added benefit that it is not present in humans, thus avoiding the development of an immune reaction towards the body itself.

Side effects have included a local reaction at the site of injection. This skin reaction is thought to occur due to the aluminum hydroxide, an adjuvant used in vaccines to enhance the body's own antibody production. No other serious secondary effects were directly related to the vaccine. Overall, the safety of the drug and its ability to elicit an immune response were remarkable. While many trials against Alzheimer's disease stubbornly continue to target amyloid, our study dares to attack the disease from another standpoint. This is the first active vaccination to harness the body's ability to produce antibodies against pathological tau. Even though this study is only a phase 1 trial, its success so far gives the authors confidence that it may be the answer they are looking for to halt the progress of this devastating disease.

A Summary of the NIA Interventions Testing Program
https://www.fightaging.org/archives/2016/12/a-summary-of-the-nia-interventions-testing-program/

The NIA Interventions Testing Program (ITP) is a fairly old-school effort to rigorously test all the plausible claims of modestly slowed aging in mice via pharmaceuticals, dietary supplements, and environmental factors like calorie restriction. For those of us more interested in outright rejuvenation through damage repair after the SENS model, rather than merely slowing aging a little, I think there still a number of things worth learning from the ITP results to date. For example, firstly, that almost all claims of slowed aging in mice due to supplements and drugs made in past years were artifacts or otherwise erroneous results, and vanish when evaluated with greater rigor. That suggests that any result of around 10% life extension in mice should probably be taken with a grain of salt, given that the ITP researchers have observed variance in the life spans of control mice raised in identical environments at different study sites. Secondly, that it is very hard to evaluate small differences in aging and life span. This is a part of the larger point I try to make on efforts to slow aging: that for a number of reasons it is more expensive and more challenging than attempts to produce rejuvenation by reverting the established differences between old and young tissues, such as accumulations of metabolic waste, senescent cells, and other forms of molecular damage. Rejuvenation therapies, when they work, should reliably result in larger differences in life span - there should be absolutely no ambiguity at all about the outcome.

The Interventions Testing Program (ITP) was established by the National Institute on Aging (NIA) to investigate the potential of dietary interventions to promote healthy aging. The ITP uses a four-way cross genetically heterogeneous mouse model (UM-HET3) to reduce the impact of strain-specific characteristics on outcomes. Lifespan tests are done in parallel, using the same protocol, at three independent sites to increase robustness of the findings. Population sizes are large enough that the protocol will detect a 10% change in mean lifespan, in either sex, with 80% power, pooling data from as few as two sites. Standard operating procedures were designed to maintain as much consistency as possible among the three sites, including caging, bedding, food, and light/dark cycles. Interventions for testing are proposed by the research community through an annual call-for-proposals, and proposed compounds have ranged from drugs and dietary supplements to micronutrients and metabolic intermediates.

Before the ITP embarks on testing a compound, pilot studies are done to maximize the chances of a successful test. Goals of the pilot studies include demonstrating that the compound is stable in food and that it is uniformly mixed in the food, determining blood levels after short-term treatment (bioavailability), showing evidence of an effect from the short-term treatment (bioactivity), and in some cases, testing for toxicity. The testing of rapamycin is a good case-in-point for analyzing stability of the compound in the food. Pilot analysis showed that about 85% of the rapamycin was degraded by the food preparation process, leading to the use of microencapsulation to deliver stable doses of the compound in food.

The list of all compounds tested by the ITP and in progress is on the ITP website. To date, six compounds have shown significant extension of lifespan: aspirin in males only; rapamycin in males and females (with a greater effect in females); 17αEstradiol in males only; acarbose in males and females (with a greater effect in males); nordihydroguaiaretic acid (NDGA) in males only, and protandim in males only. The positive findings illustrate some important aspects for aging interventions research. The effective interventions appear to include several disparate mechanisms, demonstrating that many cellular pathways might be exploited to influence lifespan and aging. Rapamycin modulates the nutrient-sensing pathways via its interaction with mTOR. Acarbose was anticipated to work as a caloric restriction mimetic due to its ability to reduce the rate of absorption of carbohydrates, but its mechanism of action appears more complex, since caloric restriction results in significant lifespan extension in both male and female UM-HET3 mice, while the effects of acarbose were much larger in males. Aspirin is known for its anti-inflammatory and antioxidant activities, NDGA also has anti-inflammatory and antioxidant activities, 17αEstradiol has neuro-protective properties independent of binding to the estrogen receptor, and protandim activates Nrf2 transcriptional regulator. This diverse group of interventions demonstrates the complex nature of the biology of aging.

Another major surprise is the extent of sex differences in response to the interventions. Four of the six positive interventions only worked in one sex, and the two that had an effect in both sexes showed sex-specific differences in the extent of the effect. Blood levels of a compound sometimes differed between males and females, but that did not always explain the sex difference in lifespan extension. For rapamycin, achieving approximately equivalent blood levels in males and females by treating with different doses did result in similar increases in lifespan. But for NDGA, even at doses giving similar blood levels in males and females, females still did not respond. The ITP's findings illustrate how important it is to examine the effects of interventions in both sexes and suggest that further studies on the mechanism of these sex effects may yield important insights into the underlying biology, and guidance for eventually clinical studies. Multi-site testing protocols also add value to the design because some site-to-site variation is unavoidable even with every effort made to minimize differences between sites. For example, the ITP has consistently found that control male mice at one site weigh less and live longer than the control males at the other two sites, even though each site uses the same food preparations and standardized husbandry. Positive findings replicated in different labs are inherently stronger than a finding from one lab, while disparate findings convey a valuable caution and emphasize the need for replications in other laboratories, other mouse stocks, and other drug doses.

More Evidence for the Importance of BACE1 in Alzheimer's Disease
https://www.fightaging.org/archives/2016/12/more-evidence-for-the-importance-of-bace1-in-alzheimers-disease/

BACE1 is a target for Alzheimer's therapies as it is involved in the production of amyloid-β. The condition is characterizing by rising levels of this form of amyloid in the brain, which in turn produces a halo of harmful biochemical interactions that damage and kill brain cells. Researchers are working on a range of ways to reduce the amount of amyloid-β, and interfering with its production is one approach, albeit so far not as effective as striving to remove the amyloid, such as via immunotherapies. Here, researchers explore some of the biochemistry surrounding BACE1; cellular machinery never acts in isolation, and there are always relationships linking many different proteins relevant to any mechanism. Thus there are always multiple options and targets when it comes to achieving a specific result in the operation of cells.

Scientists have found that reduced levels of a protein called Rheb result in spontaneous symptoms of memory loss in animal models and are linked to increased levels of another protein known to be elevated in the brains of Alzheimer's disease patients. The researchers investigated the link between Rheb and an important enzyme called BACE1, which is elevated in older adults and people with Alzheimer's disease. "We know that Rheb regulates BACE1, which is a major drug target in Alzheimer's disease. Studies of the autopsied brains of Alzheimer's patients have found a significant reduction in Rheb, so it is possible that an increase in Rheb could reverse the buildup of amyloid plaque or help reduce or even reverse age-related memory loss."

To uncover the impact of eliminating Rheb, researchers put genetically altered mice through a battery of behavior tests beginning at around six months of age. While Rheb depletion did not affect the overall body weight or motor activity of the animals, it did have subtle and selective effects on certain memory tasks they performed, such as navigating a maze and memory recall. The researchers compared these symptoms to memory deficits that occur in humans with Alzheimer's disease and related dementia. They also found that Rheb depletion increased BACE1 levels, which was consistent with previous research showing that higher BACE1 levels may be a contributing factor for memory deficits.

The fact that some research shows that Rheb messenger RNA is induced during protein starvation in fruit flies, led researchers to theorize that a high-protein diet in humans might be a risk factor for decreasing Rheb levels with age, resulting in mild-to-severe cognitive deficits, as seen in animal models. "This is an indication that nutrient signaling might regulate cognitive functions in mammals through alteration of Rheb-BACE1 pathway activity. Overall, our study demonstrates that forebrain Rheb depletion promotes aging-associated cognitive defects. Targeting the Rheb pathway may offer some therapeutic potential for aging- or Alzheimer's disease-associated memory deficits."

A Method to Partially Compensate for Failing Wound Healing in Skin
https://www.fightaging.org/archives/2016/12/a-method-to-partially-compensate-for-failing-wound-healing-in-skin/

The healing of wounds in skin falters with age and in conditions such as diabetes for a variety of reasons, some better understood than others. The cells responsible for building the replacement skin lose their coordination and in the worst cases this can lead to wounds that do not heal at all. The research noted here doesn't address the underlying reasons for this failure of healing, the molecular damage of aging, but attempts to work around the problem by providing some of the structure and functions that the cells are failing to achieve on their own, and by delivering signals that are known to generally increase cell performance in growth and regeneration.

A team of researchers has demonstrated for the first time that their peptide-hydrogel biomaterial prompts skin cells to "crawl" toward one another, closing chronic, non-healing wounds often associated with diabetes, such as bed sores and foot ulcers. The team tested their biomaterial on healthy cells from the surface of human skin, called keratinocytes, as well as on keratinocytes derived from elderly diabetic patients. They saw non-healing wounds close 200 per cent faster than with no treatment, and 60 per cent faster than treatment with a leading commercially used collagen-based product.

Until now, most treatments for chronic wounds involved applying topical ointments that promote the growth of blood vessels to the area. But in diabetic patients, blood vessel growth is inhibited, making those treatments ineffective. Researchers have been working with their special peptide - called QHREDGS, or Q-peptide for short - for almost 10 years. They knew it promoted survival of many different cell types, including stem cells, heart cells and fibroblasts (the cells that make connective tissues), but had never applied it to wound healing. "We thought that if we were able to use our peptide to both promote survival and give these skin cells a substrate so they could crawl together, they would be able to close the wound more quickly. That was the underlying hypothesis."

The researchers compared the Q-peptide-hydrogel mix to the commercially available collagen dressing, to hydrogels without the peptide, and to no treatment. They found that a single dose of their peptide-hydrogel biomaterial closed the wounds in less than two weeks. "Currently, there are therapies for diabetic foot ulcers, but they can be improved. Diabetic wound healing is a complicated condition, because many aspects of the normal wound healing process are disrupted." This finding could have big implications for many types of wound treatments, from recovery after a heart attack to healing post-surgery. Accelerated healing times also introduces the added benefit of reducing the opportunity for infection.

An Example of Reducing or Altering Cellular Senescence
https://www.fightaging.org/archives/2016/12/an-example-of-reducing-or-altering-cellular-senescence/

Researchers have demonstrated a number of genetic and pharmacological approaches that seem to modulate cellular senescence, either by somewhat lowering the number of cells that become senescent or by somewhat reducing the impact of the senescence-associated secretory phenotype (SASP). Senescent cells are one of the root causes of aging. They produce damage and age-related disease through the signals they secrete, which cause inflammation, remodel surrounding tissue structures, and alter the behavior of normal cells for the worse. Many of the methods that over the years have been demonstrated to modestly slow aging in laboratory animals have some sort of effect on the properties of cellular senescence, but a potential therapy based on these methods would have to be far, far more effective in order to compete with selective destruction of senescent cells as an approach to the problem. The cell culture research here is an example of present explorations into altering the processes of senescence rather than simply destroying the unwanted cells, but I can't say that I see it as being all that promising for anything other than the production of greater knowledge of the senescent state.

Cellular senescence is a hallmark of aging and senescent cells accumulate with age in vivo in mammals; this is thought to drive aging by limiting tissue replicative capacity and causing tissue dysfunction. Developing strategies to delay the onset of senescence or remove senescent cells may provide a route to preventing age-related disease. Targeting senescence as a means to combat aging and age-related diseases is, however, challenging due to its antagonistically pleiotropic nature - any treatment needs to limit the deleterious impacts of senescent cells without impacting the potent barrier against tumorigenesis. While caloric restriction has been reported to extend healthspan in macaques, the most promising candidate for a longevity therapeutic in mammals is rapamycin.

Rapamycin mechanistically acts by binding the protein FKBP12, producing a complex which can bind and inhibit mTOR. mTOR constitutes the point at which diverse environmental signals are coordinated into a cellular response, regulating pathways including cell growth, proliferation, survival, motility and protein synthesis. mTOR is present in two complexes in metazoa, mTORC1 and mTORC2, which have different components and functions. Rapamycin inhibits mTORC1, but chronic treatment may also disrupt mTORC2. While rapamycin extends lifespan in mice even when administered in middle age, it has significant side-effects that may limit its use in humans. We have therefore explored the potential of second generation rapalogs i.e. pharmacological agents that inhibit mTORC but act not through binding to FKBP12 but instead as mTORC-specific ATP mimetics. AZD8055 is an ATP-competitive inhibitor of mTOR kinase in both mTORC1 and mTORC2. AZD8055 has anti-proliferative effects similar to those of rapamycin and has been taken forward into clinical trials against various forms of cancer.

Here, we test whether acute mTORC inhibition can alter features of senescence in cells that have already undergone a large number of population doublings (PD) - as they are about to undergo senescence but are currently still proliferating, we term these populations 'near-senescent'. Such high cumulative PD (CPD) near-senescent cells show many signs characteristic of senescence including increased size and granularity, SA-β-gal staining, high lysosomal content and accumulation of actin stress fibers. They are still capable of cell proliferation, albeit with a reduced rate of proliferation compared with cells at lower CPD. Here, we test the effect of inhibiting both mTORC1 and mTORC2 using the TOR-specific ATP mimetic AZD8055. Remarkably, we demonstrate significant reversal of major phenotypes of senescence on short term low dose pan-TOR inhibition. We therefore suggest that AZD8055 may prove useful in modulating health outcomes in late life.

A Discussion of Calico Labs
https://www.fightaging.org/archives/2016/12/a-discussion-of-calico-labs/

Google founded the California Life Company, or Calico Labs, to work on aging, and has put a large amount of money into this project. It is all comparatively secretive, but so far the evidence suggests that this will, sadly, turn out much the same way as the Ellison Medical Foundation, which is to say (a) work on extending the map of all cellular biochemistry relevant to the progression of aging at the most detailed level coupled to (b) attempts to slightly slow aging via pharmaceuticals. The project is headed by someone who has little interest in translational research, the business of bringing therapies to market, and those involved - for the most part - are not people with a track record of paying attention to the SENS program of repairing damage to produce rejuvenation. The SENS research agenda is to my eyes the only viable way forward to produce meaningful extension of healthy life any time soon, and certainly the only way to help older people by turning back aging at later stages. It is also far closer to realization and far less expensive to develop than efforts to safely alter human metabolism to slow the rate at which damage is done. The field of aging research has all too little funding in comparison to its potential, but it doesn't suffer from a lack of fundamental research anywhere near as much as it suffers from a lack of taking what is already well known about the forms of cell and tissue damage that cause aging in order to build therapies here and now.

David Botstein is Calico's chief scientific officer. He is 74, with a grizzled shadow of beard reaching up from his collar. In November, I found him at a lecture hall at MIT, where he offered a rare window onto experiments under way at Calico. Botstein, a well-known Princeton geneticist whom Calico recruited out of near retirement, was in town to celebrate the birthday of a successful former student, now a sexagenarian. "The pleasure is coming to see old friends. The not-so-­pleasure is if these guys are 60, what am I?" In his lecture, Botstein described several technologies - four, in fact - that Calico has for isolating old yeast cells from the daughter cells that bud off them. These old cells are tracked and subjected to a comprehensive analysis of which genes are turned up or turned down, a technique that is Botstein's specialty. Botstein told me Calico is exactly what Google intended: a Bell Labs working on fundamental questions, with the best people, the best technology, and the most money. "Instead of ideas chasing the money, they have given us a very handsome sum of money and want us to do something about the fact that we know so little about aging. It's a hard problem; it's an unmet need; it is exactly what Larry Page thinks it is. It's something to which no one is really in a position to pay enough attention, until maybe us."

Botstein says no one is going to live forever - that would be perpetual motion which defies the laws of thermodynamics. But he says ­Cynthia Kenyon's experiments on worms are a "perfectly good" example of the life span's malleability. So is the fact that rats fed near-starvation diets can live as much as 45 percent longer. The studies Botstein described in yeast cells concerned a fundamental trade-off that cells make. In good times, with lots of food, they grow fast. Under stresses like heat, starvation, or aging, they hunker down to survive, grow slowly, and often live longer than normal. "Shields down or shields up," as ­Botstein puts it. Such trade-offs are handled through biochemical pathways that respond to nutrients; one is called TOR, and another involves insulin. These pathways have already been well explored by other scientists, but Calico is revisiting them using the newest technology. "A lot of our effort is in trying to verify or falsify some of the theories," Botstein says, adding that he thinks much of the science on aging so far is best consumed "with a dose of sodium chloride." Some molecules touted as youth elixirs that can act through such pathways - like resveratrol, a compound in red wine - never lived up to their early hype.

According to Botstein, aging research is still seeking a truly big insight. Imagine, he says, doctors fighting infections without knowing what a virus is. Or think back to cancer research in the 1960s. There were plenty of theories then. But it was the discovery of oncogenes - specific genes able to turn cells cancerous-that provided scientists with their first real understanding of what causes tumors. "What we are looking for, I think above everything else, is to be able to contribute to a transformation like that. We'd like to find ways for people to have a longer and healthier life. But by how much, and how - well, I don't know." Botstein says a "best case" scenario is that Calico will have something profound to offer the world in 10 years. That time line explains why the company declines media interviews. "There will be nothing to say for a very long time, except for some incremental scientific things. That is the problem."

To some, Calico's heavy bet on basic biology is a wrong turn. The company is "my biggest disappointment right now," says Aubrey de Grey, an influential proponent of attempts to intervene in the aging process and chief science officer of the SENS Research Foundation, a charity an hour's drive from Calico that promotes rejuvenation technology. It is being driven, he complains, "by the assumption that we still do not understand aging well enough to have a chance to develop therapies." Indeed, some competitors are far more aggressive in pursuing interventions than Calico is. "They are very committed to these fundamental mechanisms, and bless them for doing that. But we are committed to putting drugs into the clinic and we might do it first," says Nathaniel David, president and cofounder of Unity Biotechnology. This year, investors put 127 million behind Unity, a startup in San Francisco that's developing drugs to zap older, "senescent" cells that have stopped dividing. These cells are suspected of releasing cocktails of unhelpful old-age signals, and by killing them, Unity's drugs could act to rejuvenate tissues. The company plans to start with a modestly ambitious test in arthritic knees. De Grey's SENS Foundation, for its part, has funded Oisin Biotechnologies, a startup aiming to rid bodies of senescent cells using gene therapy.

Arguing for Some Clonal Expansion of T Cells in the Aging Immune System to be a Beneficial Adaptation
https://www.fightaging.org/archives/2016/12/arguing-for-some-clonal-expansion-of-t-cells-in-the-aging-immune-system-to-be-a-beneficial-adaptation/

Growth in the clonal expansion of immune cells, the creation of many similar cells of the same lineage, and a reduction in the diversity of such lineages, is characteristic of the aged, dysfunctional immune system. The context in which this is usually discussed is the way in which the proportion of memory T cells, particularly those devoted to persistent pathogens such as cytomegalovirus that cannot be effectively cleared from the body, expands at the expense of other types of immune cell. An immune system burdened with too many memory cells focused on just a few pathogens is one that cannot effectively carry out all of its other tasks. In the research here, however, the authors argue that some forms of this age-related clonal expansion represent an attempt by the immune system to compensate for the damage and disarray of aging. Interestingly the class of cells examined here are senescent, and most other evidence suggests that various forms of senescent immune cells are not beneficial - they produce harmful effects, just like other cells do when they fall into a senescent state.

Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal αβT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR.

The accumulation of NK-like CD28null T cells with advancing age represents a remodeling of the immune repertoire as a compensatory mechanism for the general age-related losses in conventional T cell-dependent immunity. There is thymic atrophy with age leading to impaired production of new naïve T cells, making older adults unable to respond to new and emerging pathogens in an antigen-specific manner. With antigenic exposure through life, there is progressive contraction of the naïve T cell compartment, with corresponding expansion of memory and senescent T cell compartment. These events over the lifespan result in the contraction of diversity of the clonotypic TCR repertoire. With cycles of expansion and death of T cells during antigenic challenges, the phenomenal accumulation of apoptosis-resistant CD28null NK-like T cells is likely a protection against clinical lymphopenia, which is very rare among older adults.

The acquisition of a diverse array of NK-related receptors on CD28null T cells maintains immunologic diversity in old age. There is co-dominant expression of diverse NK-related receptors along clonal lineages of CD28null T cells in late life. This is in stark contrast to the conventional clonotypic TCR diversity that is characteristic of the young. Signaling of these NK-related receptors effectively imparts an innate function to aged T cells; hence, we had originally introduced the term "NK-like T cells" to emphasize their NK-related receptor-driven, TCR-independent effector function. NK-like T cells compensate for the corresponding age-related functional loses in the NK cell compartment. Induction of NK-related receptors on T cells may not be surprising since T cells and NK cells originate from a common lymphoid progenitor. Thus, inducibility of NK-related receptors in senescent CD28null NK-like T cells is consistent with functional plasticity of T cells. Although the intricacies of T cell plasticity are still being investigated, such plasticity re-directs the elaboration of effector activities to ensure a vigorous immunity. In old age, signaling of effector activities of NK-like T cells through NK-related receptors is an adaptation of the aging immune system. Such adaptation is a way to maintain immune homeostasis despite the inefficiency of classical TCR signaling and the contraction of diversity of the repertoire of clonotypic TCRs. NK-like T cells are highly resistant to cell death and may represent Darwin's "fittest" lymphocytes that contribute to immune function into old age.

The expression of NK-related receptors along clonal lineages of CD28null T cells with aging clearly represents a reshaping or remodeling of the immune repertoire. T cell signaling through these receptors independent of the TCR also illustrates the emerging theme that cell senescence may not necessarily be synonymous with dysfunction. One scientific challenge is to determine what drives the induction of diversity of expression of NK-related receptors on T cells with advancing age. Another is to determine whether the TCR-independent effector function of NK-like T cells translates into vigorous immune defense and/or immune surveillance in late life.

MicroRNA Differences Across the Course of Aging Correlate with Life Span
https://www.fightaging.org/archives/2016/12/microrna-differences-across-the-course-of-aging-correlate-with-life-span/

A cell might be considered a state machine whose state and state transitions are determined by the amounts of various proteins present. The process of gene expression by which genetic blueprints are converted into proteins is enormously complex, and a large fraction of the various types of molecule assembled inside a cell have much more to do with manipulating the steps involved in gene expression than with other cellular activities. Every facet of gene expression, from the pace at which proteins are produced to which protein is produced when there are multiple options for a given stretch of DNA, is subject to a constant, ever-changing set of interactions, feedback loops between production and influence over production. Researchers are these days putting a great deal of effort into mapping the classes of protein machinery involved in regulation of gene expression, such as microRNAs (miRNA), and some of that work is focused on aging:

Biomarkers of aging are biological parameters that change in a predictable direction with aging in most individuals and, when assessed early in life, may predict subsequent longevity better than chronological age alone. Beyond their prognostic utility, the discovery of biomarkers of aging is attractive because they may shed light into the intrinsic mechanism of aging as a biological process. Identifying biomarkers of aging may also provide insight into the biological mechanisms that accelerate or decelerate aging. miRNAs have emerged as important regulators of biological mechanisms that are relevant for aging. miRNAs are short non-coding RNAs that regulate gene expression. With over 1800 human miRNAs reported, miRNAs influence a wide range of biological functions, such as stem cell self-renewal, cell proliferation, apoptosis, and metabolism.

Profiles of miRNAs found in plasma and serum have been linked to numerous cancers, cognitive impairment, Alzheimer's disease and other neurodegenerative disorders, and other pathologies, indicating that miRNAs are a new class of biomarkers of human diseases present in blood. Because of the close relationship between these diseases and longevity, miRNAs may also serve as biomarkers of human aging. Our prior work has shown that miRNAs can serve as genetic biomarkers of aging in the nematode C. elegans. Because miRNAs and aging genetic pathways are conserved from nematodes to humans, an increasing number of human miRNA studies have been carried out over the past several years. These studies have shown differential abundance of multiple miRNAs in peripheral blood mononuclear cells (PBMCs) or serum/plasma when comparing younger and older adults. We used miRNA PCR arrays to measure miRNA levels in serum samples obtained longitudinally at ages 50, 55, and 60 from 16 participants of the Baltimore Longitudinal Study of Aging (BLSA) who had documented lifespans. We compared miRNA expression changes not only across (i.e., between older and younger participants) but also within participants (using the three samples taken at different ages from each individual). In accordance with recent research that found a strong association between circulating miRNAs and human aging, our study suggests that circulating miRNAs are biomarkers of longevity.

Many interesting expression profiles were observed between study participants with different lifespans. For example, when comparing samples analyzed at age 50 between the long-lived and short-lived subgroups, we identified the 10 most differentially higher and lower expressed miRNAs. The most upregulated miRNA in long-lived participants, miR-373-5p, is part of the miR-373 family, which functions as a tumor suppressor in breast cancer. The most downregulated miRNA in long-lived participants, miR-15b-5p, has been found to be upregulated in oral cancer cells. Because lifespan is a complex trait characterized by escaping, delaying, or surviving fatal age-related diseases, including cancers, further scrutiny of the potential roles of the identified miRNAs in human aging is of great importance and interest. Six of the nine miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) may serve as useful biomarkers, as each of the six miRNAs were correlated with lifespan and were significantly up- or downregulated. Future studies can identify how examining expression of multiple miRNAs simultaneously versus one or a few miRNAs individually would affect these correlations. While some miRNA biomarker or disease-association studies have found significant correlations only by analyzing a profile of expression of multiple miRNAs, our study did identify miRNAs that individually correlate with lifespan. Further, it is striking that miRNA expression at ages 50, 55, and 60 correlates with the eventual, quite varied lifespans of the 16 participants in our pilot study.

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