Fight Aging! Newsletter, May 14th 2018

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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  • Reason Launches Repair Biotechnologies, a Venture to Bring Rejuvenation Therapies to the Clinic: Chief Scientist Sought
  • The First Set of Videos from the Undoing Aging 2018 Conference are Available Online
  • Ladies and Gentlemen, We Are All Dying
  • Circular RNAs are Enigmatic, and Grow in Number with Age
  • SENS Research Foundation 2017-2018 Annual Report
  • The Extracellular Matrix may Determine Regenerative Capacity in Mammals
  • Blocking an Astrocyte Receptor Produces Benefits in an Alzheimer's Mouse Model
  • The Gut Microbiome as a Contributing Cause of Sarcopenia
  • CAR-T Therapy Eliminates Metastatic Colorectal Cancer in Mice
  • HMGB1 Accelerates Tissue Regeneration by Increasing Stem Cell Activity
  • Mesenchymal Stem Cell Therapy Aids Spinal Cord Regeneration in Rats
  • Elite Chess Players and Elite Athletes Have Similar Advantages in Life Expectancy
  • Aging of the Locus Coeruleus and Loss of Focus in Older Individuals
  • Burying Dead Cells Requires Oxidative Signaling
  • Investigations of p66(Shc) Knockout Mice Continue

Reason Launches Repair Biotechnologies, a Venture to Bring Rejuvenation Therapies to the Clinic: Chief Scientist Sought

Starting a company is a sizable commitment, made in order to produce a better future. With this in mind I have founded Repair Biotechnologies, a new venture that will focus on the development of gene therapies relevant to human rejuvenation. My partner in this, Bill Cherman, is an investor in our rejuvenation research community. He has supported a number of interesting startup biotechnology companies in the past few years, including several that I've also helped in one way or another. Together we intend to carry forward some of the most promising advances produced by the scientific community, picking the best of the many lines of research relevant to human rejuvenation undertaken in recent years. Given even a cursory glance through the Fight Aging! archives, you'll see that we are spoiled for choice: it is a great time to be working in this field.

We are in search of a Chief Scientist! If you have a scientific background in gene therapy, experience in the field, and a taste for the biotechnology startup life, then give some thought to joining our team. The role is a hands-on Chief Scientist: someone with an interest in building new gene therapies for the treatment of aging as a medical condition, and capable of running an ambitious biotechnology program from its earliest stages onward. A history of working through the US or European regulatory system of clinical trials would also be helpful, but is not required. If you are an entrepreneurially minded scientist who knows the ins and outs of modern gene therapy, then we would very much like to hear from you.

The many variants of gene therapy, alongside other novel, long-lasting methods of delivering proteins into cells, collectively form a technology platform that will power much of the future of medicine. This is particularly true for rejuvenation therapies. Just look at the SENS research portfolio: gene therapies are fundamental to, for example, the LysoSENS efforts to deliver enzymes capable of breaking down metabolic waste, or the MitoSENS project to copy mitochondrial genes into the cell nucleus. These are far from the only broad areas of development that are or can be built atop gene therapy, of course.

Out of the gate, our initial focus is on the development of gene therapies to spur regeneration of the thymus. This has the potential to restore production of T cells in older individuals, or other cases in which patients suffer from immunodeficiency and its consequences. The thymus is where T cells mature after their creation in the bone marrow, and its capacity places a limit on the rate at which new T cells take up their duties in the body. The thymus atrophies quite profoundly at the end of childhood, in a process called involution, cutting the rate of T cell creation dramatically. It then declines further over the course of adult life. This loss of function, and falling rate of T cell creation, is an important contribution to the age-related loss of immune function that makes old people frail and vulnerable in comparison to their younger counterparts. This isn't just a matter of defending against pathogens or responding to the yearly influenza vaccination: the immune system is also responsible for suppressing cancerous and senescent cells. All of these functions falter alongside the loss of active thymic tissue.

This can be reversed! It has been reversed in mice, and must now be brought to human medicine. We are embarking upon our first program of work in partnership with the team at Ichor Therapeutics, one of the success stories in the transition of our broader community of scientists and advocates from research to commercial development. Later, other lines of development are planned. Looking at the broader field, as defined in the SENS rejuvenation research proposals, there is a certainly a great deal to accomplish on the road ahead - from where we stand today, all the way to the advent of a comprehensive suite of first generation rejuvenation therapies. We aim to do our part and more in pushing the present state of the art towards that goal. Even in our starting point, consider that there is considerable promise in any meaningful degree of restoration of the aged immune system.

For now, the grand vision of what can be achieved through widespread availability of thymic regeneration therapies lies ahead, past many initial steps: pre-clinical development, clinical trials, validation. We are very excited to embark on this journey, towards the goal of bringing benefits to patients, the goal of turning back aspects of aging and age-related disease. Bill and I look forward to future success in this endeavor.


Nothing in this post should be construed as an offer to sell, or a solicitation of an offer to buy, any security or investment product. Certain information contained herein may contains statements, estimates and projections that are "forward-looking statements." All statements other than statements of historical fact in this post are forward-looking statements and include statements and assumptions relating to: plans and objectives of Repair Biotechnologies' management for future operations or economic performance; conclusions and projections about current and future economic and political trends and conditions; and projected financial results and results of operations. These statements can generally be identified by the use of forward-looking terminology including "may," "believe," "will," "expect," "anticipate," "estimate," "continue", "rankings" or other similar words. Repair Biotechnologies does not make any representations or warranties (express or implied) about the accuracy of such forward-looking statements. Accordingly, you should not place reliance on any forward-looking statements.

The First Set of Videos from the Undoing Aging 2018 Conference are Available Online

The first set of presentation videos from Undoing Aging are now available online, via the conference YouTube channel. The conference was held earlier this year in Berlin, jointly hosted by the SENS Research Foundation and Forever Healthy Foundation. The former should need no introduction here, while the latter was founded by philanthropist and investor Michael Greve, a strong supporter of the SENS rejuvenation research programs. By all accounts the conference was a rousing success, adding to a series of past events that have brought together research and industry interests focused on the development of rejuvenation therapies after the SENS model of damage repair. Undoing Aging will return again next year:

Due to the incredible success of the 2018 Undoing Aging Conference in Berlin, Germany, SENS Research Foundation and Michael Greve's Forever Healthy Foundation are pleased to announce that Undoing Aging will return in 2019. This will be an annual conference series, co-sponsored by SRF and FHF to promote awareness of age-related disease and the ongoing scientific breakthroughs in rejuvenation biotechnology. Undoing Aging 2019 will once again focus on bringing together scientists from around the globe in their respective fields who are leading the charge in combating age-related disease. It is through the collaborative efforts of these scientists, investors, policy makers, and media that we will continue to expand the rejuvenation biotechnology industry and reimagine aging.

Kelsey Moody at Undoing Aging 2018

​Kelsey Moody is CEO and Founder at Ichor Therapeutics, a pre-clinical biotechnology company with a focus on drug development for age-associated disease. The two SENS categories that have, arguably, seen the greatest contribution from research funded by the SENS Research Foundation are those relating to damage within cells: mitochondrial mutations and "garbage". Our in-house team has made immense progress recently in rendering mitochondrial mutations harmless by installing "backup copies" in the nuclear genome, while Ichor Therapeutics has taken on one strand of the garbage removal work. Kelsey Moody will describe the state of play in relation to elimination of one of the best-characterised types of intracellular garbage, part of the lipofuscin that drives development of macular degeneration.​

Brian Kennedy at Undoing Aging 2018

Brian Kennedy is internationally recognized for his research in the basic biology of aging and as a visionary committed to translating research discoveries into new ways of delaying, detecting, preventing and treating human aging and associated diseases. From 2010 to 2016 he was the President and CEO of the Buck Institute for Research on Aging, and is now Director of the Center for Healthy Ageing at the Yong Loo Lin School of Medicine at National University Singapore. He here talks about the arrival of Singapore in the aging research community, outlining some of the lines of research underway in that country.

Ladies and Gentlemen, We Are All Dying

Ladies and gentlemen, we are all dying. Our bodies and brains will fail gradually over the next few decades, rendering us first incapacitated, and later dead. Our children will not be spared; they too will suffer this fate a few decades after we do. We face nothing less than a rolling, continual apocalypse. Everyone we know will die. Everything we maintain will crumble in our absence. All we understand and feel, save for the tiny portion of the human experience that we can record, will vanish. We will end.

Do you like life? It is being stolen from you. Inexorable physical processes are degrading the bodily systems needed to walk, think, and enjoy a sunny day for what it is. Muscles weaken. The mind slows. The skin becomes fragile. A billion tiny failures in our cells and their chemistry cascade forward over the years. We rust like iron, distortions and accretions and structural failures taking place in an accelerating and ultimately fatal corrosion.

Ah, but we are complacent in its slowness! To be young is to take function for granted. The old are not real - to be old is not real. Yet the day will come when you can look back and remember a stronger arm and faster mind. The grasping delays when a word or a concept will not come to you, because the internal mechanisms of your brain are faltering? That will happen sooner than you would like. You do not have as much time as you might think. How many summers are there in a life? How many victories? Countless when they lie ahead. All too few when they are half done.

Friends, the progression of medical science from idea to therapy in the clinic is the work of a career. Fifteen to twenty years can pass from start to finish. The young adults who today look upon the opening years of rejuvenation research with interest will no longer be young when the first generation biological repair toolkit of the Strategies for Engineered Negligible Senescence is complete. They will be discovering the first small and concerning failures of their own personal supporting infrastructure. The researchers who led the effort will be retired or retiring, insofar as researchers ever choose to do that. The watch will have changed, the apocalypse taken place, another part of the world lost, destroyed, and mourned again.

And the new young people will be immortal, in their own slow time.

To live is to change. The rolling apocalypse will not go away, but it will be made kind, almost gentle. All that we build will crumble in time, as interest is lost, individuals will evolve to the point of disavowing their earlier selves, knowledge will come and go, and the time after will always be a foreign country to the time before. But there will be no death, no suffering on the vast scale that causes our present world to end over and again. To effect this transformation is the point of our efforts, to sustain human health for as long as we choose through periodic repair of the biological damage that causes aging.

How could we do otherwise? To let aging continue would be barbarism, a rejection of the core precepts of medicine and progress. If we are not building a better world, then why act at all? The capacity to build a better world is the only thing distinguishing us from a rabbit or a rockfall. Everything other than this we do because we must, driven by the biology we inherited, rolling downhill for no reason other than gravity. Are we to be human in truth rather than only in name? Then then we must break all of our physical constraints, not just the few achieved so far. We must prevent all of the suffering, not the little so far addressed. We must bring an end to the poor hand that nature has dealt us, and indeed stop playing the game entirely. In this new era of biotechnology, it is time to grow up, to become adult, to take ownership.

Circular RNAs are Enigmatic, and Grow in Number with Age

Large swathes of cellular biochemistry remain comparatively unexplored and uncategorized. Any process or cellular component discovered in the past twenty to thirty years still has, at the very least, sizable gaps in the body of knowledge relating to it. Cells as a whole are by no means fully understood at the detail level - and this is exactly why, if we want to see significant progress towards human rejuvenation in the next few decades, the approach taken has to be to reverse the known root causes of aging, while tampering as little as possible with the way in which cells work, and let the cells take care of everything else. Other approaches are based on altering the way in which cells operate. These require far too much new work and new knowledge in order to safely implement, or even understand how to produce effective results.

Today's topic is circular RNA (circRNA), a form of RNA quite prevalent in cells, but that was only discovered in the 1990s. These molecules are highly varied in form and function, and what exactly those functions might be remains largely unknown. Interestingly, the open access paper I'll point out today reports that circRNAs increase in number inside cells with advancing age, particularly in long-lived cells. Does that mean they are significant in aging? Perhaps, perhaps not. It is a topic to watch in the years ahead, but the research community is presently some distance removed from being able to answer questions of this sort regarding circRNAs. Work is still focused on the foundation of a basic understanding. The sort of extensive investigation of relationships and mechanisms that takes place for other forms of RNA still lies ahead for circRNAs.

Global accumulation of circRNAs during aging in Caenorhabditis elegans

Circular RNAs (circRNAs) have recently been identified as a natural occurring family of widespread and diverse endogenous RNAs. They are highly stable molecules mostly generated by backsplicing events from protein-coding genes. The expression trends of circRNAs are only recently emerging. Most circRNAs are derived from protein-coding genes, and thus one challenge in mapping and quantifying circRNAs is to distinguish reads that can be uniquely ascribed to circular molecules versus linear RNAs emanating from the same gene. Elements located within introns flanking circularizing exons play a role in promoting circRNA biogenesis, and several RNA binding proteins and splicing factors have been shown to influence circRNA expression.

Despite the current interest in circRNAs, their functions are only beginning to emerge. Recent reports have identified roles for circRNAs in regulating transcription, protein binding, and sequestration of microRNAs. Some circRNAs can be translated via cap-independent mechanisms to generate proteins. Moreover, circRNAs have been implicated in antiviral immunity, and expression patterns of circRNAs in the brain suggest that they might serve important functions in the nervous system.

Several RNA-seq studies have found that circRNAs are differentially expressed during aging. Over 250 circRNAs increased in expression within Drosophila head tissue between 1 and 20 days of age. Trends for increased circRNA expression have also been identified during embryonic/postnatal mouse development, suggesting that circRNA accumulation might begin early in development. We recently reported that circRNAs were biased for age-accumulation in the mouse brain. In hippocampus and cortex, ~5% of expressed circRNAs were found to increase from 1 month to 22 months of age, whereas ~1% decreased. This accumulation trend was independent of linear RNA changes from cognate genes and thus was not attributed to transcriptional regulation. CircRNA accumulation during aging might be a result of the enhanced stability of circRNAs compared to linear RNAs. Age-related deregulation of alternative splicing leading to increased circRNA biogenesis might also play a role.

C. elegans is a powerful model organism for studying aging. Previously, thousands of circRNAs were annotated from RNA-seq data obtained from C. elegans sperm, oocytes, embryos, and unsynchronized young adults. Here, we annotated circRNAs from very deep total RNA-seq data obtained from C. elegans at different aging time points and uncovered 575 novel circRNAs. A massive trend for increased circRNA levels with age was identified. This age-accumulation was independent of linear RNA changes from shared host genes. Our findings suggest that circRNA resistance to degradation in post-mitotic cells is largely responsible for the age-upregulation trends identified both here in C. elegans, and possibly in neural tissues of other animals.

SENS Research Foundation 2017-2018 Annual Report

The latest annual report from the SENS Research Foundation is out, covering progress in 2017 and early 2018. The SENS Research Foundation remains one of the very few philanthropic organizations focused on speeding the development of rejuvenation therapies - something we hope to see change in the years to come, as more support arrives for this field. The foundation staff use the charitable donations provided by our community to fund research programs specifically focused on areas of biotechnology that are presently blocked or neglected, but that can potentially give rise to ways to repair, remove, or work around the cell and tissue damage that causes aging. They also support networking, advocacy, and conference series designed to build bridges between academia and industry in order to smooth the road towards commercial development of advances developed in the laboratory.

Along with the Methuselah Foundation, where the SENS rejuvenation research programs started, the SENS Research Foundation has done a great deal to change the way in which the scientific community and broader public view aging. Back at the turn of the century, when the SENS program was proposed, and Aubrey de Grey presented his synthesis of existing evidence for seven broad categories of molecular damage that caused aging, the leaders in the research and funding communities actively suppressed any effort to work on or discuss the treatment of aging as a medical condition. It was career suicide to openly work towards that goal. The change achieved since then has been profound, and now researchers openly debate how best to go about treating aging to extend healthy life spans. This required a great deal of hard work.

A few strands of rejuvenation research have moved into clinical development in recent years: the removal of senescent cells, and clearance of a few kinds of harmful metabolic waste. As a part of its efforts, the SENS Research Foundation can now point to the ongoing development of startup biotechnology companies that it helped to seed fund, in some cases in partnership with the Methuselah Foundation. We will be seeing more of this in the years ahead: successful young companies can typically raise a great deal more funding than is available via philanthropy, and their efforts also go a long way towards attracting more validation and attention to the field.

SENS Research Foundation 2018 Annual Report

The valley of death - the chasm between innovation and availability that has become such a common theme in drug development - is especially wide for the field of rejuvenation biotechnology. Besides the time and resources required to develop any medicine, the few who initially strove to develop this field faced the added challenge of demonstrating that we could feasibly intervene to prevent age- related disease by redressing the underlying damage that causes such disease. There is scarcely a biotech organization that hasn't used, at some point, a 'bridging the gulf' metaphor to address the valley of death. But it has been such an integral part of our identity that we built it into our brand; the multi-colored ribbon of our logo having been designed to evoke both double-helix and suspension bridge imagery (and yes, it's always had seven twists).

Upon the launch of his project to build the Golden Gate Bridge, Chief Engineer Joseph Strauss had this to say: "It took two decades and two hundred million words to convince people the bridge was feasible." We have at times wondered whether even that would be sufficient. But with the diligent efforts of our own research teams and those of a growing number of institutions, the question of feasibility has increasingly fallen away. Today we see our research programs successfully translating into development, our former students becoming rejuvenation biotechnologists and developers, new collaborative energy from the investment arena, and the groundwork being laid for regulatory models for rejuvenation interventions.

Programmatic Investments

Antoxerene, a portfolio company of Ichor Therapeutics, is a small molecule drug discovery company that focuses on molecular pathways of aging. To our knowledge, Antoxerene is the first and only company with small molecule hits on the p53/FOXO4 pathway, which has been implicated in cellular senescence. Antoxerene is developing these hits for eventual clinical use.

Lysoclear, a portfolio company of Ichor Therapeutics, is an ophthalmology company developing an enzyme therapy for age-related macular degeneration and Stargardt's disease. In 2017, the company completed pivotal proof-of-concept studies with its first generation enzyme lead and conducted extensive mechanistic work to clarify the role of retinal lipofuscin in the onset and progression of macular degeneration. These results have been submitted for peer-reviewed publication. Lysoclear is now optimizing its enzyme into a drug candidate in preparation for IND enabling studies.

Oisín is developing a highly precise, patent-pending, DNA-targeted intervention to clear senescent cells. There are two major challenges to clearing senescent cells using this approach: Designing and creating the DNA construct that recognizes that a cell has become senescent and then destroys it, and safely and efficiently delivering this construct into cells throughout the body. Both goals have been achieved in pioneering proof of concept experiments in 2016. Now they are embarked on experiments that will show improvements in both healthspan and lifespan in model organisms from mice to primates.

Arigos has made great strides towards the banking of human organs, demonstrating functional and structural recovery of similarly-sized tissues from below -120°C. Their ability to cryopreserve large, complex tissue structures is a breakthrough in medical research. Stable banking for larger tissue structures and organs could more than double the number of transplants performed each year and would eliminate five of the current organ waiting lists within a few years.


The MitoSENS team is working on a potential rejuvenation biotechnology to sustain and recover electron transport chain (ETC) function: allotopic expression of functional mitochondrial genes. Allotopic expression involves placing "backup copies" of all of the protein-coding genes of the mitochondria in the "safe harbor" of the nucleus, which can then deliver the proteins mitochondria need to build their ETC and continue producing energy normally, even when the original mitochondrial copies have been mutated. The team is working to establish a "landing pad" in mouse cells to enable reliable and safe gene therapy for animal studies, via the Maximally-Modifiable Mouse Project. They expect to soon begin preliminary in vivo testing of allotopic ATP8 in transgenic mice. Meanwhile, they are also looking to expand the strategy to other mitochondrial genes and further improve allotopic expression of the ATP6 gene.

A major cause of crosslink accumulation in aging is Advanced Glycation Endproducts (AGE), and one AGE in particular - called glucosepane - is currently thought to be the single largest contributor to tissue AGE crosslinking, with consequences such as arterial stiffening. The Yale team is developing new reagents and approaches to accelerate glucosepane research. They now are able to synthesize all three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are also working to generate antibodies that can then be used to label glucosepane crosslinks in tissue samples and in vivo. Further, the Yale team has identified some potential glucosepane-breakers, about which we hope to be able to make further announcements this year pending publication in a peer-reviewed journal.

One of the reasons why senescent cells secrete inflammatory signals is to attract Natural Killer (NK) immune cells, which then clear senescent cells from the tissue. Despite this, senescent cells accumulate over the course of the lifespan. A critical question is therefore that of how some senescent cells are able to escape immune surveillance and what might be done to overcome their defenses. Dr. Judith Campisi, a renowned pioneer in senescence research, is answering this question and developing strategies to enhance immune clearance of senescent cells. Campisi's group has already discovered that one of the key NK cell binding markers on the surface of senescent cells begins to disappear within weeks of the cell becoming senescent. Without this marker ligand, NK cell binding cannot occur, and the NK cells' killing ability cannot be unleashed. Early results suggest some potential strategies for restoring NK cell immunosurveillance of senescent cells.

Aggregates composed of aberrant tau protein accumulate with age, both inside and outside of neurons. These aggregates are an important driver of neurodegenerative diseases of aging. One possible basis for this intracellular accumulation may be as a consequence of age-related lysosomal dysfunction that is driven by the accumulation of other kinds of intracellular aggregates. As such, this deleterious accumulation might be reversed if lysosomal function could be restored. This line of investigation will inform strategy: do we need a custom solution just for intracellular tau aggregates, or will clearing other age-related lysosomal junk be sufficient to restore an existing capacity to eliminate these aggregates? The Andersen lab is testing this possibility using neurons that express mutant versus wild-type human tau.

Atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity but ultimately fall prey to that same toxicity themselves. Dr. O'Connor's team has identified a family of small molecules that may be able to selectively remove toxic forms of cholesterol from human blood, which would help combat the development of atherosclerosis. They have been testing its effects and those of closely-related compounds in human blood samples, seeking potential modifications and combinations that would maximize selectivity for toxic cholesterol byproducts while leaving native cholesterol alone.

The Extracellular Matrix may Determine Regenerative Capacity in Mammals

Very shortly after birth, mammals are capable of far greater feats of regeneration than is the case for older individuals. The research community has put a fair amount of effort into determining why this is the case, though far less progress has been made here than in investigations of the biochemistry of highly regenerative species such as salamanders and zebrafish. This popular science article captures some of the present state of knowledge and uncertainty. Near future advances in medicine arising from this line of research seem unlikely at the present time, as by the look of it there is further to go yet in building a foundation of understanding sufficient to start talking about therapies.

Newborn mice are able to repair damaged heart tissue better than animals injured just a few days later in their lives. What accounts for this regenerative capacity, and exactly when and why it disappears, have been unanswered questions. A new report posits that the extracellular matrix (ECM) gets in the way of heart tissue renewal. The investigators also found that scarring was minimal in mice injured on their first day of life, but damage occurring after that, even just a day later, led to large fibrotic scars. Other scientists are skeptical that what the researchers observed is true regeneration, arguing that the team did not actually show the growth of new muscle. "There is a problem in this research field that we rely on this fibrosis hallmark because the extent of ventricle outgrowth is very hard to determine. If fibrosis is absent, people are very eager to conclude, 'OK, this is regeneration.' But it is not evidence of myocardial regrowth."

Because the adult mammalian heart cannot regenerate to any significant degree, an injury, such as that caused by a heart attack, damages the muscle irrevocably and can ultimately lead to heart failure and death. Following a 2011 paper that showed newborn mice could regenerate their hearts after having a chunk removed, some scientists began speculating that if they could figure out the mechanisms behind this renewal and recapitulate them in human heart attack victims, they might be able to prevent heart failure. The researchers reasoned that determining precisely when in the first week of life this capacity ceases might enable the identification of the factors involved. It was known that heart muscle cells continue to copy their DNA for a few days after birth, so one idea was that the heart's renewal capacity might be linked to this replication.

Researchers cut out the apical tips from the hearts of newborn mice on day 1, 2, 3, 4, or 9 after birth. Three weeks later, the researchers sacrificed the mice and reexamined their hearts. Animals whose hearts were resected on day 1 showed minimal scarring and the hearts were approximately the same size and shape as those of control animals. By contrast, animals who underwent heart surgery on day 2, 3, 4, or 9 exhibited large fibrotic scars in place of regrowth. Given the different recoveries of day 1 and day 2 mice, the team looked for differences between the animals' transcriptomes. "We were actually expecting to find differences in cell cycle genes, but that was not the case. The main difference that we found was in genes related to the extracellular matrix." The group saw a general upregulation of genes for ECM components and went on to show that the ECMs of day 2 mouse hearts were approximately 50 percent stiffer than those of day 1 hearts.

To determine whether ECM stiffness and regeneration were causally linked, researchers disrupted ECM formation in developing pups. They treated the pups with β-aminopropionitrile (BAPN) - an inhibitor of the ECM cross-linking enzyme LOX - during pregnancy (via the mothers' drinking water) and for three days after birth (through the mothers' milk). As a result, three-day-old pups were able to regenerate their hearts with significantly reduced fibrosis compared with controls whose ECMs were intact. Other researchers note that the proof that these mice are actually regenerating heart tissue wasn't provided, but the team is confident: "When there is no regeneration, you can see that the heart ventricular apex is missing a bit, and is replaced by a white patch (a scar). In contrast, it is not possible to distinguish, morphologically, a heart that completely regenerated from one that was not amputated."

Blocking an Astrocyte Receptor Produces Benefits in an Alzheimer's Mouse Model

Researchers here produce an interesting demonstration in a mouse model of Alzheimer's disease. With a comparatively simple change, they rein in the abnormal behavior of astrocyte cells in the brain, and thereby reverse the symptoms of the condition. As noted in the publicity materials, the relevance of mouse models of Alzheimer's to the real thing in humans is often strained - the models are highly artificial, as mice and most other mammals don't normally suffer anything resembling Alzheimer's disease. Thus in cases like this it is hard to say without further work whether or not the discovery is relevant to human biochemistry.

Nonetheless, the supporting cells of the brain, the various categories of neuroglia such as the astrocytes noted here, cannot be ignored in the progression neurodegenerative conditions. They perform a wide range of important functions: clearing up debris and waste; supplying necessary proteins and other molecules to neurons; participating in the maintenance and operation of synaptic connections between neurons; and much more. In neurodegenerative conditions such as Alzheimer's disease, the neuroglia malfunction or change their behavior in harmful ways. Chronic inflammation is one consequence, but also disruption of the normal function of neural networks.

In studies in mice, researchers were able to show that blocking a particular receptor located on astrocytes normalized brain function and improved memory performance. Astrocytes are star-shaped, non-neuronal cells involved in the regulation of brain activity and blood flow. "The brain contains different types of cells including neurons and astrocytes. Astrocytes support brain function and shape the communication between neurons, called synaptic transmission, by releasing a variety of messenger proteins. They also provide metabolic and structural support and contribute to the regulation of blood flow in the brain."

Similar to neurons, astrocytes are organized into functional networks that may involve thousands of cells. "For normal brain function, it is crucial that networks of brain cells coordinate their firing rates. Interestingly, one of the main jobs of astrocytes is very similar to this: to keep neurons healthy and to help maintain neuronal network function. However, in Alzheimer's disease, there is aberrant activity of these networks. Many cells are hyperactive, including neurons and astrocytes. Hence, understanding the role of astrocytes, and targeting such network dysfunctions, holds a strong potential for treating Alzheimer's."

Researchers tested this approach in an experimental study involving mice. Due to a genetic disposition, these rodents exhibited certain symptoms of Alzheimer's similar to those that manifest in humans with the disease. In the brain, this included pathological deposits of proteins known as amyloid-beta plaques and aberrant network activity. In addition, the mice showed impaired learning ability and memory. The scientists targeted a cell membrane receptor called P2Y1R, which is predominately expressed by astrocytes. Previous experiments had revealed that activation of this receptor triggers cellular hyperactivity in mouse models of Alzheimer's. Therefore, the researchers treated groups of mice with different P2Y1R antagonists. These chemical compounds can bind to the receptor, thus switching it off. The treatment lasted for several weeks.

"We found that long-term treatment with these drugs normalized the brain's network activity. Furthermore, the mice's learning ability and memory greatly improved. On the other hand, in a control group of wild type mice this treatment had no significant effect on astrocyte activity. This indicates that P2Y1R inhibition acts quite specifically. It does not dampen network activity when pathological hyperactivity is absent. This is an experimental study that is currently not directly applicable to human patients. However, our results suggest that astrocytes, as important safeguards of neuronal health and normal network function, may hold the potential for novel treatment options in Alzheimer's disease."

The Gut Microbiome as a Contributing Cause of Sarcopenia

Sarcopenia is the name given to more severe manifestations of the characteristic age-related loss of muscle mass and strength that occurs in all older people. A review of the literature will find ongoing debates over many possible contributing causes of this muscle degeneration, some with better evidence than others, many related to one another: lower dietary intake of protein in the elderly; a failure to correctly process dietary amino acids, particularly leucine; degeneration in the connections between muscle and nervous system; declining activity in muscle stem cell populations; chronic inflammation such as that produced by senescent cells; lack of exercise, particularly strength training; and so forth. From where I stand, I'd say the stem cell explanation is by far the most robust, but then one has to think about why the stem cell populations are in decline.

The open access paper here weighs in with thoughts on age-related changes in the types and behavior of bacteria in the gut as a contributing cause of sarcopenia. A great deal of attention has been given to the gut microbiome in the context of aging in recent years. It is most likely in the same order of magnitude of influence as diet when it comes to the relationship between metabolism and natural variations in the pace of aging, as it mediates diet. These bacteria also produce a wide range of compounds that affect cellular populations throughout the body in various ways, and appear particularly relevant in the chronic inflammation that arises in older individuals. But is it as important as other mechanisms in driving accumulation of the forms of cell and tissue damage outlined in the SENS rejuvenation research proposals, which in turn produce outcomes such as stem cell decline? Perhaps, perhaps not.

The progressive loss of skeletal muscle mass and strength/function, referred to as sarcopenia, is increasingly recognized as a relevant determinant of negative health outcomes in late life. However, the incomplete knowledge of the pathophysiology of sarcopenia hampers the identification of targets that could be exploited for drug development. A growing body of evidence suggests that the innumerable microorganisms that populate the mammalian gastrointestinal tract (gut microbiota) are tightly linked to the aging process of their host. Indeed, this microbial community, mostly composed of bacteria, participates in crucial activities of the gut barrier including the generation of metabolites essential for several host functions and the mediation of exogenous chemical effects on their host.

Age-related changes in the bacterial composition of the microbiota are well known, and alterations of gut microbiota driven by the diet may affect the health of elderly people. However, the complexity of mammalian gut microbiota and the technical challenges in isolating specific "prolongevity" microbial variants limit the knowledge of the microbiota to taxonomic and metagenomic profiling. The functions of individual microbial genes and the molecular mechanisms through which they intervene in host aging are yet to be elucidated. Even less is known about the implications of microbiota-immune system crosstalk on muscle aging.

Most gut microbial changes observed during aging are attributable to diet composition. Both environmental and behavioral factors, including loss of sensation, tooth loss, chewing difficulties, changes in lifestyle, increased consumption of high sugar-fat foods and reduction in plant-based foods have been suggested to influence age-associated diet variations. Taken as a whole, current data supports a link between aging and microbiota alterations relying on a proinflammatory loop. In this context, the age-related decline in masticatory function together with a reduction of appetite and gastrointestinal motility induces dietary changes (reduction in fruits and vegetables) that is reflected in microbiota rearrangement (dysbiosis). This alteration, in turn, can activate a proinflammatory loop fueled by the immunosenescence of gut-associated lymphoid tissue releasing proinflammatory mediators which further favors microbiota rearrangements.

Gut microbiota plays a crucial role in maintaining the balance of pro- and anti-inflammatory responses. Aged gut microbiota may elicit an inflammatory response and display lower capability of counteracting adverse microbes or removing their metabolites. The entrance of pathogens into the intestinal mucosa is also facilitated by the secretion of mucins by intestinal epithelial cells, which is triggered by a reduction in short-chain fatty acids (SCFA) levels in the intestines. SCFA serves within the gut not only as an energy source for colonic epithelial cells but also as strong anti-inflammatory molecules regulating host metabolism and immunity. Increased intestinal permeability to lipopolysaccharide (LPS) is another element in support of a mechanistic link between microbial dysbiosis and systemic inflammation.

In such a context, chronic inflammation may represent the unifying trait of microbial alterations and the development of muscle-wasting conditions in advanced age through a gut microbiota-muscle crosstalk. The molecular players involved in this process are not yet fully understood, but results from several studies indicate the relevant contribution of microbial changes and activity in the gut to the repertoire of inflammatory molecules involved in the milieu characterizing muscle aging. This represents an important matter to be addressed by future investigations to unravel the signaling pathways that may serve as targets for interventions.

CAR-T Therapy Eliminates Metastatic Colorectal Cancer in Mice

Chimeric antigen receptor T-cell (CAR-T) therapies are a very promising form of cancer immunotherapy. Initially developed for use against blood cancers, they are now showing their worth in the treatment of solid tumors. The most important aspect of this technology platform is not that it is effective, but rather that it can be adapted at an incremental cost to many types of cancer. The future of cancer treatment is entirely determined by choice of strategy: without a broadly applicable therapy with a low cost of adaptation, or ideally a universal therapy that can be applied as-is to any cancer, then there are too few researchers and far, far too many different types of cancer for the progress we'd like to see. If we wish to see cancer controlled in our lifetimes, then the development of general therapies that can be applied to most or all types of cancer is a requirement.

Immunotherapy has given patients and oncologists new options, which for some patients, has meant cures for diseases that had been untreatable. Colorectal cancer has a high mortality rate in advanced stages of the disease with few effective therapies. Researchers have shown that a type of immunotherapy called CAR-T cell therapy, successfully kills tumors and prevents metastases in mouse models of the disease. The work is the last step of preclinical testing prior to human clinical trials. "The antigen we target for colorectal cancer is one that is shared across several high mortality cancers including esophageal cancer and pancreatic cancer. Taken together, 25 percent of people who die from cancer could potentially be treated with this therapy."

CAR-T immunotherapy involves removing a patient's immune cells, engineering them to target the tumor (and only the tumor) and then multiplying those cells en masse before infusing them back into the patient. This powerful burst of targeted immune cells, quickly overcomes the cancer's own immune-suppression to kill the tumors, but requires a marker or homing beacon specific to the cancer. For colorectal cancer that beacon, or tumor antigen, is called GUCY2C. Researchers created a CAR-T therapy made specifically to treat GUCY2C-expressing cancers such as colorectal cancer.

In this study, the researchers tested a human-ready version of the therapy in mice. They showed that mice with human colorectal tumors treated with CAR-T therapy successfully fought the tumor cells. All of the mice studied survived without side effects for the duration of the observation period - or 75 days, compared to a 30-day average survival of mice with control treatment. In order to more closely replicate late-stage disease in humans, researchers also looked at a mouse model of colorectal cancer that developed lung metastases, a common site for metastasis in colorectal cancer patients. Mice that were treated with the CAR-T therapy survived over 100 days with no metastases, whereas the control group survived an average of 20 days. The next steps for the researchers would be a phase 1 clinical trial in humans.

HMGB1 Accelerates Tissue Regeneration by Increasing Stem Cell Activity

Researchers here outline a method of pushing stem cells in several different tissues into greater activity, thereby accelerating regeneration from injury and potentially improving ongoing tissue maintenance. Given a few more decades of development, regenerative medicine will probably bear little resemblance to today's approaches of cell transplantation, and will instead rely upon a combination of (a) delivering signal molecules or otherwise controlling cell behavior, and (b) repairing damage that accumulates in important cell populations, such as stem cells. If stem cells are kept in a well maintained state, and can be directed to perform as needed, then a major component of the progression of aging will be eliminated. This is, of course, a very large project. There are hundreds of types of cell in the body, and every tissue has its own distinct stem cell populations, all significantly different from one another. The present state of the art in stem cell research is barely the first step on a long road ahead.

Adult stem cells are an essential component of tissue homeostasis with indispensable roles in both physiological tissue renewal and tissue repair following injury. The regenerative potential of stem cells has been very successful for hematological disorders. In contrast, there has been comparatively little clinical impact on enhancing the regeneration of solid organs despite continuing major scientific and public interest. Strategies that rely on ex vivo expansion of autologous stem cells on an individual patient basis are prohibitively expensive, and success in animal models has often failed to translate in late-phase clinical trials. The use of allogeneic cells would overcome the problems of limited supply but commonly entails risky lifelong immunosuppressive therapy. Some safety concerns remain about induced pluripotent stem cells. Furthermore, successful engraftment of exogenous stem cells to sites of tissue injury requires a supportive inductive niche, and the typical proinflammatory scarred bed in damaged recipient tissues is suboptimal.

An attractive alternative strategy, which overcomes many of the limitations described above, is to promote repair by harnessing the regenerative potential of endogenous stem cells. This requires identification of key soluble mediators that enhance the activity of stem cells and can be administered systemically. An interesting observation was made in 1970 that a priming injury at a distant site at the time of or before the second trauma resulted in accelerated healing. This phenomenon was explained only recently, when it was shown that a soluble mediator is released following the priming tissue injury which transitions stem cells elsewhere in the body to a state the authors termed GAlert, which is intermediate between G0 (quiescence) and G1. In the presence of activating factors the primed GAlert cells enter the cell cycle more rapidly than quiescent stem cells, leading to accelerated tissue repair. However, the identity of the soluble mediators that transition stem cells to GAlert remain to be clarified.

Our long-standing interest in tissue injury has recently centered on alarmins, a group of evolutionarily unrelated endogenous molecules with diverse homeostatic intracellular roles, which, when released from dying, injured, or activated cells, trigger an immune/inflammatory response. Much effort has been focused on their deleterious role in autoimmune and inflammatory conditions, and of the few studies that have investigated their role in tissue repair, none has used a combination of human tissues and multiple animal-injury models to characterize their effects on endogenous adult stem cells in vivo. Here we show that high mobility group box 1 (HMGB1) is a key upstream mediator of tissue regeneration which acts by transitioning CXCR4+ skeletal, hematopoietic, and muscle stem cells from G0 to GAlert and that, in the presence of appropriate activating factors, exogenous administration before or at the time of injury leads to accelerated tissue repair.

Mesenchymal Stem Cell Therapy Aids Spinal Cord Regeneration in Rats

Arguably the most reliable of first generation stem cell therapies is the transplantation of mesenchymal stem cells. The cells don't last long in the recipient, which is a problem characteristic of all such cell therapies, but the signals they secrete while still alive act to change native cell behavior and suppress inflammation for an extended period of time. Since chronic inflammation degrades tissue maintenance and regeneration, this respite can allow some degree of healing that wouldn't have otherwise occurred - though that benefit is much less reliable than the initial suppression of inflammation.

In the study reported here, researchers turn this set of mechanisms towards regeneration from spinal injury, demonstrating improvements in rats. This is still a long way from comprehensive repair, and much of the discussion centers around just how variable and poorly controlled the cell behavior is in this "most reliable" of cell therapies, but it is a good deal better than failing to intervene in the inflammation that causes scarring following nerve injury. Nerves are in principle capable of regeneration in absence of that scar formation: the mechanisms to support that regeneration exist in mammals, but are not deployed at the right time and in the right way. One line item is the behavior of macrophages, an important player in the intricate dance of cell types involved in regeneration, and whether they adopt the beneficial M2 polarization or the inflammatory M1 polarization. This topic shows up in a lot of regenerative research these days.

There are numerous studies of the therapeutic potential of combinatorial approaches based on mesenchymal stem cell (MSC) therapy and biomaterials for spinal cord injury (SCI) treatment. The transplantation of bone marrow-MSCs combined with a gelatin matrix into the area of complete rat spinal cord transection in the subacute period improves inflammation, stimulates angiogenesis, reduces abnormal cavitation and promotes regeneration of nerve fibers. Human umbilical cord blood-derived MSCs combined with hydrogel implanted into the area of injury can significantly modify the immune response in a proinflammatory environment within the area of SCI by increasing the macrophage M2 population and promoting an appropriate microenvironment for regeneration.

We have studied the effects of the application of adipose-derived mesenchymal stem cells (AD-MSCs) combined with a fibrin matrix on structural and functional recovery following SCI in a subacute period in rats. Our results demonstrated that the AD-MSC application is found to exert a positive impact on the functional and structural recovery after SCI that has been confirmed by the behavioral/electrophysiological and morphometric studies demonstrating reduced area of abnormal cavities and enhanced tissue retention in the site of injury.

We have also assessed astroglial and microglial cells in this study. The results obtained confirm the evidence that AD-MSCs are able to prevent the second phase of neuronal injury by contributing to astroglia and microglia suppression. The latter is consistent with past results, which showed that intravenous injection of AD-MSCs after acute SCI in dogs may prevent further damage through enhancement of antioxidative and anti-inflammatory mechanisms including through lesser microglial infiltration in injured tissue.

Considering their unique therapeutic properties, their ease of accessibility and expansion, AD-MSCs combined with a scaffold reveals a potential for a widespread use in clinical medicine. Nevertheless, there remain critical challenges - (1) standardization of generation protocols, including cell culture conditions, (2) the heterogeneity of secretory phenotype of the MSC population, (3) cellular mechanisms and biological properties of MSCs should be disclosed more clearly, (4) translation to the clinic will need preclinical studies on larger animals, (5) randomized, controlled, multicenter clinical trials are necessary to determine the optimal conditions and doses for MSC therapy.

Elite Chess Players and Elite Athletes Have Similar Advantages in Life Expectancy

We can file the study noted here alongside a 2015 twin study as a compelling piece of evidence that stands in opposition to a significant role for high levels of exercise in human longevity. These two are still vastly outnumbered by studies supporting the idea that exercise drives a modestly slower pace of aging, particularly when it comes to the difference between no exercise and some exercise, but they are nonetheless quite clear in and of themselves and quite hard to ignore. The association between athletic performance and greater life expectancy is well proven, but if similar benefits are observed in more cerebral sports, what does that tell us about the underlying mechanisms?

This isn't just a question about physical activity or its absence, or about the confounding correlations between social status, education, intelligence, wealth, and health. There is a growing line of evidence to suggest that associations between intelligence and longevity may be as much mediated by genetics as by greater odds of economic success and sustained better health practices. Natural variation in human longevity is an intensely complex subject, which is one of the many reasons that I'm more in favor of forging ahead with rejuvenation therapies rather than spending significant time trying to understand the present state of aging.

In recent decades much research has been conducted into the longevity of a wide variety of sporting achievers. Almost all of the studies have been focused on a wide range of physical sports. A recent meta-analysis and several recent reviews have consistently found that elite athletes engaged in physical sports have a significant lower rate of mortality compared with the general population. The most comprehensive review, which involved nearly half a million individuals from 57 studies, indicates that the survival advantage for elite athletes was generally between 4 to 8 years longer.

Much less is known about those engaged in mind sports such as chess where the mental exercise component dominates. A search for articles reporting longevity of players of mind sports identified only one early study involving 32 chess players born before 20th century. This study found that professional chess players had shorter lifespans than those players who had careers outside of chess and argued that this might be due to the mental strain of international chess competition.

In the present study, we focused on survival of International Chess Grandmasters (GMs) which represent players, of whom most are professional, at the highest level. In 2010, the overall life expectancy of GMs at the age of 30 years was 53.6 years, which is significantly greater than the overall weighted mean life expectancy of 45.9 years for the general population. In all three regions examined, mean life expectancy of the GMs was longer than that of the matched general population, with gaps between them ranging from 1 to 14 years depending on age. Across the combined sample from 28 countries, the survival advantage over the general population significantly increased over time.

While intelligence may be a potential confounding factor given its positive effect on longevity, evidence of the link between IQ and chess ability is inconclusive. Several studies have failed to find a superiority of expert chess players in a variety of intellectual dimensions. A more likely channel is that to attain the Grandmaster title an individual may be encouraged to make necessary health improvements to improve one's cognitive performance. Although there has been some concern that chess training promotes a sedentary lifestyle that may reduce participation of the chess players in physical activities, this is not supported by existing evidence.

Another causal argument on the effect of developing chess expertise on survival relates to socioeconomic mechanisms. Becoming a chess grandmaster may provide an economic and social boost, which has been strongly linked to increased life expectancy. The relative income and social status benefits of GMs are plausibly highest for individuals in Eastern Europe, which would explain the particularly substantial relative survival advantage we found in this region.

Aging of the Locus Coeruleus and Loss of Focus in Older Individuals

Cognitive ability has many different dimensions. While all decline with age, it is quite possible for any given individual to find them declining at different rates and at different times, according to the individual distribution of damage and atrophy in the brain. The research noted here illustrates one of many links between a particular cognitive function and a particular location in the brain. In most cases we can look at this sort of evidence and consider that it would be very helpful to have a way to (a) spur greater generation of new cells in the brain, that can integrate into tissues, repair areas of damage, and restore lost function, and (b) clear out the protein aggregates and other forms of metabolic waste associated with the progression towards neurodegenerative disease.

Older adults appear more easily distracted by irrelevant information than younger people when they experience stress or powerful emotions - and a specific network in the brain recently identified as the epicenter for Alzheimer's and dementia may be to blame. A study finds that seniors' attention shortfall is associated with the locus coeruleus, a tiny region of the brainstem that connects to many other parts of the brain. The locus coeruleus helps focus brain activity during periods of stress or excitement.

Increased distractibility is a sign of cognitive aging. The study found that older adults are even more susceptible to distraction under stress or emotional arousal, indicating that the locus coeruleus' ability to intensify focus weakens over time. For instance, if an older adult is taking a memory test in a clinician's office, he or she may be trying hard to focus but will be more easily distracted than a younger adult by other thoughts or noises in the background.

The locus coeruleus appears to be one of the earliest sites of tau pathology, the tangles that are a hallmark of Alzheimer's disease. "Initial signs of this pathology are evident in the locus coeruleus in most people by age 30. Thus, it is critical to better understand how locus coeruleus function changes as we age." The locus coeruleus connects to many parts of the brain and controls the release of the hormone norepinephrine, which influences attention, memory and alertness. Normally, norepinephrine increases the "gain" on neural activity - highly active neurons become more excited, while less active neurons get suppressed.

The researchers recorded physiological arousal and locus coeruleus activity in 28 younger adults and 24 older adults using both brain scans and the measurement of pupil dilation in participants' eyes - an outwardly visible marker for emotional arousal and locus coeruleus activity. During the scans, study participants were shown pairs of photographs. Some trials started with a tone that warned participants that they might receive an electric shock at the end of the trial. Other trials started with a tone indicating that there would be no shock. Participants showed greater pupil dilation and sweat during trials when they might get a shock, indicating greater physiological arousal.

The brain's parahippocampal "place area" becomes active when a person is looking at images of places. In younger adults, expecting a shock amplified activity in the place area when they looked a clear, highlighted image of a building. Pathways in their brains linking the locus coeruleus, the place area, and the frontoparietal network - regions of the brain's cortex that help control what to pay attention to and what to ignore - were uninterrupted. This enabled them to more effectively ignore the information that wasn't important. Older adults, however, showed less activity in the frontoparietal network when anticipating a shock. Their network seemed to no longer effectively respond to signals from the locus coeruleus.

Burying Dead Cells Requires Oxidative Signaling

The research here considers how the debris of dead cells is cleared away, something that has to happen efficiently in order to avoid inflammation and other issues in tissue. As is true of a range of beneficial processes in the body, this turns out to require a certain level of oxidative signaling. This is probably one of the reasons why long-term general use of antioxidants appears to be, on balance, modestly harmful to health and longevity. The process is interesting when considered in the context of recent work on necroptosis, a fairly recently discovered form of programmed cell death that results in inflammatory cell debris, as well as past considerations of cellular debris as a mechanism by which excess fat tissue produces chronic inflammation. Is this sort of thing important in the progression of aging, more of a root cause of many issues rather than a downstream consequence of failing maintenance processes? That is an interesting question.

Billions of cells die daily as a consequence of regular wear and tear, tissue turnover and during an inflammatory response. The body dedicates a significant amount of energy in the specific recognition and uptake of these dead cells via specific pathways. If you don't bury the dead cells, they can burst open and cause harm, however the underlying mechanisms are incompletely characterized. Now, researchers have uncovered how NADPH-oxidase is activated to generate reactive oxygen species (ROS) in macrophages, a kind of white blood cell that eats dead cells. These cells also are involved in getting rid of viruses and bacteria.

The presence of ROS is critical as its generation drives additional mechanisms involved in the digestion of cellular corpses to perform at an optimal level. This allows the macrophage to complete the digestion process of efferocytosis. "Independent of their role in microbial killing, we are gaining even greater appreciation of ROS for their huge role in the regulation of host immune response. Uncovering this role of ROS in the clearance of dead cells sheds some mechanistic insights on how oxidants function in limiting of host inflammation rather than activating it. When our bodies produce too much or too little ROS, we become pre-disposed to autoimmune disease and chronic inflammation. Producing just enough - the optimal level - is what's needed."

Investigations of p66(Shc) Knockout Mice Continue

Gene knockout of p66(Shc) is one of the many genetic alterations shown to extend mouse life span. The role of p66(Shc) in the intersection of aging and metabolism has been investigated for more than two decades now, though its ability to extend life is disputed by at least some researchers - the data isn't as reliable as is the case for some other approaches. This is a common issue for methods that alter the operation of metabolism, as metabolism is very complex, and all sorts of other factors beyond the intended genetic adjustment might have a meaningful influence.

To the extent that p66(Shc) knockout improves health and function in mice, it appears to work via an improvement in mitochondrial activity, or a slowing in the age-related mitochondrial dysfunction that affects unmodified mice. Mitochondria in older individuals produce more oxidative molecules, are less efficient at their primary task of producing chemical energy stores, and their appearance changes, all of which is slowed in p66(Shc) knockout mice. Which is interesting, but what do we get out of this at the end of the day? The papers produced as a result of research into p66(Shc) this year look little different in content and character from those of decade ago; there is little apparent likelihood of a therapy to slow the progression of aging emerging from this fundamental science in the near future.

In the last years, more cases of cooperation between reactive oxygen species (ROS) and aging-regulating genes have been established in senescence and aging development. The adaptor protein p66Shc is a genetic determinant of lifespan that regulates ROS metabolism and cellular apoptosis. p66Shc ablation in mice is translated into a significant decrease in mitochondria-produced ROS and a 30% increase in lifespan. These knockout mice for p66Shc (p66Shc(-/-)) have been shown to be thinner, to exhibit an increased metabolic rate, and to have less body fat than their wild-type littermates. And more remarkably, they have been described as an animal model of healthy aging with better cognitive abilities at adulthood in a spatial memory task and improved physical performance at senescence.

Based on the improved bioenergetics parameters observed in p66Shc(-/-) mice and the already accepted downregulated mitochondrial biogenesis in aging, it is interesting to study how p66Shc impacts on mitochondrial quantity and structure. The mitochondrial content of a sample can be determined using different methods that provide information about mitochondrial biogenesis and tissue's oxidative capacity. Mitochondrial DNA (mtDNA) content relative to nuclear DNA was determined by real-time qPCR in brain samples of the study groups and shown as a percentage of the 3-month-old wild type (WT) relative mtDNA content. During aging, mitochondrial content was reduced by 30% in the WT group, while in the p66Shc(-/-) group, a 45% increase was observed.

For both WT and p66Shc(-/-) 3-month-old mice, normal size and volume mitochondria were observed, with predominantly tubular-shaped mitochondria (70% of total measured mitochondria), while the remaining displayed round (fragmented) morphology. However, at the end of their life, the time point of maximal ROS production, 24-month-old WT mouse brain slices were characterized by decreased tubular mitochondria (-44%) and increased round-shaped mitochondria (+120%). This age effect in mitochondrial morphology was partially mitigated in 24-month-old p66Shc(-/-) mice, to the extent that both types of mitochondrial populations coexisted in this group (55% tubular mitochondria) showing an intermediate phenotype between 3- and 24-month-old WT mice.


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