Biology

Fight Aging! Newsletter, February 17th 2020



Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
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Contents

  • Notes on the 2020 Longevity Therapeutics Conference in San Francisco
  • Nicotinamide Riboside Improves Hematopoiesis and Immune Cell Populations in Mice
  • The Prospects for Telomerase Gene Therapy as a Treatment for Heart Disease
  • Video and Transcript of Aubrey de Grey Presenting to the Effective Altruism Community
  • PTTG1 as Prompt for Discussion of the Evolutionary Genetics of Aging
  • Thymic Involution Contributes to Immunosenescence and Inflammaging
  • The Potential for Exosome Therapies to Treat Sarcopenia
  • Correlations of Mitochondrial DNA Copy Number and Epigenetic Age Measures
  • Evidence for PASK Deficiency to Reduce the Impact of Aging in Mice
  • The Aging Retina, a Mirror of the Aging Brain
  • Evidence for Loss of Capillary Density to be Important in Heart Disease
  • Aspects of Immune System Aging Proceed More Rapidly in Men
  • Deacetylation of the NLRP3 Inflammasome as a Way to Control Chronic Inflammation
  • Transplantation of Senescent Cells is an Issue in First Generation Stem Cell Therapies
  • Transplantation of Young Bone Marrow into Old Mice Produces Systemic Benefits

Notes on the 2020 Longevity Therapeutics Conference in San Francisco

https://www.fightaging.org/archives/2020/02/notes-on-the-2020-longevity-therapeutics-conference-in-san-francisco/

I recently attended the 2020 Longevity Therapeutics conference in San Francisco. I presented on the work ongoing at Repair Biotechnologies, but as is usually the case the more important parts of the visit took place outside the bounds of the conference proper. Longevity Therapeutics is one of the four or five core conferences for the longevity industry, at which you’ll meet many of the early participants – a mix of scientists, entrepreneurs, and investors, and patient advocates. As such, most of the conference goers have already seen my updates, or are otherwise aware of the Repair Biotechnologies programs aimed at thymic regeneration and reversal of atherosclerosis. This year was heavily biased towards the entrepreneurial component of the community. It was even the case that most of the scientists attending were presenting in the context of a company that is advancing their work towards the clinic. As the longevity industry expands, ever more researchers in the aging field are finding the opportunity to start a company, or otherwise hand off their work for clinical development.

The first day was a lightly populated set of workshops prior to the conference proper. In the morning, Aubrey de Grey of the SENS Research Foundation and AgeX Therapeutics gave his usual overview of the state of rejuvenation research and development, with a little more emphasis than usual on clinical development and investment in the field. Irina Conboy discussed the plasticity of aging; she is one of the more noted researchers involved in the modern investigations of parabiosis, in which old and young mice have their circulatory systems linked. She gave a tour of differences observed in old mice during parabiosis, such as improved liver regeneration. The argument of beneficial factors in young blood versus detrimental factors in old blood has resolved, by the sound of it, to the conclusion that both mechanisms are relevant – there are a lot of different factors, of different importance. She noted that she is starting a company to push forward some of her work on upregulation or downregulation of factors identified in parabiosis, particularly the combination of oxytocin and TGF-β. Michael Fossel talked about the hallmarks of aging and what to do with them. His point was that metabolism and aging are enormously complicated, forming a system that exhibits risk factors rather than deterministic behaviors. The focus should be on finding the best point of intervention, which is not the same thing as understanding the system. Greater understanding only makes finding the best point of intervention easier, it isn’t absolutely required.

The afternoon was more focused on clinical translation, with presentations from companies further along in the process of conducting trials with the FDA. Mark Allen of Elevian talked about indication choice as a challenging process for companies targeting aging. Elevian is a GDF11 company, and they presently think that prior issues with contradictory results for GDF11 delivery in animal models were due to poor manufacture of the protein. Indication choice is challenging for therapies intervening in aging because so many different indications can be considered, but most are dead ends. It is very important to consider how the choice of indication affects time to market: one is looking for short treatments that can produce large effects. Further, if you want the FDA on your side, you really have to go after large unmet needs for serious diseases. The Elevian team used a matrix/scoring approach to assess different indications. Outside expertise is vital; you can’t do this yourself.

Elizabeth Jeffards and Erin Newman from Alkahest further elaborated on this process of indication selection, and then moved on to talk about how to run trials. Their high level point was that the operation of trials becomes your whole company, determining everything about how you are seen and how you proceed. The two talked about the central matter of payer willingness to pay for your therapies – whether insurance giants, Medicare, and other entities will toe the line. This is a very important matter, at all stages of the process of figuring out which indication to pursue. They also emphasized the need to build a very specific target product profile, the exact cost and performance of your therapy, well in advance of any sort of data. Another vital issue is manufacturing: getting the timing right, given the lengthy duration of GMP manufacture, and the huge cost of that process. This is challenging and needs very careful management. Peter Milner of Retrotope talked about their orphan disease trials, and reinforced the points already made. Retrope uses deteurium stabilized lipids to treat neurodegenerative conditions in which lipid peroxidation is a serious concern. In talking about about the Retrotope clinical trials, he again pointed out that cost and time are very important in their choices of indications – one has to to look for large effects achieved in quick trials.

The first day of the conference opened with a keynote by Nathaniel David of UNITY Biotechnologies. He surveyed the common approaches to research aimed at intervention in aging, that small changes between species biochemistry leads to large changes in species life span, and so forth. Regarding UNITY, he discussed their human data on the performance of senolytics for osteoarthritis and for degeneration of the retina, such as dry macular degeneration. They are in phase II for osteoarthritis, with data coming out late in 2020. For the eye, they are still working on phase 1 safety data, also coming out late 2020. They are also in the earlier stages of developing senolytic treatments for lung and kidney diseases.

Following that, Joan Mannick of ResTORbio opened her presentation by lauding mTORC1 as a target, pointing to the large body of research in short-lived species. Following failure on their phase III trial for reducing influenza incidence, they are now focusing on neurodegenerative disease, particularly Parkinson’s disease. They believe that raised autophagy via mTORC1 inhibition may help with aggregates in these conditions, and discussed some of the supporting evidence in animal models. Peter Fedichev of Gero presented on their AI program for small molecule drug repurposing and discovery. Based on their models of biochemical data from mice and humans, they divide aging into two overlapping processes that they call “aging” and “frailty” – these are names for portions of a data model, and don’t necessarily map well to the common meanings of the words. Mice and humans have quite different proportions of “aging” versus “frailty”. Gero has new data from lifespan and rejuvenation studies using compounds that they intend to repurpose: they have achieved some degree of slowing or reversal of aspects of aging via their drugs in mice. This essentially shows they can pick drugs that perform comparably to some of the historical efforts to achieve this sort of outcome, and can do so faster than was possible in the past.

Gino Cortopossi of UC Davis is working on new approaches to upregulate mitochondrial function. He discussed how his group carried out the discovery of drug candidates to try to target mitochondrial function, SHC, and MTORC1. This presentation was an exercise in thinking about how to test interventions of this nature, what sort of a path leads forward from there to the clinic, and how to organize a handoff from academia to Big Pharma. Hanadie Yousef of Juvena Therapeutics talked about their AI-driven program of mining the secretome of pluripotent cells. The Juvena staff are searching for secreted molecules that can delivered as therapies to upregulate regenerative and stem cell capacity in old people. Their initial focus is on muscle regeneration in the context of age-related sarcopenia. In one of the more interesting presentations of the day, Matthias Hackl of TAmiRNA talked about biomarker development in the microRNA space. The TAmiRNA folk think that they should be able to use a blood sample to produce simultaneous measures of senescent cell burden in many different tissues via assessment of circulating miRNAs from the senescence-associated secretory phenotype (SASP): each tissue has a signature. They are not quite there yet, but this will be very useful if it works out. Dana Larocca of AgeX Therapeutics talked on the topic of exosomes. That AgeX is focused on production of useful cell lines via induced pluripotency gives them a good head start on the production of useful exosomes via harvesting cell cultures of those cell lines. They are presently engaged in the search for interesting exosomes that might form the basis for therapies that make adult stem cells more active.

Jay Sarkar of Turn.bio discussed their approach to transient epigenetic reprogramming in order to force cell function to become more youthful. They use mRNA for reprogramming, as they feel it gives them greater control, and precise control is very important in their work – they must not push cells all the way into pluripotency, just shock them into better operations, and there is a fine line between those two outcomes. The Turn.bio staff are using in vitro cell data to suggest that they can affect various hallmarks of aging: changing certain cell properties and the overall transcription landscape. The approach doesn’t lengthen telomeres, which is interesting; the most important thing it does, I would say, is to restore mitochondrial function. He showed data for chondrocytes, relevant to osteoarthritis, and the Turn.bio team are also trying a cell therapy approach on this front, to reprogram cells and then transplant them to see if they help. Additionally, they have worked in skin models to show reversal of aspects of aging there. Turn.bio is one of a growing number of companies working with Entos Pharmaceuticals to produce a non-toxic lipid nanoparticle vector to deliver their therapy in vivo. Given that, it isn’t surprising that that they are also working with Oisin Biotechnologies, who also use the Entos Pharmaceuticals platform, to see how senolytics plus reprogramming work in synergy.

Rich Allsop of University of Hawaii talked on the role of FOXO3, one of the few robustly longevity associated genes in humans, in influencing telomere shortening and inflammaging. It touches on the IGF-1 pathway, and a variant is associated with greater longevity in humans. These researchers think that the behavior of the variant is more to do with enhancer or promoter effects on gene expression, not functional differences in the protein, as the difference is in a non-coding region of the gene. There is some question as whether inflammation causes a difference in the pace of telomere shortening, such as via faster replication of immune cells in response to inflammatory signaling, or whether the relationship functions in a different way. Michael Fossel of Telocyte discussed his view on telomeres, cellular senescence, and telomerase gene therapy. He argues that the data shows that you need to increase telomere length to a large degree in order to see reductions in cancer risk, meaning lots of telomerase, not just a little – too little and there will be more cancer. His company is presently looking for funding to run an Alzheimer’s disease trial of telomerase gene therapy; they have everything planned, and just need the backing.

Steve Turner of InVivo Biosystems presented on a system that can be used to determine quickly, say in 3 months, whether or not a therapy will extend lifespan and healthspan. To achieve this result they use C. elegans and zebrafish, and assess omics results, with some degree of automation in their platform. In a related presentation, Gordon Lithgow of the Buck Institute outlined their work on small molecule discovery with a C. elegans platform. A fair number of varied approaches to cost-effectively use these short-lived species in conjunction with automation, omics, and AI are out there under development these days. Kristen Fortney of Bioage Labs talked on their AI-driven discovery in human aging omics data, in search of pathways that can be drugged. They take a holistic view of aging: don’t study age-related diseases, study aging as a whole, look for important processes. Given pathways, they perform screening in vitro, then take drug candidates to a sizeable vivarium of 3,000 mice (expanding to 12,000 all too soon), and test the outcome there. They outlined a few example targets and the data supporting their ongoing work, including approaches to reduce neuroinflammation. Andrea Maier of the University of Melbourne talked at a high level on the development of potential aging-targeting repurposed drugs in Australia. This was a very nuts and bolts outline regarding how one plans and conducts human trials for specific age-related diseases. They were largely focused on lifestyle intervention, and are only now starting to think about drugs. Rounding out the first day, Wim von Schooten of Teneobio presented on the use of a CD38 inhibitor as a way to upregulate NAD+ levels and mitochondrial function. CD38 is somewhat connected to the proximate causes of NAD+ reduction in aging mitochondria, but it has other roles as well. It is also anti-inflammatory. CD38 is upregulated with age, in concert with NAD+ drop and inflammation rise, and the position in this presentation is that CD38 is causal of NAD+ decline.

The second day of the conference kicked off with a presentation by Sergio Ruiz on the topic of the Methuselah Fund and their progress to date in supporting new and important companies in the longevity industry. He gave a general overview on the state of investment in early stage companies in the field: what investors are looking for; how to transition from lab to clinic; the recent evolution of the longevity industry and the field of aging research. He noted that this is a huge opportunity for changing the human condition, not just a chance for a sizable return on investment. The team is presently working on raising their second fund. The first fund writes 50k-500k checks, second fund will be much larger and write 1m-5m checks.

Ronald Kohanski of the National Institute on Aging gave the NIA/NIH perspective on rejuvenation and accelerated aging as therapeutic targets. They see the Interventions Testing Program and other programs as ways in which the NIA supports industry. He noted a range of ongoing work at the NIA that connects to the hallmarks of aging. They are starting to think about using omics data from the Interventions Testing Program and other studies to better understand what is taking place in aging-related pathways, as well as to develop ways to measure rejuvenation and aging. The presentation mostly dwelled on parabiosis and small molecules that slow aging as interventions to consider in this context. Nir Barzilai of the Albert Einstein College of Medicine followed to talk about the challenges inherent in making therapies to target aging or age-related diseases. The first problem is that animal models are not great, there is too much failure in translation to human medicine. Then there is the issue of payers (insurance companies, medicare, and so on) that don’t want to pay for interventions that slow aging, which is related to the challenge of there being no FDA-approved indication for aging. The lack of an indication is largely why payers will not pay, even if therapies could be approved in some useful way. He mixed this in with his usual talk about centenarians and data on their health habits, genetics, and so forth.

Kevin Perrott of OpenCures presented on collecting data from people who are trying interventions themselves, self-experimenters, to try to reduce the time taken to develop new therapies. He is conducting proteomic analysis of blood samples from people in the self-experimentation community to measure outcomes, and the OpenCures team are also carrying out volunteers studies of supplement-regulated compounds, somewhat similar to phase 1 trials in organization, with proteomic measurements to assess effects. Julie Andersen of the Buck Institute talked about cellular senescence as a driver of Alzheimer’s disease – something I would like to see a lot more work on, given the potential for meaningful benefits to patients. She noted the evidence for senescent glial cells, such as astrocytes, to contribute to neurodegenerative pathology. It is now thought possible for post-mitotic neurons to undergo senescence as well, contrary to earlier dogma. That might present a challenge, but equally obvious issues with cognitive function haven’t manifested yet in animal studies of senolytics. She presented in vitro evidence for amyloid-β to cause senescence in brain cells, and suggested that the spread of senescence via the SASP occurs without amyloid-β in the later stages of the condition. The initial presence of amyloid-β is required, but not thereafter, and might be why removing amyloid-β doesn’t help once this process is underway.

Richard Marshak of Torcept Therapeutics undertook a discussion on how to go about rational drug development with aging as the target. The company conducts drug discovery of mTORC1 inhibitors, and he talked about their pipeline and evidence. There is still skepticism from Big Pharma regarding the whole of the longevity industry: there are no clear endpoints; the technical and regulatory risk is far greater than Big Pharma entities are usually prepared to engage with; and the expense of testing against aging as a target is believed to be high. Once again this included a discussion of payers versus regulators, and what these two groups are looking for. Payers are interested in extending healthy longevity, it is worth bearing this in mind – there are strong economic incentives here that may help to overcome other issues. The development of endpoints for interventions in aging is important, since we can’t use aging itself right now. Yet surrogate outcomes (measurements of biomarkers rather than patient outcomes) are not popular with anybody in the regulatory system at this time.

Marco Quarta at Rubedo Life Sciences presented on their small molecule discovery of senolytic and anticancer compounds. They are at the preclinical stage and would like to start looking at other cell changes that occur with age as well, such as loss of stem cell function. They are claiming a 60-70% clearance of senescent cells in multiple tissues via their lead senolytic, which is larger than most of the published literature to date – but it is hard to say how this compares with the state of the art in the various companies working on new senolytics. A range of other mouse model data on toxicity, safety, and effectiveness was presented. Andy Schile of Jackson Laboratory gave a plug for their aged mice, a source for studies. He surrounded that with examples of some of their studies of mice at different ages, presenting data on their usefulness in various models of age-related disease and dysfunction. Pan Zheng from the University of Maryland Baltimore talked about the role of CD24 in the inflammatory response to tissue damage, such as in the context of graft versus host disease, for example. This research group is attempting to influence the CD24 pathway to reduce inflammation in bone marrow grafts, HIV patients, and during immunotherapy. They have a CD24 fusion protein that works via affecting immune checkpoints to dampen the response.

Jean-Marc Brondello of ISERM discussed cellular senescence as a cause of osteoarthritis, with a focus on the details of the manifestations of the condition and how senescence contributes to these issues. This team is processing omics data to identify possible new senotherapeutics that might address the issue. John Lewis of Oisin Biotechnologies gave the usual presentation on the Entos Pharmaceuticals lipid nanoparticle platform and its application as a senolytic therapy when delivering a suicide gene therapy triggered by expression of p16 or p53. An important point emphasized here is the exceptional safety profile of these nanoparticles – massive doses can be supplied to mice and other mammals with no signs of toxicity. Andrei Gudkov at Genome Protection discussed retrotransposons and their role in aging. Of particular interest is that retrotransposon activity drives chronic inflammation via cellular senescence. This team is developing therapies to try to ameliorate these issues. He presented an interesting view of aging as a species-specific cliff of mortality, and argues that DNA damage (i.e. retrotransposon activity) is the cause of the cliff, via production of chronic inflammation at a time dictated by loss of suppression of retrotransposon activity. Genome Protection studies retrotransposons in dogs, as breed variations in lifespan may be largely caused by retrotransposon based changes – the differences in genetics between dog breeds tend to cluster appear in locations connected to retrotranspon activity. Lastly, Lewis Gruber from SIWA Therapeutics presented on their program focused on a senolytic monoclonal antibody. They originally started out by targeting oxidative stress and glycolysis: these aspects of cell dysfunction have a common advanced glycation endproduct surface marker for a monoclonal antibody to bind to. Given that binding, immune cells then destroy the errant cell. He pointed out that these marked cells are largely senescent, but others might only be dysfunctional. That can include cancerous cells.

All in all it was a interesting event, a good chance to catch up with existing members of the community and meet some new faces. If one has an interest in joining the longevity industry in some way, Longevity Therapeutics should be on the list of conferences to attend, along with Undoing Aging in Berlin, Ending Age-Related Diseases in New York, and Longevity Leaders and the Longevity Week events in London.

Nicotinamide Riboside Improves Hematopoiesis and Immune Cell Populations in Mice

https://www.fightaging.org/archives/2020/02/nicotinamide-riboside-improves-hematopoiesis-and-immune-cell-populations-in-mice/

Mitochondria are the power plants of the cell. They produce the chemical energy store molecule ATP that is used to power cellular operations. Unfortunately, mitochondrial function falters throughout the body with advancing age, and while this is harmful in all tissues, the effects are particularly problematic in energy-hungry tissues such as the muscle and brain. Research of recent years has implicated the loss of nicotinamide adenine dinucleotide (NAD+) in mitochondria in this process. Evidence suggests that loss of effectiveness in mitophagy, the process that recycles worn and damaged mitochondria, is the important issue connected to NAD+ deficiency. NAD+ is largely produced by recycling its products, rather than by synthesis, but both the recycling and synthesis pathways suffer a loss of effectiveness with advancing age.

Various approaches to boost levels of NAD+ have been assessed in animals and are readily available for application to humans. Delivering NAD+ directly is inefficient in comparison to providing precursors and metabolites used in the synthesis and recycling pathways. Nicotinamide riboside supplementation is at present the only approach to upregulation of NAD+ in mitochondria with human trial data. The results from a small trial show a modest reduction in blood pressure in older hypertensive individuals, comparable with what can be achieved through lifestyle choices, due to improved smooth muscle function in blood vessels. One would expect there to be many more forms of benefit resulting from systemic improvement in mitochondrial function, but it is always hard to predict the size of effect in advance, and thus whether or not a particular approach to aging is actually worth it.

The research here is interesting for suggesting that NAD+ upregulation via nicotinamide riboside will lead to gains in immune function via improving the generation of immune cells in bone marrow. This is something that can be tested and quantified in humans without too much trouble, via examination of immune populations in a blood sample. That sort of effort is well within the reach of the self-experimentation community – though, as ever, it is more likely that the research community will get around to running a formal trial before self-experimenters organize sufficiently to produce robust data. The question at the end of the day is the size of effect: is it actually larger than that produced by exercise, and how does that vary by age?

Targeting mitochondria to stimulate hematopoiesis

Hematopoietic stem cells (HSCs) consist of a small cell-population in the bone-marrow (BM) that are responsible for lifelong production of all mature blood cells in an organism. A delicate balance of different HSC fates, namely, quiescence, self-renewal, and differentiation is decisive in maintaining the HSC pool and blood cell homeostasis. Cellular metabolism has emerged as one of the fundamental regulators of HSC fate decision process. HSCs rely primarily on anaerobic glycolysis while downstream progenitors use mitochondrial metabolism to fulfil their energy requirements.

In a recent study we have tested the mitochondrial modulator and NAD+ boosting agent, Nicotinamide Riboside (NR), in the context of regenerative hematopoiesis. One week of NR dietary supplementation to wild type mice resulted in increased BM cellularity and expansion of hematopoietic progenitor cells, this reflected in a significant increase in terminally differentiated circulating blood and immune cells. Importantly, mitochondrial profiling of HSCs derived from mice supplemented with NR revealed significant reduction of mitochondrial membrane potential (an indirect readout on mitochondrial activity), indicating that NR has a direct effect on HSC metabolism when administered systemically.

To understand the molecular mechanisms driving the effect of NR, we performed transcriptome analysis (by RNA sequencing) on ex vivo cultured HSCs. We found upregulation of autophagy (and mitophagy) and of NAD salvage pathway genes upon NR treatment, and a concomitant downregulation of mitochondrial metabolism pathway genes (TCA cycle and Oxidative Phosphorylation). NR-induced mitophagy was confirmed by image analysis of in vitro cultured HSCs and by bone marrow analysis of mitophagy reporter mice (mito-QC). We discovered that mitophagy induction was coupled with activation of mitochondrial unfolded protein response (UPRmt), that has been recently proposed as a conservation mechanism of the HSCs pool during aging. We hypothesize that NR-induced mitochondrial stress leads to the clearance of damaged mitochondria unable to coop with the metabolic stress. This complex mechanism initiates an instruction process where cells are primed toward asymmetric self-renewing cell division via differential distribution of active mitochondria in daughter cells.

Given that previous studies have implicated the importance of mitophagy and autophagy in HSC function and aging, we believe that NAD boosting strategies could be used to improve functionality of the hematopoietic stem cell pool in the elderly, where HSCs lose their capacity to produce a balanced immune system, being strongly primed toward a myeloid fate.

The Prospects for Telomerase Gene Therapy as a Treatment for Heart Disease

https://www.fightaging.org/archives/2020/02/the-prospects-for-telomerase-gene-therapy-as-a-treatment-for-heart-disease/

Telomerase gene therapy is considered in some quarters to be a viable treatment for aging. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. They are an important part of the mechanism limiting the number of times that somatic cells in the body can divide, the Hayflick limit. A little telomere length is lost with each cell division, and short telomeres trigger cellular senescence or programmed cell death, halting replication. Stem cell populations use telomerase to lengthen their telomeres and thus self-renew to provide a continual supply of new somatic daughter cells with long telomeres to replace those lost to the Hayflick limit. Average telomere length is reduced over the course of aging because stem cell function declines.

This division between a few privileged stem cells and the vast majority of limited somatic cells is the way in which higher forms of life have evolved to reduce the risk of cancer. Somatic cells largely do not last long enough to develop mutational damage sufficient to become cancerous. When cancer does occur, most cancer lineages use expression of telomerase in order to lengthen their telomeres, allowing for unfettered replication. This biochemistry of cancer is the primary reason for caution in the matter of the clinical application of telomerase gene therapies in human medicine. While in mice cancer incidence is actually reduced by telomerase upregulation, possibly because immune system activity is improved to the point at which the destruction of potentially cancerous cells is efficient enough to outweigh risk due to greater replication of damaged cells with lengthened telomeres, it is still a question as to whether human tissues will see the same outcome over time.

Some groups look on telomerase gene therapy as being primarily a form of regenerative medicine, able to improve stem cell and progenitor cell function and thus lead to greater tissue maintenance and regeneration. This is the case in today’s open access review paper. It may also act to prevent cells from becoming senescent, and thus lower the burden of cellular senescence in old tissues by allowing slowed and declining clearance mechanisms to catch up. Allowing damaged cells to continue to replicate by lengthening their telomeres may be less harmful than the presence of more lingering senescent cells. It no doubt has other effects on cell function: the mechanisms of action for telomerase gene therapy are far from fully catalogued, but the evidence for benefits to result in mice is quite solid. While a number of humans have undergone forms of telomerase gene therapy via medical tourism and similar arrangements, there is little that can be said of the therapy or the outcomes there, as these applications are few in number, comparatively recent, and undertaken outside the bounds of formal clinical trials.

Telomeres as Therapeutic Targets in Heart Disease

Although there could be asynchrony of telomere length among different tissues, peripheral leukocyte DNA has been most commonly used in clinical studies to measure leukocyte telomere length (LTL). Traditional risk factors for cardiovascular diseases (CVD), such as smoking, diabetes mellitus, dyslipidemia, hypertension, obesity, and shift work, have been associated with short LTL. In the prospective WOSCOPS (West of Scotland Primary Prevention Study) trial, subjects in the lowest tertile of LTL had a 44% increased risk of 5-year major cardiovascular events compared with subjects in the highest tertile of LTL. In a prospective WHI (Women’s Health Initiative) study, hen patients developed chronic heart failure, they were also observed to have shorter LTL. Moreover, short LTL was also associated with congestive heart failure severity and clinical outcome.

Robust epidemiological and genetic evidence linking telomere length and CVD risk support the therapeutic hypothesis that genetic manipulations of the telomere system can be a potential treatment target for CVDs. Telomerase gene therapy was first achieved by delivering mouse TERT with an adeno-associated virus (AAV) into young and old mice. This nonintegrative gene therapy resulted in elongated telomeres, extended lifespans, and delayed age-associated pathologies. Importantly, telomerase-treated mice did not develop cancer at a higher rate than the corresponding control group. With the nonintegrative and replication incompetent properties of AAVs, this strategy restricted TERT expression to a few cell divisions and provided a relatively genome-safe TERT activation.

A report for age-associated diseases, such as CVDs, demonstrated improved ventricular function and limited infarct scars after acute myocardial infarction with TERT gene therapy in a preclinical mouse model. TERT gene therapy is a promising candidate that deserves further research efforts for clinical implementation for the treatment of age-associated diseases. Apart from direct TERT delivery by nonintegrative AAV vectors, new gene therapy methods using modified mRNA for in vitro encoding of TERT in human fibroblasts can transiently increase telomerase activity, rapidly extend telomeres, and increase proliferative capacity without the risks of insertional mutagenesis and off-target effects. In addition to proof-of-concept experimental data in mice, the development of safe strategies for transient and controllable telomerase activation in humans can be a subject of future studies.

Video and Transcript of Aubrey de Grey Presenting to the Effective Altruism Community

https://www.fightaging.org/archives/2020/02/video-and-transcript-of-aubrey-de-grey-presenting-to-the-effective-altruism-community/

Aubrey de Grey administers the scientific programs at the SENS Research Foundation, and is a leading figure in the rejuvenation research community and newly formed longevity industry. Here find a transcript of his present commentary on the state of rejuvenation research, lightly tailored for delivery to an audience of effective altruists. Effective altruism is a useful movement, I feel, if nothing else for the pressure that advocates might bring to bear on the corruption and ineffectiveness of much of present day institutional philanthropy. Further, while it might seem self-evident to much of the Fight Aging! audience that the most efficient use of charitable donations, if one aims to reduce suffering in the world, is to fund rejuvenation research programs, the public at large is still far removed drawing this same conclusion. More persuasion is needed, and effective altruists are already engaged in exactly that sort of effort.

The effective altruism community has a culture of running the numbers and arguing from data, and this is attached to a culture of advocacy for their view on how to conduct philanthropy in a more efficient way. Once one starts to run the numbers and argue from data, it is quite hard to avoid the conclusion that aging is by far the worst problem affecting humanity, and thus working to treat aging, in an era in which this is a plausible goal, is by far the most effective form of philanthropy. Aging is the greatest cause of suffering and death in the world, far more so than even infectious disease, war, and poverty. Given this, effective altruists have the potential to become vocal advocates for the cause of human rejuvenation.

Aubrey de Grey: Rejuvenation Technology – Will “Age” Soon Cease to Mean “Aging”?

What I’m going to do today is try to explain why I believe it makes sense for effective altruists (EAs) to prioritize the issue of aging. To make that case, there are a number of questions that need to be answered in the affirmative. First, is aging a really big problem? I believe that it is, by a good distance, the world’s biggest problem. But I understand that this group thinks very carefully about such statements, so I need to justify my opinion. The second argument I need to make is that we have a sufficient understanding today of what aging is, and generally how we might go about addressing it. Therefore, if we throw money at this problem, there’s a good chance of having a significant impact. This is not trivial. Other times that I’ve spoken at EA events, I’ve received a lot of pushback. Many EAs believe we understand so little about aging that what we do at the SENS Research Foundation is essentially random, and therefore spending money on it is unjustified. The third argument I need to make is very new. It’s really only arisen over the past few years, and it is this: philanthropy is still critical, even though private investment in the study of aging has exploded.

To address the first point – why aging is important – I’m just going to tell you why I think that is clearly true. To me, it’s just a fact that aging causes far more suffering than anything else in the world today or in the foreseeable future. It’s not just the death part. We’re talking about effective altruism here, and altruism means worrying about other people. People dying makes other people unhappy. That’s not arguable. But what might be much more important is that when people die of aging, they do it slowly. They do it as a consequence of a chronic, progressive accumulation of damage in the body, a decline in mental and physical function. So, to me, it’s self-evident that aging is, by far, the source of the largest amount of suffering in the world today. You could even argue that it was true a long time ago.

Now I’m going to address the second question. In order to do that, I’m going to fill in a lot of background information. Aging is the combination of two processes, metabolism and damage, which together result in pathology. A network of processes keeps us alive – that’s what metabolism means – and, over time, generates damage. Currently, the overwhelming majority of money and effort spent to prevent the pathologies of late life is spent wrongly. It is spent on trying to break the link between damage and pathology. Damage, by definition, is accumulating, which means that efforts to stop it from causing pathology are bound to become progressively less effective as someone gets older. It’s obvious. What we might be able to do is separate the component processes of metabolism and damage from each other. That’s the maintenance approach – it’s damage repair. We might be able to periodically repair some of the damage that metabolism generates, so that even though it continues to generate it, the damage does not reach a level of abundance that causes pathology. I think it is reasonable to call this the common sense alternative.

Seventeen years ago, I described the damage of aging in only seven words, as seven types of damage: cell loss or atrophy, division-obsessed cells, death-resistant cells, mitochondrial mutations, intracellular waste products, extracellular waste products, extracellular matrix stiffening. What’s most important is the fact that for each of these types of damage, we can describe a generic therapy that could potentially represent the maintenance approach – the way to repair this type of damage. However, one thing I want to emphasize is that I’m not the only one saying this anymore. Five or 10 years ago, this was an argument that still needed to be made. But now it has been made. As an illustration, the Hallmarks of Aging paper came out only six years ago, and will be by far the most highly-cited paper this decade in the whole of the biology of aging. It’s simply a restatement of what I said more than a decade earlier. The important point is that a divide-and-conquer, damage-repair approach is now a completely mainstream, orthodox idea.

On the the third point, that philanthropy still matters despite the growth of a longevity industry, SENS Research Foundation views itself these days as the engine room of that industry. We work on early-stage projects for as long as it takes to establish sufficient proof of concept to spin them out into startup companies. We’re not the only ones. The Longevity Research Institute (LRI) is a new organization that’s working in a more narrowly defined space. But they may grow, and, of course, there are going to be other organizations like this. Philanthropy matters enormously in this. We believe that we can get all – or at least almost all – of the key technologies in rejuvenation biotechnology into clinical trials within a few years. But the key point here is that the things being funded effectively by the private sector are the low-hanging fruit. And damage repair is an inherently divide-and-conquer concept. You can’t just focus on the low-hanging fruit. You’ve got to address all of the components. It’s more important than ever to make progress on the most difficult areas, and that is still a goal for philanthropy.

PTTG1 as Prompt for Discussion of the Evolutionary Genetics of Aging

https://www.fightaging.org/archives/2020/02/pttg1-as-prompt-for-discussion-of-the-evolutionary-genetics-of-aging/

Aging is under genetic control in the sense that species have different genomes, different life spans, and different manifestations of aging within those life spans. Within any given species, it is far from clear that genetic variation has a large enough influence to care about. Individuals vary, but the evidence strongly suggests that this is near all due to environmental rather than genetic differences. Where there are genetic differences, the old who survive to benefit from them are still old people, greatly impacted by aging and trapped in a downward spiral of dysfunction.

The author of this commentary uses the gene PTTG1 as a starting point for a discussion of the genetics and evolution of aging across species, but again, this really doesn’t have to mean that PTTG1 and its effects on metabolism are necessarily a place to start the development of therapies to treat aging in humans. Relevance in the former does not automatically lead to relevance in the latter. The research community should look less to differences between individuals and more to addressing the known causes of aging, mechanisms that are the same in all individuals of a given species.

Of mice, genes and aging

Why do we get old? How much of aging is genetic? And in what genes? There is clearly a genetic basis of aging, as demonstrated from yeast to worms to humans. As one example, different mouse strains have different potential lifespans. Much effort has been invested in understanding the genetic underpinnings of lifespan differences between the long-lived C57Bl/6 strain and the short-lived DBA/2 strain, with 50% mortality in captivity by 914 and 687 days, respectively. Quantitative trait loci mapping in C57Bl/6 X DBA/2 (BXD) recombinant inbred strains identified a locus on chromosome 11 that is linked to lifespan. Subsequent analyses revealed that this locus confers differential expression of the pituitary tumor-transforming gene-1 (Pttg1)/Securin gene. PTTG1 level-dependent impacts on chromosomal segregation during mitosis could influence longevity.

Natural selection only acts to promote longevity to the extent that it benefits the passage of genetic material to subsequent generations. Different animals have evolved different strategies for somatic maintenance that maximize reproductive success, and the extension of youth through additional investment in tissue maintenance would be disfavored if the costs (often manifested through reduced investment in reproduction) outweigh benefits. For a small vulnerable animal like a field mouse that faces high extrinsic hazards (such as predation), natural selection has favored a “fast” life history – a breed early, breed often strategy with little investment in longevity. For larger animals like humans, elephants, and whales, or for animals like tortoises, moles, bats and birds that have evolved other strategies to greatly reduce extrinsic hazards, natural selection has favored a “slow” life history, with greater and/or prolonged tissue maintenance leading to longer potential lifespans.

While we understand how natural selection has shaped the pathways that control longevity, we know less about what these pathways actually are. Studies from model organisms have clearly demonstrated that modulation of the insulin-like growth factor-1 (IGF-1) pathway, which positively regulates the mTOR pathway and negatively regulates autophagy, can significantly impact longevity. Decreases in IGF-1 and mTOR, or increases in autophagy, have been shown to prolong lifespans in organisms ranging from yeast to mammals. Additional studies have shown how inflammation can contribute to aging-associated phenotypes, and polymorphisms in genes controlling the IGF-1 pathway and inflammation are enriched in human centenarians, but the extent to which these polymorphisms and their impact on inflammation are contributing to differences in longevity has not been established.

While genetic screens in model organisms have revealed key pathways that regulate lifespan, the mechanisms employed by natural selection in the evolution of lifespans largely remain a mystery. Although one could argue that the selective breeding to generate different mouse strains over the last couple of centuries may not qualify as “natural” selection, the studies focused on PTTG1 reveal at least one potential (and novel) mediator of lifespan control. Key questions remain: Do variations in PTTG1 expression or activity contribute to lifespan differences across species, and perhaps within a species (including variability in the human population)? Would modulation of PTTG1 expression or activity promote the extension of healthspan or lifespan? How do activities known to modulate lifespan, such as dietary restriction and exercise, influence PTTG1 activity? Are there links between known aging pathways such as via IGF-1 and PTTG1? Good science generates good questions, leading to new insights (and sometimes even solutions). As a senior colleague once told me after I had told him that I worked on aging – “Hurry up”.

Thymic Involution Contributes to Immunosenescence and Inflammaging

https://www.fightaging.org/archives/2020/02/thymic-involution-contributes-to-immunosenescence-and-inflammaging/

The thymus is an underappreciated organ, responsible for the complex process of generating mature T cells of the adaptive immune system. Unfortunately it atrophies with age in a process called thymic involution. By age 50 most people have little active thymic tissue left. They must coast for the rest of their lives on the adaptive immune cells that they have at that point, replicating in the periphery of the body without a meaningful supply of new reinforcements. This inevitably leads to an immune system made up of damaged, overspecialized, and malfunctioning cells, incapable and inflammatory.

That part of the overall decline in immune function that is driven by thymic atrophy is a noteworthy component of aging, and this is why restoration of thymic tissue and activity is an important goal for the rejuvenation biotechnology research and development community. Since there are a number of us working on this, including Repair Biotechnologies, Lygenesis, and others, we might hope that a viable rejuvenation therapy for thymic function will arrive sooner rather than later in the years ahead.

The aged immune system has various characteristics. One of which is immunosenescence, which describes the vast and varied changes in the structure and function of the immune system as a result of age. Many of the early observations, such as reduced ability to fight new infections, diminished vaccine immunity, and reduced tumor clearance are generally categorized as immune insufficiencies. Immunosenescence is not due to the lack of immune cells, but due to reduced immune repertoire diversity, attributed to insufficient production of naïve immune cells and amplified oligo-clonal expansion of memory immune cells. Immunosenescence is therefore linked to the thymus. Natural aging causes the thymus to progressively atrophy, a process called thymic involution. This phenomenon is readily observed in most vertebrates and results in structural alterations, as well as functional decline, ultimately resulting in significantly decreased thymic output of naïve T cells that reduces the diversity of the T cell antigen receptor (TCR) repertoire, culminating in disrupted T cell homeostasis.

The second characteristic of aged immunity is termed inflammaging. Inflammaging describes the elevated self-reactivity in the elderly, resulting in the typical chronic, low-grade, but above baseline, systemic inflammatory phenotype observed in the absence of acute infection. Although immunosenescence and inflammaging appear to be opposing phenotypes, they comprise two sides of the same coin when attempting to holistically understand age-related immune dysfunction. It has been proposed that the basal inflammatory state in the elderly, defined by inflammaging, greatly contributes to many age-related degenerative diseases.

T lymphocyte (T cell) development and selection occurs in the thymus. Included in this process is central tolerance establishment. First is thymocyte negative selection, during which the majority of self (auto)-reactive T cells are depleted from the repertoire via apoptosis. Second is the generation of CD4 single positive FoxP3+ regulatory T (Treg) cells, whose primary function is to suppress T cell-mediated self-reactivity and preserve immune homeostasis in the periphery. These arms of central T cell tolerance work in tandem, and Treg cells most likely compensate for imperfections of negative selection, as some self-reactive T cells escape negative selection. With age, however, the atrophied thymus declines in its capacity to establish central tolerance, thereby, causing increased self-reactive T cells to escape to the periphery and participate in the process of inflammaging.

The Potential for Exosome Therapies to Treat Sarcopenia

https://www.fightaging.org/archives/2020/02/the-potential-for-exosome-therapies-to-treat-sarcopenia/

The authors of this open access review walk through some of the evidence for delivery of exosomes, such as those derived from stem cells, to be a basis for treating sarcopenia. Sarcopenia is the progressive loss of muscle mass and strength that takes place with aging. While a fair degree of sarcopenia is preventable, being the consequence of an age of comfort, leisure, and too little exercise, the rest of it is still inevitable absent some way to interfere in the mechanisms of aging that disrupt muscle tissue maintenance. The delivery of cell signals encapsulated in exosomes might be capable of forcing muscle stem cells into greater activity, overriding their natural reaction to an aged tissue environment. While this class of therapy doesn’t address the underlying causes of the problem, the benefits may still be large enough to be worth chasing.

Sarcopenia is one of the hallmarks of the aging process. Human muscle undergoes constant changes with the most alterations taking place with age. As shown by different studies, on average, the prevalence of sarcopenia in older adults aged 60-70 years lies at 5-13%, increasing to 11-50% in people aged 80 or older. Sarcopenia is closely related to negative outcomes in older adults, such as an increased risk of falls and fractures and impaired cognitive function and physical performance. Researchers estimated that the economic costs for sarcopenia in the USA were about 18.5bn in 2000. Strikingly, if the prevalence of sarcopenia would be reduced by only 10%, it would save 1.1bn in medical costs per year in the US health care expenditures. Therefore, it is urgent to develop more effective research strategies and therapeutic approaches for preventing sarcopenia based on a better understanding of the potential mechanisms of this disease.

Over the years, many researches have investigated physiological and pathological conditions related to poor muscle regeneration in sarcopenia. However, the underlying molecular mechanisms associated with sarcopenia remain not completely understood. Some evidence suggests that such factors as anabolic resistance and endothelial dysfunction may contribute to the development of sarcopenia. Another one of the recent studies reported that exosomes released by muscles into the bloodstream may also play an essential role in muscle regeneration. This opens a novel field of research in preventing muscle loss. It is hypothesized that exosomes as carrier of a cargo of proteins, mRNA, miRNA, and other non-coding RNAs play a crucial role in myogenesis and muscle development. It has been shown in a mouse model of muscle injury that human skeletal myoblasts-derived exosomes containing all sorts of signal molecules can promote muscle regeneration.

Although the treatment of sarcopenia remains challenging, it is widely accepted that such strategies as nutritional supplementation and physical training (both aerobic exercise and resistance exercise) are the key interventions that can help maintain skeletal muscle mass. However, the molecular mechanisms behind the prevention from the age-related muscle loss by nutrition and exercise are still poorly understood. More recent data indicate that exercise attenuates sarcopenia mainly through increasing peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) signalling, which can be activated by heat shock protein 60-bearing exosomes released after physical training. This connection between sports and release of exosomes supports the assumption about the key role of exosomes in muscle regeneration.

Other recent data also indicates that exosomes, secreted by skeletal muscle cells and carrying miRNAs and other factors, may act as vital modulators of skeletal muscle function, and may have the potential in the research strategies of sarcopenia. Owing to their diverse pathological and therapeutic effects, exosomes has attracted more attention in the scientific community in recent years. It has been shown that exosomes are related to organ crosstalk and can be beneficial in research of many diseases, including kidney injury, myocardial infarction, Parkinson’s disease, and cancer. Importantly, the present data suggest that exosomes may mediate and enhance the beneficial effects of exercise. Emerging evidence has presented that exosomes as carriers can increase muscle regeneration after skeletal muscle injury and improve muscle protein synthesis and hypertrophy, which could support exosomes as vectors for future research strategies of sarcopenia. All these mechanisms are interconnected, but the underlying pathways are still not understood completely and should be examined more thoroughly in future studies.

Correlations of Mitochondrial DNA Copy Number and Epigenetic Age Measures

https://www.fightaging.org/archives/2020/02/correlations-of-mitochondrial-dna-copy-number-and-epigenetic-age-measures/

Mitochondria are the power plants of the cell, a herd of bacteria-like organelles that produce the chemical energy store molecule ATP. They have their own DNA, a circular genome distinct from that of the cell nucleus, sometimes several copies per mitochondrion. The number of those mitochondrial DNA copies in a cell is a measure of mitochondrial health that declines with age, as mitochondria become dysfunctional throughout the body. The proximate causes of this dysfunction involve changes in mitochondrial structure and dynamics that inhibit the quality control process of mitophagy, responsible for recycling worn and damaged mitochondria. Connections to deeper causes are not well understood, but these issues must in some way result from the underlying damage of aging.

The DNA methylation (DNAm) based estimator of biological age, DNAm-Age, has become a well-known molecular measure of human aging. DNAm-Age has been associated with cancers, cardiovascular diseases, neurological diseases, and chronic inflammation diseases. Subsequently, another DNAm based marker, DNAm-PhenoAge, was developed to be an improved predictor of mortality and health span using phenotypic age estimated from a range of aging-related clinical measures. Most recently, another metric, DNAm-GrimAge, has been developed to predict all cause mortality and health span.

Unfortunately, the underlying biological and molecular processes that drive these epigenetic age biomarkers are still unknown. Despite the observation that the DNAm-Age is associated with metabolic processes, the relationship between mitochondrial health and DNAm-Age remains understudied. Mitochondria are vital for metabolic processes as they are responsible for ATP production and are known to be involved in the aging process, become larger and less numerous with age. In addition, mitochondrial function may be related to DNAm aging. Activity of DNA methyltransferases (DNMT), as with any cellular enzyme, depend on ATP levels and impaired energy production as a result of mitochondrial dysfunction may influence normal function of DNMTs.

Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genome abundance, is commonly used as a reflection of the mitochondria’s response to oxidative stress as well as general dysfunction. Mitochondria DNA (mtDNA) is sensitive to oxidative stress because it lacks a robust DNA repair system to restore oxidative stress induced damage and mtDNA damage persists longer compared to genomic DNA. Typically, mtDNA will increase when the endogenous antioxidant response is no longer able to recover its redox balance, possibly as a compensatory response. Previous studies have shown that mtDNAcn decreases with age and is positively associated with telomere length.

Recently, our group has shown that mtDNAcn is negatively correlated with DNAm-Age and hypothesized mtDNAcn may be a proxy of mitochondrial buffer capacity. Reduced mtDNAcn may be a consequence of exhausted mitochondrial buffering capacity, leading to adverse outcomes such as aging. In a population of 812 aging male veterans, we found contrasting results between cross-sectional and prospective analyses of mtDNAcn with aging biomarkers DNAm-Age, DNAm-PhenoAge, DNAm-GrimAge and leukocyte telomere length. We observed that mtDNAcn is negatively associated with cross-sectional measures of DNAm-Age and DNAm-PhenoAge. We found suggestive evidence that mtDNAcn is positively associated with prospective measures of DNAm-PhenoAge and negatively associated with prospective measures of leukocyte telomere length. These results suggest that while the negative cross-sectional associations reflect the opposing time-trends of mtDNAcn and aging biomarkers, it may be driven by unmeasured confounders such as underlying biological processes that drives both the decrease of mtDNAcn over time and the increase of DNAm-Age and DNAm-PhenoAge over time.

Evidence for PASK Deficiency to Reduce the Impact of Aging in Mice

https://www.fightaging.org/archives/2020/02/evidence-for-pask-deficiency-to-reduce-the-impact-of-aging-in-mice/

There are many ways to slow aging to a measurable degree in short-lived species such as mice, and the work noted here is a recently discovered example. Mice have evolved to have a sizable variability of life span in response to environmental circumstances, and thus the cellular machinery relating to various stress responses has an equally sizable influence on health and longevity. Since there are many ways to adjust the operation of that machinery, by increasing or decreasing levels of specific proteins, there are also many ways to slow aging. Few of them are going to be all that useful, unfortunately, as longer-lived species such as our own have a far less plastic life span. An increased operation of stress response mechanisms does not increase human life span by anywhere near as great a proportion as is the case in mice.

Several reports indicate that caloric restriction and intermittent periods of fasting may reduce the risk of complications associated with aging. Cells use nutrient sensing to identify and respond to differences in nutrient levels; the sensing mechanisms are dysregulated during the aging process. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) pathways are nutrient sensors that have been involved in lifespan. Additionally, PASK (a serine/threonine kinase that contains PAS domains) can sense intracellular oxygen, redox state, and various metabolites.

We have previously described how PASK is a critical regulator of AMPK and mTOR pathways in the hypothalamus and liver, as well as a key regulator of oxidative stress and glucose and lipid liver metabolism. PASK-deficient mice are protected against the development of obesity and insulin resistance induced by a high-fat diet (HFD). PASK has recently been described as a target of mTORC1 during regenerative myogenesis in muscle stem cells.

To investigate PASK’s role in hepatic oxidative stress during aging, we analyzed the mitochondrial function, glucose tolerance, insulin resistance, and lipid-related parameters in aged PASK-deficient mice. Hepatic Pask mRNA decreased in step with aging, being undetectable in aged wild-type (WT) mice. Aged PASK-deficient mice recorded lower levels of reactive oxygen species and reactive nitrogen species compared to aged WT. The regulators of mitochondrial biogenesis, PGC1a, SIRT1, and NRF2, decreased in aged WT, while aged PASK-deficient mice recorded a higher expression of NRF2, GCLm, and HO1 proteins and CS activity under fasted conditions. Additionally, aged PASK-deficient mice recorded an overexpression of the longevity gene FoxO3a, and maintained elevated PCNA protein, suggesting that hepatic cell repair mechanisms might be functional. PASK-deficient mice have better insulin sensitivity and no glucose intolerance. PASK may be a good target for reducing damage during aging.

The Aging Retina, a Mirror of the Aging Brain

https://www.fightaging.org/archives/2020/02/the-aging-retina-a-mirror-of-the-aging-brain/

Retinal degeneration is a feature of old age, and here researchers show that it correlates quite well with a loss of volume in portions of the visual cortex of the aging brain. These two portions of the nervous system are are connected and related, but it is unclear as to whether there is a direction of causation, or whether this is a case of similar structures being similarly affected by the same underlying mechanism of aging. Chronic inflammation, for example, operates throughout the body, and many aspects of aging are correlated because inflammation accelerates tissue dysfunction in a systemic, whole-body manner.

Age-related retinal diseases, such as late-stage macular degeneration have an impact on cortical morphology. For example, researchers found that the regions of the striate cortex that usually sample the visual input from the injured area of the retina were thinner in participants with macular disease when compared to controls. On the contrary, regions corresponding to non-damaged areas demonstrated a significant increase in cortical thickness. Overall, these findings suggest a strong retinocortical coupling of structural and functional changes in retinal disorders.

Healthy aging is characterized by diverse structural changes in both brain and retina, which association remains to be studied. Concerning the former, there is substantial evidence suggesting that widespread cortical shrinkage takes place with increasing aging. The nature of such effects in early visual areas remains controversial. Whereas some studies have shown volume loss or cortical thinning of visual cortices, others have reported a certain sparing of these areas during aging. Specifically to the primary visual cortex such discrepancy in the literature could be explained by methodological issues, since they demonstrated that different sub-regions of primary visual cortex were unequally affected by aging, depending on their retinotopic eccentricity. Nonetheless, studies directly examining the structure and function of primary visual areas are scarce in healthy aging, in spite of the fact that the organization of early visual areas is well documented in young adults.

The retina also undergoes substantial modifications throughout the lifespan. Histological studies have reported a reduction in the density of photoreceptors, ganglion cells, and pigment epithelial cells with age. Overall, retinal thickness studies using optical coherence tomography (OCT) imaging have revealed regional age-dependent differences in global macular integrity. The improvement of OCT image processing techniques has now allowed for the automatic segmentation of retinal individual layers, which provides a more detailed and specific perspective on such alterations.

we aimed to investigate the association of retinal layer and cortical integrity, in a healthy cohort aged between 20-80 years old. To that end, we performed magnetic resonance structural data imaging measurements of cortical thickness in the primary visual cortex – BA17, the cortical area that receives direct retinal input – and OCT to measure the thickness of the macula and their individual layers, in the same set of participants. We found an age-related decay of primary visual cortical thickness that was significantly correlated with a decrease in global and multiple layer retinal thicknesses. The atrophy of both structures might jointly account for the decline of various visual capacities that accompany the aging process. Furthermore, associations with other cortical regions suggest that retinal status may index cortical integrity in general.

Evidence for Loss of Capillary Density to be Important in Heart Disease

https://www.fightaging.org/archives/2020/02/evidence-for-loss-of-capillary-density-to-be-important-in-heart-disease/

Loss of capillary density, and thus flow of blood through tissues, is a known feature of aging, though the causes of this change in tissue maintenance are far from completely explored. It is proposed to be quite important in loss of tissue function, particularly in organs with high metabolic demands, such as muscle and the brain. Researchers here provide evidence to suggest that this loss of capillary density is a noteworthy mediating mechanism linking the age-related impairment of heart function with the presence of chronic kidney disease. The latter is already known to correlate with impaired capillary structure in the heart, and here data from patients shows that this is a factor in the progression to heart disease.

People with chronic kidney disease have a higher risk for heart disease and heart-disease death. Coronary microvascular dysfunction, or CMD, is decreased blood flow in the small blood vessels inside the heart muscle that provide oxygen and fuel to feed the pumping heart. A new study links kidney disease to progressive heart disease via this mechanism. In healthy hearts, visualized postmortem, these blood vessels look like a tight filigree network that fills the heart muscle tissue. A diseased postmortem heart has lost much of this network. In living patients, however, those small blood vessels inside the heart muscle cannot be visualized; blood flow scans of living patients visualize only the larger, exterior coronary arteries.

Thus researchers needed an indirect way to gauge CMD. That measure is coronary flow reserve, or CFR, assessed via positron emission tomography. CFR is the maximum increase in blood flow through the coronary arteries above the normal resting volume. In a longitudinal study of 352 patients with chronic kidney disease, all with healthy heart function as measured by ejection fraction and none with signs of overt coronary artery disease, the researchers measured CFR and also measured signs of subclinical heart dysfunction. The patients were then followed a median of 4.4 years for major adverse cardiac events. A total of 108 patients had such major events, including death and hospitalization for non-fatal heart attack or heart failure.

The researchers found that CMD was a significant predictor of abnormal mechanics of the left ventricle – the heart’s major pumping chamber – and a significant predictor of clinical risk of adverse cardiovascular outcomes. A statistical model called mediation analysis examined the relationship between impaired kidney function and heart disease. It showed that CMD accounted for 19 to 24 percent of left ventricle diastolic dysfunction, 19 to 42 percent of left ventricle systolic dysfunction and 32 percent of major adverse cardiovascular events. This evidence suggests that the development of severe microvascular dysfunction likely signals the transition from physiological to pathological left ventricle remodeling that increases the risk of heart failure and death in patients with chronic kidney disease.

Aspects of Immune System Aging Proceed More Rapidly in Men

https://www.fightaging.org/archives/2020/02/aspects-of-immune-system-aging-proceed-more-rapidly-in-men/

Men do not live as long as women. This is a consistent effect across populations and eras, and there are any number of theories as to why this is the case. This might lead us to expect measurable aspects of aging to be more pronounced in older males than in older females, and researchers here show that this is the case for the age-related dysfunction of the immune system. As we age, the immune system becomes both overactive and less capable, leading to chronic inflammation alongside decreased resistance to infection and cancer. This is an important contribution to age-related frailty, disease, and mortality.

Human peripheral blood mononuclear cells (PBMCs) undergo both cell-intrinsic and cell-compositional changes (i.e., cell frequencies) with age, where certain immune functions are impaired and others are remodeled1. Analyses of human blood samples uncovered significant aging-related changes in gene expression and DNA methylation levels. Recent studies revealed that chromatin accessibility of purified immune cells, especially CD8+ T cells, change significantly with aging, impacting the activity of important receptor molecules, signaling pathways, and transcription factors. Together, these changes likely contribute to aging-related immunodeficiency and ultimately to increased frequency of morbidity and mortality among older adults. However, it is unclear to what extent these aging-associated changes are shared between men and women.

Immune systems of men and women function and respond to infections and vaccination differently. For example, 80% of autoimmune diseases occur in women, who typically show stronger immune responses than males. Stronger responses in women produce faster pathogen clearance and better vaccine responsiveness, but also contribute to increased susceptibility to inflammatory and autoimmune diseases. Although not systematically described, these differences likely stem from differences in both cell frequencies and cell-intrinsic programs. For example, a study in young individuals showed that women have more B cells (percentage and absolute cell counts) in their blood than men. Moreover, hundreds of genes are differentially expressed between young men and young women in sorted B cells.

Despite the importance of sex and age in shaping immune cell functions and responses, it is not known whether men’s and women’s immune systems go through similar changes throughout their lifespan, and whether these changes occur at the same time and at the same rate. To study this, we profiled PBMCs of healthy adults by carefully matching the ages of male and female donors. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity.

Deacetylation of the NLRP3 Inflammasome as a Way to Control Chronic Inflammation

https://www.fightaging.org/archives/2020/02/deacetylation-of-the-nlrp3-inflammasome-as-a-way-to-control-chronic-inflammation/

Chronic inflammation is an important component of degenerative aging. Excessive inflammatory signaling and activation of the immune system arises due to a combination of many factors, of which some are more important than others, such as the presence of lingering senescent cells. Most of the research focused on controlling inflammation is more interested in sabotaging the mechanisms of control than in removing root causes, however. The work here is an example of the type, in which scientists identify an important feature of the regulatory system controlling inflammation. Forcing a sizable reduction of inflammation via this regulatory system is a fairly blunt tool, as some degree of transient inflammation is vital to health, such as in the response to infection or injury. Nonetheless, the benefits may be large enough to outweigh the side-effects, as is the case for a number of past approaches to limiting inflammation in, for example, the treatment of autoimmune conditions.

Chronic inflammation, which results when old age, stress, or environmental toxins keep the body’s immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer’s and Parkinson’s to diabetes and cancer. Researchers now show that a bulky collection of immune proteins called the NLRP3 inflammasome – responsible for sensing potential threats to the body and launching an inflammation response – can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation. Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes, and dementia. The results suggest that drugs targeted toward deacetylating, or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration in general.

By studying mice and immune cells called macrophages, the team found that a protein called SIRT2 is responsible for deacetylating the NLRP3 inflammasome. Mice that were bred with a genetic mutation that prevented them from producing SIRT2 showed more signs of inflammation at the ripe old age of two than their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome. The team also studied older mice whose immune systems had been destroyed with radiation and then reconstituted with blood stem cells that produced either the deacetylated or the acetylated version of the NLRP3 inflammasome. Those who were given the deacetylated, or “off,” version of the inflammasome had improved insulin resistance after six weeks, indicating that switching off this immune machinery might actually reverse the course of metabolic disease.

“We are asking to what extent can aging be reversed. And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases. I think this finding has very important implications in treating major human chronic diseases. It’s also a timely question to ask, because in the past year, many promising Alzheimer’s disease trials ended in failure. One possible explanation is that treatment starts too late, and it has gone to the point of no return. So, I think it’s more urgent than ever to understand the reversibility of aging-related conditions and use that knowledge to aid a drug development for aging-related diseases.”

Transplantation of Senescent Cells is an Issue in First Generation Stem Cell Therapies

https://www.fightaging.org/archives/2020/02/transplantation-of-senescent-cells-is-an-issue-in-first-generation-stem-cell-therapies/

Researchers here demonstrate that comparatively simple regenerative cell therapies, of the sort presently widely used, in which stem cells are derived from adipose tissue, will tend to introduce senescent cells into the recipient in the case of older donors. Senescent cells are constantly created and destroyed in the body, but the processes of clearance decline with age, and these cells are harmful when they linger for the long term: their secreted signals cause chronic inflammation, while also contributing to tissue dysfunction in a number of other ways. The presence of senescent cells in older individuals is one of the contributing causes of degenerative aging, and adding more such cells is something to be avoided.

Adipose-derived mesenchymal stem cells (ADSCs) or “preadipocytes” have been increasingly suggested for use in regenerative medicine as a treatment for a wide range of diseases due to their multipotency and accessibility. Older adults represent most likely recipients of ADSC therapies given the high burden of diseases in this population. Since autologous ADSCs are preferred in the clinic, it is essential to understand age-related changes influencing these cells. Emerging evidence suggests that ADSCs from aged donors have reduced regenerative potential, leading to diminished therapeutic efficacy. However, it is unknown whether transplanting ADSCs from aged donors might cause unexpected or even harmful effects in recipients. This is especially important for older adults, since they tend to be more vulnerable and less resilient to such stresses.

To examine this, we isolated ADSCs from 12 young (6-7 months, referred to as young ADSCs) and 12 old (28-31 months, referred to as old ADSCs) C57BL/6 male mice. We transplanted ADSCs from young or old donors into syngeneic 20-month-old C57BL/6 male mice. Four to six weeks after transplantation, we tested maximal walking speed, grip strength, physical endurance, daily activity, food intake, and body weight change to assess overall physical function in recipients, based on criteria used in clinical practice. ADSCs from old donors significantly impaired walking speed, grip strength, endurance, and daily activity of older recipient mice after transplantation, compared with mice transplanted with the same number of ADSCs from young donors.

Using single-cell transcriptomic analysis, we identified a naturally occurring senescent cell-like population in ADSCs primarily from old donors that resembles in vitro-generated senescent cells with regard to a number of key pathways. Overall, these findings suggest that ADSCs from old donors can induce physical frailty, which is highly associated with morbidity and loss of independence. Our study potentially begins new avenues of research to discover whether pharmacological interventions, such as senolytic drugs or anti-inflammatory drugs, can prevent or reverse dysfunction caused by transplanting ADSCs or even organs from old donors and improve clinical outcomes of transplantation for older patients.

Transplantation of Young Bone Marrow into Old Mice Produces Systemic Benefits

https://www.fightaging.org/archives/2020/02/transplantation-of-young-bone-marrow-into-old-mice-produces-systemic-benefits/

Researchers here report that transplanting bone marrow from young donor mice into old recipient mice produces a range of benefits, such as improvement in the behavior of macrophage cells. Bone marrow stem cells are responsible for producing blood and immune cells, among other important populations, and this capability is degraded in a number of ways with age. Introducing younger stem cells and their supporting structures is a plausible means to at least partially reverse this process. That said, this sort of approach is unlikely to arrive in human medicine in exactly the same form, given the challenges involved in bone marrow transplantation. It is not a procedure one would want to undergo unless there were no other options, and deploying it widely as a preventative therapy doesn’t seem feasible in the present environment. The more likely outcome is for researchers to continue to work in mice so as to better identify specific mechanisms involved in bone marrow aging, those that might be manipulated with small molecule drugs, gene therapies, and the like.

The bone marrow is an important reservoir of stem cells and progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immunosenescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury. The bone marrow is also an important source of endothelial progenitor cells (EPCs) which participate in the generation and repair of vasculature endothelium; aging leads to a decline in circulating EPC number and function.

Different strategies have been proposed to rejuvenate the aged bone marrow such as pharmacological treatments, gene therapy, and dietary interventions. However, most approaches have focused on the effect of rejuvenation on HSC differentiation and EPC colony formation rather than effects on peripheral tissues. Therefore, we hypothesized that reconstituting aged mice with young bone marrow leads to stable engraftment of young cells in aged mice and rejuvenates tissue repair responses.

We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction. Aged mice were reconstituted with young Sca-1+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells, increases epicardial derived cell migration/activation, and enhances the acute inflammatory response that follows myocardial infarction in aged mice.

Beyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia. Within the retina these cells secrete cytoprotective factors such as fibroblast growth factor-2 and insulin-like growth factor-1 which limit cell death following ischemia/reperfusion injury. More recently, we also demonstrated that bone marrow rejuvenation leads to the introduction of young bone marrow-derived microglia in the brain and that these cells act to improve learning and memory responses compared with mice receiving old bone marrow. Mechanistically, young bone marrow-derived microglia adopt a neutral or anti-inflammatory phenotype while old bone marrow-derived microglia adopt a pro-inflammatory phenotype. These results are consistent with studies which have linked increased neuroinflammation to a decline in cognitive function.

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