Fight Aging! Newsletter, October 24th 2022

Fight Aging! Newsletter
October 24th 2022

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, please visit: https://www.fightaging.org/newsletter/

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Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

An Update on Senolytics Company Cleara Biotech Testing Narrow Epigenetic Clocks in Centenarians Notes from the Rejuvenation Startup Summit, Held in Berlin in October 2022 A View of the Road Ahead to Viable Xenotransplantation There is Such a Thing as Too Much of a Focus on Low-Hanging Fruit in the Longevity Industry SIRT3 Knockout Increases Life Extension Resulting from Calorie Restriction HDL Level, Age, and Smoking are the Largest Determinants of Mortality Risk in Old People The Future of Treating Aging Will Rejuvenation Therapies Be Useful for Progeria Patients? Amyloid-β Binding Exosomes in Blood Samples as a Biomarker of Alzheimer's Disease SFRP4 Knockdown Suppresses the Senescence-Associated Secretory Phenotype in Senescent Skin Cells Cognitive Impairment Indicative of Later Dementia can be Detected Early LXA4 Levels in the Brain Decrease With Age, Perhaps Increasing Inflammation and Accelerating Neurodegeneration Senescent Cells in Muscle Tissue Harm Muscle Stem Cell Function RNA Splicing Dysfunction in Alzheimer's Disease

An Update on Senolytics Company Cleara Biotech
https://www.fightaging.org/archives/2022/10/an-update-on-senolytics-company-cleara-biotech/

Senescent cells accumulate with age, and that accumulation is responsible for a meaningful fraction of degenerative aging. Many groups are working on ways to remove these cells and thereby reverse aspects of aging. Among their number, Cleara Biotech was founded four years ago on to advance initially promising work on the FOXO4-p53 interaction in cellular senescence, a possible targeted way to destroy senescent cells. This approach will join the numerous other mechanisms already being exploited as the basis for potential rejuvenation therapies.

A couple of companies have been looking into FOXO4 biochemistry in the context of cellular senescence, with very little new information emerging in recent years. Four years isn't that long in the biotech field, in which every aspect of development is challenging, but silence suggests that making something of the early FOXO4-related research has proved to be harder than expected.

Still, the Cleara principals appear confident enough in their present approach to be gearing up to prepare for clinical development. Certainly, there will be room for many different approaches and specializations in the clearance of senescent cells; it is coming to be a crowded field of many biotech startups and other entities pursing a diverse set of approaches and development programs.

Cleara Biotech Raises 2.5 Million in Seed Financing to Advance FOXO4-Therapeutics Pipeline for Treating Cancer and Chronic Diseases

Cleara Biotech B.V., a preclinical-stage biotechnology company focused on developing innovative, proprietary therapies for treating different pathologies of "scarred cellular" senescence, including late-stage cancer and chronic diseases, today announced that it closed a 2.5 million seed financing round earlier in the year, led by Apollo Health Ventures, with participation from Curie Capital B.V., ROM Utrecht Region, and Longevity Tech Fund. Cleara has optimized two lead developmental candidates, CL04177 and CL04183, that can eliminate scarred cancer cells found in several late-stage cancers and chronic diseases in humans. The company is aiming to develop precision medicine tools that treat specific diseases with clear niche-directed, anti-senescent lead candidates, accompanied with associated biomarkers, around its FOXO4-based D-amino acid peptides and pipeline against subtypes of senescence. Designed and optimized based on an extensive (3D) structural, molecular and cellular understanding of cell scarring's mechanism of action and how FOXO4 restrains this particular form of the cell guardian p53, both lead compounds potently counter viability of scarred cancer cells in 2D culture and 3D organoids, as well as strongly reduce the metastatic burden and infiltration in mouse in vivo models for metastatic colon cancer and triple-negative breast cancer. Furthermore, they show favorable pharmacokinetics and tissue distribution in mice, with an maximum tolerable dose that is well above their efficacious dose.

Testing Narrow Epigenetic Clocks in Centenarians
https://www.fightaging.org/archives/2022/10/testing-narrow-epigenetic-clocks-in-centenarians/

Many different epigenetic clocks have been proposed and tested in recent years, all using different weighted combinations of DNA methylation status at various CpG sites on the genome, some using fewer than ten sites, others using hundreds of sites. DNA methylation is in constant flux, regulating gene expression in cells, but some changes are characteristic of age, and machine learning approaches have produced clocks with strong correlations to chronological age. Where clock age is higher than chronological age, individuals have been shown to have greater incidence and risk of age-related disease and mortality.

Researchers still, however, do not have more than the rudimentary beginnings of a map to link methylation at specific CpG sites to the underlying damage and dysfunction of aging. Thus it is hard to treat epigenetic clock data as actionable for any given individual and their treatments. The clocks are quite good good for unmodified aging, but what we really want is a way to cost-effectively, rapidly assess the outcome of potential rejuvenation therapies, each of which will tend to only directly affect one of the many mechanisms of aging, without undertaking the time and expense of life span studies.

Given this, it is hard to trust narrow epigenetic clocks that use few CpG sites. They seem very unlikely to accurately reflect all of the processes of aging, and thus even trying to calibrate them against specific therapies seems likely to produce poor results. Nonetheless, since such narrow clocks are cheaper than broad clocks using hundreds of CpG sites, many research groups are working in this direction.

Centenarians consistently present a younger epigenetic age than their chronological age with four epigenetic clocks based on a small number of CpG sites

The study of DNA methylation in human aging has revealed the occurrence of two types of age-related DNA methylation changes. The first, known as epigenetic drift, is characterized by the progressive divergence of the methylome of individuals acquired environmentally and stochastically across their lifespan, which even affects monozygotic twins. The second type of DNA methylation changes is called the epigenetic clock and refers to all age-related DNA methylation variations that consistently increase or decrease in every individual, thereby correlating to their chronological age. The latter type of epigenetic modifications has been widely used as biomarkers of aging in several age-prediction models to estimate the chronological and biological age of individuals, mainly from blood DNA samples. These models are based on multiple regression, machine learning, and deep learning approaches using either a large number of CpGs requiring high-throughput technologies such as genome-wide epigenotyping array or a smaller number of CpGs requiring high resolution locus-specific methods such as pyrosequencing. DNA methylation-based age (DNAmage) prediction has proven to be of great interest in several bio-medical applications. It could notably give a better estimation of the biological age than chronological age and could also be a good indicator or predicator of different risks, health conditions and age-related diseases when compared to the chronological age. In the present study, we investigated the DNAmage of French long-lived individuals (LLI) including centenarians and semi-supercentenarians (n = 214), as well as nonagenarian's and centenarian's offspring (n = 143) of the CEPH aging cohort using blood extracted DNA and four epigenetic clocks based on a small number of CpGs and locus-specific pyrosequencing. These clocks, known as Bekaert, Thong, Garali MQR and Garali GBR clocks, were developed from 2 to 4 CpGs located in the promoters of 1 to 4 genes (ASPA, EDARADD, ELOVL2, KLF14, PDE4C, and TRIM59). Compared to their chronological age, DNAmage of centenarians and semi-supercentenarians was strongly underestimated (15 to 28.5 years in average), which was still strongly significantly underestimated when compared to control group DNAmage (10.8 to 21 years in average). This might indicate that the epigenetic clock and potentially aging were decelerated in exceptionally long-lived individuals, who presented younger DNAmage and potentially also younger biological age.

Notes from the Rejuvenation Startup Summit, Held in Berlin in October 2022
https://www.fightaging.org/archives/2022/10/notes-from-the-rejuvenation-startup-summit-held-in-berlin-in-october-2022/

A fair number of longevity industry and related companies presented this past weekend in Berlin, at the Rejuvenation Startup Summit hosted by the Forever Healthy Foundation. Unlike the past Undoing Aging events, this is much more focused on the industry rather than on scientific programs, but there was nonetheless a great deal of science on display. I took a few notes in between other activities, for posterity. As Michael Greve noted in his introduction to the participants, these are the early years of what will become the largest industry on the planet. Everyone ages, and everyone is a customer for the rejuvenation therapies and related technologies that lie just around the corner.

Eric Verdin of the Buck Institute gave the opening keynote, discussing recent work on biomarkers of aging, and specifically the most promising line of epigenetic clocks based on assessment of DNA methylation status. Given ways to reliably extend life in mice (e.g. rapamycin and senolytics), we now need a way to measure that outcome that doesn't involve waiting around for the results of a life span study. The point made in this presentation was that different immune cell populations exhibit sizable differences in assessed epigenetic age, which probably means that all clock data based on blood samples is suspect. The Buck Institute researchers have found differences of as much as ~20 years in epigenetic age between immune cell types, as well as differences based on infection and inflammation status, so clearly more care needs to be taken here. In an attempt to address this issue, the team built a new clock that is invariant across immune cell subpopulations. We will no doubt be hearing more about this as it progresses, given the prevalence of work that uses epigenetic age derived from blood samples.

Lou Hawthorne of Nanotics gave an outline of their technology platform, a way to produce particles that bind specific molecules in the blood stream in a controllable way, depleting them for minutes to hours. Heterochronic parabiosis research has led to evidence for harmful factors to circulate in the aged bloodstream, maintaining inflammation and dysfunction, which naturally leads to the desire to remove these factors in a targeted way. Nanotics is particularly focused on pro-inflammatory factors, and their view of aging is inflammation-centric. Thus the cytokine storm of sepsis is not a bad starting place to test this sort of therapy in the clinic. The Nanotics platform allows the targeting of signal processes that are inaccessible to small molecule therapeutics, so offers ways to potentially dial down inflammatory signaling without also blocking necessary immune functions.

Alexander Schueller of cellvie discussed their view of the mitochondrial dysfunction observed in aging, and the relevance of mitochondrial damage caused by ischemia to the cell death and dysfunction following ischemic injury. The cellvie approach is to deliver replacement mitochondria to be taken up by cells in need. Like the other companies working on this approach, they are near entirely focused on the logistics and process development needed for this goal. Their intent to is to generate allogeneic mitochondria, harvested from standard cell lines. Once ready, cellvie is looking at sarcopenia as a first indication for clinical development, based on promising animal data.

Vlad Vitoc of Maia Biotechnology gave an impressive overview of their progress towards a near-universal cancer therapy. They develop therapies based delivery of THIO, a compound that is metabolised and utilized by telomerase, and then incorporated into telomeres to produce cell death. Since near all cancer cells aggressively utilize telomerase, these are the cells that die when THIO is introduced. The company has orphan drug designations for a variety of cancers, and are well advanced in the path to clinical trials. A first phase 1 is running now, with further trials coming up in next few years, including one phase 2 just starting in Australia. These trials are conducted in partnership with Regeneron, and they put THIO into patients in conjunction with a Regeneron-developed checkpoint inhibitor therapy. The company went public recently, and they are using the sizable funding they have raised to date in order to build new and more efficient versions of THIO. We should expect the important questions regarding telomerase as a target to be answered in the years ahead, now that it is an ongoing project, such as how to manage the effects of telomerase-targeted therapeutics on stem cell function, and what those effects are in practice.

Chris Rinsch of Amazentis talked about the use of urolithin A as supplement-based approach to improving mitochondrial function in aged individuals. Their initial aim is to look at muscle function in aging, attempting to produce modest improvements via this approach. They hold the consensus view that urolithin A works by improving both mitophagy and mitochondrial biosynthesis, though as for many such compounds exactly how it achieves this outcome is far from settled.

Unfortunately, I had to miss the presentation by Alex Blyth of LifT Biosciences. This company pursues an interesting approach to cancer via transplantation of donor leukocytes; you might recall the original work on granulocyte transfer presented at SENS meetings back in the day. The original research showed great promise, and the company has been doing well these past few years, judging from the public updates.

Dobri Kiprov of Lyfspn presented on the merits of therapeutic plasma exchange. He presented a range of human data from patients in past years, including a reduction of epigenetic age via this approach, as well as immune improvements, improvement in joint issues, and improved liver and kidney function. Their view is that the most important aspect of this removal of bad factors is that it modulates the immune system, reducing the state of inflammaging and consequent harm and dysfunction. But the data they have is not rigorous, it results from clinical practice, and thus they founded this company to generate high quality data via clinical trials. They acknowledge that these are still the early days for therapeutic plasma exchange, and they still lack firm, defensible answers to even simple questions such as how long the benefits last from one treatment.

Pankaj Kapahi of Juvify discussed the science supporting this supplement company spinout from the Buck Institute. Their product is a modulator of glycation, acting to reducing the impact of sugar consumption and obesity on long-term health. Their hypothesis is that the generation of advanced glycation endproducts (AGEs) is the major problem that is produced by sugar metabolism. They work with compounds that target one type of shorter-lived AGE, methylglycoxal AGEs. Thus benefits may be a matter of reducing inflammatory signaling caused by AGEs via the RAGE pathway, but they think that RAGE is not the only mechanism of interest here. Interestingly, these compounds suppress appetite, so somehow short-lived AGEs are acting as appetite enhancers. Ongoing studies in mice also indicate that this interference in short-lived AGEs, conducted over the long term, decreases growth hormone signaling and reduces the burden of cellular senescence, among other benefits. Since appetite is reduced, is it possible that the benefits are all simply benefits of calorie restriction? They think that this is a factor, but only part of story.

Yuri Deigin of Youth Bio presented on partial reprogramming, a huge potential market, based on evidence from animal studies showing rejuvenation in many different tissues. Certainly, investors believe it will be huge, judging by the vast financial support for this part of the industry, dwarfing investment elsewhere. Youth Bio are an early stage preclinical company, at the point of having completed mouse studies showing reversal of measures of aging. They are working on a few different projects in parallel. Firstly they are attempting to produce new reprogramming approaches with novel factors and tissue-specificity. They avoid the liver and intestine for safety reasons, as mice tend to die when these are repeatedly reprogrammed. Secondly, they are working towards viable therapies based on use of the existing OSKM factors. Alzheimer's disease is their first indication on this side of the house, and they propose the use of a one-time gene therapy that introduces inducible genes, followed by delivery of small molecules for periodic activation of those genes.

Silke Hüttner of Rejuvenate Biomed outlined their approach to combinatorial therapies using small molecules identified through screening and later optimization. They are, unfortunately, cagey about the details of their compounds, but their present lead therapeutic candidate is a combination of two compounds that they have developed, which positively affects inflammation and other properties relevant to aging. The company is initially focused on sarcopenia, but they want to move on from there to other age-related conditions and then aging itself as a target. The company has produced successful studies in both progeroid mice and naturally aged mice, with early human trials ongoing.

Mourad Topors presented as the CSO of Repair Biotechnologies, the company that I co-founded with Bill Cherman. We develop a means of safely breaking down excess intracellular free cholesterol, delivered as a gene therapy to arbitrary cells in the body, or as a cell therapy of engineered cells equipped with this capability. We work towards reversal of atherosclerosis, the primary cause of human mortality, resulting at root from the presence of excessive cholesterol deposits in arterial walls. We are finding a faster path to the clinic in treatment of nonalcoholic steatohepatitis (NASH), however, largely because the delivery systems for liver-targeted gene therapies are far more developed. We presented recent results showing reversal of liver inflammation and fibrosis in NASH model mice, and noted that we're raising funds to start our clinical development program leading to human trials. Therapies to reverse atherosclerosis progression will follow shortly on the heels of this work on NASH.

Robin Mansukhani of Deciduous Therapeutics discussed their approach to immune system modulation via small molecules, training invariant natural killer cells to attack senescent cells. The point was made that engaging the immune system may be a way to work around many of the present unknowns regarding senescent cell status, biomarkers, and subtypes. Interestingly, a one-time treatment via their approach rouses immune cells for at least months thereafter, consistently clearing senescent cells over that time.

Mike Kope of Cyclarity presented on their approach. Cyclarity is the renamed Underdog Pharmaceuticals, a spinout from the SENS Research Foundation that employs engineered cyclodextrins to bind 7-ketocholesterol. This is essentially a test of the degree to which 7-ketocholesterol is a meaningful cause of pathology in human atherosclerosis and other conditions. They have great cell data, showing that they can reverse the foam cell state that arises from 7-ketocholesterol exposure, and they also test in human plaques obtained from cadavers and surgical procedures. Despite a lack of animal models for 7-ketocholesterol presence in atherosclerotic disease, Clarity has engineered a fast path to the clinic, based on the safety profile of cyclodextrins as a class. They will begin their first clinical trials next year.

Cristiana Banila of Mitra Bio discussed the need for better ways to measure skin aging. They have developed a way to measure epigenetic age in skin non-invasively, with no biopsy. They obtain cells from the skin surface via adhesive tape and have shown that this produces the same results as are obtained using biopsies. The company uses this approach to assess methods that are alleged to reverse skin aging, and presented data for an example treatment that can in fact reverse epigenetic age in UV-damaged skin. They plan to test many more of the established and potential skin-focused interventions that exist, to generate personalized recommendations for patients.

Brian Kennedy talked about his scientific work at the National University of Singapore. This spans a range of preclinical studies, including efforts to produce treatments based on the hallmarks of aging and work on biomarkers and epigenetic clocks. They tend to run 6-9 month interventions in mice, starting at 18 months of age, and assessing frailty and biomarkers of aging rather than using life span as a measure of success. Similarly, they run human studies, presently small ones, and again 6-9 months of intervention in healthy older people, while assessing biomarkers. The researchers are focused on the standard panoply of well-known small molecule geroprotectors, such as rapamycin, largely calorie restriction mimetics. In nematode worms, the development of automation now allows this research group to run studies of combinations of such compounds, tens of thousands of these studies every year; this capacity has led to a new company that intends to ramp up to millions of studies or more per year. One of the more interesting conclusions from the work carried out to date is that combinations produce unexpected results. The individual outcome of two small molecules is no guide as whether the combination will be better, worse, or indifferent. Any and all polypharmacy, or even combination of supplements, is a walk in the dark.

Chris Shepard of Thymofox gave an overview of the importance of thymic involution to the aging of the immune function. The insight leading to the creation of this company is that a young thymus regenerates from injury, but this capacity is much reduced in adults, and further so with aging. They are looking for the regulators of this decline, upstream of FOXN1. They aim to produce small molecules to indirectly upregulate FOXN1 expression in the thymus, searching via a high-throughput screen they they designed. They believe that along the way so far they have discovered some genetic regulators of FOXN1 level that may be useful in other ways, but details on their progress to date are light.

Mark Allen of Elevian gave his outline on their work on GDF11, one of the first candidate factors for the effects of parabiosis, back when it was though that the effects of parabiosis might be mediated by beneficial factors in young blood, rather than a dilution of harmful factors in old blood. This line of research has been underway for a while now, and they are narrowed down to applications in stroke recovery as the first clinical indication. Their evidence in mice shows recombinant GDF11 to promote vascular regeneration, activate various stem cell and progenitor cell populations, suppress inflammatory to some degree, and improves metabolism. They think that indications could be addressed via GDF11 therapies, and the first clinical trial for stroke recovery will begin in 2023. Further, they have identified an regulatory responsible for the age-related downregulation of GDF11 expression, and are working towards an antibody therapy as an alternative to delivery of recombinant GDF11.

Matthias Breugelmans of Elastrin Therapeutics discussed the regeneration of damaged elastin fibers in the extracellular matrix to restore elasticity in aged tissues. The company employs an albumin nanoparticle decorated with antibodies that bind to damaged elastin to deliver their therapy in a very targeted way. The nanoparticle contains EDTA and a proprietary PGG compound. In their eyes, damaged elastin in blood vessels and other tissues produces a local inflammatory response which in turn provokes calcification and other woes. They are targeting a variety of indications, including vascular calcification, aneurysm, hypertension, and a few rare orphan conditions. The company has obtained large reductions of vascular calcification in animal models, and a first phase 1 trial starts in 2023. Beyond the nanoparticle approach, they are working with delivery of mRNA encoding tropoelastin in order to stimulate the production of new elastin, but this is quite new, and earlier in development.

Matthew Rosen of CoRegen outlined a regulatory T-cell (Treg) based approach to defeating many different types of cancer. This is a spin out from Baylor College of Medicine, and uses the college infrastructure. One of the ways in which solid tumors subvert the immune system is to co-opt Treg cells, which then prevent other immune cells from attacking the cancer. Researchers have seen that gene knockdown of SRC-3 in Tregs will stop this from happening, however, and the CoRegen therapy is based on this finding. SRC-3 controls a lot of other genes, including checkpoint inhibitors, and it is thus fair to say it is a master regulator of immune capabilities against cancer. The company engineers Tregs by knocking out SRC-3, and then injects those cells, either systemically or into a tumor. This appears to provide lasting benefits in terms of resistance to cancer, and complete remission of existing cancer in mice: a small number of engineered Tregs outweighs the effects of native Tregs. The company is aiming at a first phase 1 in 2023.

Peter Fedichev of Gero presented on the company's use of AI and animal models to characterize the split of degenerative aging into two quite different processes, which they term (a) damage (or frailty) and (b) loss of resilience. These are two quite different things, and the balance between these portions of aging is different in mice and humans. Humans are more resilient, meaning a greater resistance to perturbations to equilibrium in later life. In the Gero view, the hallmarks of aging are all linked, and a drug working on any one will have effects on all. They predict that most small molecules that slow aging in mice will have little effect on aging in healthy humans, because humans are already resilient in ways that mice are not. The company is running drug discovery programs based on this philosophy, and beginning to collaborate with big pharma entities.

Aaron Cravens of Revel Pharmaceuticals presented the company as developing a platform to produce enzyme therapies generally, at a fraction of the cost and time of past efforts. High throughput enzyme engineering, in essence. They use computational modelling of enzyme libraries to suggest new variants and desired properties, then validate in vitro. You will recall that they launched to work on enzymes to break glucosepane, CML, and other cross-links involved in aging, and that remains the initial application of their platform. This is an early stage effort, and they have not yet tested candidate molecules in animals. They intend to raise a series A next year.

Hans S. Keirstead outlined work under way at Immunis, one of the more advanced of the companies presenting at the event. They harvest the secretome of carefully tailored progenitor cell lines, and package those molecules as a therapeutic product. The result contains factors that can modulate the immune system, as well as provide other useful effects on cell behavior. This program is fairly advanced in its progression through the IND process with the FDA. They have demonstrated in IND-enabling studies that delivery of this secretome as a therapeutic helps with sarcopenia and fibrosis, reduces inflammation and arterial stiffness, and improves adaptive immunity. A phase 2 human trial for muscle atrophy is starting up now.

Robert Cargill of Glionics presented work on the use of engineered microglia to deliver therapeutic molecules throughout the brain. It is otherwise hard to get many types of compound into the brain, with good biodistribution, because of the blood-brain barrier. But microglia will naturally spread throughout the brain, provided that native microglia are cleared via some form of CSF1R inhibitor. The company is starting with klotho as the therapeutic molecule of choice. They have demonstrated repopulation following clearance in mice. Just a few thousand microglia will replicate and move throughout the brain, delivering a factor as they go, BDNF in that case. The intent is to generate therapeutic microglia from universal iPSC lines, a popular choice in research and development at the moment.

Rob Konrad Maciejewski of Biolytica outlined a vision for data-driven approach to personalized medicine and lifestyle changes. This is a software company; they build a visualization product for complex health data in order to help patients understand tests, make choices, aim towards goals, and navigate the sizable amount of data that can be obtained these. Then on top of that add recommendations for lifestyle and supplement choices, and managing relationships with doctors and providers. The initial aim is to help people who could in principle make sizable gains in long-term health via lifestyle changes to make use of the present medical assay environment in order to achieve those gains.

Joshua McClure of Maxwell Biosciences presented on their drug discovery platform, based on producing variations on an antimicrobial peptide that is effective against pathogens of many types, including fungi, bacteria, and viruses. The story started with examination of blood plasma from young and old mice, finding a heat shock protein LL-37, a protein that is also an antimicrobial peptide that (a) seems to have broadly beneficial effects on many systems and (b) is downregulated with age. It attacks many targets from cancers to pathogens, acting via membrane disruption. Unfortunately it can't be used as a drug, as is rapidly cleared from circulation, so instead the company makes similar peptides that have the same function while also being stable. This can be, in principle, a replacement for existing antibiotics and antivirals, with additional beneficial effects to health via heat shock protein mechanisms. The company is quite well advanced in their preclinical program, and intends to raise sizable amounts for clinical development in the coming year.

Sophie Chabloz presented on Avea, a standard issue modern dietary supplement company. They presently offer formulations incorporating nicotinamide mononucleotide and the like, aiming to produce NAD+ upregulation.

Felix Frueh of PAGE Therapeutics discussed the value of targeting metastasis in cancer therapy. Prevention of metastasis would make solid tumors far less dangerous, in any cancer. The company pursues an interesting mechanism: cancers produce circulating tumor cells, but only clusters of these circulating cells actually produce metastasis, not single cells. So why not dissolve the clusters? They found an existing drug that achieves this outcome and blocks metastasis in mice. This can then be combined with other cancer therapeutics. A trial in breast cancer patients is ongoing as a proof of concept. Despite all of this backstory from academia, they are actually in quite an early stage as a company, working to produce novel small molecule drugs targeting this cancer cell clustering mechanism via screening.

Jürgen Reeß of the very early stage company Mogling Bio introduced their work aimed at restoration of immune function in older individuals. They wish to use derivatives of CASIN to inhibit CDC42, shown in academic work to rejuvenate the immune system with a single treatment. CASIN appears to improve function in stem cell populations generally, but in the case of hematopoietic stem cells this leads to an improved, more youthful production of immune cells. The company is just getting starting, based on promising mouse data, and will target the obvious indications relating to age-related immune dysfunction.

All told, it was quite an interesting selection of ongoing work. The cancer side of the house in particular is looking very promising these days, with numerous quite general approaches under development that should be both effective and applicable to many different types of cancer.

A View of the Road Ahead to Viable Xenotransplantation
https://www.fightaging.org/archives/2022/10/a-view-of-the-road-ahead-to-viable-xenotransplantation/

In principle, engineering pig organs to survive in humans is a viable project for this age of biotechnology. Pig organs are the right size, and strategies exist to address the known issues in rejection of tissues, transfer of retroviruses, and the like. An entire industry is coming into being based on enabling cells and tissues from one individual to be introduced into another without rejection. Much of the work needed to make that possible between individuals of the same species also enables transplantation between species.

In a world in which organs fail, and transplants are in limited supply, there are several roads ahead towards providing an unlimited, on-demand supply of replacements. Xenotransplantation is one of them, farming engineering pigs for their organs. Secondly, there is decellularization, taking a donor organ and stripping it of cells, leaving the extracellular matrix and all of its chemical cues, before introducing the recipient's cells to repopulate the empty organ. Further, researchers are working to be able to build organs from scratch, from a cell sample. This is a challenging process in which the major hurdle remains the establishment of complex small-scale capillary networks. Lastly, there is the longer-term prospect of entirely artificial, machine organs, a field that receives less attention and seems likely to fall behind given advances in biotechnology.

It has hard to say which of the biological approaches will win out in the next few decades. Many of the difficulties are yet to be discovered in each case. Xenotransplantation is running at ahead of the others at this stage, but equally, as the first human studies are conducted, this is where the unknown difficulties start to arise.

Developing pig-to-human organ transplants

Over 100,000 people in the US are currently waiting for organ transplants. Because the human organ donor pool cannot keep pace with this demand, many patients die without receiving the life-saving transplant they need. Pigs are similar to humans in organ size and physiology, so the transplantation of pig organs to humans offers a potential solution to this problem and raises the prospect of scheduled, elective transplantation of quality-controlled organs, even for patients who would not currently meet the criteria for allocation of a scarce human organ. Although other technologies, such as tissue engineering, may eventually offer alternative solutions to this shortage, there is currently no substitute for transplantation of a fully formed, functioning organ. Several developments in the past year, most notably the first pig-to-human transplants, bring this promising solution closer to fruition, but challenges remain. Transplants from one species to another are called xenotransplants. Because nonhuman primates (NHPs) are closest to humans phylogenetically, early human xenotransplantation efforts used NHP organs. However, graft survivals were short, and the use of NHPs for xenotransplantation was later deemed to be unsafe owing to potential virus transmission, impractical because of limited animal availability, and more ethically challenging than the use of pigs, which consequently became the xenograft source animal of choice. However, transplantation of pig organs into NHPs resulted in rapid "hyperacute" rejection (HAR) owing to the binding of preexisting "natural" antibodies (NAbs) in the NHP to targets on endothelial cells lining the transplant organ's blood vessels. Activation of complement and coagulation cascades then resulted in ischemic organ death within minutes to hours. NAbs exist in the absence of any known exposure to pig tissues owing to cross-reaction with antigens that are shared by common microbes. During the 1990s, pigs transgenically expressing human complement regulatory proteins were developed, and it was discovered that most human and NHP anti-pig NAbs recognize a single carbohydrate, α-galactose-1,3-galactose (Gal), making it possible to remove these antibodies by adsorption. These advances extended the survival of pig organs to days or weeks in NHPs. Enthusiasm for xenotransplantation was nevertheless dampened by the identification of porcine endogenous retroviruses (PERVs) and concerns about the possibility that new viral illnesses might arise in humans as a result. Guidelines have been developed to mitigate the risk of pathogen transmission from pigs to humans. Notably, PERV infection has not been detected in any pig-to-human or pig-to-NHP transplant recipient, although PERVs may have lower affinity for NHP forms of its receptor than of the human receptor. PERV loci have also been suppressed or deleted from some pigs, further improving safety. Consequently, there is broader acceptance of the likely safety of pig-to-human xenotransplantation with appropriate animal husbandry and microbial surveillance of the source animals, recipients, and their close contacts. These encouraging developments have set the stage to proceed with clinical xenotransplantation. The first trials of pig-to-human organ xenotransplantation took place in 2021.

There is Such a Thing as Too Much of a Focus on Low-Hanging Fruit in the Longevity Industry
https://www.fightaging.org/archives/2022/10/there-is-such-a-thing-as-too-much-of-a-focus-on-low-hanging-fruit-in-the-longevity-industry/

The longevity industry includes a few companies that will genuinely revolutionize the medical industry, such as Maia Biotechnology, the first deployment of a near-universal cancer therapy based on targeting telomerase activity. For every such gem there are, unfortunately, a half dozen companies that are marketing dietary supplements and the like that will do just about nothing to change the human condition. It is a great deal easier to market a supplement than it is to revolutionize the medical industry by developing a completely new biotechnology, and this truth has a significant impact on the funding available to a company based on their strategy of choice.

Venture funds that invest in biotech startups obtain their funds from limited partners, ranging from high net worth individuals to large holding companies. Venture partners running the fund are the industry experts, while the limited partners tend to know a lot less about the markets that they invest in. They are, in effect, hiring the fund to manage this opportunity. However, venture funds exist in a competitive marketplace for limited partner funds, and limited partners are primarily interested in financial outcomes rather than changing the world. Thus we see that all too many funds, company builders, and the like that focus on the longevity industry choose to make only safe, incremental investments in companies that are working on safe, incremental projects that cannot even in principle produce large gains in health and longevity.

In the article I want to point out today, Maximon is one such example. I'm not singling out the Maximon principals for any reason other than the fact that they drifted past my eyes recently; numerous other funds have taken the same approach, and just haven't spoken in public on the topic of their investment strategies of late. All use the current hype for longevity in order to obtain limited partner investment, and then fund projects that are prioritized by how likely they are to keep the limited partners happy with the bottom line at the end of the day. Unfortunately, a safe project in this context usually means that it is unambitious and unlikely to greatly affect the bottom line of human health. Is this outcome the fault of the limited partners, venture partners, entrepreneurs, or all three? There is a question to think on.

Meet the company builders that think they can reverse ageing

Marc Bernegger, a former crypto entrepreneur, cofounded the longevity company builder Maximon in 2021. He and his partners ran a two-day longevity investor conference last month in Gstaad in the Swiss Alps. The agenda included both investments opportunities and an overview of scientific research, with speakers including the investor Christian Angermayer and Eric Verdin, CEO of the Buck Institute for Research on Aging. "We had quite a few billionaires flying in from all over the world. That is a good indication that there's now serious money coming into this field. And having some well-known guests coming to an event like this makes it more tangible for investors," Bernegger says. The enthusiasm, and the capital, for the field is there - the longevity market is projected to reach 44bn by 2030 - but time is, ironically, not on this industry's side. Maximon's strategy is to look for more low-hanging fruits, says Bernegger. So far, the company builder has invested in Swiss supplement startup Avea and Biolytica, another Swiss startup which is combining health data analytics and personalised longevity programmes. Bernegger believes that although a lot of longevity supplements, such as NMN and NAD+ boosters, already exist on the global market, the "made in Switzerland" selling point will be beneficial to lure customers away from other brands, as well as attract new customers. Low-hanging fruit or not, Maximon is looking for ways to bring longevity technology to the masses. One way to do this - as both organisations are already about to - is by building longevity clinics, where people can go and find out what supplements and treatments would be beneficial to them on a personal level.

SIRT3 Knockout Increases Life Extension Resulting from Calorie Restriction
https://www.fightaging.org/archives/2022/10/sirt3-knockout-increases-life-extension-resulting-from-calorie-restriction/

Unexpectedly, researchers find that knockout of SIRT3, involved in mitochondrial function, increases the gain in life span exhibited by calorie restricted mice. Yet it does so while reducing physical fitness. Work on SIRT3 and aging typically focuses on upregulation of SIRT3, as this is beneficial to mitochondrial function, particularly in the damaged tissue environment of later life. Loss of SIRT3 modestly accelerates aging; add calorie restriction, however, and it becomes beneficial to life span, while still having a negative impact on physical performance. The data here for the combination of SIRT3 knockout and calorie restriction is an illustration of the point that everything in cellular biology and aging is a great deal more complex than we would like it to be.

One of the hallmarks of calorie restriction (CR) is the preservation of mitochondrial function through reducing oxidative stress, enhancing fuel utilization, and maintaining mitochondrial dynamics and integrity. Previous studies have proposed that Sirtuin3 (SIRT3)-dependent deacetylation may play a major role in modulating mitochondria under CR. Nonetheless, direct evaluation of the contribution by SIRT3 to CR-dependent lifespan extension and mitochondrial performance during aging is lacking. Here, using male Sirt3+/+ (wild type) and Sirt3-/- mice, we report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/-) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/-CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

HDL Level, Age, and Smoking are the Largest Determinants of Mortality Risk in Old People
https://www.fightaging.org/archives/2022/10/hdl-level-age-and-smoking-are-the-largest-determinants-of-mortality-risk-in-old-people/

An interesting epidemiological study here stratifies the contributions of various metrics to mortality in later life, age 70 and older. The authors find that the largest effects arise from HDL level, chronological age, and smoking. The largest single cause of death in our species is atherosclerosis, a progressive malfunction in clearance of cholesterol from blood vessel walls that leads to fatty plaques, narrowed arteries, stroke, and heart attack. HDL particles carry excess cholesterol from blood vessel walls back to the liver for excretion, and - thus over a lifetime - the more HDL in circulation one has, the greater the metabolic dysfunction needed to begin in earnest the development of atherosclerotic plaque.

The Duke Established Populations for Epidemiologic Studies of the Elderly (D-EPESE) is a longitudinal cohort of community-dwelling older adults designed to overcome the above-mentioned limitations. D-EPESE included 1507 participants, aged ≥71 years with biomarker data and 27 years of death data from the time of blood sample acquisition in 1992. This research aimed to identify clinical and molecular biomarkers that predict, and causally affect, longevity, from 186 clinically accessible measures that geriatricians and clinicians can, and frequently obtain in a clinic setting. We studied the relationships of patient-reported outcomes and questionnaires, and clinically available medical tests with survival status and identified optimal predictors. We chose to explore 2-, 5- and 10-year longevity since these time horizons are clinically relevant for this cohort of mean age 78 years with mean life expectancy of 9.37 years (men) and 10.92 years (women). These time horizons are also relevant for clinical decision-making that considers the benefits and burdens of tests (e.g., colon, breast, and prostate cancer screening), and treatment (stringency of lipid and blood pressure lowering), based on life expectancy. We identified a relatively small number of putative direct causes of longevity from among 186 clinically accessible variables, with 8 to 15 variables containing the totality of signal for each time horizon. Greater concentrations of small HDL particles, younger age, and fewer pack years of cigarette smoking were the strongest determinants of longevity at 2-, 5- and 10-years, respectively.

The Future of Treating Aging
https://www.fightaging.org/archives/2022/10/the-future-of-treating-aging/

Here find a sensible, readable paper discussing the years ahead in the treatment of aging as a medical condition. The potential to slow and reverse aspects of aging, demonstrated in animal studies in the laboratory, is now beginning to reach the clinic. A great shift in the provision of medicine, expectations for health in later life, and priorities in research and development will occur over the next few decades. Where we stand today, with senolytic drugs, the first form of rejuvenation therapy worthy of the name, in initial clinical trials, is merely the opening of a lengthy, world-changing process. The human condition will change for the better, in ways that are just as profound as those that attended the advent of antibiotics and the sudden ability to greatly control infectious disease.

Population aging is expected to yield a greater proportion of older adults in the United States than ever before. Therefore, the health of this age group, and that of the U.S. population more broadly, will depend greatly on improved prevention and management of chronic diseases. While age is known to be a risk factor for many conditions that affect healthspan and lifespan, age has been considered largely immutable, and the increased risk of disease has been accepted as a fact of life. However, recent developments in geroscience research suggest that the biological processes underlying aging may be more plastic. The potential of this finding is significant in that appropriate interventions may enable a paradigm shift from the management of diseases associated with advanced age to broad prevention of many illnesses through which individuals may increase the number of years they live in good health. In terms of both humanistic and economic factors, there is an emerging incentive to develop treatments and monitoring techniques that can properly assess and treat the hallmarks of aging. While classifying aging as a disease could be detrimental to older adults, treating the underlying biological processes that occur in every individual may provide a means to broadly improve health, given the strong links between these processes and the development of chronic disease. However, without key scientific evidence to clinically define biological aging, measure its progress and effects, and produce an appropriate indication for geroscientific treatments, regulatory approval ensuring the safety and efficacy of products will continue to be an obstacle. The development of gerotherapeutics that can be administered across the lifespan will require an in-depth assessment of biomarkers for the aging process, and the acceptance of these biomarkers by scientific communities as well as by the FDA. This challenge has drawn the interest of clinicians, patients, caretakers, entrepreneurs, sociologists, and government officials alike. Through deliberate collaboration among these important stakeholders, we will be able to pave a path forward to improve the healthspan of older adults and the population at large.

Will Rejuvenation Therapies Be Useful for Progeria Patients?
https://www.fightaging.org/archives/2022/10/will-rejuvenation-therapies-be-useful-for-progeria-patients/

Progeroid conditions are colloquially described as accelerated aging, but they are not in fact accelerated aging. They are only tangentially related to normal aging, in the sense that they are a form of molecular damage run rampant, and such damage tends to produce tissue and organ dysfunction that broadly resembles aging. It is not the same, however. Some progerias arguably involve forms of damage that do exist in normal aging and do contribute to normal aging, but when that damage represents near 100% of the total damage burden, rather than the normal much lesser fraction, the outcome ceases to be something that we can legitimately call aging. We cannot use it to teach us much about normal aging, and most of the rejuvenation treatments that will be beneficial to normally aged individuals will likely do little for a progeria patient. Only where the form of damage in a progeria aligns with a specific approach to rejuvenation through damage repair might there be utility.

All of the so-called "premature aging" diseases are in one critical sense entirely different from aging, inasmuch as they are the result of a relatively simple, unitary problem: patients carry just one key mutation in their cells. By contrast, real aging is the result of many different kinds of damage - and that damage accumulates as an unintended result of normal, healthy genes carrying out normal, life-sustaining metabolic processes that unfortunately inflict damage on previously healthy, non-mutated cells. In aging, there is no underlying mutation to fix, and we interfere with normal metabolic processes at our peril. So repairing the many different kinds of cellular and molecular aging damage is our best path to a future where we can live free of age-related ill-health. "Damage-repair" rejuvenation biotechnologies might very well help progeria patients by removing, repairing, or replacing the subset of their cellular abnormalities that occur in their bodies and line up closely enough with forms of cellular and molecular aging damage targeted by these SENS-like damage-repair approaches. For instance, the high burden of what appear to be senescent cells in Hutchinson-Gilford Progeria Syndrome (HGPS) patients and mouse models is the result of a mutation in the gene for LMNA, whose encoded proteins are important structural components of the nuclear envelope, leading to senescent-cell-like phenotypes. The accumulation of senescent cells is, of course, involved in normal aging. Even if the abnormal cells accumulating in HGPS patients' bodies aren't true senescent cells, there's still every reason to expect these patients to benefit from destroying the aberrant cells. This isn't just a reasonable prediction from first principles: it has proof-of-concept. In an animal study, scientists destroyed large numbers of the senescent-like cells in the tissues of mice with the same mutation as HGPS patients engineered into their genome. However, even after this senolytic treatment, however, these mice still aren't nearly as healthy or as long-lived as normal mice. HGPS causes other abnormalities in non-"senescent" cells, and both these mice and HGPS patients are rapidly accumulating these abnormal cells in comparison to normal individuals.

Amyloid-β Binding Exosomes in Blood Samples as a Biomarker of Alzheimer's Disease
https://www.fightaging.org/archives/2022/10/amyloid-%ce%b2-binding-exosomes-in-blood-samples-as-a-biomarker-of-alzheimers-disease/

Several research groups are in the later stages of developing a number of different approaches to blood-based assays to detect the early stages of Alzheimer's disease, or at least the buildup of amyloid-β in the brain that takes place over a span of years, long before symptoms manifest. Early detection should lead to means of early intervention, always a good deal easier than later intervention. Here, researchers outline a novel approach to detection of amyloid-β burden, finding amyloid-β levels correlated with those of a form of exosome carried in the circulation.

One of the primary causes of Alzheimer's disease is the accumulation of amyloid β (Aβ) in the brain, where it forms plaques. Alzheimer's disease is mostly seen in individuals over 65 years of age, and cannot currently be stopped or reversed. In addition to the lack of effective treatments of Alzheimer's, there are few methods to diagnose Alzheimer's. Alzheimer's can only be definitively diagnosed by direct examination of the brain-which can only be done after death. Aβ accumulation in the brain can be measured by cerebrospinal fluid testing or by positron emission tomography; however, the former is an extremely invasive test that cannot be repeated, and the latter is quite expensive. Thus, there is a need for a diagnostic test that is economical, accurate and widely available. Previous work has shown that Aβ build-up in the brain is associated with Aβ-binding exosomes secreted from neurons, which degrade and transport Aβ to the microglial cells of the brain. Exosomes are membrane-enclosed sacs secreted by cells that possess cell markers on their surface. The team established a way to quantify the concentration of Aβ-binding exosomes in as little as 100 µL of blood. The device they developed traps molecules and particles in a sample one-by-one in a million micrometer-sized microscopic wells on a measurement chip and detects the presence or absence of fluorescent signals emitted by the cleaving of the Aβ-binding exosomes. When tested on mouse models, the Aβ-binding exosome assay showed that the concentration of Aβ-binding exosomes increased with the increase in age of the mice. This is significant as the mice used were Alzheimer's disease model mice, where Aβ builds up in the brain with age. Clinical trials of the technology are currently underway in humans.

SFRP4 Knockdown Suppresses the Senescence-Associated Secretory Phenotype in Senescent Skin Cells
https://www.fightaging.org/archives/2022/10/sfrp4-knockdown-suppresses-the-senescence-associated-secretory-phenotype-in-senescent-skin-cells/

Researchers here note that SFRP4 is expressed in aged skin cells, and especially in senescent skin cells. Gene knockdown of SFRP4 in mice was shown to reduce the harmful signaling generated by these cells, the senescence-associated secretory phenotype (SASP), and improve measures of skin aging in the treated animals. On the whole, modulating the SASP seems a poor strategy in comparison to selectively destroying senescent cells with senolytic therapies. For one, a SASP-suppressing treatment is unlikely to suppress all of the diverse molecular components of the SASP, and secondly has to be taken continuously over time. A senolytic treatment definitely gets rid of the SASP, whether or not researchers can currently measure it, and needs to be taken only intermittently.

There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzled-related protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.

Cognitive Impairment Indicative of Later Dementia can be Detected Early
https://www.fightaging.org/archives/2022/10/cognitive-impairment-indicative-of-later-dementia-can-be-detected-early/

Researchers here present epidemiological evidence from a large population database to suggest that measurable cognitive decline occurs quite early in the progression towards dementia, years before diagnosis. Thus better screening could open the door for widespread use of existing preventative interventions and the development of new and better preventative interventions. Prevention is almost always an easier prospect than effective treatment of later stage disease, and something to be encouraged.

Neurodegenerative diseases present a significant health, social, and economic burden. Disease-modifying therapies and effective preventive strategies are lacking. Treatment trials are typically conducted after symptoms have emerged, which may be too late in the disease process to alter its course. Understanding the earliest, pre-diagnostic phase in neurodegenerative disease could open opportunities for more effective preventive and treatment trials. We use UK Biobank data demonstrate cognitive and functional antecedents of several idiopathic neurodegenerative syndromes in the years prior to diagnosis. In line with findings of pre-symptomatic cognitive decline in familial mutation carriers of Alzheimer's disease and frontotemporal dementia, these changes were identified at a baseline assessment averaging 5 to 9 years before diagnosis. The pre-diagnostic linear decline in a number of measures supports our supposition that these changes represent early progressive neurodegeneration rather than a low cognitive or functional baseline.

LXA4 Levels in the Brain Decrease With Age, Perhaps Increasing Inflammation and Accelerating Neurodegeneration
https://www.fightaging.org/archives/2022/10/lxa4-levels-in-the-brain-decrease-with-age-perhaps-increasing-inflammation-and-accelerating-neurodegeneration/

Chronic inflammation in brain tissue is connected to the onset and progression of neurodegenerative conditions, so it is reasonable to expect that researchers will, from time to time, discover evidence for regulators of inflammation to be involved in aging and neurodegeneration. Here, scientists discuss LXA4, which has a role in resolution of the inflammatory response, and declines in abundance with age. Delivery of LXA4 produces functional benefits and greater resistance to inflammation in mouse models, making it a potentially interesting target for the development of therapies. The question, as always for attempts to suppress age-related inflammation, is whether this will reduce pathological, excess inflammation only, leaving necessary inflammation untouched. The side-effects of reducing necessary inflammation include increased cancer risk and vulnerability to pathogens, particularly undesirable in later life.

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Senescent Cells in Muscle Tissue Harm Muscle Stem Cell Function
https://www.fightaging.org/archives/2022/10/senescent-cells-in-muscle-tissue-harm-muscle-stem-cell-function/

Researchers here use fisetin as a senolytic in progeroid mice to demonstrate that senescent cells in muscle tissue are harmful to tissue function via a negative impact on muscle stem cells. Mice with this form of progeroid mutation generate a lot of senescent cells, far more than occurs during normal aging, but the principle may nonetheless hold, that senescent cells are providing a meaningful contribution to age-related loss of muscle mass and strength. The proof lies in running the studies.

Muscle progenitor/stem cells (MPCs) progressively lose their capacity for proliferation and myogenic differentiation during the ageing process, likely through both autonomous and non-autonomous mechanisms. The cell autonomous mechanism mainly involves increased DNA damage, telomere shortening, and activation of chronic inflammatory signalling (i.e. NF-κB), whereas the cell non-autonomous mechanism involves the regulatory roles of other types of neighbouring cells in the tissues on the function of local stem cells. However, the mechanism of MPCs being regulated by neighbouring cells during the ageing process of muscles remains largely unknown. Adjacent to MPCs in the skeletal muscle are myofibres, immune cells, blood vessel endothelial cells and fibro-adipogenic progenitors (FAPs). FAPs are tissue-resident mesenchymal stromal cells (MSCs) characterized by the high expression of PDGFR-α that play important roles in the homeostasis and repair of multiple tissues. By studying the muscles and primary cells of age matched wild-type (WT) mice and Zmpste24-/- (Z24-/-) mice, an accelerated ageing model for Hutchinson-Gilford progeria syndrome (HGPS), we examined the interaction between FAPs and MPCs in progeria-aged muscle, and the potential effect of senolytic drug fisetin in removing senescent FAPs and improving the function of MPCs. We observed that, compared with muscles of WT mice, muscles of Z24-/- mice contained a significantly increased number of FAPs (2.4-fold) and decreased number of MPCs (2.8-fold). FAPs isolated from Z24-/- muscle contained about 44% SA-β-gal+ senescent cells, in contrast to about 3.5% senescent cells in FAPs isolated from WT muscle. The treatment of the in vitro co-culture system of Z24-/- FAPs and WT MPCs with the senolytic drug fisetin led to increased apoptosis of Z24-/- FAPs (14.5-fold) and rescued the impaired function of MPCs by increasing the number of MHC-positive myotubes for 3.1 times. Treatment of Z24-/- mice with fisetin in vivo was effective in reducing the number of senescent FAPs and restoring the number of muscle stem cells (2.6-fold), leading to improved muscle pathology in Z24-/- mice. These results indicate that the application of senolytics in the progeria-aged muscles can be an efficient strategy to remove senescent cells, including senescent FAPs, which results in improved function of muscle progenitor/stem cells. The senescent FAPs can be a potential novel target for therapeutic treatment of progeria ageing related muscle diseases.

RNA Splicing Dysfunction in Alzheimer's Disease
https://www.fightaging.org/archives/2022/10/rna-splicing-dysfunction-in-alzheimers-disease/

RNA splicing is the process by which RNA is assembled from portions of a gene, joining exon sequences together while omitting intron sequences. Like all aspects of cellular biochemistry, RNA splicing runs awry with age in a variety of ways, and this is thought to lead to dysfunction in cells. Here, researchers dive into a very specific issue in RNA splicing that appears associated with Alzheimer's disease, though as always in this sort of research one has to ask whether the effect size is meaningful, and whether the animal models are decent reflections of what happens in humans. Mice do not naturally develop Alzheimer's, and so the models all are based on some assumptions about the important mechanisms; those assumptions may produce dementia in mice, but may or may not be relevant to the human condition.

Researchers previously revealed that a specific component of the RNA splicing machinery, called the U1 small nuclear ribonucleoprotein (snRNP), creates aggregates in the brains of individuals with Alzheimer's. The U1 snRNP complex is essential in RNA splicing. Now, the team have demonstrated that the dysfunction of the U1 snRNP contributes to neurodegeneration, opening new avenues of research for Alzheimer's treatment. The study found that RNA splicing dysfunction due to U1 snRNP pathology helps cause neurodegeneration. The researchers created a novel mouse model of RNA splicing defects called N40K-Tg. The scientists observed basic neurodegeneration when they deregulated the splicing machinery, but they wanted to understand why that was the case. Inhibitory neuron activity prevents the brain from getting over-excited. If the inhibitory neuron activity is repressed, the neurons become more active, but it can cause toxicity. The researchers found a significant impact on synaptic proteins in the new mouse model, in particular the proteins involved in inhibitory neuron activity. "Excitatory toxicity is very important because it is already known in the Alzheimer's disease field. Even 20-30 years ago, people recognized that neurons become super excited, and now we find that the splicing machinery may be contributing to the excitatory toxicity observed in Alzheimer's patients."

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