Fight Aging! Newsletter
January 16th 2023

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Contents

The Gut Microbiome of Centenarians
https://www.fightaging.org/archives/2023/01/the-gut-microbiome-of-centenarians/

The state of the gut microbiome is arguably as influential on health as exercise. Various microbial species present in the gut produce beneficial metabolites, such as butyrate, or harmful metabolites, such as isoamylamine, or can provoke chronic inflammation in a variety of ways. An individual can have a better or worse microbiome, assessing these and other functional contributions to health. With age, the balance of populations shifts towards fewer benefits and greater harm, unfortunately.

Since the composition of the microbiome can be assessed accurately and cheaply via 16S rRNA sequencing, understanding of the gut microbiome is advancing rapidly. There is no one optimal gut microbiome, but some species are more helpful than others. Looking at human populations, researchers are beginning to see patterns emerge from the study of the gut microbiome in healthier and more long-lived people. Today's open access paper is an example of this sort of work, in which the microbiomes of centenarians are assessed and compared with the broader population.

This is all interesting, but a short-cut to improving the aged gut microbiome does exist, in advance on understanding all of the desired component species, proportions, and effects on health. That is to conduct a fecal microbiota transplant from a young donor into an older recipient, using screened stool samples from a service such as Human Microbes. In animal studies, lasting rejuvenation of the gut microbiome, along with improved health and extended life span, can be achieved in this way. Robust human data has yet to be obtained, despite the use of fecal microbiota transplantation as a treatment for severe dysbiosis, but that is just a matter of time.

Gut microbiota as an antioxidant system in centenarians associated with high antioxidant activities of gut-resident Lactobacillus

Clinical studies have also shown that the diversity and composition of the gut microbiota is non-linear with age. In centenarians, the abundances of Roseburia and Escherichia were significantly higher than in non-centenarians, while Lactobacillus, Faecalibacterium, Parabacteroides, Butyricimonas, Coprococcus, Megamonas, Mitsuokella, Sutterella, and Akkermansia were significantly lower in centenarians than in non-centenarians. The age-related trajectories of the human gut microbiome are characterized by a loss of genes for short-chain fatty acid production and an overall decrease in glycolytic potential, while proteolytic functions are more abundant than in the gut metagenome of young adults.

A study using metagenomic sequencing to identify compositional and functional differences in the gut microbiota associated with age groups in Sardinia, Italy. The data showed that the gut microbiota of Sardinian centenarians was mainly characterized by depletion of Faecalibacterium prausnitzii and Eubacterium rectale, while enriched Methanobrevibacter smithii and Bifidobacterium adolescentis compared with young and old. Functional analysis showed that centenarians had higher metabolic capacity, especially glycolysis and fermentation of short-chain fatty acids (SCFAs), and lower genes encoding carbohydrate-degrading enzymes, including fiber and galactose.

Studies have shown that centenarians have a unique gut microbiome rich in microorganisms capable of producing unique secondary bile acids, including various isomers of lithocholic acid (LCA). These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of pathogenic infection and thus may contribute to the maintenance of intestinal homeostasis. Although we believe that longevity appears to be achieved by maintaining gut microbiota homeostasis, whether changes in gut microbiota are a consequence or a cause of aging, and the exact relationship between gut microbiota and aging remains to be further explored.

In this study, we combined metagenomic sequencing and large-scale in vitro culture to reveal the unique gut microbial structure of the world's longevity town - Jiaoling, China, centenarians, and people of different ages. Functional strains were isolated and screened in vitro, and the possible relationship between gut microbes and longevity was explored and validated in vivo, revealing associations of the gut microbiota with age and a number of clinical and metabolic parameters.

We uncovered age-specific gut microbiota characteristics, including a core set of seven microbial taxa enriched in centenarians and the gut microbiota of centenarians exhibited higher xenobiotics biodegradation and metabolism, oxidoreductase. We revealed age-related gut microbial characteristics in all populations, including increased alpha diversity and increased levels of abundances of the health-related bacteria such as Akkermansia, Lactobacillus, and short-chain fatty acid (SCFA) producers, and targeted screening an age-related gut-resident Lactobacillus with independent intellectual property rights, which metabolites and itself have good antioxidant effects.

CASIN Alters Epigenetic State to Produce Lasting Improvement in Aged Stem Cell Function
https://www.fightaging.org/archives/2023/01/casin-alters-epigenetic-state-to-produce-lasting-improvement-in-aged-stem-cell-function/

In recent years, researchers have shown that a single injected dose of CASIN, an inhibitor of CDC42, can improve immune function in old mice, resulting in a lasting gain in health and extended life span. CASIN appears to work by altering epigenetic state in the hematopoietic stem cell populations responsible for producing new immune cells. This is also observed to be the case in other stem cell populations. Raised levels of CDC42 are observed with aging, and have been shown to impair hematopoietic stem cells. This is the case in both mice and humans, so there is some hope that some form of CDC42 inhibition can be used as the basis for a human therapy.

Mogling Bio was recently founded to develop therapies based on the results obtained with CASIN. As I understand it, while CASIN appears safe in animal studies, it isn't as bioavailable as might be desired. The animal doses are large enough that human equivalent doses would require an intravenous infusion rather than a simple injection. The Mogling Bio founders are likely to work on alternative approaches, or tinker with the structure - the usual approach for a new biotech company starting from the position of an interesting compound. That compound is the foundation for improvements that can be patented, providing the monopoly required to support the high company valuation that is needed to raise the sizable funding required to enter the regulatory process. It isn't the best of systems, given the incentives it places on development.

Still! Therapies for which a single dose produces a lasting effect, and where that effect is visible rejuvenation of function in old animals, are much more intriguing than those that require constant dosing over time. I would imagine that we'll see some interest in the self-experimenter community regarding CASIN as matters move ahead with development based on this compound, though (a) the logistics of use, given the large doses and need for injection, make it a more challenging project than is the case for most compounds, and (b) there is no human safety data, perhaps the more important point here. There are other CDC42 inhibitors with at least some human data, predictable emerging from the cancer research community, but these are not specific inhibitors of CDC42, and it is something of a question as to whether they would have similarly useful effects as CASIN.

Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice

The ability to restore or rejuvenate aged tissues by targeting endogenous stem cells is a central goal of regenerative medicine. However, systemic rejuvenation of aged stem cells remains a challenge and it is still unclear to what degree do stem cells contribute to overall organism health- and lifespan. Here, we show that a brief systemic treatment of aged mice with the Cdc42-activity inhibitor CASIN improves the regenerative potential of endogenous aged muscle stem cells (MuSCs) and hematopoietic stem cells (HSCs) in vivo.

We report that after CASIN treatment aged MuSCs divisional kinetic and myogenic capacity in vitro are enhanced and, after injuring the muscle in vivo, tissue regeneration is improved. Supporting that the MuSC improvement after CASIN might contribute to extend mouse healthspan, CASIN mice performed better than aged control mice in endurance and strength tests in steady-state and also after damage. Moreover, we report on systemic CASIN affecting Cdc42 and tubulin polarity as well as H4K16ac epigenetic polarity in aged HSCs. The data on H4K16ac obtained by histological analyses of whole mount bone marrow sections aligns to those previously reported on the DNA-methylation-based epigenetic clock and strongly support at least some traits of epigenetic rejuvenation in HSCs after systemic CASIN treatment.

Furthermore, the histological analysis shows an intriguing effect of CASIN also on aged HSC localization, which after the treatment is closer to arteries and endosteum, like young blood stem cells. At the transcriptional level, stress response, and inflammation constitute the major signaling pathways targeted by CASIN in vivo. Consistently, we have previously reported a significant reduction in the levels of inflammatory cytokines (IL1α, IL1β, and INFγ) in peripheral blood serum of aged mice after in vivo CASIN treatment. These same cytokines were also shown by others to play critical roles in aging of the blood and other tissues

The hematopoietic system is the carrier for many rejuvenation factors, and this leaves open the possibility that rejuvenating aged HSCs might represent an effective strategy to improve aging of the whole organism. Here we show that upon transplantation rejuvenated blood stem cells are sufficient to increase murine lifespan of aged immunocompromised mice. Altogether these results raise critical considerations for refining the targets and goals of anti-aging strategies focusing on a possible central role of HSCs and of the hematopoietic system. To note, previous data associated increased Cdc42 activity to aging in humans and in aged human HSCs, supporting the translational potential of these findings.

These data, together with the recent data supporting an improved activity of aged intestinal and hair follicle stem cells after CASIN treatment support that the increased activity of Cdc42 with aging impairs the function of several somatic stem cells in different tissues. Therefore, systemic treatment with CASIN can elicit distinct positive biological effects in vivo, which might depend on the doses and way of administration. Besides, recently Cdc42 activity has been shown to limit the lifespan of the budding yeast, hinting at a phylogenetically conserved mechanism of the Cdc42-polarity axis in affecting organism aging.

A High Level View of Efforts to Modulate Inflammaging and Immunosenescence of the Aged Immune System
https://www.fightaging.org/archives/2023/01/a-high-level-view-of-efforts-to-modulate-inflammaging-and-immunosenescence-of-the-aged-immune-system/

Change and disruption in the immune system is an important component of degenerative aging. Broadly, the immune system becomes ever more inflammatory (inflammaging) while also becoming ever less effective (immunosenescence). The immune system is not only responsible for defending against invasive pathogens and destroying errant cells, but it is also tightly integrated into the normal processes of tissue maintenance and operation. When immune cells become inflammatory, they abandon the range of tasks needed to keep tissues functional. Short-term inflammation is necessary in response to injury and infection, but unresolved, chronic inflammation is a major issue, highly disruptive, and contributing to the onset and progression of many age-related conditions.

That immune aging is a major issue is widely recognized, and many research and development initiatives are aimed at restoration of at least some aspect of lost immune function: largely reduction of inflammation, but also restoration of immune capacity in defense against pathogens or clearance of cancerous and senescent cells. The most promising direct approaches involve (a) improvement of hematopoietic stem cell function, (b) restoration of the thymus to enable greater production of T cells, (c) clearance of misconfigured and damaged immune cell populations. Removing the stimuli for chronic inflammation should also prove helpful, such as via clearance of senescent cells.

Immune system modulation in aging: Molecular mechanisms and therapeutic targets

Inflammation is a key factor for the onset and progression of almost all chronic diseases affecting aged individuals, with immunosenescence and inflammaging being two relevant phenomena that modulate the immune system during aging. Therefore, characterization of the molecular and cellular mechanisms underlying the immune system dysfunction will surely help to develop effective therapeutic strategies to prevent the negative outcomes of infectious diseases on aged individuals.

For that reason, several pharmacological and cellular/genetic strategies have been developed to slow down or reverse the deleterious effects of immunosenescence on health: (a) Induced pluripotent stem cells (iPSCs) have been employed to generate hematopoietic cells and/or various specific immune cells; (b) administration of cytokine and growth factor cocktails boosted macrophage function; (c) bone marrow transplantation is a widely used therapy for thymus regeneration; (d) the use of Cdc42 and BATF inhibitors or antioxidants enhances the number and function of lymphoid-biased hematopoietic stem cells; (e) inhibition of dual specific phosphatases 4 boosts memory CD4+ T-cell function; (f) administration of fibroblast growth factor 7 (FGF7) stimulates naive T-cell production and promotes the removal of dysfunctional cells, thereby restoring thymus function; and (g) administration of rapamycin improves CD8+ T-cell function.

Finally, a relevant non-pharmacological strategy that has been proven to enhance immunity is caloric restriction; it delays the accumulation of senescent T cells and stimulates thymopoiesis through the activation of IGF-1 and/or PPAR pathways. On the other hand, recent studies have unveiled the relevance of functional foods to ameliorate oxidative stress and inflammation and to improve the metabolism of lipids associated with metabolic diseases, via Nrf2 and/or NF-κB signaling pathways.

Some of the molecules/pathways that modulate immunosenescence have therapeutic potential. Owing to the crucial role of the activator protein 1 (AP-1) signaling pathway in macrophage-mediated inflammation, targeting of AP-1 has been approached to attenuate inflammation. Transfection of lentiviral siRNA against AP-1 in mice fed with high-fat diet resulted in the alleviation of systemic and hepatic inflammation. Interestingly, the use of rosiglitazone, a PPARγ agonist, was found to exert a positive effect on animals with sepsis, decreasing cell death and cardiac inflammation; furthermore, increased fatty acid oxidation and improved insulin resistance were also observed in human skeletal muscle. Since aging is a very complex process that involves different biological processes, therapies aimed to modulate inflammaging have to be focused on the synergic effect of more than one compound, to regulate simultaneously different pathways. For instance, a combinatory treatment using three different compounds, rapamycin, acarbose, and 17α-estradiol, converge on the regulation of both ERK1/2 and p38-MAPK pathways.

Chronic Inflammation and Endothelial Dysfunction in Vascular Aging
https://www.fightaging.org/archives/2023/01/chronic-inflammation-and-endothelial-dysfunction-in-vascular-aging/

The age-related decline and dysfunction of the vasculature kills a sizable fraction of humanity, directly through stroke and heart attack, and more indirectly through a number of other mechanisms. The rise of chronic inflammation with age can be blamed for much of this. Unresolved inflammatory signaling is highly disruptive to tissue function throughout the body. In the vasculature, it accelerates the altered macrophage behavior that lies at the root of atherosclerosis. It provokes some of the altered smooth muscle behavior that leads to hypertension as contraction and dilation of blood vessels become poorly controlled. It changes the behavior of cells in ways that lead to calcification of blood vessel walls.

The inner endothelium of blood vessels undergoes a range of detrimental functional changes with aging, and again many of these are driven at least in part by chronic inflammation. Disruption of this layer of the blood vessel wall appears to accelerate atherosclerosis, contribute to issues with the regulation of dilation and contraction, and produce leakage of the blood-brain barrier where blood vessels pass through the brain.

Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases

Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a detrimental role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above.

Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.

The prominence of inflammatory mediators, and the centrality of the inflammasome, have led scholars to set up studies to evaluate the possibility of inhibiting certain checkpoints from fighting the diseases of aging, so much so that there are ongoing trials to evaluate the efficacy of molecules that can inhibit the inflammasome from reducing cardiovascular risk. Blocking the inflammasome and reducing the blood concentrations of its products, first and foremost IL-1 beta and IL-18, could be an exciting target of future therapies, perhaps using monoclonal antibodies to tailor actions to specific targets. Compared with the past, today there are suggestive and fascinating pathways that hint at the possibility of counteracting the passage of time and the onset of age-related diseases. More pragmatically, the development of drugs of this type may enable successful aging.

A Proposal to Accelerate Progress Towards Human Rejuvenation
https://www.fightaging.org/archives/2023/01/a-proposal-to-accelerate-progress-towards-human-rejuvenation/

Here find the first draft of a proposal regarding the best way forward at the present time to accelerate progress towards the development of diverse, effective rejuvenation therapies. The key is to use philanthropic funding to (a) prove efficacy in low-cost clinical trials, and then (b) market that data to ensure physician adoption of the first working rejuvenation therapies. A PDF version of this draft also exists.

Executive Summary

1. Aging is by far the greatest cause of human morbidity and mortality.

2. Rejuvenation therapies that will greatly reduce unnecessary late life suffering and death are under development, but slowly, and with limited funding.

3. Accelerating the development of rejuvenation therapies is an important goal that, if achieved, will improve quality of life and save many lives in the years ahead.

4. At present there is only limited public support for the goal of human rejuvenation.

5. Faster progress towards rejuvenation therapies will follow greater public and institutional support for rejuvenation therapies. It will mean more funding, more research programs, more biotech companies.

6. A few low-cost rejuvenation therapies exist today, already approved by US regulators for other uses. They can in principle be prescribed off-label in the US, but are not yet widely used.

7. Broad public and institutional support to accelerate the development of rejuvenation therapies will emerge following the widespread use of at least a few rejuvenation therapies.

8. Widespread use of the first rejuvenation therapies will require physician adoption of those therapies, as patients largely follow the options presented by physicians.

9. Physician adoption of an off-label rejuvenation therapy requires a convincing presentation of safety and efficacy in the treatment of common age-related conditions. This can be provided by favorable results from low-cost, few-hundred-patient clinical trials conducted by a reputable organization, and then marketed to physicians and physician organizations.

10. The cost of clinical trials to produce robust, trustworthy data for an existing therapy, already approved by regulators, can be a fraction of that required for clinical trials aimed at regulatory approval of a new treatment.

11. Given this funding, a number of existing organizations are well placed to conduct these trials and publicize the results. All that is needed is the will to act.

Aging is the Greatest Cause of Human Morbidity and Mortality

Age-related disease is by far the greatest cause of human morbidity and mortality. The many different ultimately fatal degenerative conditions of old age result from a much smaller number of underlying mechanisms of aging. These include the accumulation of senescent cells and forms of metabolic waste such as cross-links and amyloids, DNA damage, and more. [1][2]

The First Rejuvenation Therapies Exist ...

Historically, treatments for age-related disease have focused on the symptoms rather than the causes, and thus comparatively little headway has been made towards prevention and reversal - towards actual rejuvenation. Even though this remains true today, it is nonetheless the case that the first rejuvenation therapies exist, each capable of reversing to some degree a single contribution to degenerative aging.

For example, the senolytic combination of dasatinib and quercetin has been shown in human clinical trials to significantly reduce the burden of senescent cells in aged tissues following a single course of treatment. [3] Senescent cells grow in number with age, and their inflammatory secretions are disruptive of tissue structure and function, contributing to many of the common fatal age-related diseases. [4] Dasatinib is an FDA-approved drug that can be prescribed off-label at low cost, while quercetin is a supplement, readily available to all at an even lower cost.

As a second example, fecal microbiota transplant (FMT) from young to old individuals has been demonstrated in animal studies to produce a lasting reset of the aged gut microbiome and improved health. [5][6] Restoring the balance of microbial populations in the intestine to a youthful state reduces the harmful effects of an aged gut microbiome on long-term health, including raised inflammation, increased generation of toxic metabolites, and reduced generation of beneficial metabolites. One implementation of this treatment was recently approved by the FDA for treatment of C. difficile infection. [7] This makes it available off-label, in principle at least, and gives support to the community of practitioners that has for years been conducting FMT procedures on an ad hoc basis to treat various forms of dysbiosis.

... But are Not Widely Adopted

Despite the existence of these rejuvenation therapies, and evidence for their benefits in the context of aging, the two treatments noted above are neither widely used nor widely known. The broader public still sees aging as largely set in stone, and treatment of aging as the domain of frauds and snake oil salesmen. The public does not realize that a small number of low-cost medical therapies can, with a single program of treatment, produce a lasting improvement to late life health by addressing one of the contributing causes of aging. Comparatively few physicians are both aware of these therapies and comfortable prescribing them. Comparatively few research groups are working on human clinical trials that would produce further supporting evidence.

If must be noted that clearance of senescent cells and adjustment of the gut microbiome, while supported by evidence to show them to be individually beneficial, are not on their own sufficient for comprehensive rejuvenation of the old. Other contributing causes of aging must also be addressed, such as protein aggregates, cross-linking, stem cell decline, mitochondrial dysfunction, and so forth. [1] A faction within the biotech industry is working on new classes of rejuvenation therapy, and the funding for this effort has risen to a few billion dollars, spread unevenly across a few score companies. [8] This sounds like a lot, but it is an insignificant fraction of the funding devoted to more mainstream medical development; the end to end cost of developing a single therapy was reportedly more than 2 billion in 2013. [9]

If we wish to see rapid progress towards the effective treatment of aging within our lifetimes, a dramatic reduction of age-related disease, an end to frailty and dementia, then initiatives aimed at the production of rejuvenation therapies must greatly expand in size and number, and do so sooner rather than later. At the large scale, public support and understanding is necessary for the biggest, most conservative institutions to choose to put their shoulders to the wheel and advance the field of rejuvenation research. That support and understanding is missing at present, in large part because the first rejuvenation therapies are not widely used, and therefore remain largely unknown and unappreciated.

The problem we face is circular in nature. Little use of existing rejuvenation therapies means little knowledge of those therapies. Little knowledge in turn ensures little use. Presently sparse research and development means a slow pace of transmission of knowledge from the scientific community to thought leaders and the public at large. That lack of broad knowledge ensures that there is comparatively little support for greater funding and an expanded range of initiatives.

A slow process of bootstrapping is the usual way forward when faced with such self-reinforcing roadblocks, years of slow and incremental growth to open up a new field. There are other, faster ways paths ahead, however, enabled by the cost-effective deployment of philanthropic funding.

To Ensure Adoption, Persuade Physicians to Prescribe

The best way to break the cycle described above is to focus on physician adoption, to ensure that physicians and clinicians become comfortable prescribing and providing the few presently available rejuvenation therapies. Most patients only become familiar with the medical technologies presented by their physicians. Ensuring widespread off-label use by the medical community of the few existing, easily implemented, low-cost rejuvenation therapies would lead to a sizable improvement in public knowledge and attitudes regarding human rejuvenation.

A world in which most physicians choose to prescribe beneficial rejuvenation therapies to older patients is a world in which both the public and larger, conservative institutions will come to support further development of this form of medicine, aimed at ever more effective control of aging and age-related disease. Just as importantly, expanding the use of beneficial rejuvenation therapies is a great good in and of itself, a way to alleviate suffering and mortality in the older population.

Clinical Trial Data Persuades Physicians

The best way to convince physicians that a given FDA-approved treatment can be used off-label to treat many diseases of aging, or aging itself, is for reputable organizations to publish favorable results from multiple human clinical trials that employ the treatment. Such trials do not have to be anywhere near as expensive as the formal clinical trials conducted to persuade the FDA to approve a new therapy, as they do not need to be encumbered by the full set of regulatory concerns. They only need to be well run, such that the data produced is of high quality, and run by organizations with a good reputation, to ensure that the message is heard.

Trials of the few existing rejuvenation therapies are taking place, but only to a limited degree, and very slowly. The Mayo Clinic was one of the first groups to run clinical trials using dasastinib and quercetin in kidney disease [10], pulmonary fibrosis [11], and Alzheimer's disease [12], for example. But only for these few age-related conditions, with a limited budget, and at a sedate pace over years. Data has been published for only two of these trials over the last five years. Much more than the work of this single organization is needed to move the needle when it comes to persuading physicians.

It is possible to run a well-managed clinical trial of a low-cost, FDA-approved therapy in as many as two hundred patents for under 1 million, provided that the primary goal is to produce robust data rather than to satisfy regulators. Consider the PEARL trial for rapamycin [13], for example, which was crowdfunded with under 200,000 in charitable donations [14]. Trials for dasatinib and quercetin treatment or fecal microbiota transplantation need not be that much more expensive.

Existing Organizations Can Administer Clinical Trials

Given philanthropic funding for such trials, a number of reputable organizations are well positioned to undertake the task of trial administration. In practice this requires connections to potential principal investigators and clinics capable of performing the work, project management as the work progresses, and analysis and presentation of the results. Again, this is far less onerous for the type of clinical trial envisaged here than is the case for formal clinical trials conducted for regulatory approval of new therapies.

The non-profit Lifespan.io runs crowdfunding campaigns to support research goals, and has collaborated with AgelessRx [15] to fund and organize the PEARL clinical trial for rapamycin. The non-profit Forever Healthy Foundation [16] performs research analysis and holds conferences, is connected to the Kizoo Technology Ventures fund that invests in biotech companies, and could make the transition to organizing small trials. The LongevityTech investment fund [17] is constructing a network of clinics in a number of different locations for the express purpose of running first-in-human clinical trials for new therapies relevant to aging.

Each of these organizations has an existing reputation that can be built upon and expanded by taking on the task of running clinical trials aimed at persuading physicians to make use of the first rejuvenation therapies worthy of the name.

Outreach to Physicians

Given favorable data and reputable trial-running organizations, outreach to physicians is more or less a solved problem. It only requires funding and effort. Organizations that market therapies to physicians and clinical practices exist, while established physician networks and conferences can act as channels for broader discussion and outreach.

In Summary

The first rejuvenation therapies worthy of the name already exist, but are barely used. Ensuring a reasonable proof of efficacy and more widespread use of the first few of these will not just improve late life health, but also change the public perception of the treatment of aging. Physician adoption of these therapies is the key to widespread use, and can be achieved by running multiple, rapid, low-cost clinical trials for the first rejuvenation therapies, followed by marketing favorable results to physicians and physician organizations. Widespread physician-led adoption of the first rejuvenation therapies will produce far greater public and institutional support for progress towards a comprehensive set of rejuvenation therapies, technologies that, together, are capable of producing a dramatic reduction in late life suffering and mortality.

References

[1]: Intro to SENS Research. (2022, December 23) SENS Research Foundation. https://www.sens.org/our-research/intro-to-sens-research/

[2]: López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The Hallmarks of Aging. In Cell (Vol. 153, Issue 6, pp. 1194-1217). Elsevier BV. https://doi.org/10.1016/j.cell.2013.05.039

[3]: Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T. J., … Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. In EBioMedicine (Vol. 47, pp. 446-456). Elsevier BV. https://doi.org/10.1016/j.ebiom.2019.08.069

[4]: Di Micco, R., Krizhanovsky, V., Baker, D., & d'Adda di Fagagna, F. (2020). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. In Nature Reviews Molecular Cell Biology (Vol. 22, Issue 2, pp. 75-95). Springer Science and Business Media LLC. https://doi.org/10.1038/s41580-020-00314-w

[5]: Smith, P., Willemsen, D., Popkes, M., Metge, F., Gandiwa, E., Reichard, M., & Valenzano, D. R. (2017). Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. In eLife (Vol. 6). eLife Sciences Publications, Ltd. https://doi.org/10.7554/elife.27014

[6]: Parker, A., Romano, S., Ansorge, R., Aboelnour, A., Le Gall, G., Savva, G. M., Pontifex, M. G., Telatin, A., Baker, D., Jones, E., Vauzour, D., Rudder, S., Blackshaw, L. A., Jeffery, G., & Carding, S. R. (2022). Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. In Microbiome (Vol. 10, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1186/s40168-022-01243-w

[7]: Office of the Commissioner. (2022, November 30). FDA Approves First Fecal Microbiota Product. U.S. Food And Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-first-fecal-microbiota-product

[8]: AgingBiotech.info. (2023, January 05). https://agingbiotech.info/companies/

[9]: DiMasi, J. A., Grabowski, H. G., & Hansen, R. W. (2016). Innovation in the pharmaceutical industry: New estimates of R&D costs. In Journal of Health Economics (Vol. 47, pp. 20-33). Elsevier BV. https://doi.org/10.1016/j.jhealeco.2016.01.012

[10]: Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., Kellogg, T. A., Khosla, S., Koerber, D. M., Lagnado, A. B., Lawson, D. K., LeBrasseur, N. K., Lerman, L. O., McDonald, K. M., McKenzie, T. J., … Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. In EBioMedicine (Vol. 47, pp. 446-456). Elsevier BV. https://doi.org/10.1016/j.ebiom.2019.08.069

[11]: Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., & Kirkland, J. L. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. In EBioMedicine (Vol. 40, pp. 554-563). Elsevier BV. https://doi.org/10.1016/j.ebiom.2018.12.052

[12]: Gonzales, M. M., Garbarino, V. R., Marques Zilli, E., Petersen, R. C., Kirkland, J. L., Tchkonia, T., Musi, N., Seshadri, S., Craft, S., & Orr, M. E. (2021). Senolytic Therapy to Modulate the Progression of Alzheimer's Disease (SToMP-AD): A Pilot Clinical Trial. In The Journal of Prevention of Alzheimer's Disease (pp. 1-8). SERDI. https://doi.org/10.14283/jpad.2021.62

[13]: Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study (PEARL) (2022, October 04) https://clinicaltrials.gov/ct2/show/NCT04488601 ClinicalTrials.gov

[14]: Hill, S. (2021, September 1). PEARL Is Funded, Rapamycin Longevity Clinical Trials Begin. https://www.lifespan.io/news/pearl-is-funded-rapamycin-longevity-clinical-trials-begin/

[15]: AgelessRx. (2022, June 30). PEARL Trial to Prolong Life With Longevity Products. https://agelessrx.com/pearl/

[16]: forever-healthy. (2022, December 23). Forever Healthy - today, tomorrow and far beyond . . . Forever Healthy. https://forever-healthy.org/

[17]: LongevityTech.fund - Home. (2023, January 05). https://www.longevitytech.fund/

More Popular Science Commentary on the Longevity Industry
https://www.fightaging.org/archives/2023/01/more-popular-science-commentary-on-the-longevity-industry/

It is interesting to see the present state of popular science commentary on efforts to treat aging as a medical condition, given the recollection of widespread skepticism and mockery even as recently as a decade ago. The large-scale funding, many serious research programs, and dozens of new biotech companies are ensuring that the popular science press at least does its homework on the science underlying the prospects for human rejuvenation before committing an opinion to paper. Today's bootstrapping era of progress is very different from the turn of the century, a great deal more is being accomplished, but these are still only the first steps on a longer road, populated by many more travelers than presently the case.

Scientists now have a good handle on what causes us to age, biologically speaking: The so-called "hallmarks" of the aging process range from damage to our DNA - the instruction manual within each of our cells - to proteins that misbehave because of alterations to their chemical structure. Most excitingly, we now have ideas of how to treat them. By the end of 2023, it's likely that one of these ideas will be shown to work in humans. One strong contender is "senolytics," a class of treatments that targets aged cells - which biologists call senescent cells - that accumulate in our bodies as we age. These cells seem to drive the aging process - from causing cancers to neurodegeneration - and, conversely, removing them seems to slow it down, and perhaps even reverse it.

A 2018 paper showed that in experiments in which mice were given a senolytic cocktail of dasatinib (a cancer drug) and quercetin (a molecule found in colorful fruit and veg), not only did they live longer, but they were at lower risk of diseases including cancer, were less frail (they could run further and faster on the tiny mouse-sized treadmills used in the experiments), and even had thicker, glossier fur than their littermates not given the drugs.

There are more than two dozen companies looking for safe and effective ways to get rid of these senescent cells in people. The biggest is Unity Biotechnology, founded by the Mayo Clinic scientists behind that mouse experiment and with investors including Jeff Bezos, which is trialing a range of senolytic drugs against diseases like macular degeneration (a cause of blindness) and lung fibrosis. There are many approaches under investigation, including small proteins that target senescent cells, vaccines to encourage the immune system to clear them out, and even gene therapy by a company called Oisín Biotechnologies.

Dehydration as an Accelerator of Aging
https://www.fightaging.org/archives/2023/01/dehydration-as-an-accelerator-of-aging/

Animal studies show that long term inadequate hydration shortens life span, causing changes in cell behavior similar to that of aging. Using sodium levels in blood samples as a proxy measure for hydration, researchers here show that high sodium (meaning poor hydration) correlates with increased risk of age-related disease in large study populations. The effect size is fairly large, in the same ballpark as sizable lifestyle differences. Given the low cost of adjusting water intake, perhaps something to bear in mind.

In this study, we report on serum sodium in the upper part of the normal range being a risk factor for accelerated aging. In the Atherosclerosis Risk in Communities (ARIC) study, odds to be biologically older than chronological age was increased in the study participants whose serum sodium exceeded 142 mmol/l, reaching 50% increased odds at sodium levels exceeding 144 mmol/l. Such elevated biological age at middle age (47-68 years) translates into an approximate 20% increased risk of premature mortality at sodium levels greater than 144 mmol/l and increased risk to develop chronic diseases, that was already evident at sodium concentrations greater than 140 mmol/l and increased to approximately 40% higher risk in 143-146 mmol/l group.

The results of our study support the hypothesis that optimal hydration can potentially be such systemic preventive approach that is able to prolong diseases-free lifespan. Our data are consistent with previous reports from epidemiological and interventional studies that link hypohydration biomarkers including higher serum sodium and copeptin as well as low fluid intake with adverse health effects and increased risk of mortality. In agreement with the ARIC data from four U.S. communities that were used in current study, similar sodium levels, greater than 144 mmol/l, were found to be associated with increased risk of all-cause and chronic disease associated mortality within 3-6 years for U.S. adults aged 51-70 years in 2009-2012 National Health and Nutrition Examination Survey (NHANES).

The main limitation of our study is its observational nature resulting in the possibility of residual confounding. This common limitation of the observational studies is reduced to some degree in our case, because the idea for this analysis originated from a well-controlled mouse study in which lifelong water restriction shortened life span and promoted degenerative changes in multiple organ systems. In addition to the direct effect of life-long water restriction on life span and degenerative changes in the mouse model, pro-aging effects of hypohydration is also supported by other results from previous basic research studies. In those studies, increased sodium in cell culture models as well as water restriction in mouse model triggered the same changes that have been identified as underlying factors for accelerated aging and are currently considered as targets for anti-aging interventions.

Commentary on More Drastic Scenarios of Partial Brain and Full Body Replacement
https://www.fightaging.org/archives/2023/01/commentary-on-more-drastic-scenarios-of-partial-brain-and-full-body-replacement/

Is outright replacement of tissues a viable option for the treatment of aging? There are factions within the longevity-interested community who think that the paths to either (a) engineering replacement brain tissue for parts of the brain not involved in memory, or (b) transplantation of an old head onto a young body or brain into a young body, are short enough to be worth pursuing, where "short enough" means a few decades of work given sufficient funding. To my mind, major surgery of the sort implied by replacement of large sections of tissue or entire organs is something to be avoided in later life, given the risks and cost. It is better to pursue a strategy of introducing new stem cells or repairing existing cell populations, a more gentle approach that would avoid the need for surgery, and at this point doesn't seem to require a much longer timeline for development.

Brain or cerebral organoids are very specific neuronal cell cultures that were developed from human-induced pluripotent stem cell cultures, but with a slightly modified protocol. Grown spheroids of pluripotent stem cell cultures can be integrated within special solubilized membrane matrices which can support growing cells in a 3D environment, hence, producing organoids. Several scientific publications have already successfully shown that such cerebral organoid cultures present diverse populations of neurons and display processes like cortical development and cell migration. They also excrete their own extracellular matrix with many physiologically relevant components like hyaluronic acid, proteoglycans, and various functional enzymes.

Human embryonic stem cell-derived brain organoids have been implemented with needles into the damaged brain parts of cortical impact-modeled severe combined immunodeficient mice. Grafted organoids not only survived, but also differentiated, showed electroactivity, and extended long signal projections. Moreover, they promoted brain tissue repair and vascularization, learning and memory ability, and reduced glial scarring. The study also raised more questions, like how far the transplanted grafts can go in terms of repairing traumatic brain damage and scarring, as well as how to improve the survival of these neural stem cells in the brain in the future.

Since 2012, there have been some efforts regarding brain transplantation in mice models. A Chinese orthopedic surgeon, famous for being a part of the team that successfully performed the first hand transplant, tried to graft a mouse's head onto another mouse, and the grafted heads survived for about half a year. Somewhere around the same time, an Italian brain surgeon published the protocol that claimed it would make human head transplantation possible. A later review discussed various protective strategies in head transplantation, as well as several protocols to keep the vascular systems connected and brains under hypothermia.

In 2017, further work took place on a cross-circulated bicephalic model of head transplantation to study the long-term effects of transplant rejection and blood flow restrictions during the head transference phase. By using vascular grafts, they connected the thoracic aorta and the superior vena cava from one rat to the carotid artery and extracorporeal veins of another rat. A third rat was used as a blood reservoir and its carotid artery and extracranial vein were connected to the donor rat with silicone tubes before the thoracotomy was performed on the donor rat. A pump and a heating device were connected to the silicone tubes to ensure regular blood supply and to prevent brain hypothermia. After performing the transplant surgery, the donor rat had pain and corneal reflexes, and the surgery opened up the possibility for the long-term survival of the patient.

Such scientific procedures have always drawn a lot of media frenzy and raised many ethical dilemmas. The first feeling people get when they hear "head transplant" or "brain transplant" is simply an ick. Funnily enough, they don't seem to respond in the same way when they hear about liver or kidney transplants. So far, head transplant surgeries have not been successful on live animal models, let alone on humans. While the ethical implications of such a procedure are immense, the technological limitations are such that it is too early to think about ethics. The largest technical limitation, like with any transplant, is still the immune response against the new "foreign" body. Even with increasing numbers and more frequent organ transplantations, particularly liver transplants, rejection still occurs very often, sometimes even a year after the surgery.

Neuroinflammation Is a Prominent Feature of Alzheimer's Disease
https://www.fightaging.org/archives/2023/01/neuroinflammation-is-a-prominent-feature-of-alzheimers-disease/

Researchers are increasingly considering chronic, unresolved inflammation in brain tissue to be an important pathological mechanism in Alzheimer's disease. Removing senescent cells from the brain has reduced pathology in mouse models of Alzheimer's disease. While, as ever, the issue with all such models is their artificiality, as mice do not naturally suffer anything resembling Alzheimer's disease, it is well established that inflammation is a feature of Alzheimer's disease in humans. We have a good idea as to the major causes of this inflammation: senescent cells, an altered gut microbiome, debris from stressed cells that provokes an innate immune reaction, and so forth. Targeting the causes of excessive inflammation without suppressing the whole immune response may well prove to be a useful preventative treatment for many age-related conditions.

Alzheimer's disease (AD) should be viewed as a systemic disease that involves dynamic processes in the peripheral and central immune compartments. The conceptualization of the pathogenesis of AD remains elusive, with many competing hypotheses, particularly those based on proteopathic and immunopathic mechanisms. The peripheral and central immune systems are dysregulated in AD and are related to the cognitive function and clinical status. They may change in a non-linear manner over time, and burgeoning evidence also suggests that the roles of the innate and adaptive immune processes differ depending on the pathological stage of AD.

Animal studies have provided insights into the possible mechanisms of peripheral and central immune communication, including direct pathways that involve peripheral immune cell infiltration of the central nervous system (CNS), as well as indirect pathways that involve the systemic-inflammation-driven modulation of the microglial function. The possibility of the involvement of other processes, such as the immune system, in AD remains underexplored, even though many immune mechanisms, such as phagocytosis, aid in the reduction in AD pathologies and, on the contrary, the dysfunction of the immune system has largely been painted as detrimental to the AD pathology. Recently, there has been increasing interest in the role of the immune system in neurodegeneration due to the accumulating evidence stressing the role of the immune system as an essential factor or a major driver of neuroinflammation processes, Alzheimer's pathogenesis and AD progression. In fact, immunosenescence is a dysregulation of the immune system that accompanies aging.

Immunotherapies and neuroimmune manipulations, which can treat a wide array of diseases, can effectively treat the disease and the changes it makes to our body's watchdog, the immune system. Moreover, the suppression of inflammatory cytokines has been seen to be beneficial in immunomodulation. In order to fight neuroinflammation under chronic neurodegenerative conditions, systemic immunity should be boosted rather than suppressed. Thus, we stress the idea that, in efforts to fight AD, it might be possible to target the immune system rather than directly target specific disease-escalating factors within the brain. The rebalancing of the immune response and its exploitation to wipe toxic plaques from the brain may bring new hope for a safe and effective treatment for this devastating illness.

Evidence for Age-Related Hearing Loss to Contribute to Cognitive Impairment
https://www.fightaging.org/archives/2023/01/evidence-for-age-related-hearing-loss-to-contribute-to-cognitive-impairment/

Age-related hearing loss and cognitive impairment may arise from the same underlying processes of neurodegeneration, but equally there is evidence for each of these forms of impairment to contribute to the other. Today's paper is an example of this sort of analysis, in which the researchers employed data on hearing aid use in older patients as a way to investigate this relationship. They find that hearing loss appears to contribute to cognitive impairment.

Modifiable risk factors for dementia include untreated mid-life hearing loss, and it has been estimated that 8% of dementia cases globally are attributable to this factor. Proposed mechanisms underlying the relationship between hearing loss and the development of dementia include (i) common underlying pathology (probably vascular), (ii) impoverished input affecting brain structure and function, (iii) cognitive resources overoccupied in listening unavailable for higher functions and (iv) interaction between auditory function and dementia pathology. These mechanisms are not mutually exclusive.

Health records data from 380,794 Veterans who obtained hearing aids from the US Veterans Affairs healthcare system were analysed. Consistent with previous findings, we found that patients over 60 years of age without cognitive impairment at the time of hearing-aid fitting, who remained persistent hearing-aid users, had 27% reduced odds of receiving a dementia diagnosis 3.5-5 years after hearing-aid fitting than patients who did not persist in hearing-aid use. Our odds ratio (OR) of 0.73 is broadly in line with the hazard ratio of 0.82 found in a large sample of adults over 66 years of age with diagnosed hearing loss. The adjusted OR for incident dementia was 0.73 for persistent (versus non-persistent) hearing-aid users. The adjusted OR for hearing-aid use persistence was 0.46 in those with pre-existing dementia (versus those remaining free of mild cognitive impairment and dementia).

This suggests that of the four possible mechanisms linking hearing loss and dementia, the first (common pathology) is not dominant, since hearing-aid treatment cannot affect that pathology. Further probing of candidate mechanisms would at the very least require data on duration of hearing loss, which was not available in our dataset. This study provides (to the authors' knowledge) the first quantitative evidence that the diagnosis of dementia is associated with subsequent lower persistence of hearing-aid use. This may be due to reduced abilities to perform instrumental activities, or diverse other mechanisms, including memory problems, reduced motivation to engage in social interaction, and carers prioritising other aspects of care.

Do TDP-43 Aggregation and Tau Aggregation Have Overlapping Mechanisms?
https://www.fightaging.org/archives/2023/01/do-tdp-43-aggregation-and-tau-aggregation-have-overlapping-mechanisms/

The diverse processes of neurodegeneration are all running at the same time in an aging brain, with some individuals exhibiting more of one or less of another. It is challenging to pick apart distinct mechanisms in aging tissue to decide whether not they contribute to one another, or share specific underlying causes. The question of the direction of causation for specific mechanisms in aging is similarly challenging. Here, researchers discuss possible links and overlapping mechanisms for the aggregation of altered forms of TDP-43 and tau, both characteristic of the aging brain.

Autopsy-based research has revealed that comorbid pathology often has a disease-specific manner, in terms of the biochemical properties, morphological characteristics, and spatial distributions of aggregates, and has an impact for clinical phenotypes. Genetic studies have identified overlapping genetic risk factors between limbic-predominant age-related TDP-43 encephalopathy (LATE) and Alzheimer's disease (AD) or between TDP-associated ALS and frontotemporal dementia or tauopathies. These facts indicate that comorbid pathology is not an incidental bystander, but a part of the disease pathogenesis. It will be important to determine when a TDP-43 or tau pathology is comorbid during disease pathogenesis; antemortem studies using functional neuroimaging to target aggregated proteins will be useful in the future.

Basic research findings have suggested that the molecular pathways are partially overlapped between TDP-43 proteinopathies and tauopathies. In vivo studies have revealed that aggregated TDP-43 altered the splicing of tau or exacerbated tau aggregation. Moreover, perturbation of the autophagosome-lysosome system-related molecules has been reported in both TDP-43 proteinopathy and tauopathy models. However, it currently seems to be difficult to reproduce the condition of double proteinopathy comprising TDP-43 and tau pathologies by altering just one of the known related molecules or genes. This fact suggests that pathogeneses of TDP-43 proteinopathies and tauopathies arise from multifactorial and polygenetic processes. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.

Using Engineered Cancer Cells to Rouse an Immune Response Against Tumors
https://www.fightaging.org/archives/2023/01/using-engineered-cancer-cells-to-rouse-an-immune-response-against-tumors/

Researchers here report on an interesting approach to encouraging the immune system to attack cancer cells in an established tumor. They engineer cancer cells to be more visible to the immune system and then return them to the body, where they will naturally home to the site of the tumor. At present the proof of concept is established in animal models; time will tell as to whether this line of work attracts the support needed to progress further towards the clinic.

Cancer vaccines are an active area of research for many labs, but the new approach to treating the brain cancer glioblastoma that researchers have taken is distinct. Instead of using inactivated tumor cells, the team repurposes living tumor cells, which possess an unusual feature. Like homing pigeons returning to roost, living tumor cells will travel long distances across the brain to return to the site of their fellow tumor cells. Taking advantage of this unique property, the team engineered living tumor cells using the gene editing tool CRISPR-Cas9 and repurposed them to release a tumor cell killing agent.

In addition, the engineered tumor cells were designed to express factors that would make it easy for the immune system to spot, tag, and remember them, priming the immune system for a long-term antitumor response. The team tested their repurposed CRISPR-enhanced and reverse-engineered therapeutic tumor cells in different mice strains, including one that contained bone marrow, liver, and thymus cells derived from humans, mimicking the human immune microenvironment. The team also built a two-layered safety switch into the cancer cell, which, when activated, eradicates therapeutic tumor cells if needed. This dual-action cell therapy was safe, applicable, and efficacious in these models, suggesting a roadmap toward therapy.

The Genetic Basis for Aging: Much Data, Few Conclusions
https://www.fightaging.org/archives/2023/01/the-genetic-basis-for-aging-much-data-few-conclusions/

As this paper notes, there is a great deal of data regarding genetics and aging, but as yet little in the way of useful conclusions when it comes to applying this knowledge to extend the healthy human life span. From a reductionist point of view, it is clear that genetic differences lie at the root of the large differences in trajectory of aging and life span that are observed between species. The evidence to date suggests that genetic variance within a species has little impact on life span, however. The observe range of life expectancy within a species is mostly a matter of environment and lifestyle. A great deal of funding and effort goes into the continued investigation of the genetics of human longevity, but it isn't at all clear that this will lead to ways to meaningfully extend healthy life span.

The search for key genes of aging and longevity and the study of intracellular signaling pathways can become the basis for the development of methods for diagnosis and correction of conditions that accompany the aging process and for the development of therapeutic methods that increase the duration and quality of life. Numerous studies using model organisms, study of the main mechanisms of cellular aging, large-scale genome-wide association studies in humans, and genetic studies of long livers made it possible to identify various evolutionary conservative metabolic pathways that are similar in various species of organisms and humans, as well as individual genetic loci that affect key traits of human aging and life expectancy.

A significant increase in the life expectancy and the inevitable demographic aging of mankind are pushing researchers to focus more and more on the search for genetic determinants of healthy aging and longevity. In this regard, there is a need to create publicly available high-quality resources with open and integrated databases. Currently, there are already several large resources containing databases of candidate genes and genetic variants associated with human longevity and aging.

Despite the success in identifying genes and metabolic pathways that may be involved in the life extension process in model organisms, the key question remains to what extent these data can be extrapolated to humans, for example, because of the complexity of its biological and sociocultural systems, as well as possible species differences in life expectancy and causes of mortality. New molecular genetic methods have significantly expanded the possibilities for searching for genetic factors of human life expectancy and identifying metabolic pathways of aging, the interaction of genes and transcription factors, the regulation of gene expression at the level of transcription, and epigenetic modifications. This review presents the latest research and current strategies for studying the genetic basis of human aging and longevity: the study of individual candidate genes in genetic population studies, variations identified by the GWAS method, immunogenetic differences in aging, and genomic studies to identify factors of "healthy aging."

Implanted Hair Follicle Cells Produce Remodeling of Scar Tissue
https://www.fightaging.org/archives/2023/01/implanted-hair-follicle-cells-produce-remodeling-of-scar-tissue/

Researchers here report on an interesting approach to treating scar tissue in skin. Noting that hair follicles appear to promote regeneration in healthy skin, they implant follicles into scar tissue. The result is some degree of beneficial remodeling of the scar. While the next logical step is to better understand the signaling involved in this effect, it is worth noting that researchers have been attempting to understand the mechanisms of skin regeneration for some time now. It is a very complex situation involving many different cell types, structures, and phases of activity that change over time. There is unlikely to be a simple solution that recapitulates the influence of follicle tissue on skin structure and maintenance.

Compared to scar tissue, healthy skin undergoes constant remodelling by the hair follicle. Hairy skin heals faster and scars less than non-hairy skin - and hair transplants had previously been shown to aid wound healing. Inspired by this, the researchers hypothesised that transplanting growing hair follicles into scar tissue might induce scars to remodel themselves. In a new study involving three volunteers, skin scars began to behave more like uninjured skin after they were treated with hair follicle transplants. The scarred skin harboured new cells and blood vessels, remodelled collagen to restore healthy patterns, and even expressed genes found in healthy unscarred skin.  

After transplantation, the follicles continued to produce hair and induced restoration across skin layers. Scarring causes the outermost layer of skin - the epidermis - to thin out, leaving it vulnerable to tears. At six months post-transplant, the epidermis had doubled in thickness alongside increased cell growth, bringing it to around the same thickness as uninjured skin. Scar maturation leaves the dermis with fewer cells and blood vessels, but after transplantation the number of cells had doubled at six months, and the number of vessels had reached nearly healthy-skin levels by four months. Scarring also increases the density of collagen fibres which causes them to align such that scar tissue is stiffer than healthy tissue. The hair transplants reduced the density of the fibres, which allowed them to form a healthier, 'basket weave' pattern, which reduced stiffness.

The researchers are unsure precisely how the transplants facilitated such a change. In their study, the presence of a hair follicle in the scar was cosmetically acceptable as the scars were on the scalp. They are now working to uncover the underlying mechanisms so they can develop therapies that remodel scar tissue towards healthy skin, without requiring transplantation of a hair follicle and growth of a hair fibre. They can then test their findings on non-hairy skin, or on organs like the heart, which can suffer scarring after heart attacks, and the liver, which can suffer scarring through fatty liver disease and cirrhosis. 

Assessment of Somatic Mosaicism as a Biomarker of Aging
https://www.fightaging.org/archives/2023/01/assessment-of-somatic-mosaicism-as-a-biomarker-of-aging/

Random mutations in stem cells lead to a pattern of mutations throughout the tissue supported by those stem cells, as daughter cells are imprinted with a particular combination of mutations based on the ancestor stem cell and the timing of cell division versus timing of mutations. In principle, one can take a sample of somatic cells and reverse engineer the progression of mutations in the underlying stem cell and progenitor cell populations from the variety and combination of mutations observed in the sample. That progression can then be used as the basis for a measure of chronological or biological age, a novel form of aging clock to join the many others derived from age-related changes in biological data.

Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge.

Here we show that somatic mutations detected using single-cell RNA sequencing (scRNAseq) from hundreds of cells can be used to construct a cell lineage tree whose shape correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. Penalized multiple regression is used to select from over 30 possible metrics characterizing the shape of the phylogenetic tree resulting in a Pearson correlation of 0.8 between predicted and chronological age and a median absolute error less than 6 years.

The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a single number for biological age, it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. This complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.