Fight Aging!

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Contents

• The Future of Cryopreservation
• Does the Gut Microbiome Contribute to Age-Related Anabolic Resistance
• Nicotinamide Riboside Supplementation Beginning in Mid-Life Slows Osteoporosis in Mice
• A Gene Therapy Platform Applied to Skin Rejuvenation
• It is Faintly Ridiculous to Propose that Human Life Span Cannot be Increased by Altering Metabolism
• Cap-Independent Translation of mRNA as a Common Mechanism of Longevity
• A Model to Demonstrate the Excessive T Cell Expansion and Differentiation of an Aged Immune System Produces Chronic Inflammation in Tissues
• Targeting Cell Maintenance Processes to Improve Mitochondrial Function and Slow Aging
• Loss of Neurogenesis with Age is in Part Mediated by Inflammatory Signaling in the Brain
• In Horses, the Gut Microbiome Interacts with Mitochondria to Improve Function
• Noting the Work of Jim Mellon to Advance the Longevity Industry and Related Research
• COVID-19 Data Shows the Importance of Thymic Atrophy in Aging
• Yuva Biosciences as an Example of the Cosmeceuticals Path to Development of Aging Interventions
• Lysosomal Dysfunction and the Death of Neurons via Ferroptosis
• Treating Sleep Apnea Lowers Dementia Risk By 20-30%

The Future of Cryopreservation
https://www.fightaging.org/archives/2021/04/the-future-of-cryopreservation/

The ability to cryopreserve and thaw organs via vitrification, without ice formation and significant tissue damage, allowing for indefinite storage time, would go a long way towards simplifying the logistics and reducing the costs of present organ donation and future tissue engineering of organs for transplantation. Cryopreservation via vitrification also offers the possibility of indefinitely storing the terminally ill and recently deceased until such time as medical science advances to the point of restoration. This has been practiced for several decades by the small cryonics industry.

Cryonics is a long shot, but better odds by far than the grave. The challenges to progress in cryonics seem largely technical: it is presently possible to vitrify organs, but thawing them safely is another story entirely. Scaling up the reliability of vitrification processes to the whole body continues to be a work in progress, even while practiced by the cryonics community. The funding for technological progress in this field remains sparse, a situation that could be remedied by an industry of organ cryopreservation associated with donation and transplantation. Given a world in which it is routine to vitrify and thaw donated organs, it will be far easier to accept the cryopreservation of terminally ill individuals in hope of a better, more capable future, and more funds will be drawn to that goal.

Cryopreservation has multiple and important applications, particularly in medicine. The fact that it can significantly slow down all biochemical reaction kinetics renders cryopreservation highly attractive as a means to preserve organs and therefore facilitate the transplantation process. The lack of organ availability constitutes a major challenge and a significant medical burden for society. According to the World Health Organization (WHO), only 10% of the worldwide need for organ transplantation was met in 2010. The lack of transplantable organs stems partially from a shortage of suitable donated organs, but more importantly from the lack of preservation capability. Although the number of transplanted organs is much lower than what is actually needed worldwide, it was estimated that approximately two thirds of potential donor hearts are discarded.

Kidneys and hearts have been the most widely studied organs, but neither has been consistently recovered after cooling to temperatures lower than -45 °C. Nevertheless, sporadic survival of kidneys has been claimed after cooling to lower temperatures. Along those lines, researchers reported success in vitrifying a rabbit kidney at -130 °C which was rewarmed using a special conductive warming technique combined with perfusion. After warming, the kidney was transplanted into a recipient rabbit that lived for 48 days with a working kidney before being sacrificed.

Cryopreservation is an interdisciplinary endeavour between medicine, biology, bioinformatics, chemistry and physics. The main challenges still to overcome are scaling up current methods to larger volumes and complex tissues. The larger the organ, or tissue volumes to be vitrified, correspondingly more time is required to cool and warm the organ. Not only thermal conductivity is an issue here but cryoprotective agent (CPA) viscosity limits for perfusion systems play a role. The protocols for cell lines, or even small tissues, such as sperm, eggs, or corneas, cannot be replicated in larger human organs, which necessitate toxically high CPA concentration to inhibit ice formation during the longer time spent between the melting temperature and the glass transition temperature, and of course gives more time for toxic insults to accumulate.

The best techniques to get around these problems in small tissues use combinations of CPAs to reduce toxic effects of any single agent, using CPAs with weak water interactions to minimise disruption of hydration layers around biomolecules, using CPAs with mutual toxicity neutralisation effects, and reducing penetrating CPA concentrations by adding non-penetrating CPAs and ice blockers. Nonetheless, little is known about the mechanisms at work.

The challenges in cryobiology are not insurmountable. Future research will focus on ever more complex ways to prevent ice formation and mitigate cryoprotectant toxicity; novel cryoprotectants which exert disproportionately large cryoprotective effects compared to their concentration, in silico molecular modelling, and enhanced understanding of the processes that occur during cryopreservation will all be employed. One could envision a universal cryoprotectant solution, suitable for use in a range of tissue types, and physical advancements enabling high cooling and warming rates, or the manipulation of ice formation for large volume vitrification or freezing.

Whilst the concepts have been long known, the dedicated field of cryobiology dates back only around 70 years. In that time, it has advanced from freezing spermatozoa using glycerol, to vitrifying tissues, and even small organs using complex multi-component solutions. This is remarkable progress given that cryopreservation is as yet a relatively niche field of study, without garnering much attention in schools or undergraduate courses and utilising a fraction of the funding which is allocated to other causes. As such, there are still many opportunities that lie ahead, from short-term improvements in transplantation biology, to ambitions that may once have been viewed as science fiction, such as the building of organ banks or long-term suspended animation.

Does the Gut Microbiome Contribute to Age-Related Anabolic Resistance
https://www.fightaging.org/archives/2021/04/does-the-gut-microbiome-contribute-to-age-related-anabolic-resistance/

The gut microbiome is a highly varied collection of microbial populations that acts in symbiosis with the body to process food and provide needed metabolites. With age, there is a detrimental shift in these populations. Those generating useful metabolites, such as butyrate, diminish in number. Those capable of infiltrating tissue, generating inflammatory compounds, or otherwise interacting with the immune system to provoke chronic inflammation increase in number. Researchers have demonstrated that this is a meaningful process in short-lived species by transplanting a youthful gut microbiome into older individuals. In killifish, for example, this produces extension of life. In mice, it has been shown to beneficially change measures of metabolic aging. In aged humans, better health at a given age corresponds to a younger gut microbiome configuration.

In today's open access review paper, researchers look at just one set of processes that may be influenced by the gut microbiome, those contributing to age-related anabolic resistance. Muscle growth depends on anabolism - the construction of proteins needed for cellular structures, new cells, and tissue mass - and an aged body does not produce the same level of anabolic response to stimuli such as exercise or increased protein intake. This leads to sarcopenia, the characteristic, steady loss of muscle mass over the years. Why does anabolic resistance arise with age? It is proposed that the changing populations of the gut microbiome play a role, though as is usually the case in aging, assigning a relative importance to different processes is considerably harder than identifying those processes in the first place.

Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance

The aging process is associated with pervasive physiological declines that are exemplified by reductions in size and function of skeletal muscle (i.e., sarcopenia). Given the association between sarcopenia with adverse health outcomes (e.g., falls, fractures, and mobility limitations) and mortality, a more definitive understanding of the biological mechanisms underlying sarcopenia is warranted.

The regulation of skeletal muscle mass is dictated by temporal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Though the effect of aging on whole body protein turnover was initially a subject of great contention, it is now generally accepted that healthy aging is not accompanied by accelerated MPB. Furthermore, comparable rates of basal MPS and turnover have been observed in healthy older and younger adults. However, in older animals and humans alike, the sensitivity of MPS to anabolic stimuli, such as protein feeding, is substantially diminished when compared with that in the young. This blunted anabolic responsiveness, termed anabolic resistance, is highly characteristic of aging skeletal muscle, and much effort is being devoted to delineating the etiology of this phenomenon. Greater insight into this area may help to optimize the rehabilitative role of protein intake for the maintenance and/or recovery of skeletal muscle tissue in older adults.

The gut microbiota refers to the collective of bacteria, archaea, viruses, and eukaryotic microbes that reside in the gastrointestinal tract. Though best known for its role in nutrient uptake, the gut microbiome is also intricately connected to a diverse array of physiological systems; influencing metabolic function, protecting against pathogens, and modulating immune response. Recent studies by several independent research groups have provided evidence for a bidirectional gut-muscle axis with profound implications for aging skeletal muscle and sarcopenia. As studies supporting a role for the gut microbiome in regulating muscle mass and function continue to accumulate, whether baseline microbial signatures may influence anabolic potential is deserving of deeper inquiry.

The purpose of this review will be to provide evidence in support of the hypothesis that age-associated changes in gut microbiota composition contribute to anabolic resistance following protein feeding in older adults that underlie sarcopenia. We will begin by outlining how changes in gut microbiota that are hallmarks of aging may impact protein digestion and amino acid absorption, reduce circulating amino acid availability, contribute to anabolic hormone deficiencies or impair responsiveness, and play a role in intramuscular signaling deficits - all of which may underlie age-related anabolic resistance.

A bidirectional gut-muscle axis with implications for aging skeletal muscle size, quality, and function has been proposed. Extending on this aging gut-muscle axis, we propose that age-related changes in gut microbiota may detract from the anabolic response of skeletal muscle to protein feeding in older adults. Intriguingly, many of these adverse microbial modifications seem to be avoided in long-lived models of highly successful aging. Through the above, we describe how commonly observed age-related changes in the gut microbiome may compromise anabolic responsiveness through their impact on protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and anabolic intramuscular signaling.

While some of these age-associated gut microbiome alterations may simply be a product of the natural aging process, we believe that lifestyle modification (i.e., improved diet, exercise, sleep, and reducing medication use) may help to preserve gut microbial equilibrium in a manner that would be anticipated to maintain anabolic capacity in older years. To validate this hypothesis, interventional studies attempting to manipulate microbial ecology as a means to potentiate muscle protein synthetic responses to anabolic stimuli (i.e., protein feeding) in older individuals are needed.

Nicotinamide Riboside Supplementation Beginning in Mid-Life Slows Osteoporosis in Mice
https://www.fightaging.org/archives/2021/04/nicotinamide-riboside-supplementation-beginning-in-mid-life-slows-osteoporosis-in-mice/

In today's open access paper, researchers report that long-term supplementation with nicotinamide riboside in mice, starting from mid-life and continuing into old age, slows the pace of osteoporosis. The extracellular matrix of bone tissue is constantly remodeled over time, broken down by osteoclasts and built up by osteoblasts. Osteoporosis is caused by a growing imbalance between these two processes that favors destruction over creation. Bones lose mass and become brittle as a result, eventually becoming a serious health issue.

Many mechanisms are proposed to contribute to osteoporosis. Chronic inflammation, for example, alters the behavior of bone cells in ways that favor the activity of osteoclasts. Senescent cells accumulate with age and the source of a great deal of inflammatory signaling. Selectively destroying senescent cells via senolytic treatments has been shown to reverse osteoporosis to some degree. Another related mechanism involves the formation of advanced glycation endproducts (AGEs) that cross-link matrix proteins. This also is thought to be related to the chronic inflammation of aging.

Of relevance to today's research materials, mitochondrial dysfunction is also implicated in the development of osteoporosis, via its effects on cell development and activities. Mitochondria are the power plants of the cell, and when the supply of chemical energy store molecules created by mitochondria is diminished, near all cell processes suffer in some way.

In recent years, loss of NAD+ has been identified as one of the proximate causes of this issue, this being an important component in the chemical engines that operate inside mitochondria. NAD+ levels fall with age, for reasons that are far from fully explored. Various approaches to NAD+ upregulation have been assessed in mice and human trials, mostly supplementation with compounds derived from vitamin B3 such as nicotinamide riboside. The results in humans have overall been mixed at best. Nonetheless, results such as this one continue to accumulate in mice.

A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

Here we show that NAD+ supplementation by the NAD+ precursor nicotinamide riboside (NR) can restore a youthful number of osteoprogenitor cells and attenuate skeletal aging in female mice. These, along with the findings that the levels of NAD+ decline with age in osteoblast progenitors, strongly suggest that NAD+ is a major target of aging in osteoblastic cells. A decrease in NAD+ was also seen in bone marrow stromal cells from 15-month-old when compared to 1-month-old mice. In agreement with our findings, long-term administration of NMN increased bone mineral density in male C57BL/6 mice. In contrast, administration of NMN to 12-month-old mice for only 3 months was not sufficient to alter bone mass.

We also found that the protein levels of Nampt in osteoblastic cells from old mice were lower than in cells from young mice. These along with the findings that deletion of Nampt in mesenchymal lineage cells is sufficient to decrease bone mass support the premise that the age-associated decrease in NAD+ in osteoblast progenitors attenuates bone formation. Further support is provided by evidence that NR administration increases osteoprogenitor number and mineralizing surface in aging mice. In tissues such as muscle and intestine, progenitor cells are critical targets of the anti-aging effects of NR. Nonetheless, the systemic nature of NR treatment precludes definitive conclusion about the target cells responsible for the beneficial effects on the skeleton.

We and others have shown that osteoprogenitors from old humans or mice exhibit markers of cellular senescence. Elimination of senescent cells via genetic or pharmacologic manipulations increases bone mass in aged mice, suggesting that cellular senescence contributes to skeletal aging46. Our present findings that NR administration decreases markers of senescence in osteoblast progenitors from old mice provide strong support for the contention that a decline in NAD+ is a major contributor to the age-associated bone cell senescence. This contention is further supported by evidence that a decrease in NAD+ exacerbates replicative senescence in bone marrow-derived stromal cell cultures. NR administration also attenuates cellular senescence in brain and skin of aged mice. Interestingly, in macrophages and endothelial cells Cd38 expression can be induced by factors associated with the senescence-associated secretory phenotype (SASP), suggesting that cellular senescence re-enforces the decline in NAD+.

Based on the results of the present work, we propose that intrinsic defects in osteoblast progenitors that cause a decrease in NAD+ contribute to the age-related decline in bone formation and bone mass. Repletion of NAD+ with precursors such as NR, therefore, may represent a therapeutic approach to age-associated osteoporosis as it does for other age-related pathologies.

A Gene Therapy Platform Applied to Skin Rejuvenation
https://www.fightaging.org/archives/2021/04/a-gene-therapy-platform-applied-to-skin-rejuvenation/

MRBL is one of the many projects relevant to the treatment of aging that is in George Church's orbit. This is a collection of gene therapy technologies intended for delivery of vectors to areas of skin directly, coupled with analysis of age-related and disease-related gene expression changes in skin cell populations to provide targets. It is a viewed as a basis for approaches in cell reprogramming that could make aged skin cells behave in a more youthful fashion, overriding their response to the age-damaged local environment.

In terms of mechanisms known to be of interest in aging, upregulation of collagen production is an obvious goal, generally agreed upon to be beneficial if achieved. A more interesting but more challenging result to aim for would be the deposition of elastin in a structurally correct manner. Beyond these two, there are many other more subtle issues in cell misbehavior related to the aging of skin, from stem cell activity to coordination of wound healing in the dermis and epidermis.

That said, it isn't clear that forcing more a youthful behavior in cells via gene therapies is the best way forward in all matters relating to aging. It neglects root causes in favor of trying to override them selectively, allowing those root causes to continue to produce all of their other consequences. Chronic inflammation, for example, has a broadly negative impact on tissue function in skin, as is also the case in other organs. Clearing senescent cells, and removing other causes of systemic inflammation, are likely better approaches than trying to force cells to perform correctly, one gene at a time, in an inflamed environment.

MRBL: Next-Generation Gene Therapy for Molecular Skin Rejuvenation

The skin is the largest organ in the body, and carries out multiple vital functions, including protective barrier functions against the loss of moisture and mechanical, UV, and other injuries, immune defense functions, as well as sensory functions. For maintaining its integrity and multifaceted performances, skin relies on a range of different cell types that compose and support its layered organization, each expressing specific molecules that together facilitate physical cell interactions and communication between them, as well as specialized functions.

The gradual decline in the production of many of those molecules is associated with the natural aging process of skin. Separately, a plethora of skin diseases are driven by mutations in single genes that can strike much earlier in life. In both cases, targeted therapeutics that could slow skin aging and directly interfere with the disease pathology of monogenic skin diseases are not available. Commonly applied treatments are merely palliative, reducing the severity symptoms or simply masking the visible damage caused to the skin without actually addressing the condition.

To overcome the lack of truly curative and targeted treatments, a multidisciplinary team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated virus (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin. Strategically targeting both disease (short-term) and aging (long-term), this next generation skin gene therapy platform builds on the insight that the pathology of genetic diseases often recapitulates specific age-related degenerations.

Fortuitously, researchers found that key targets in aging biology could be leveraged as therapeutics for monogenic diseases, as the genes affected in such diseases were also powerful determinants of the aging process. Using their new-found understanding of aging dynamics, the team has built a time-resolved genetic network of skin aging, and is currently validating novel age-driving genetic targets identified from the resulting map in cell and animal studies.

Denitsa Milanova on MRBL - Gene Therapy for Skin Rejuvenation

I'm working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It's a platform technology and has a variety of applications. We started the project looking at the hardest problem - how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we're trying to get there by modifying the levels of the right fingerprint of genes in the skin.

This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.

Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a "factory" to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.

It is Faintly Ridiculous to Propose that Human Life Span Cannot be Increased by Altering Metabolism
https://www.fightaging.org/archives/2021/04/it-is-faintly-ridiculous-to-propose-that-human-life-span-cannot-be-increased-by-altering-metabolism/

Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.

Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.

Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.

This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.

The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum life­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.

Cap-Independent Translation of mRNA as a Common Mechanism of Longevity
https://www.fightaging.org/archives/2021/04/cap-independent-translation-of-mrna-as-a-common-mechanism-of-longevity/

Researchers here show that increased levels of cap-independent translation (CIT) of messenger RNA (mRNA) take place in a diverse set of interventions known to modestly slow aging in mice, suggesting it to be a common phenomenon in these shifts of metabolism towards a slower pace of aging. CIT is a process that in part drives the movement of mRNA, produced from genetic blueprints, into ribosomes for the production of proteins. Since protein levels determine cell behavior, the way in which translation of mRNA into proteins takes place is important. The work here makes a compelling case to link altered CIT levels to mTORC1 inhibition, suggesting that mTOR, already a popular area of study, may play a role in more age-slowing interventions than thought.

Several dietary and pharmacological treatments are known to extend lifespan, including rapamycin (Rapa), acarbose (ACA), and 17-α-estradiol (17aE2). The mechanisms by which these treatments lead to lifespan extension are not well understood. Rapa inhibits the activity of the mammalian target of rapamycin (mTOR), leading at optimal doses to 20%-25% lifespan extension in male and female mice. ACA is an inhibitor of the α-glucosidase hydrolase enzymes and α-amylases, enzymes that digest carbohydrates in the small intestine, leading to reduction in glucose absorption and in peak glucose levels in blood. ACA extends lifespan by around 20% in males and around 5% in female mice. 17aE2 is a non-feminizing steroid that has a reduced affinity for the classical estrogen receptors. 17aE2 has reproducible and robust effects on male median and maximum lifespan, with no lifespan effect in females.

We hypothesized that Rapa, ACA, which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA knockout, and growth hormone receptor knockout mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT).

Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.

A Model to Demonstrate the Excessive T Cell Expansion and Differentiation of an Aged Immune System Produces Chronic Inflammation in Tissues
https://www.fightaging.org/archives/2021/04/a-model-to-demonstrate-the-excessive-t-cell-expansion-and-differentiation-of-an-aged-immune-system-produces-chronic-inflammation-in-tissues/

Researchers here use a novel model to demonstrate that T cells made to exhibiting the greater replication and differentiation characteristic of an aged immune system, leading to cellular senescence, cause chronic inflammation in heart tissue in young animals. The age-related decline of the adaptive immune system is thus sufficient to cause this sort of issue in and of itself, independently of other contributing causes, leading to tissue dysfunction. Clearing out harmful immune cells via senolytic drugs or other targeted approaches is one option, but a source of replacement T cells is also needed. A large part of the dysfunction of the aged adaptive immune system arises because the thymus, where T cells mature, atrophies in later life. Medical development must focus on at least two goals: restoring the thymus and selectively destroying harmful T cells.

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage.

Herein, we sought to clarify the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions.

In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages, and dendritic cells in the heart.

Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Targeting Cell Maintenance Processes to Improve Mitochondrial Function and Slow Aging
https://www.fightaging.org/archives/2021/04/targeting-cell-maintenance-processes-to-improve-mitochondrial-function-and-slow-aging/

Many approaches shown to slow aging in animal studies involve an increased efficiency of cell maintenance processes such as the ubiquitin-proteasome system and various types of autophagy. Here researchers discuss the improvement of autophagy in order to slow the age-related decline of mitochondrial function. Mitochondria are the power plants of the cell, with the vital role of producing chemical energy store molecules to power cellular operations. Autophagy involves targeting damaged cell structures and molecules for recycling, conveying them to be engulfed by a lysosome for disassembly into raw materials that can be reused. The subset of autophagic processes targeting damaged mitochondria for removal is termed mitophagy. Loss of mitochondrial function with age appears connected to a loss of efficiency in mitophagy, allowing for worn and dysfunctional mitochondria to persist in a cell, with various lines of supporting evidence arriving at this conclusion from different directions.

Aging manifests in a continuous decline of organismal homeostasis. Accumulating defects on the cellular level can result in cellular dysfunction that impairs normal physiology. This damage can be of extrinsic origin e.g., mutagenic radiation and toxins, or intracellular origin, like harmful reactive oxygen species (ROS) generated by defective mitochondrial respiration, advanced glycation end products or the accumulation of toxic protein aggregates. The consequences of such harm are particularly devastating to post-mitotic, fully differentiated cells with low cellular turnover rates, such as neuronal cells and cardiomyocytes.

To mitigate the detrimental effects of extrinsic and intrinsic harms, eukaryotic cells have developed various protective mechanisms. One such mechanism is proteostasis, a collective term for a network of protein quality control and degradation pathways that ensure the normal expression, folding, and turnover of proteins. During aging, proteostasis, like other cellular functions, suffer from a progressive decline, which renders the body more vulnerable to damage and age-related diseases.

In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

Loss of Neurogenesis with Age is in Part Mediated by Inflammatory Signaling in the Brain
https://www.fightaging.org/archives/2021/04/loss-of-neurogenesis-with-age-is-in-part-mediated-by-inflammatory-signaling-in-the-brain/

The immune system is intimately involved in tissue function throughout the body, but particularly so in the brain. The immune system of the brain is distinct from that of the rest of the body, the two separated by the blood-brain barrier, and the immune cells of the brain participate in a range of activities necessary to the function of neurons, as well as the creation, destruction, and maintenance of synaptic connections between neurons. It isn't surprising to find links between immune aging, inflammatory signaling, and dysfunction of many systems in the brain. The focus in the commentary noted here is on age-related loss of neurogenesis, the creation of new neurons from neural stem cells, followed by their integration into existing neural circuits. Immune cells contribute to this loss of neural stem cell activity via their inflammatory signaling.

Why neurogenesis is attenuated in elderly individuals is an intriguing question that has raised renewed interest. Mechanisms associated with declined neurogenesis in the aged brain have been attributed to inflammatory cytokines. More recently, a specific role for interferon-γ (IFN-γ) produced by CD8-expressing cytotoxic T cells has been implicated. These observations suggest a scenario in which neurogenesis, at least in part, is regulated by immune cells within the aging brain. This raises several interesting questions with regards to the characteristics of specific immune cells within the brain, the signals for their expansion and maintenance, and their role in affecting neurogenesis and cognition during normal brain aging.

Further detailed insights into these processes have now been provided. In a recently published study, researchers analyzed the subtypes, frequencies, and location of immune cells in young and aged brains. Strikingly, an abundant population of natural killer (NK) cells in the dentate gyrus of brains from old humans was observed. NK cells are innate lymphocytes, with some adaptive features, that normally play a critical role in fighting virus infections and tumors. These NK cells outnumbered neutrophils, monocytes, and adaptive T lymphocytes and B lymphocytes in the brain, and were characterized by the expression of specific activation and cytotoxicity markers. These and other observations led the authors to conclude that NK cells may accumulate in specific regions of the human brain with age, in particular in the dentate gyrus. Similar observations were made in mouse studies.

It was found that the NK cell chemokine CCL3 and the growth factors GM-CSF, IL-2 and, particularly, IL-27 were produced in relatively high amounts in the interstitial fluid of the aged dentate gyrus. In studies determining whether IL-27 derived from aged neuroblasts was necessary for local expansion and accumulation of NK cells in the aged dentate gyrus, it was observed that an IL-27-neutralizing antibody blocked these effects. Together, these and other results suggested that neuroblasts sustain NK cells and augment their cytotoxicity in the aged dentate gyrus mediated, at least in part, via IL-27.

In summary, in the brain, NK cells increase with age. They predominantly reside in the dentate gyrus, a neurogenic niche where neuroblasts are also found. As the brain ages, neuroblasts undergo cellular senescence, start to express RAE-1, and produce high levels of IL-27 that induces expansion of NK cells. Notably, RAE-1 is a ligand for the NK cell activation receptor NKG2D. These age-related alterations trigger cytotoxic activity by the NK cells leading to loss of neuroblasts, concomitantly preventing regeneration of neurons resulting in cognitive decline.

In Horses, the Gut Microbiome Interacts with Mitochondria to Improve Function
https://www.fightaging.org/archives/2021/04/in-horses-the-gut-microbiome-interacts-with-mitochondria-to-improve-function/

The study here is carried out in horses, but it is reasonable to expect to find very similar mechanisms in other mammals. The beneficial populations of the gut microbiome provide metabolites that steer cell function and exist in symbiosis with the host animal. Mitochondria, the power plants of the cell, are the evolved descendants of ancient symbiotic microbes, now an integral part of cellular processes. It is reasonable to think that the one can influence the other directly via signaling processes, as researchers discuss in these materials and elsewhere. In humans, for example, researchers have found that propionate generated by some populations of gut microbes can enhance athletic performance. There are no doubt other signals and metabolites at work as well, yet to be cataloged.

Mitochondria, which can be briefly described as the energy provider of cells, have been shown in recent studies to be interdependent with gut bacteria. In fact, many diseases associated with mitochondrial dysfunction in humans, such as Parkinson's and Crohn's have been linked to changes in the gut microbiome in many previous studies.

"Studying horses is a good way to assess the link between gut bacteria and mitochondria, because the level of exercise, and thereby mitochondrial function, performed by a horse during an endurance race is similar to that of a human marathon runner. For this study we took blood samples from 20 healthy horses of similar age and performance level, at the start and end of the International Endurance Competition of Fontainebleau, an 8-hour horse race in France. These samples provided information about the chemical signals and expression of specific genes, which is the process by which DNA is converted into instructions for making proteins or other molecules. To understand the composition of the horse's gut bacteria metabolites, we obtained fecal samples at the start of the race."

The researchers found that certain bacteria in the gut were linked to the expression of genes by the mitochondria in the cells. Furthermore, the genes that were expressed, or "turned on", were linked to activities in the cell that helped it to adapt to energetic metabolism.

"Interestingly, mitochondria have a bacterial origin - it is thought they formed a symbiotic relationship with other components to form the first cell. This may explain why mitochondria have this line of communication with gut bacteria. Improving our understanding of the intercommunication between the horse and the gut microbiome could help enhance their individual performance, as well as the method by which they are trained and dietary composition intake. Manipulating the gut microbiota with probiotic supplements as well as prebiotics, to feed the good bacteria, could be a way for increasing the health and balance of the microbiome and horses, to better sustain endurance exercise."

Noting the Work of Jim Mellon to Advance the Longevity Industry and Related Research
https://www.fightaging.org/archives/2021/04/noting-the-work-of-jim-mellon-to-advance-the-longevity-industry-and-related-research/

In the past few years Jim Mellon, high net worth investor and philanthropist, has put in a great deal of time and effort to help push forward the development of a biotech industry focused on intervention in human aging. He has donated to non-profits in the aging research space, set up aging-focused conference series, founded and raised funding for a sizable biotech company in the space, invested in other biotech startups personally, and in general has been very personable and helpful to his fellow travelers and advocates. Would that there were more people with the resources and will to dive into advancing the state of the field in this way.

How does an idea that is too unconventional for mainstream channels get funded? Today, the concept of longevity research is rapidly gaining adoption, but it wasn't long ago that angel investors and the rare NIH grant were the only options for people fighting for increased longevity. Longevity enthusiasts are likely to know names like Peter Thiel, Dmitry Itskov, J. Craig Venter, Sergey Brin, Larry Ellison, and Jeff Bezos for their personal contributions, both as philanthropists and investors. Among angel investors, Jim Mellon was one of the earliest adopters of longevity research. While his fortune has come from various other sectors, he founded Mann Bioinvest, published Cracking the Code, and started praising the healthy longevity strategy back in 2012. With all the progress and setbacks of the last decade, Jim remains optimistic about the field, recently claiming that the world is on the brink of three major revolutions, with increased longevity being one of them.

In biotech, Jim Mellon is most well-known for his role in Juvenescence, which is both a book he authored on biotech investment and a longevity company he co-founded. Juvenescence has its hand in tissue regeneration and cell therapy approaches to healthy longevity via AgeX Therapeutics and LyGenesis. While still at the preclinical stage, LyGenesis has been perhaps the most successful tissue engineering and regenerative medicine company thus far. Separately from Juvenescence, Jim Mellon also played a role as chairman of Regent Pacific during its acquisition of AI firm Deep Longevity last year. He's also invested in Repair Biotechnologies and various other companies outside the scope of Juvenescence.

Beyond his investments, Jim Mellon has also made various donations to longevity nonprofits in recent years, including the UCL Institute of Healthy Ageing, Methuselah Foundation, and SENS Research Foundation, among others. In 2020, he donated £1 million to Oriel College in order to support and advance the study of Longevity Science at Oxford University, the largest donation of its kind.

For better or worse, high-net-worth individuals are imperative to the translation of treatments from the bench to bedside. While some media organizations make negative comments that billionaires are simply attempting to buy their own immortality without regard for anyone else's health, these concerns are largely overblown. Overall, few people have done as much to increase human longevity as Jim Mellon. Beyond putting up his own capital, he's also played a major role in convincing others to do the same, thereby accelerating longevity research and moving us towards a healthier future.

COVID-19 Data Shows the Importance of Thymic Atrophy in Aging
https://www.fightaging.org/archives/2021/04/covid-19-data-shows-the-importance-of-thymic-atrophy-in-aging/

The decline of the immune system is of great importance in aging. Vulnerability to infection, a decreased surveillance of senescent cells and cancerous cells, and growing chronic inflammation all take their toll. A sizable fraction of this problem stems from the diminished supply of new T cells of the adaptive immune system. T cells begin life as thymocytes in the bone marrow, then migrate to the thymus where they mature. Unfortunately, the thymus atrophies with age, a process known as thymic involution, in which active tissue is replaced by fat. The T cell supply falters, and as a result the existing T cell population becomes ever more damaged and dysfunctional. Researchers have shown that raised cancer risk over time maps very well to the pace of thymic involution, and here more data is deployed to point out the same correlation for vulnerability to infectious disease.

Here we report that COVID-19 hospitalisation rates follow an exponential relationship with age, increasing by 4.5% per year of life. This mirrors the exponential decline of thymus volume and T-cell production (decreasing by 4.5% per year). COVID-19 can therefore be added to the list of other diseases with this property, including those caused by MRSA, West Nile virus, Streptococcus Pneumonia, and certain cancers, such as chronic myeloid leukemia and brain cancers. In addition, incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. For under 20s, COVID-19 incidence is remarkably low.

A Bayesian analysis of daily hospitalisations, accounting for contact-based and environmental transmission, indicates that non-adults are the only age group to deviate significantly from the exponential relationship. Our model fitting suggests under 20s have 53-77% additional immune protection beyond that predicted by strong thymus function alone. We found no evidence for differences between age groups in susceptibility to overall infection, or, relative infectiousness to others. The simple inverse relationship between risk and thymus size we report here suggests that therapies based on T-cell mechanisms may be a promising target.

Yuva Biosciences as an Example of the Cosmeceuticals Path to Development of Aging Interventions
https://www.fightaging.org/archives/2021/04/yuva-biosciences-as-an-example-of-the-cosmeceuticals-path-to-development-of-aging-interventions/

Yuva Biosciences is attempting to treat skin aging by improving mitochondrial function, and they are taking a cosmeceutical approach. It is far faster and less costly to bring treatments to market via the cosmetics regulatory pathway than via the Investigational New Drug pathway. One has to accept considerable restrictions over what sort of approaches can be used, meaning that one is largely constrained to using combinations of known compounds, taken from a list of those that have been well characterized already. This in turn means that effect sizes tend not to be large.

Historically this has been an industry in which profit is driven by marketing rather than efficacy, so developers have not been all that incentivized to produce products that worked. Targeting the mechanisms of aging will gradually introduce some degree of efficacy into this field, however. Or at least we can hope that this will be the case. We can look at the reduction of cellular senescence in skin following months of topical low dose rapamycin treatment, for example, or the conceptually similar but technically different OneSkin approach to topical senotherapeutics.

With an initial focus on developing cosmeceuticals, US start-up Yuva Biosciences aims to harness mitochondrial science to address skin aging and age-related hair loss. The company has developed a natural topical treatment, imminently about to enter human trials, which it hopes will demonstrate an ability to promote hair growth and reduce skin wrinkles.

During founder Keshav Singh's work to explore whether mice induced with mitochondrial dysfunction were more likely to develop cancer, he came across a surprising result. "The first thing we noticed was that, within four weeks or six weeks, these mice developed skin wrinkles, and lost hair. When we restored the mitochondrial function, the hair grew back. So that gave us a direct link between mitochondrial dysfunction and hair loss and skin aging." The results convinced Singh that he should try to discover a compound that would drive similar results and set about testing a range of natural and pharmaceutical products.

"We derived fibroblast cells from these mice, and did a very targeted screening. And, lo and behold, within a month we found a natural compound that can prevent skin wrinkles and hair loss in mice. So we started Yuva Biosciences and have started work towards commercialising both the initial compound discovered, plus a pipeline of compounds, with a focus on natural compounds, because those can go to market as cosmeceuticals. We're actually starting human trials, and we'll be conducting three trials over the next couple months - two for skin, one for hair. And so that'll provide a lot of exciting results and hopefully some exciting products."

Lysosomal Dysfunction and the Death of Neurons via Ferroptosis
https://www.fightaging.org/archives/2021/04/lysosomal-dysfunction-and-the-death-of-neurons-via-ferroptosis/

Here find supporting evidence for the SENS view of lipofuscin and lysosomal dysfunction in aging. Lysosomes are the recycling units of the cell, packed with enzymes to break down unwanted structures and molecules into raw materials. Over time, long-lived cells such as the neurons of the central nervous system are negatively affected by the build up of resilient metabolic waste that is challenging to break down. Collectively this waste is called lipofuscin, but it contains many different problem compounds, and overall is poorly catalogued. Lysosomes in old neurons are observed to be bloated and dysfunctional, leading to cells that become overtaken with broken machinery that cannot be recycled. As noted here, the end result is cell death, and an accelerated pace of neural cell death is the road to neurodegenerative conditions.

A toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for human neurons. This is the upshot of the first-ever CRISPR screens at the genome-wide level in these cells. Researchers used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis.

Zeroing in on that pathway, the researchers found that in the absence of the lysosomal protein prosaposin (PSAP), glycosphingolipids accumulate in the lysosomes, setting off oxidative stress. This results in a toxic mesh of ferrous ions and peroxidized lipids that can kill neurons via the ferroptosis pathway. The findings connect pathways that have been implicated separately in neurodegenerative disease, and support the idea that iron-rich "aging pigments" of lipofuscin, commonly spotted in older brains, might not be so benign after all.

What is the connection between PSAP and ferroptosis? Examining PSAP knockout neurons, the researchers found that the lysosomes were dramatically enlarged, and chock-full of glycosphingolipids. Strikingly, they found that these lipid-logged organelles were also electron-dense, suggesting they were loaded with iron. In fact, these densities bore an uncanny resemblance to lipid-iron granules called lipofuscin, also known as aging pigment. Lipofuscin soaks up the metal ions from the detritus of iron-rich organelles such as mitochondria, and this iron is thought to provoke the production of reactive oxygen species via the Fenton reaction.

Could this cascade play out in the aging brain? All of the culprits are there. For one, oxidative stress is known to rise in the brain with age, and lysosomal function also flags. Levels of not only lipofuscin, but also reactive iron increase in aging brains and even more so in neurodegenerative disease.

Treating Sleep Apnea Lowers Dementia Risk By 20-30%
https://www.fightaging.org/archives/2021/04/treating-sleep-apnea-lowers-dementia-risk-by-20-30/

The results of this epidemiological study suggest that suffering from untreated sleep apnea can raise the risk of later dementia and mild cognitive impairment by 20-30%. How the repeated hypoxia in the brain produced by sleep apnea results in a raised risk of dementia isn't understood in detail, but it has been shown to lead to structural changes in brain regions connected to memory. It is also possible that the correlation of obesity with sleep apnea muddies the waters, and that sleep apnea isn't actually the primary issue, given the harms dcaused by excess visceral fat tissue. That makes the data here interesting, in that it compares treated and untreated patients exhibiting sleep apnea, and finds a meaningful difference.

To examine associations between positive airway pressure (PAP) therapy, adherence, and incident diagnoses of Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia not-otherwise-specified (DNOS) in older adults, this retrospective study utilized Medicare data of 53,321 beneficiaries, aged 65+, with an obstructive sleep apnea (OSA) diagnosis prior to 2011.

Study participants were evaluated using ICD-9 codes for neurocognitive syndromes [AD(n=1,057), DNOS(n=378), and MCI(n=443)] that were newly-identified between 2011-2013. PAP treatment was defined as presence of ≥1 durable medical equipment (HCPCS) code for PAP supplies. PAP adherence was defined as ≥2 HCPCS codes for PAP equipment, separated by ≥1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses.

In this sample of Medicare beneficiaries with OSA, the majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio 0.78). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (odds ratio 0.82). PAP adherence was associated with lower odds of incident diagnoses of AD (odds ratio 0.65). In conclusion, airway pressure treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce risk of subsequent dementia.