Fight Aging!

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Contents

• Request for Startups in the Rejuvenation Biotechnology Space, 2023 Edition
• A Shabby Pop-Sci Article on the Minicircle Trial of Follistatin Gene Therapy
• Lifelong Stimulation of the Ghrelin Receptor Modestly Increases Mouse Life Span
• Epigenetic Clock Data from the CALERIE Trial of Calorie Restriction
• Digging Deeper into the Epigenetics of Supercentenarians
• Inhibiting Formation of Amyloid Oligomers as a Strategy to Slow Alzheimer's Disease
• SIRT3 Upregulation as a Basis for Improving Mitochondrial Function in the Aging Brain
• Towards Ways to Sabotage the Immune Evasion of Senescent Cells in Aged Tissues
• Loss of Hippocampal Neurogenesis in Alzheimer's Disease
• Reviewing the Characterization of Cellular Senescence in Aging
• An Alternative to Clearance for Reduction of Activated Microglia in the Aging Brain
• MLKL Knockout Slows Some Aspects of Immune Aging
• A New Record for the Longest Lived Laboratory Rat, Resulting from Plasma Dilution
• Reviewing Exercise as a Means to Slow Neurodegeneration
• Microglial Autophagy in Parkinson's Disease

Request for Startups in the Rejuvenation Biotechnology Space, 2023 Edition
https://www.fightaging.org/archives/2023/02/request-for-startups-in-the-rejuvenation-biotechnology-space-2023-edition/

It is time once again for my once-yearly set of unsolicited thoughts on biotech startups that I'd like to see join those already working hard on the basis for human rejuvenation. The industry is growing rapidly, but patchily. Partial reprogramming has received enormous attention, as has the development of senolytics. Meanwhile, other important goals in rejuvenation research languish, or presently have only one or two companies involved in clinical translation of promising academic projects. Many plausible paths forward go undeveloped; there are just as many opportunities to make a real difference in the world as there were a decade ago.

Cell Therapy for Thymus Regrowth

The thymus atrophies with age, reducing the production of new T cells to a fraction of what it once was. The adaptive immune system declines as a result, becoming cluttered with dysfunctional, broken, and worn cells. One of the more promising approaches to regrowing the aged, atrophied thymus involves intravenous delivery of cells, either progenitor thymocytes or endothelial cells, that home to the thymus. Once there, they promote growth of active thymic tissue. This has been demonstrated in mice, but the groups involved have moved on to try to find small molecule approaches, so far with only very limited progress to show for it. So why not take this cell therapy approach and bring it to the clinic? Production of universal cells from lines engineered to avoid immune rejection is presently a going concern. This is a good time to be innovating in the cell therapy sphere.

Bring Fecal Microbiota Transplantation into Widespread Use

One particular implementation of fecal microbiota transplantation was recently approved by the FDA for use in the treatment of C. difficile infection. Beyond this formal arena of medicine, there is a thriving community of individuals attempting to treat their own dysbiosis, and informal clearing houses that attempt to characterize and screen donor samples for safer use. It is well demonstrated in animal models that fecal microbiota transplantation from young to old produces a lasting rejuvenation of the gut microbiome, improved health, reduced inflammation, and extended life span. The timing has never been better to establish a venture that demonstrates the merits of this approach in humans, and then does its best to make fecal microbiota transplants available to the millions of older people who could benefit.

A Better Approach to Reversing Tissue Calcification

The state of the art in reversal of the calcium deposition and consequence loss of elasticity in the aged cardiovascular system and elsewhere is typified by Elastrin's technology, which is to say a focus on ways to improve on the established mode of EDTA chelation therapy by using a far more targeted delivery system. Is there a better way forward that can lead to larger effect sizes, a greater reduction in calcification? One would think that there should be, indeed must be if this aspect of aging is to be fully reversed.

Solutions to the Systemic Delivery Issues of Gene Therapy

Presently available gene therapy delivery techniques struggle to achieve a number of important goals. Delivery to the liver may be more or less a solved problem, but many other problems remain unsolved. Sufficient delivery throughout the body without excessive delivery to the lungs or liver following intravenous injection, for example. Or delivery to a specific minor internal organ, with minimal delivery elsewhere, following intravenous injection. Delivery platforms that can provide relatively off the shelf, 80/20 solutions to delivery of gene therapy payloads in these and other important circumstances have yet to be brought into being, but are very much needed.

A Way to Inhibit Alternative Lengthening of Telomeres

Targeting telomerase and telomeres in the clinical treatment of cancer has started in earnest with Maia Biotechnology. It remains the case that something like ~10% of cancers use alternative lengthening of telomeres (ALT) rather than telomerase to bypass limits on cell replication, however, and there is as of yet no good approach to inhibition of ALT. One of the reasons why ALT is an attractive target is that it does not operate in normal, non-cancerous cells, which removes many of the normal issues regarding off-target effects in the inhibition of cellular mechanisms. There is room here for a group to perform a broad screen for ALT inhibitor small molecules, in search of a useful lead for a preclinical development program.

Safely Replace the Hematopoietic System

The generation of immune cells occurs in the bone marrow, the responsibility of hematopoietic stem cells and descendant progenitor cell populations. While the mechanisms of aging, particularly chronic inflammation, are disruptive of the niche structures that support hematopoietic cells, there is also damage to the cells themselves. It has long been possible to replace hematopoietic cells, but this is a procedure that requires aggressive chemotherapy to clear existing populations, and comes with a non-trivial degree of risk. To introduce a new population of engineered hematopoietic stem cells into most old people, an entirely new, safer, and more gentle strategy will be needed. Consider the production of universal or patient-matched hematopoietic stem cells that are changed in ways that allows them to outcompete native cells and take over stem cell pools in the bone marrow, for example.

A Shabby Pop-Sci Article on the Minicircle Trial of Follistatin Gene Therapy
https://www.fightaging.org/archives/2023/02/a-shabby-pop-sci-article-on-the-minicircle-trial-of-follistatin-gene-therapy/

Minicircle is working towards the upregulation of follistatin, an inhibitor of myostatin and thus an interesting target for improved muscle growth and treatment of sarcopenia. Follistatin and myostatin are well studied genes in this context, and there are any number of animal studies, as well as human trials of various approaches to myostatin inhibition. As I have long said, follistatin and myostatin are probably the most compelling, least risky genes to start working on if interested in gene therapy development. There is a great deal of animal and human data to support this work.

It is always annoying to see shabbily written popular science articles in which ignorance is brandished with a sort of pride. The author of today's article couldn't get Minicircle to comment on the details of their work, has no real idea as to what is going on under the hood, and so forges ahead with a mix of snark and commentary from various people who also don't know what Minicircle is doing, or the nature of their gene therapy approach.

I am a participant in the Minicircle follistatin trial. I've also signed a non-disclosure agreement, so don't ask me for details. The company has an interesting, novel technology for the delivery of gene therapies, and is undertaking a responsible, low-cost, first-in-human clinical trial outside the US with educated volunteer participants from the self-experimentation community. It consistently amazes me, the degree to which hostility is poured upon those who choose not to engage with the journalistic and regulatory priesthoods in exactly the approved fashion.

The present system of regulation, and the enormous costs it imposes on development and discovery, must change. We live in an era in which a prototype gene therapy can be safely assembled for a few thousand in cost of goods. It cannot continue to be the case that development only progresses at a cost of tens of millions to reach initial human trials, and hundreds of millions to billions to allow the average person to be permitted to use a treatment.

This biohacking company is using a crypto city to test controversial gene therapies

Over the past few years, a parade of newly released gene therapies have consecutively claimed the title of most expensive drug in the world; the current honor goes to the 3.5 million hemophilia B treatment Hemgenix, launched in November 2022. Minicircle is taking something of a different tack. The startup, which is registered in Delaware, aims to fuse elements of the traditional drug testing path with the ethos of "biohackers" - medical mavericks who proudly dabble in self-experimentation and have long hailed the promise of DIY gene therapies.

The eccentricities don't end there. Minicircle's trials are going ahead in Próspera, an aspiring libertarian paradise born from controversial legislation that has allowed international businesses to carve off bits of Honduras and establish their own micronations. It's a radical experiment that is allowing a private company to take on the role of the state. While much attention has been paid to the charter city's use of Bitcoin as legal tender, the partnership with Minicircle is an important milestone toward another goal - becoming a hotbed of medical innovation and a future hub of medical tourism.

It's against this unusual backdrop that Minicircle is trying to lead biohacking's charge into the mainstream, or at least somewhere near it-studying gene therapies that target familiar conditions like muscular disorders, HIV, low testosterone, and obesity, and doing so with the backing of tech moguls and under the purview of bespoke "innovation-friendly" regulation. It ultimately aims to democratize access to gene therapies, with an emphasis on discovering the right nucleic cocktail to promote longevity.

Most scientists I spoke with are less than enthusiastic about Minicircle's undertaking, expressing skepticism about its methods and aims, while experts in medical ethics are concerned about how the trials will move forward - and what they could mean for the burgeoning and sometimes unscrupulous medical tourism industry. These experts also say the red-tape-trimming stance of special economic zones like Próspera can set off alarm bells (though the charter city staunchly defends its regulations).

At least one prominent scientist sees a potential upside to growth in the biohacking space: George Church, a professor of genetics at Harvard Medical School who has previously consulted on biohacking endeavors, tells me he welcomes the evolution of biohacking self-experimentation into full-blown clinical trials. He isn't familiar with Minicircle's work specifically, but he says of the general premise, "As long as nothing goes wrong, it could herald a revolution in cost reduction." That, of course, is a big caveat.

Lifelong Stimulation of the Ghrelin Receptor Modestly Increases Mouse Life Span
https://www.fightaging.org/archives/2023/02/lifelong-stimulation-of-the-ghrelin-receptor-modestly-increases-mouse-life-span/

The evidence of recent years from studies of calorie restriction and intermittent fasting might lead one to suspect that the length of time spent being hungry is an important determining factor, on a par with calorie intake. In the course of physiological hunger, a range of signaling processes kick in and cell behavior changes in response. Is this important in distinction to the lower level nutrient sensing processes inside cells? So much changes in the course of fasting or calorie restriction that it is challenging to pick out the most relevant mechanisms.

One of the noteworthy mechanisms of hunger is ghrelin signaling. In this study, researchers stimulate the ghrelin receptor using a suitable small molecule for much of the lifespan of mice, and observe the results. The overall extension of life span is a quarter of that produced by calorie restriction, and so we might draw some conclusions from that as to the relative importance of hunger in the benefits resulting from the practice of calorie restriction or fasting. Interestingly, the short term weight gains observed in mice given this ghrelin receptor agonist in the past don't appear in this long term study, in which the controls are the heaver animals. This is possibly because the researchers didn't allow the mice to overeat, by pairing their consumption with that of the untreated control animals.

The effect of a pharmaceutical ghrelin agonist on lifespan in C57BL/6J male mice: A controlled experiment

Of the well-studied effects on lifespan in mouse models, detailed mechanisms underlying the health and longevity benefit of caloric restriction (CR) are still being investigated despite some limitations on the practical applications to humans. A major limitation of animal models is that they cannot self-report hunger or other physiological sensations that would inform mechanistic work. Since ghrelin was first described and noted as a growth hormone secretagogue receptor (GHS-R) agonist, much study has focused on the effects on hunger and appetite regulation along with other aspects of energy balance.

Investigators examining effects on cognition in mouse models have posited that the mechanism may involve interoceptive cues or signaling, rather than reduced energy intake per se. In those studies, oral administration of a ghrelin agonist (LY444711, an orally active compound that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a [GHS-R1a] receptor, reduces Alzheimer's disease pathology and improves cognition in the APP-SwDI mouse model. Treatment also reduced levels of amyloid beta (Aβ) and neuroinflammation (as measured by microglial activation) at 6 months of age compared to controls, like the effect seen in the 20% CR group (gp) but with no significant difference in body weight (BW) or percentage body fat.

LY444711 binds to the human ghrelin receptor (GHS-R1a) and is a functional agonist. This agonist produced orexigenic behavior in rodents, including stimulated energy intake (food consumption is 40% than controls at 10 mg/kg and 50% greater than controls at 30 mg/kg dose), positive energy balance (23% greater BW with 2 weeks treatment at 10 mg/kg), acute higher respiratory quotient (RQ) with increased dose, and increased adiposity (greater fat mass but no significant difference in lean mass). The authors conclude this substance is orally active with an extended half-life relative to native ghrelin.

Despite various studies on ghrelin effects on food intake and body composition, studies of ghrelin agonists on lifespan-extending effects in rodent models are lacking. We tested the hypothesis that a pathway related to perceived hunger, as induced by an oral, exogenously administered orexigenic agent (i.e., a synthetic ghrelin agonist), would affect lifespan in mice. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily, animals were fed LY444711 or a placebo control until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by controls (ad libitum feeding) the prior week. Results indicate an increased lifespan effect for GhrAg versus controls, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms.

Epigenetic Clock Data from the CALERIE Trial of Calorie Restriction
https://www.fightaging.org/archives/2023/02/epigenetic-clock-data-from-the-calerie-trial-of-calorie-restriction/

The practice of calorie restriction extends life notably in short-lived mammals, but not in long-lived mammals, despite the short-term benefits to health appearing quite similar in mice and humans. This may be because many of the beneficial shifts in metabolism triggered by a low calorie intake are already built in to long-lived species, as a part of the history of evolutionary change that led to those species becoming long-lived. Since calorie restriction alters near every aspect of cellular biochemistry, coming up with a comprehensive understanding of the important mechanisms has been a slow process, never mind how those differences might then generate the large variation in effects on life span across species.

In today's open access paper, researchers apply epigenetic clocks to samples from a noted human study of calorie restriction that was conducted a while back. The clocks show little to no effect on biological age, but do suggest improvement in health that is on a par with the better lifestyle choices, such as choosing not to smoke or avoiding obesity. In the short term calorie restriction does indeed produce significant improvement in a range of markers of health related to inflammation, cardiovascular risk, and so forth. It is interesting that the presently favored epigenetic clocks are largely insensitive to this intervention.

Calorie restriction slows pace of aging in healthy adults

The CALERIE Phase-2 randomized controlled trial, funded by the US National Institute on Aging, is the first ever investigation of the effects of long-term calorie restriction in healthy, non-obese humans. The trial randomized 220 healthy men and women at three sites in the US to a 25 percent calorie-restriction or normal diet for two years. To measure biological aging in CALERIE Trial participants, the team analyzed blood samples collected from trial participants at pre-intervention baseline and after 12- and 24-months of follow-up. The team analyzed methylation marks on DNA extracted from white blood cells. DNA methylation marks are chemical tags on the DNA sequence that regulate the expression of genes and are known to change with aging.

In the primary analysis researchers focused on three measurements of the DNA methylation data, sometimes known as epigenetic clocks. The first two, the PhenoAge and GrimAge clocks, estimate biological age. The third measure studied by the researchers was DunedinPACE, which estimates the pace of aging, or the rate of biological deterioration over time. "In contrast to the results for DunedinPace, there were no effects of intervention on other epigenetic clocks. The difference in results suggests that dynamic 'pace of aging' measures like DunedinPACE may be more sensitive to the effects of intervention than measures of static biological age." The intervention effect on DunedinPACE represented a 2-3 percent slowing in the pace of aging, which in other studies translates to a 10-15 percent reduction in mortality risk, an effect similar to a smoking cessation intervention.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm), and is established to increase healthy lifespan in multiple species. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 years.

We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies, and contrasting with reports that biological aging may not be modifiable. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.

Digging Deeper into the Epigenetics of Supercentenarians
https://www.fightaging.org/archives/2023/02/digging-deeper-into-the-epigenetics-of-supercentenarians/

Supercentenarians, much as one might expect, exhibit signs of being biologically younger than their years. It is a lower burden of age-related damage and dysfunction that allows them the chance to survive. That said, it is worth noting that many characteristics so far observed in studies of supercentenarians are also present in large numbers of people who die well before reaching a century of life. The fortunately biochemistry of supercentarians adjusts small odds of survival to be slightly more favorable, but still small odds of survival. It is far from an assurance, and it certainly doesn't prevent one from becoming frail and dependent. Supercentenarians are greatly impacted by aging, exhibiting a roughly 50% yearly mortality rate.

For these reasons, efforts to better understand the survival of supercentenarians seem to me to be a matter of scientific interest, but not a matter of practical interest. It is not the path that will lead to ways of ensuring meaningfully greater health and longevity for all. Today's open access paper is an example of this sort of research, a deeper dive into differences in epigenetic patterns exhibited in supercentenarians. Epigenetic decorations to DNA determine the expression of genes and thus behavior of cells. Given the advent of epigenetic clocks, measures of biological age based on characteristic age-related changes in specific sets of epigenetic marks on the genome, it is now possible to look at areas of the age-related portion of epigenetics, and declare that an individual's biochemistry appears either older or younger than the norm. Perhaps unexpectedly, supercentenarians are a mix of both.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study

Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.

Our findings show that the epigenetic ages of Japanese centenarians and supercentenarians were remarkably lower than their chronological ages, consistently with previous findings for Italian semi-supercentenarians, suggesting that their healthy longevity has an epigenetic basis. However, whether these epigenetic ages also reflect biological age has not yet been validated. Whether healthy longevity depends on slowing epigenetic ageing or on having a younger baseline DNA methylation state would be the next subject of interest. For our multiple-sampled centenarians and supercentenarians, the longitudinal changes in epigenetic age showed that their epigenetic ageing was slower than that indirectly inferred from the cross-sectional non-centenarian cohort. Further research comparing the longitudinal epigenetic change of centenarians and supercentenarians with non-centenarians will help to answer this question.

Our study further suggests a link between the specific epigenetic states and exceptional healthy longevity in centenarians and supercentenarians. Some epigenetic signatures in centenarians and supercentenarians were maintained at young states, whereas others were maintained at advanced (or old) states. Young-state DNA-methylation signatures were overrepresented around cancer-related and neuropsychiatric disease-related genes. Conversely, CpG sites with accelerated (advanced) demethylation were also detected in centenarians and supercentenarians. Knowledge-based analyses indicated that some of these demethylated CpG sites can affect the activity of TGF-β, a major anti-inflammatory cytokine. Given that many age-related diseases can develop as a consequence of excessive pro-inflammatory responses, anti-inflammatory responses, such as those mediated by TGF-β and other cytokines, are crucial for healthy ageing and longevity. For instance, immunoassays have identified greater TGF-β activity in centenarians than in younger controls.

Inhibiting Formation of Amyloid Oligomers as a Strategy to Slow Alzheimer's Disease
https://www.fightaging.org/archives/2023/02/inhibiting-formation-of-amyloid-oligomers-as-a-strategy-to-slow-alzheimers-disease/

Finding ways to inhibit the formation of toxic amyloid-β oligomers in the aging brain may prove to be a useful treatment for Alzheimer's disease, but it remains the case that therapies targeting amyloid-β have yet to show meaningful patient benefits. It is possible that the wrong type or location of amyloid-β was targeted, or that amyloid-β is not directly responsible for Alzheimer's disease, but rather a side-effect of other disease processes. Regardless, a great deal of effort still goes into targeting aspects of amyloid-β biochemistry, in the hopes that one of these approaches will succeed where past efforts have failed.

Because plaques are visible under a microscope, scientists long believed that they are responsible for damaging neurons in Alzheimer's disease etiology. Many clinical trials took place and billions in funding were invested over more than a quarter of a century to generate molecules and antibodies targeting and preventing formation of fibrils and plaques. Such treatments proved unsuccessful and caused intolerable side effects. Over time, fibrils and plaques themselves were deemed non-toxic, and instead earlier soluble intermediates known as oligomers are now considered the culprits in this insidious disease.

Recent clinical trials using antibodies to target oligomers have shown promising results. Researchers are now developing small cyclic peptides that have proven effective in animal models in treating the disease by targeting oligomers. When these molecules were combined in a test tube with the small protein amyloid beta, the generation of oligomers was completely blocked, and no subsequent aggregation occurred. In the next stage, the researchers incubated human neurons with the toxic oligomers and the cyclic peptides. Most neurons remained alive, but those in the control group that were exposed to the oligomers without cyclic peptides were severely damaged and died.

Next, transgenic mouse models of Alzheimer's disease in the pre-symptomatic stage were treated with the cyclic peptides and observed over time for memory functions and amount of amyloid beta oligomers in the brain. Through molecular imaging, the researchers determined that the mice didn't generate substantial amounts of oligomers and, consequently, didn't develop any sign of Alzheimer's.

SIRT3 Upregulation as a Basis for Improving Mitochondrial Function in the Aging Brain
https://www.fightaging.org/archives/2023/02/sirt3-upregulation-as-a-basis-for-improving-mitochondrial-function-in-the-aging-brain/

SIRT3 beneficially affects mitochondrial function, and its upregulation is a calorie restriction mimetic strategy, since it mediates some of the benefits resulting from a lowered calorie intake. Given this, there is some interest in this as a basis for treatments for neurodegenerative conditions, in which loss of mitochondrial function in the brain is thought to be an important contribution to pathology. Mitochondria are the power plants of the cell, and the brain requires a great deal of energy to operate. So far, efforts to improve mitochondrial function in aged tissues by targeting the expressed levels of specific proteins or metabolites important to mitochondrial metabolism have yet to surpass the effects of exercise or the practice of calorie restriction itself. It seems unlikely that manipulating SIRT3 expression will prove to be any different.

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3's functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise.

SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. Alzheimer's disease (AD) has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3's roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

Towards Ways to Sabotage the Immune Evasion of Senescent Cells in Aged Tissues
https://www.fightaging.org/archives/2023/02/towards-ways-to-sabotage-the-immune-evasion-of-senescent-cells-in-aged-tissues/

Senescent cells are created constantly throughout life, largely the result of somatic cells reaching the Hayflick limit on cellular replication. In youth, these cells are rapidly removed by the immune system, but this clearance falters in later life for reasons yet to be fully explored. Nonetheless, enough is understood to propose a variety of avenues by which the immune clearance of senescent cells can be improved.

Cellular senescence is a complex process involving a close-to-irreversible arrest of the cell cycle, the acquisition of the senescence-associated secretory phenotype (SASP), as well as profound changes in the expression of cell surface proteins that determine the recognition of senescent cells by innate and cognate immune effectors including macrophages, NK, NKT, and T cells. It is important to note that senescence can occur in a transient fashion to improve the homeostatic response of tissues to stress. Moreover, both the excessive generation and the insufficient elimination of senescent cells may contribute to pathological aging.

Attempts are being made to identify the mechanisms through which senescent cell avoid their destruction by immune effectors. Such mechanisms involve the cell surface expression of immunosuppressive molecules including PD-L1 and PD-L2 to ligate PD-1 on T cells, as well as tolerogenic MHC class-I variants. In addition, senescent cells can secrete factors that attract immunosuppressive and pro-inflammatory cells into the microenvironment. Each of these immune evasion mechanism offers a target for therapeutic intervention, e.g., by blocking the interaction between PD-1 and PD-L1 or PD-L2, upregulating immunogenic MHC class-I molecules and eliminating immunosuppressive cell types.

In addition, senescent cells differ in their antigenic makeup and immunopeptidome from their normal counterparts, hence offering the opportunity to stimulate immune response against senescence-associated antigens. Ideally, immunological anti-senescence strategies should succeed in selectively eliminating pathogenic senescent cells but spare homeostatic senescence.

Loss of Hippocampal Neurogenesis in Alzheimer's Disease
https://www.fightaging.org/archives/2023/02/loss-of-hippocampal-neurogenesis-in-alzheimers-disease/

Neurogenesis is the process by which new neurons are produced from neural stem cells and then integrated into existing neural circuits in the brain. Adult neurogenesis is important to memory function, as well as to the resilience of the brain to injury and degeneration. Neurogenesis declines with age, and is noted to be one of the many aspects of neural biology that is negatively impacted by the onset of Alzheimer's disease. Is this loss of neurogenesis secondary to the better known disease mechanisms associated with Alzheimer's? Is it important enough to be pursued as a basis for therapy? Researchers here discuss the topic.

The hippocampus, a critical hub for cognition and memory, is one of the first brain regions to be affected in Alzheimer's disease (AD) patients. The dentate gyrus (DG), a hippocampal subfield implicated in learning and memory, particularly in pattern separation, shows substantial age-related functional decline in humans, non-human primates, and rodents. The DG is further unique as it contains the so-called "neurogenic niche," wherein stem cells continue to generate new neurons in the adult brain, in a special form of cellular plasticity referred to as "adult hippocampal neurogenesis" (AHN). Adult-born dentate granule cells (aDGCs) functionally incorporate into the granule cell layer of the DG as part of the hippocampal circuitry, where they, via their unique physiological properties, play key roles in neural plasticity and cognition. AHN has been shown to be impacted by (several aspects of) AD pathology in both rodents and humans.

Despite a substantial focus on amyloid and tau pathologies over the past decades, disease-modifying therapies for AD are still lacking. Hence, "mapping" the full mechanistic heterogeneity of AD, i.e. beyond amyloid and tau, is an important critical step to developing novel therapeutic targets. Key mechanistic questions as to what renders an individual vulnerable or resilient to developing AD remain unanswered, but may be "hidden" in the brains of a unique group of elderly individuals with preserved cognition, despite the presence of substantial AD pathology. This "cognitive reserve" that is apparent in these subjects may likely increase resilience toward developing dementia. Notably, AHN levels in postmortem brains were recently correlated with ante-mortem cognition in mild cognitive impaired (MCI) and AD patients, pointing toward a potential active role of AHN in the buildup of cognitive reserve, which can later on confer resilience to AD-related dementia.

Here, we critically discuss current knowledge on the putative role of AHN in AD pathophysiology and resilience, focusing primarily on the human brain. We emphasize the importance of the multicellular complexity of the neurogenic niche where AHN resides, and hence the relevance of integrating both intrinsic and extrinsic signals from distinct cellular populations, into any future therapeutic strategies aimed to "rejuvenate" the AD brain.

Reviewing the Characterization of Cellular Senescence in Aging
https://www.fightaging.org/archives/2023/02/reviewing-the-characterization-of-cellular-senescence-in-aging/

The accumulation of senescent cells with age is an important contributing cause of age-related disease and eventual mortality. These errant cells secrete a potent mix of pro-growth, pro-inflammatory signals that disrupt normal tissue maintenance and change cell behavior for the worse, leading to structural changes and loss of organ function throughout the body. Damping senescent cell signaling, such as by selectively destroying senescent cells, has shown considerable promise as a basis for rejuvenation therapies, and the sooner that the existing approaches are widely adopted for use by the elderly population, the better.

An increase in life expectancy in developed countries has led to an insurgency of chronic aging-related diseases. In the last few decades, several studies provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype (SASP) resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers.

Strategies to prevent the pathological effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiological functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies.

An Alternative to Clearance for Reduction of Activated Microglia in the Aging Brain
https://www.fightaging.org/archives/2023/02/an-alternative-to-clearance-for-reduction-of-activated-microglia-in-the-aging-brain/

Microglia are innate immune cells of the central nervous system. Microglia in the aging brain respond to the age-damaged environment by becoming more activated, inflammatory, and ultimately senescent. They amplify the inflammatory environment, contributing further to damage and loss of function. One approach is to clear these cells, readily achieved using available CSF1R inhibitor drugs, after which a new population emerges that, for a time at last, is not overly activated and inflammatory. Here, researchers discuss a different approach to reducing microglial activation, without clearing the entire population of microglia, in the context of age-related blood-brain barrier dysfunction.

While it's well established that chronic mild hypoxia promotes a robust angiogenic response, we recently found that it also triggers transient blood-brain barrier (BBB) disruption, that is associated with aggregation and activation of microglia around the leaky blood vessels. Importantly, microglial depletion markedly enhanced vascular leak, demonstrating an important vasculo-protective function for microglia in maintaining BBB integrity. As a high integrity BBB is a critical determinant of cerebral health, yet evidence suggests that BBB integrity declines with age, we recently examined how aging influences both the extent of hypoxia-induced BBB disruption and the associated vasculo-protective function of microglia. This showed that compared to young (8-10 weeks) mice, the number of hypoxia-induced vascular leaks was greatly amplified (5-10 fold) in aged (20 months) mice in all regions of the brain examined.

When we analysed the impact of aging on microglia activity, we discovered an interesting paradox. On the one hand, microglia in aged brain were far more activated as assessed by morphological criteria and expression of activation markers such as Mac-1 and CD68, but on the other hand, they displayed a marked deficit in the ability to aggregate around leaky blood vessels. These findings are consistent with the work of others who showed microglia in aged brain are typically more activated than in young mice. Interestingly, microglia in the aged brain can be re-programmed by removing all microglia with the colony stimulating factor-1 receptor (CSF-1R) antagonist PLX5622, and then allowing the central nervous system to repopulate with new microglia displaying a younger phenotype. Notably, this approach was shown to reverse age-related cognitive decline, although vascular integrity was not examined.

In our study we took the simpler approach of reducing microglial activation state in the aged brain by treating mice with minocycline and this successfully reduced the number of hypoxia-induced vascular leaks. Based on these data, we proposed a biphasic relationship between microglial activation and vasculo-protection, such that microglia need to become activated to confer protection, but if they become too activated, as in the aged brain, this protection declines.

MLKL Knockout Slows Some Aspects of Immune Aging
https://www.fightaging.org/archives/2023/02/mlkl-knockout-slows-some-aspects-of-immune-aging/

Researchers here report on the results of disabling the MLKL gene involved in necroptosis, a form of programmed cell death. This reduces age-related inflammation in female mice, and delays loss of lymphocyte production in male mice. The changes are not enough to produce differences in apparent signs of aging, such as mortality rate, however. The scientific challenge here lies in linking reduced necroptosis to the observed changes in immune aging, as is usually the case in any change that is broadly related cell survival or fundamental cell activities such as replication. This sort of activity can keep research teams busy for years, but it is unclear as to whether there is a practical outcome at the end of the tunnel given that the mice didn't fare any better for the change.

MLKL is one of the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl-/- mice on a congenic C57BL/6J genetic background.

Our extensive histopathological and immunophenotypic cohort analyses have identified several unique, sex-specific, differences between congenic C57BL/6J Mlkl-/- mice and their wild-type littermates that emerge with age. Several statistically significant findings were observed in hematological parameters across age in Mlkl-/- mice compared to wild-type littermate controls. Many of these parameters remained within normal range despite statistical significance, suggesting they are unlikely to assert biologically critical roles.

Of note, Mlkl-/- mice exhibit increased circulating lymphocyte numbers relative to wild-type littermates at 12-14 months of age. A comprehensive and unbiased blind scoring of inflammatory foci in more than 44 different sites revealed a 62% decrease in background, sterile inflammation of the skeletal muscle, bone, cartilage, adipose tissue, and connective tissue proper in 17-month-old female Mlkl-/- relative to age-matched wild-type littermates. It is important to consider, however, that these differences in age-related circulating lymphocyte numbers and tissue inflammation did not manifest in any overt differences in the general condition, mobility, or mortality of these mice up to 17 months of age.

A New Record for the Longest Lived Laboratory Rat, Resulting from Plasma Dilution
https://www.fightaging.org/archives/2023/02/a-new-record-for-the-longest-lived-laboratory-rat-resulting-from-plasma-dilution/

Many more life span studies are carried out in mice rather than rats, so it is not too surprising to see people pushing the record for longest lived rat. The longest lived mice are those in which growth hormone receptor signaling is inhibited, while the longest lived rats are the result of life-long calorie restriction. The group noted here is pursuing a strategy of processing the blood plasma from young animals and then introducing the processed plasma into old animals. A treatment starting in mid-life produced a modest gain in median life span in rats, while the one still surviving rat from the small study group has surpassed the existing record for calorie restricted mice. It is an interesting data point for the field of dilution of blood plasma to reduce harmful factors present in the bloodstream of old individuals, though as I understand it, this group favors explanations involving factors from the processed young plasma that are beneficial.

Scientists working on an experimental anti-ageing therapy claim to have broken a record by extending the lifespan of a lab rat called Sima. Named after the Hindi word for "limit" or "boundary", Sima is the last remaining survivor from a group of rodents that received infusions of blood plasma taken from young animals to see if the treatment prolonged their lives. Sima, who was born on 28 February 2019, has lived for 47 months, surpassing the 45.5 months believed to be the oldest age recorded in scientific literature for a female Sprague-Dawley rat, the researchers say. So far, Sima has outlived her closest rival in the study by nearly six months.

Researchers have rushed to produce and trial therapies based on young blood plasma after numerous experiments found that infusions could reinvigorate ageing organs and tissues. The results from the latest study will be written up when Sima dies, but data gathered so far suggests that eight rats that received placebo infusions of saline lived for 34 to 38 months, while eight that received a purified and concentrated form of blood plasma, called E5, lived for 38 to 47 months. They also had improved grip strength. Rats normally live for two to three years, though a contender for the oldest ever is a brown rat that survived on a restricted calorie diet for 4.6 years.

Results from such small studies are tentative at best, but some scientists believe the work, and similar efforts by others, has potential. A preliminary study found that infusions of young blood plasma wound back the biological clock on rat liver, blood, heart and a brain region called the hypothalamus. A patent filing on the potential therapy describes how plasma from young mammals is purified and concentrated before use. Some components, such as platelets, are removed, as they can trigger immune reactions.

Reviewing Exercise as a Means to Slow Neurodegeneration
https://www.fightaging.org/archives/2023/02/reviewing-exercise-as-a-means-to-slow-neurodegeneration/

Researchers here review the evidence for exercise to slow the onset and progression of neurodegenerative conditions. A mountain of evidence demonstrates exercise (and the practice of calorie restriction) to improve long term health and at least modestly slow age-related degeneration. For the cost, meaning essentially free, it is a good deal. The future will bring medical technologies that can greatly improve upon the benefits of exercise by targeting the underlying causes of aging, but for now it remains one of the best options on the table.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise has a positive impact on the life quality of elderly with neurodegenerative diseases. Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics. We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.

Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.

Microglial Autophagy in Parkinson's Disease
https://www.fightaging.org/archives/2023/02/microglial-autophagy-in-parkinsons-disease/

Autophagy is the name given to a collection of maintenance processes responsible for clearing waste and damaged proteins and structures from the cell. Autophagy is implicated in aging. It is thought to become dysfunctional and less efficient in cells in aging tissues. Further, evidence suggests that improved autophagy is an important mechanisms in the slowing of aging produced by calorie restriction and a range of other interventions tested in laboratory species. Here, researchers discuss the relationship between aging and autophagy specifically in the context of Parkinson's disease and the role of inflammatory microglia in the progression of that condition. One might compare this with a very similar paper noted last week.

In a healthy organism, the homeostasis of the central nervous system (CNS) is dependent on the interactions of various nerve cells. However, in the CNS of Parkinson's disease (PD) patients, there is an aberrant build-up of α-synuclein (α-Syn) and a cascade effect of gradual neuronal damage that breaks the appropriate balance, which leads to inflammation in the CNS. Autophagy is an evolutionarily conserved degradation pathway that is responsible for the digestion and recycling of the majority of intracytoplasmic proteins and organelles. Autophagy maintains homeostasis by delivering cytoplasmic materials to the lysosome for degradation. Due to poor autophagy, inappropriately aggregated α-Syn in the CNS of PD patients cannot be removed and accumulated. Overall, dysregulation of autophagy is thought to play an important role in the abnormal aggregation of α-Syn and the exacerbation of Parkinson's disease.

Microglia are CNS-specific immune cells that play an immunological role in the CNS comparable to that of macrophages, interact with neurons, and conduct a variety of tasks in the CNS. Recent research shows that microglial autophagy is involved in the function and regulation of inflammation in the CNS. These findings implied that dysregulation of autophagy in microglia may impact innate immune activities, including phagocytosis and inflammation, which, in turn, contribute to illnesses associated with neuroinflammation. To date, many researchers have considered PD to be a neuroinflammatory disease, and the role of microglial autophagy in the pathophysiology of PD has been a hot issue in the field. In this review, we present and highlight the contribution of microglial autophagy to the pathological mechanism of PD and aimed to determine whether microglial autophagy could be a potential target for therapeutic intervention.