Fight Aging!

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Contents

• Mitochondrial Dysfunction and its Interaction with Cellular Senescence
• Lobbying for the Treatment of Aging Leads to a Congressional Caucus for Longevity Science
• Inhibiting the NLRP1 Inflammasome Reduces the Senescence-Associated Secretory Phenotype
• Comparing Protein Restriction and Isoleucine Restriction in Aged Mice
• Misfolded Proteins Accumulate with Age in Nematodes and Mice
• Is Age-Related Transcriptional Noise Real?
• Evidence for Reduced Dementia Incidence to be Driven by Improved Vascular Health
• Towards Transplantation of Stem Cell Derived Neurons for Parkinson's Disease
• Cellular Senescence Promotes Malignant Brain Tumor Growth
• Extracellular Vesicles in Aging
• Targeted Protein Degradation as an Approach to Treatment
• Progress Towards Clinical Trials for Atherosclerosis at Cyclarity
• More on Extracellular Vesicles in Aging, and as a Treatment for Age-Related Conditions
• MPC Inhibition Activates Neural Stem Cells to Increase Neurogenesis
• Another New Player in the Thymus Regeneration Space

Mitochondrial Dysfunction and its Interaction with Cellular Senescence
https://www.fightaging.org/archives/2023/03/mitochondrial-dysfunction-and-its-interaction-with-cellular-senescence/

Aging is caused by a number of independent issues, forms of damage and dysfunction that arise as a consequence of the normal operation of a youthful and undamaged metabolism. If these processes remained independent, aging would be a far less challenging field of study than is the case, but unfortunately, everything interacts with everything else in cellular biology. Processes of damage encourage one another, and combine in complex ways to produce shared consequences. Those consequences can in turn interact with the underlying mechanisms of damage to alter and accelerate their effects.

In today's open access paper, researchers discuss some of the interactions between cellular senescence and mitochondrial dysfunction, two quite different mechanisms of aging. Mitochondrial dysfunction is known to promote inflammatory signaling, such as via the mislocalization of mitochondrial DNA to places in which it will trigger an innate immune response. Evidence suggests that this sort of mechanism likely drives some fraction of the harmful inflammatory signaling that is produced by senescent cells. This raises interesting questions, such as whether or not strategies intended to reverse mitochondrial dysfunction will, as a side-effect, also reduce the contribution of senescent cells to degenerative aging.

Targeting Mitochondria to Control Ageing and Senescence

Ageing is associated with increased inflammation and activation of the innate immune system. This condition is known as "inflamm-ageing" and is characterised by chronic activation of JAK-STAT signalling in the circulating immune cells of elderly patients, activation of the NLRP3 inflammasome, and higher circulating levels of inflammatory mediators such as C-reactive protein, IL-6, and fibrinogen. A leading hypothesis for the origin of "inflamm-ageing" is the build-up of senescent cells with ageing, and the consequent production of a systemic senescence-associated secretory phenotype (SASP). An important support for this hypothesis comes from experiments in which aged mouse blood is transferred to young animals, which results in features of accelerated ageing. Interestingly, previous treatment of the old donors with senolytic agents reduced "inflamm-ageing" after blood exchange, and the old blood lost its pro-ageing activity. In humans, senolytic treatments also reduce the "inflamm-ageing" of patients suffering from lung fibrosis or chronic kidney disease.

Importantly, mitochondria of senescent cells are known to play a key role in triggering the SASP. In particular, depriving senescent cells of mitochondrial DNA or mitochondria altogether seriously compromises the SASP. The detailed mechanisms connecting the mitochondria of senescent cells with the SASP are still unknown. We speculate that they could be similar to the mechanisms connecting dysfunctional mitochondria with inflammation. These may include the release of cytosolic and/or extracellular mitochondrial DNA (mtDNA), mitochondrial double-stranded RNA, N-formyl peptides (a sub-product of mitochondrial protein translation), and phospholipid species such as cardiolipin, enriched in the inner mitochondrial membrane . The most studied of these components is mtDNA.

Taken together, the evidence presented in this review shows that mitochondria dysfunctions have a close relationship with ageing and cellular senescence. Several mitochondrial pathways have already been taken into consideration as potential therapeutic targets for ageing-associated diseases, and promising compounds have been developed. Future research will have to answer numerous open questions including: is it possible to completely restore mitochondrial function in senescent and aged cells? Which age- or senescence-associated aspects are the primary drivers of mitochondrial dysfunction and vice-versa? Which ones are targetable therapeutically? Answering some of these questions could get us closer to healthy ageing, with countless medical, social and economic benefits.

Lobbying for the Treatment of Aging Leads to a Congressional Caucus for Longevity Science
https://www.fightaging.org/archives/2023/03/lobbying-for-the-treatment-of-aging-leads-to-a-congressional-caucus-for-longevity-science/

For those who believe that only governments get things done, it is frustrating to see the lack of interest in human longevity in politics, a mirror of the relative lack of interest in society at large. The past few decades have seen a number of political initiatives, largely the formation of lobbying campaigns and organizations, aimed at diverting more public funding into aging research. Little has been achieved to date as a result, but these efforts are now growing alongside the new longevity industry.

Politicians pay attention to the movement of money in the world, for the obvious reasons; they are nothing if not self-interested. Thus, as recently noted, the US Congress now has a longevity caucus. A cynic might believe that the timing of such a thing has a lot to do with the high-profile, large investments into rejuvenation biotechnology made in the past year, such as the 3 billion for Altos Labs. Politicians taking a stance in public, in effect announcing themselves to be the destination for campaign donations from those interested in further lobbying on this topic, tends to happen in the wake of sizable flows of funding in industry. We might see it as the next step along the long road to changing priorities in public funding of science.

Personally, I see lobbying as a waste of funds and time that might have used in more productive endeavors. Governments are the last to the table in any new field, and most of what they do when they do arrive is wasted, funding siphoned off by the politically connected into work that bears little resemblance to the original goal. The actually important work of building new therapies occurs as a result of philanthropy to fund the research, and venture capital to fund development: that is the way matters have progressed for therapies to slow or reverse aging, in any case.

Pushin' The Envelope: The First Longevity Caucus Launches

Although investments from the private sector are at all-time highs and foundations such as Hevolution and Impetus Grants are committing millions of dollars to aging research every year, the amount of funding that longevity and other preventative healthcare organizations receive is still a far cry from the more traditional fields of medicine. For context, when picking apart the 2023 Presidential Budget Request, a rough measure showing how much government capital is provided to the National Institutes of Health (NIH), and more specifically to the National Institute of Aging (NIA), we found that only 0.54% of the entire NIH annual budget request was dedicated towards Aging Biology.

This week, A4LI, a 501c4 non-profit proudly announced the launch of the Longevity Science Caucus - an initiative, years in the making, to help educate members of Congress about the growing field of longevity biotech and promote initiatives aimed at increasing the healthy average lifespan of all Americans. While there are numerous ways Congress can help propel this industry forward, such as making an easier FDA approval process specifically for longevity medicines, the newly launched caucus will primarily focus on increasing funding efforts to start.

Bilirakis and Tonko Kick Off Longevity Science Caucus

Congressman Gus Bilirakis (R-FL) and Congressman Paul Tonko (D-NY) are proud to announce the formation of the Congressional Caucus for Longevity Science. The "Longevity Science Caucus" aims to educate Members about the growing field of aging and longevity biotechnology, and promote initiatives aimed at increasing the healthy average lifespan of all Americans. Along with Bilirakis and Tonko, Representatives Dan Crenshaw (R-TX), Michael Burgess (R-TX) and Anna Eshoo (D-CA) are founding members of the newly created caucus. "Increasing life expectancy and promoting positive health outcomes are important priorities, and the formation of this caucus is an important step toward achieving those goals. I believe in promoting individual responsibility and supporting innovation in the pursuit of scientific discoveries that will enable Americans to live happier and longer lives. I am honored to co-chair this bipartisan effort with my colleague, Congressman Tonko. We will work with our colleagues in an effort to make a significant impact on the future health and wellness for our constituents."

Inhibiting the NLRP1 Inflammasome Reduces the Senescence-Associated Secretory Phenotype
https://www.fightaging.org/archives/2023/03/inhibiting-the-nlrp1-inflammasome-reduces-the-senescence-associated-secretory-phenotype/

A sizable portion of the chronic inflammation of aging is produced by the growing presence of senescent cells in tissues throughout the body. Senescent cells secrete a mix of pro-growth, pro-inflammatory signals (the senescence-associated secretory phenotype, SASP), useful when present in the short-term in the context of wound healing and suppression of cancer risk resulting from cell damage. When sustained over the long-term, however, this signaling becomes highly disruptive to tissue structure and function. The inflammatory mechanisms inside senescent cells that produce pro-inflammatory components of the SASP include the same mechanisms that operate in normal cells in response to inflammatory stimuli. It is therefore possible that targeted inhibition of regulatory genes and proteins could reduce the SASP.

Today's open access paper is one example of many lines of work that aim to understand how exactly the inflammatory component of the SASP arises. The authors identify the NLRP1 inflammasome as important, as inhibition diminishes the SASP. When it comes to new approaches to suppress inflammation, a great many groups are looking at inflammasomes in cells as a potential point of intervention. It is an open question as to whether this is going to be any better in practice than existing approaches (such as TNF inhibitors) that target important pro-inflammatory signal molecules. The problem with suppressing a target of this nature is that it disrupts desirable, short-term inflammation, needed for the normal immune response to operate, in addition to the undesirable chronic inflammation.

NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

Aging generates specific changes associated with a process called cellular senescence. This permanent state of cell cycle arrest promotes tissue remodelling during development but leads to the declined tissue regenerative potential and function after injury, and activates inflammation and tumorigenesis in aged organisms. Senescence promotes the production of cytokines, chemokines, proteases, and growth factors some of which are known as senescence-associated secretory phenotype (SASP). Recent studies demonstrates that chromatin is instrumental in regulating SASP and inflammation through the innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) which can be activated upon DNA sensing.

Inflammasomes are intracellular protein complexes involved in almost all human aging-associated complications such as cancer, cardiovascular, metabolic, and neurodegenerative diseases through the production of interleukin-1β (IL-1β) and IL-18. These protein platforms comprise sensing proteins of the NOD-like receptor (NLR) family, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase-1. Upon sensing of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS), some NLRs such as NLRP3 and NLRP1 to some extent associate with ASC, a response that leads to the recruitment and activation of the cysteine protease, caspase-1. Active caspase-1 cleaves pro-IL-1β, pro-IL-18, and GSDMD, thereby facilitating the secretion of IL-1β and IL-18 through plasma membrane pores formed by the N-terminal fragments of GSDMD. These pores can also release IL-1α and cause pyroptosis. Despite scientific advances in the biology of the NLRP1 and NLRP3 inflammasomes, the role that these proteins play in senescence remain controversial.

Irradiation of cells or tissues is a widely used model of stress-induced senescence, which we used to determine the role of the NLRP1 and NLRP3 inflammasomes in this process. We found that irradiation induced the expression of NLRP1, NLRP3, and SASP. Notably, inhibition of the NLRP1 inflammasome but not NLRP3 inflammasome attenuated the expression of senescence markers, responses that were GSDMD- and cGAS-dependent.

Comparing Protein Restriction and Isoleucine Restriction in Aged Mice
https://www.fightaging.org/archives/2023/03/comparing-protein-restriction-and-isoleucine-restriction-in-aged-mice/

Proteins are made up of amino acids. It is known that reducing only protein in the diet, while maintaining the same calorie intake, produces a modest slowing of aging. Some of the beneficial effects of reduced calorie intake, such as upregulation of autophagy and improved cell maintenance, are triggered by sensing protein levels rather than other components of diet. The sensor mechanisms are more specific than simply protein as a whole, however, and can be triggered by reducing levels of individual essential amino acids, meaning amino acids that are required for protein synthesis in cells, but must be consumed because they are not manufactured in the body. A good deal of work has gone into assessing the effects of lower levels of the essential amino acid methionine in the diet, for example, finding that this captures a sizable fraction of the benefits of reduced calorie intake.

In today's open access paper, researchers compare overall protein restriction (all dietary amino acids) with restriction of only the essential amino acid isoleucine, in both cases maintaining an overall calorie intake equivalent to that of a non-restricted diet. Old mice are given these different diets, and the researchers present a great deal of data on the outcomes. Restriction in older individuals doesn't help with muscle loss and frailty, which is interesting given that long-term calorie restriction does slow the progression of age-related loss of muscle mass and strength. Restricting only isoleucine produces greater benefits by some metrics, but doesn't reduce cellular senescence in tissues, unlike protein restriction. Overall, it is an interesting data set, though as ever we should remember that evidence strongly suggests that calorie restriction and its equivalents are much less effective at extending life span in long-lived mammals than in short-lived mammals.

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

An appealing alternative to reducing calories may be manipulating dietary macronutrients. Contrary to the conventional wisdom that calories from different sources are equivalent, a number of retrospective and prospective clinical trials have found that eating diets with lower levels of protein is associated with lower rates of age-related diseases including cancer and diabetes, and an overall reduction of mortality in those under age 55. While the effect of long-term protein restriction (PR) on human aging has not been tested in a randomized clinical trial (RCT), short-term RCTs in overweight or diabetic humans has found that protein restriction (PR) promotes metabolic health. Finally, PR diets have been repeatedly shown to increase the healthspan and lifespan of model organisms, including flies and rodents.

We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health in animal models. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age.

We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphatidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.

Misfolded Proteins Accumulate with Age in Nematodes and Mice
https://www.fightaging.org/archives/2023/03/misfolded-proteins-accumulate-with-age-in-nematodes-and-mice/

In order to function correctly, proteins must form a specific folded structure after assembly from amino acids in a ribosome. This folding doesn't always work as it should, and there is naturally some rate of error for processes taking place in the crowded, organized chaos of a cell interior. Protein misfolding leads to non-functional, sometimes toxic molecules. In the worst case scenario, with only a handful of proteins in the body being capable of this, a misfolded protein can encourage other molecules of the same protein to also misfold, and join into solid aggregates. Beyond this, a given error rate in folding across all proteins produced by a cell puts stress on that cell, and is addressed by a variety of quality control and housekeeping mechanisms that flag and recycle such mistakes when they occur.

To what degree is the burden of misfolded proteins an important mechanism of aging? The handful of well-known misfolded proteins that can spread from cell to cell and form solid aggregates, such as amyloid-β and α-synuclein, are a characteristic feature and likely important contributing cause of age-related neurodegenerative conditions. But beyond these few types of protein, is there a background of diverse misfolded proteins that builds up with age to cause broad cellular dysfunction, particularly in long-lived cells such as neurons? In today's open access paper, researchers argue that this is likely the case, based on data from a range of species. They identify a few hundred different proteins in which the presence of misfolded molecules appears to increase with age.

Extensive accumulation of misfolded protein aggregates during natural aging and senescence

The biological activity of cells and organisms depends on the proper function of many different proteins involved in key cellular signaling pathways. To remain biologically active, proteins need to preserve their native three-dimensional structure and solubility. Any alterations to these parameters challenge their ability to perform their normal biological function, with devastating consequences for the cell and the organism. Previously reported evidence showed a transition to insolubility of several proteins during aging in different models. Interestingly, many of these proteins are predicted to have high propensity to misfold and aggregate, similarly to protein misfolding disorders (PMDs). Based on these observations, we hypothesized that during aging several different proteins undergo progressive misfolding and aggregation to form structures similar to those found in age-related PMDs, causing widespread and chronic cellular dysfunction, which is the hallmark feature of aging.

In this study, we report the extensive and progressive accumulation of misfolded proteins during natural aging/senescence in different models, in the absence of disease. We coined the term age-ggregates to refer to this subset of proteins. Our findings demonstrate that age-ggregates exhibit the main characteristics of misfolded protein aggregates implicated in PMDs, including insolubility in detergents, protease-resistance, and staining with dyes specific for misfolded aggregates. Misfolded protein aggregates with these characteristics are thought to be implicated in some of today most prevalent diseases, including Alzheimer's disease and related forms of dementia, Parkinson's disease, Amyotrophic Lateral Sclerosis, type 2 diabetes, and even cancer. The strongest risk factor for all these diseases is aging, supporting our concept that advanced age is associated with increased accumulation of misfolded protein aggregates.

We found intracellular age-ggregation in the aged brain, where misfolded proteins are sequestered into aggresomes. Aggresomes have been studied in the context of neurodegenerative diseases, where they act as a general defense mechanism against high levels of accumulation of toxic misfolded proteins. Our results indicate that the aged brain contains relatively large amounts of misfolded species, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. By comparison with PMD, it is likely that the aging-associated misfolded protein will be non-functional or acquire a toxic activity. Therefore, we speculate that age-related protein misfolding may play a key role in the decline of those processes. Alternatively, the formation of misfolded aggregates might be a consequence of a dysfunctional proteasomal and other degradation pathways. The reproducibility of our results using various different techniques, methodologies, and model systems (invertebrates, cellular models, and rodents) indicate that protein misfolding during aging is not a stochastic phenomenon, but rather that a specific subset of proteins are prone to misfold with age.

Is Age-Related Transcriptional Noise Real?
https://www.fightaging.org/archives/2023/03/is-age-related-transcriptional-noise-real/

Transcription is the first step in gene expression, the production of RNA from sequences in the genome. Transcriptional noise describes an age-related increase in the raggedness of transcription, differences in amounts of proteins produced as individual cells become affected by the damage of aging to different degrees, and in different ways. Does this in fact happen as presently thought, however? It is certainly the case that epigenetic changes occur with age, and protein levels also alter with age. How much of this is noise versus other reactions to a changing tissue environment, such as alterations in the balance of different cell types? There is room for debate, it seems.

Aging is often associated with a loss of cell type identity that results in an increase in transcriptional noise in aged tissues. If this phenomenon reflects a fundamental property of aging remains an open question. Transcriptional changes at the cellular level are best detected by single-cell RNA sequencing (scRNAseq). However, the diverse computational methods used for the quantification of age-related loss of cellular identity have prevented reaching meaningful conclusions by direct comparison of existing scRNAseq datasets.

To address these issues we created Decibel, a Python toolkit that implements side-to-side four commonly used methods for the quantification of age-related transcriptional noise in scRNAseq data. Additionally, we developed Scallop, a novel computational method for the quantification of membership of single cells to their assigned cell type cluster. Cells with a greater Scallop membership score are transcriptionally more stable. Application of these computational tools to seven aging datasets showed large variability between tissues and datasets, suggesting that increased transcriptional noise is not a universal hallmark of aging.

To understand the source of apparent loss of cell type identity associated with aging, we analyzed cell type-specific changes in transcriptional noise and the changes in cell type composition of the mammalian lung. No robust pattern of cell type-specific transcriptional noise alteration was found across aging lung datasets. In contrast, age-associated changes in cell type composition of the lung were consistently found, particularly of immune cells. These results suggest that claims of increased transcriptional noise of aged tissues should be reformulated.

Evidence for Reduced Dementia Incidence to be Driven by Improved Vascular Health
https://www.fightaging.org/archives/2023/03/evidence-for-reduced-dementia-incidence-to-be-driven-by-improved-vascular-health/

Dementia risk for individuals has decreased in recent decades, even as the population grows and ages to the point at which overall number of cases expands. Since individual risk of suffering cardiovascular disease has also decreased over the same period of time, it is reasonable to ask whether reduced dementia risk is a direct consequence of improvements in long term vascular health. Researchers here provide evidence to suggest that this is the case, noting that levels of amyloid-β aggregates in post-mortem brains are much the same across recent decades, while vascular health improves. Misfolding and aggregation of amyloid-β is still broadly thought to be the mechanism that produces Alzheimer's disease, though there is now considerable debate given the failure of amyloid-clearing immunotherapies to help patients. Is amyloid-β actually a meaningful cause, or is it only relevant in the early stages of Alzheimer's? The situation is complicated by the fact that a sizable fraction of Alzheimer's patients also exhibit clear signs of vascular dementia.

In Europe and the U.S., proportionately fewer people are developing dementia now than in the past. Is this driven by less-prevalent Alzheimer's disease (AD) pathology? No, say researchers, who reported that among 1,550 older Americans born over a 25-year period, all had similar amounts of amyloid plaques at death, which came at an average of 90 years. If less pathology does not explain falling dementia incidence, then what does? People born in the 1920s had healthier blood vessels in their brains when they died than did those born in the 1900s, the authors found. They think better cardiovascular health among people born in more recent decades may make them more resilient to AD pathology.

Dementia incidence has steadily fallen by 20 to 25 percent over the past three decades in the U.S., U.K., Sweden, and the Netherlands. Researchers suspect that this drop was due to better overall health - especially improvements in cardiovascular health - and higher levels of education . Might these factors stave off amyloid plaques and neurofibrillary tangles? To find out, researchers quantified the extent of amyloid plaques, neurofibrillary tangles, Lewy bodies, TDP-43 aggregates, infarcts, and the severity of atherosclerosis and arteriosclerosis in cortical tissue from 1,554 participants in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) cohort. About one-quarter were born in each of four periods: 1905 to 1914, 1915 to 1919, 1920 to 1924, and 1925 to 1930. All died between 1997 and 2022.

The prevalence of postmortem AD diagnoses hovered between 64 and 68 percent in each birth epoch. The amount of Lewy bodies and TDP-43 inclusions remained the same across birth cohorts, as well. Notably, people born later had higher densities of neurofibrillary tangles than those born earlier. However, the extent of blood vessel damage, be it through atherosclerosis or arteriosclerosis, had decreased dramatically in participants born in later cohorts. About half of those born from 1905 to 1914 had moderate to severe atherosclerosis, while only 22 percent of people born in later 1920s did. All told, the researchers think that the declining prevalence of clinically diagnosed AD may be due to people having more cognitive reserve, which might be a product of better cardiovascular health and more education.

Towards Transplantation of Stem Cell Derived Neurons for Parkinson's Disease
https://www.fightaging.org/archives/2023/03/towards-transplantation-of-stem-cell-derived-neurons-for-parkinsons-disease/

The more obvious manifestations of Parkinson's disease stem from the the loss of a small population of dopamine-generating neurons. These cells are more sensitive to the underlying pathology of α-synuclein protein aggregation that drives the condition. Researchers have been working towards cell therapies that deliver new neurons for a long time now. A variety of clinical trials are underway, using a variety of cell sources; here, one of those programs has advanced to the stage of a first treated patient. None of these programs have yet emerged into widespread clinical practice. Is replacing cells the best way forward in this condition? It seems likely that ways to remove the toxic protein aggregates would be more beneficial, given that (a) they are causing other harms, and (b) transplanted cells will likely succumb to the same environmental issues caused by the aggregates.

There are around eight million people living with Parkinson's disease globally; a disease which involves loss of dopamine nerve cells deep in the brain, leading to problems in controlling movement. The standard treatment for Parkinson's disease are medications that replace the lost dopamine, but over time these medications often become less effective and cause side effects. As of today, there are no treatments that can repair the damaged structures within the brain or that can replace the nerve cells that are lost.

The STEM-PD trial is now testing a new investigational therapy aimed at replacing the lost dopamine cells with healthy ones manufactured from stem cells. The cell product that is being used has been subjected to rigorous pre-clinical tests. After being transplanted, the cells are expected to mature into new and healthy dopamine producing nerve cells within the brain. On 13th of February 2023, a transplant of stem cell-derived nerve cells was administered to a person with Parkinson's. The product is being tested in patients for the first time. The transplantation product is generated from embryonic stem cells and functions to replace the dopamine nerve cells which are lost in the parkinsonian brain.

This patient was the first of eight with Parkinson's disease who will receive the transplant. The patients in the trial were diagnosed with Parkinson's at least ten years ago and are at a moderate stage of their disease. The researchers will follow these patients closely and assessments of cell survival and potential effects will be conducted over the coming years.

Cellular Senescence Promotes Malignant Brain Tumor Growth
https://www.fightaging.org/archives/2023/03/cellular-senescence-promotes-malignant-brain-tumor-growth/

Senescent cells act to suppress risk of cancer its very earliest stage. The pro-inflammatory secretions of cells made senescent as a result of mutational damage and the response of tumor suppressor genes attract the immune system to places in which damaged cells may give rise to a tumor. When senescent cells are present in larger numbers, and linger over time, as is the case in aged tissues, they actively encourage tumor growth, however. Here, researchers produce a compelling demonstration of this harmful consequence of cellular senescence, categorizing and eliminating senescent cells present in glioblastoma tumors in mice to slow tumor growth, and demonstrating similar characteristics in human glioblastoma cells.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs.

Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry, and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

Extracellular Vesicles in Aging
https://www.fightaging.org/archives/2023/03/extracellular-vesicles-in-aging/

Extracellular vesicles of varying size classes carry a sizable fraction of all cell signaling. These are membrane-wrapped collections of molecules, generated in various ways and under various circumstances by sources cells. When researchers discuss extracellular vesicles in the context of aging, this is really a discussion of cell signaling in general. In the context of aging, vesicles are perhaps a more interesting topic than cell signaling in general because they are readily harvested and delivered as a therapy. Initially, this is being used to recapitulate the effects of stem cell transplants, delivering vesicles harvested from stem cells in culture, but it is likely that there will be further, more engineered and specific vesicle-based therapies in the future.

In recent decades, the concept of extracellular vesicles (EVs) has changed. When they were initially discovered, EVs were cellular dust; therefore, they did not have any functions; with time, this concept has changed and will probably continue being updated. Nowadays, EVs are considered critical mediators in physiological and pathophysiological processes. Therefore, this review summarizes the current knowledge on EVs from their discovery as cellular dust to their recognition as "very important particles" (VIPs) that mediate cell-cell communication and the current and newest isolation methods. Moreover, we describe the role of EVs in aging and age-related diseases and their potential use in the clinic as biomarkers for early diagnosis and as therapeutic agents for disease treatment.

EVs display several features that provide them with invaluable abilities for their application in regenerative medicine. First, the EV content mimics their parental cells. Thus, isolation of EVs from body fluids with a specific cargo is very useful as a biomarker in disease development for early diagnosis. Second, EVs have a specific set of surface proteins that indicates their target cells. This characteristic also has a valuable potential for their use as drug-delivery carriers to target cells. To date, EVs are VIPs because they act as mediators in physiological and pathological processes. Particularly, as shown in this review, EVs mediate biological aging and premature aging by their content and number released by senescent cells.

Research is still needed in the EV therapeutic field, in particular, focusing on the development of autologous EVs that would enable personalized treatment for each specific disease. Regarding the research on EV-mediated mechanisms of aging, efforts should be performed to establish a time- and cargo-dependent correlation between EVs and the incidence of age-related diseases so that EVs become a very early biomarker. It is also necessary to elucidate the exact molecular mechanisms involved in the change in EV content during aging; this understanding would help us to develop new cell-free treatments to reverse age-related diseases in the future. However, it should be mentioned that before starting antiaging therapies with EVs, safety, sensitivity, and specificity must be precisely verified. Additionally, administration, dosages, treatment intervals, and duration must be strictly certified.

Targeted Protein Degradation as an Approach to Treatment
https://www.fightaging.org/archives/2023/03/targeted-protein-degradation-as-an-approach-to-treatment/

Targeted protein degradation is a term that covers a range of possible approaches to more selectively removing specific forms of modified proteins from cells than has traditionally been possible. Researchers here provide an example of this type of work, targeting a modification of p38 in the context of Alzheimer's disease. This is a good illustration of the capabilities of this class of therapy, but probably not the best illustration of a good target: this still seems like a matter of messing with metabolism made dysfunctional by damage rather than targeting the underlying damage itself for repair.

Recent progress in the field of targeted protein degradation (TPD) has proven its immense potential as a novel therapeutic modality in drug discovery. In 2015, researchers devised a phthalimide-based small molecule that promotes degradation of transcriptional coactivator BRD4 by hijacking the Cereblon (CRBN) E3 ubiquitin ligase complex. In the same year, others also reported a TPD technology recruiting the von Hippel-Lindau (VHL) E3 ligase complex, commonly referred to as proteolysis-targeting chimeras (PROTACs). These technologies feature bifunctional small molecules that bring the proteins of interest into proximity with the E3 ubiquitin ligase complexes for ubiquitination and subsequent proteasomal degradation.

Such TPD-based small molecules have several advantages over traditional small molecule inhibitors in that they eliminate the target protein instead of modulating its function. TPD technology thus can complement nucleic acid-based gene knockdown in removing unwanted intracellular proteins. In addition, the TPD technique can target a plethora of proteins in various compartments of the cell, including disease-causing proteins that have previously been considered undruggable with the conventional small-molecule approach. Recently, several strategies have been suggested to potentiate therapeutic efficacy of TPD technology. In particular, TPD molecules that recognize and bind to the protein with specific post-translational modifications (PTMs), such as phosphorylation, may be a novel strategy to induce selective degradation of pathological proteins attributed to aberrant PTMs. However, a TPD molecule specifically targeting post-translationally modified proteins has not been reported yet.

It has been reported that phosphorylated p38 (p-p38) is significantly upregulated under pathological conditions, such as chronic inflammation, thus triggering downstream signal transduction and leading to pathological deterioration. P38 dysfunction has been implicated in a variety of medical disorders, such as neuroinflammation, ischemia, and cognitive impairment. Our previous study showed that enzymatic inhibition of p38 alleviated pathological symptoms of Alzheimer′s disease (AD), particularly neuroinflammation and accumulation of beta-amyloid (Aβ) and tau proteins. The therapeutic potential of inhibiting p38 in neurodegeneration has been investigated in several clinical trials, but there has been no success yet partly due to off-target effects and insufficient efficacy.

In this study, we use targeted protein degradation as a strategy to induce selective degradation of p-p38. Based on the phosphorylation-dependent conformational difference in p38, we rationally designed and synthesized a series of p-p38-degrading small molecules, consisting of a p-p38 ligand and pomalidomide that can recruit the CRBN E3 ubiquitin ligase complex. We found that one candidate molecule induced selective in vivo degradation of p-p38 and ameliorated neurodegenerative symptoms including neuroinflammation, Aβ deposition, and memory loss. Overall, this study highlights selective targeting of p38 bearing a specific PTM for proteasomal degradation, providing a novel therapeutic approach for the treatment of AD.

Progress Towards Clinical Trials for Atherosclerosis at Cyclarity
https://www.fightaging.org/archives/2023/03/progress-towards-clinical-trials-for-atherosclerosis-at-cyclarity/

Cyclarity is taking a fast path to the clinic for clearance of 7-ketocholesterol, a toxic altered form of cholesterol that contributes to the dysfunction of macrophage cells that lies at the root of atherosclerosis. To the degree that macrophage cells can be rescued from the local excess of cholesterol and altered cholesterol present in an atherosclerotic plaque, they will work to dismantle that plaque. The question is whether removing only 7-ketocholesterol will produce a bigger effect on established atherosclerotic plaque than the presently established approach of lowering LDL-cholesterol in the bloodstream. This is a low bar, as even greatly lowered LDL-cholesterol, while slowing the progression of the condition, actually does very little to reverse existing plaque.

Our lead drug candidate is a cyclodextrin that targets an oxidized cholesterol called 7-ketocholesterol that accumulates in various cells and tissues with age, and the main type of tissue that we are looking at is in the artery where, as I'm sure everyone knows, cholesterol is considered the bad guy that accumulates and causes plaque, the buildup inside of your arteries. What a lot of people don't know is that the most toxic and the most atherogenic is the oxidized cholesterol form. Atherosclerosis is the buildup of plaque inside of your arteries, which is formed by the accumulation of this oxidized cholesterol form. Additionally, unlike cholesterol, which you absolutely need to survive, you don't need any of this oxidized form. And so that's our target. Our lead drug candidate can go into cells and tissues and even penetrate plaque and grab onto that oxidized cholesterol, pull it out and then float away with it, so you can safely excrete it.

We studied all the cyclodextrins in the chemical catalog, and then we did all this computational modeling, and we figured out that the best way to grab onto our target was to dimerize it to basically take two cyclodextrin molecules, stick them together in the right configuration, and then modify it chemically in particular ways to give it the right shape in the binding cavity. Then what it does is, it grabs it and then it eats a single molecule of its target, a bit like Pac-Man, then wraps around it, and the inside cavity forms a shape around the target that fits it. It can then bind it with extremely high affinity and specificity and float away with the 7-ketocholesterol.

We're well into the process of preparing for clinical trials. We've brought on board a noted expert in developing cardiovascular drugs, and are building a team to plan, initiate, and run the clinical trials. Importantly, this is going to start in months, not years. We're going to start clinical trials in 2023, and.we're well along the path of getting ready for that. There's a certain number of things that you need to do with a drug candidate to be ready for that, and you can put them into two basic categories. First is safety testing your drug and the other is in the manufacturing process, and so we're in the final stages of doing the safety testing. Then we need to manufacture the actual version of the drug that will go into people. We're making several kilograms of the final drug product right now, and that's already begun. Then, all the data on both the manufacturing of the drug and the safety testing will be submitted to the regulatory body, at which point we ask for permission to initiate clinical trials.

More on Extracellular Vesicles in Aging, and as a Treatment for Age-Related Conditions
https://www.fightaging.org/archives/2023/03/more-on-extracellular-vesicles-in-aging-and-as-a-treatment-for-age-related-conditions/

The review paper here might be compared with a very similar paper noted a few days ago. Any discussion of extracellular vesicles is essentially a discussion of cell signaling in general. Extracellular vesicles are membrane wrapped packages of signaling molecules that carry a sizable fraction of all of the varied signaling molecules that pass between cells. Cell signaling changes with age because cell behavior changes with age, and thus this is a vast topic, and hard to do more than touch on summary points in a single paper. It is perhaps the case that more attention is being given to extracellular vesicles these days because they can be harvested from cell cultures and used in therapies. This initially offers a logistically less complicated alternative to stem cell transplants, but potentially more interesting and more engineered therapies in the future.

Extracellular vesicles (EVs) are membrane-enclosed particles secreted by cells and circulating in body fluids. Initially considered as a tool to dispose of unnecessary material, they are now considered an additional method to transmit cell signals. EV alteration with aging suggests that the modulation of EV release, in terms of number and content, could represent a target to slow aging and for the therapy of age-related diseases.

First, the evaluation of EV features associated with aging (i.e., number, size, specific markers, genetic and/or biochemical content) could represent a possible biomarker of aging, useful to evaluate a variety of age-delaying therapeutic approaches. Second, the decrease of EVs number, via the removal of senescent cells which are known to release a higher number of EVs, could represent a rejuvenating tool associated with treatment with senolytic drugs. Third, the administration of EVs including key components showing anti-aging effects could be an effective rejuvenating strategy, potentially safer than the administration of whole cells.

Nonetheless, these studies are still preliminary and key issues have still to be elucidated. These challenges require further studies assessing the specific content of aging-associated EVs, as well as the development of methods and tools to produce EVs containing rejuvenating factors in a safe and abundant manner. In cell models, there is agreement that cell senescence is associated with an increased release of EVs, but the functional role of these EVs is less clear, as a few studies have reported pro-senescent and pro-apoptotic effects, whereas others have described a pro-tumorigenic role.

As for body fluid EVs, further studies are needed to assess whether aging is associated with an increased or decreased number of EVs, and the main biochemical features of EVs circulating in old versus young individuals, both in humans and in animal models, need to be further elucidated. Indeed, it must be considered that these samples are subjected to mechanical, chemical, and thermal stress during sampling and processing. This may notably change the shape, size, and composition of EVs in a manner that could be possibly influenced by age-related factors. However, there is converging evidence that EVs from young subjects have a rejuvenating effect and vice versa.

MPC Inhibition Activates Neural Stem Cells to Increase Neurogenesis
https://www.fightaging.org/archives/2023/03/mpc-inhibition-activates-neural-stem-cells-to-increase-neurogenesis/

Stem cells spend much of their time quiescent, only intermittently activating to produce daughter somatic cells. Some well studied populations of stem cells are known to become increasingly quiescent with age, a response to some mix of internal damage and altered signaling environment that arises due to chronic inflammation and other age-related issues. Researchers here report on a way to force neural stem cells back into greater activity, increasing the pace at which new neurons are generated. Since this process of neurogenesis declines with age, contributing to loss of cognitive function, there is considerable interest in finding ways to increase neurogenesis in the aged brain.

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Despite its metabolic key function, the role of MPC in NSPCs has not been addressed.

We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic Mpc1 ablation in vitro and in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify an important pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation.

Another New Player in the Thymus Regeneration Space
https://www.fightaging.org/archives/2023/03/another-new-player-in-the-thymus-regeneration-space/

It seems there is ever more enthusiasm for regenerating the thymus these days, which is welcome. A number of companies are out there pursuing widely divergent scientific programs to achieve this goal, at varying stages of progress towards the clinic. At some point, someone will figure out an optimal path past the various challenges presented by the location and biology of the thymus to produce a large regrowth of this organ in older individuals. The company noted here, Thymmune Therapeutics, is taking the cell therapy approach, which I think to be one of the more viable options, given that a few cell types have been shown to home to the thymus. Still, they are not initially focused on aging, which will likely slow any application to aging of the specific approach that they choose to pursue.

The thymus gland is a small organ tucked beneath the breastbone. Its primary function is to produce T cells, which help the body ward off infections and diseases and mount an immune response to vaccines. The thymus grows weaker with age and is less capable of producing naïve T cells, leading to immune dysfunction and various chronic conditions.

Thymmune Therapeutics debuted recently with 7 million in seed financing. Thymmune aims to reverse thymic atrophy by combining machine learning with cellular engineering to mass produce thymic cells derived from induced pluripotent stem cells. With this approach, the start-up intends to create off-the-shelf cell therapies that can restore immune function minimally invasively.

The small team will first test their platform against athymia, a rare and congenital immune disorder wherein an infant is born without a thymus. Babies with athymia cannot produce T cells and are at a high risk of infection. Left untreated, athymic infants typically die by age two or three. The company is also looking at testing its platform to treat several autoimmune diseases and address organ transplant tolerance. In the future, Thymmune's platform could also boost immune function and address the biology of aging.