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- Impaired Ketogenesis Important in Testicular Aging, in Mice At Least
- SQSTM1 in Cellular Senescence and Skin Aging
- 100 Teams in the XPRIZE Healthspan Competition
- γδ T cells are Involved in the Clearance of Senescent Cells
- A Complex Relationship Between Transposable Elements and Aging
- Hearing Loss Correlates with Increased Risk of Cognitive Decline
- A Deeper Look at TP53 in the Determination of Species Life Span
- Inflammatory Immune Cells in Cerebral Small Vessel Disease
- Investigating a Methionine Restriction Mimetic Compound
- Machine Learning Applied to Polypharmacology to Slow Aging
- Synaptic Spread versus Selective Vulnerability Hypotheses of Neurodegenerative Disease
- Therapeutic Peptide Amphiphiles Prevent Misfolded Amyloid-β from Aggregating
- Phenylacetic Acid Produced by Gut Microbes Harms the Vascular Endothelium
- A Recipe to Produce Hematopoietic Stem Cells from Embryonic Stem Cells
- An Example of Proteomic Correlations with Aging
Impaired Ketogenesis Important in Testicular Aging, in Mice At Least
https://www.fightaging.org/archives/2025/05/impaired-ketogenesis-important-in-testicular-aging-in-mice-at-least/
The testes manufacture testosterone, generally important to long-term health. Further, germ cells resident in the testes manufacture sperm. This process of spermatogenesis is necessary for reproduction. Both of these functions decline with age. As is the case for near all outcomes of degenerative aging, the research community has yet to construct a clear model of cause and effect that reaches from the known root causes of aging to declining function in the tests. Cellular biochemistry is complex and incompletely mapped, and aging is a further complexity imposed upon those systems, not just as the level of individual cells, but also at the level of tissues containing enormous numbers of interacting cells of different types. It is a challenging task.
Researchers regularly uncover intermediary mechanisms in aging that appear important. Not a root cause and not a final outcome, but something in the middle layer of complex interactions that is influential enough on the progression of disease or loss of function to be worthy of note. Today's open access paper is an example of the type, in which researchers observe that loss of the capacity for ketogenesis in Leydig cells in the testes that are responsible for the production of testosterone appears important in the functional decline of the testes. This may be a target for the development of drugs to slow some of the more important age-related deterioration that takes place in this organ, though it seems that β-hydroxybutyric acid supplementation works well enough.
Impaired ketogenesis in Leydig Cells drives testicular aging
Testicular aging is characterized by a reduction in testosterone, which is linked to various male reproductive disorders and a diminished quality of life in the elderly. Currently, testosterone replacement therapy (TRT) serves as the primary intervention for alleviating symptoms associated with testicular aging. However, TRT is accompanied by notable adverse effects. Moreover, TRT fails to mimic the physiological secretion patterns of testosterone and can negatively impact spermatogenesis. Consequently, there is a pressing need to explore novel therapeutic strategies for addressing testicular aging.
Aging testes undergo profound alterations in both germ cells and somatic cells, leading to reduced functionality. Previous studies have shown that testicular aging is marked by a decline in the number of spermatogonia and spermatocytes, as well as the accumulation of DNA damage and mutations within germline cells. As the primary cells producing testosterone, Leydig cells (LCs) play a crucial role in spermatogenesis and male fertility. LCs are thought to be vulnerable to age-related damage, primarily due to oxidative stress induced by reactive oxygen species (ROS).
In this study, we characterize testicular aging by detecting the senescence marker senescence-associated β-galactosidase (SA-β-gal), identifying that LCs are the most susceptible cells to aging in the testis. Single-cell transcriptomics reveals a significant downregulation of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), which encodes the rate-limiting enzyme in ketogenesis, in aged LCs. Moreover, silence of Hmgcs2 in young LCs impairs ketogenesis, causing premature senescence and accelerating testicular aging. Mechanistically, β-hydroxybutyric acid (BHB), a ketogenic product and inhibitor of histone deacetylase 1 (HDAC1), promotes Foxo3a expression by enhancing histone acetylation, thereby alleviating LCs senescence and improving steroidogenic function.
In vivo studies further demonstrate that enhancing ketogenesis via Hmgcs2 overexpression or BHB supplementation reduces LCs senescence and improves testicular function in aged mice.
SQSTM1 in Cellular Senescence and Skin Aging
https://www.fightaging.org/archives/2025/05/sqstm1-in-cellular-senescence-and-skin-aging/
SQSTM1 is also known as P62. The protein expressed by this gene assists in the selection and transport of materials to be recycled via autophagy, an important stress response mechanism. Once a protein or structure has been decorated with a ubiquitin molecule, SQSTM1 binds to that protein or structure as a part of the complicated process of shuttling it to a lysosome where it can be broken down. Thus too little SQSTM1 impairs autophagy and more SQSTM1 can enable more efficient autophagy. This can influence the pace of aging, as illustrated by the numerous interventions that both slow aging and which feature enhanced autophagy. In at least a few such cases, such as for calorie restriction, autophagy has been shown to be necessary for slowed aging to occur. Unfortunately, this class of approaches to the treatment of aging has much larger effects on life span in short-lived species than it does in long-lived species such as our own.
In today's open access paper researchers review some of the biochemistry immediately surrounding SQSTM1 and autophagy, with a particular focus on cellular senescence and skin aging. Senescent cells accumulate in aging tissue, generating inflammatory signaling that is disruptive to tissue structure and function. More efficient autophagy appears to help resist entry to the senescent state, and can thus in principle reduce the burden of senescent cells in aged tissue to some degree over time, assuming the immune system is competent enough to catch up on its task of destroying senescent cells. Clinical trials in humans to conclusive prove this point and quantify the size of the benefits remains an aspiration, even for very well established drugs like rapamycin.
SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation
USP7 regulates intracellular protein homeostasis through selective substrate degradation. It plays a crucial role in cell cycle control, senescence, and cancer by interacting with diverse target protein. Sequestosome1 (SQSTM1 or p62), hereafter p62, an autophagy receptor, has been associated with aging and age-related diseases, including neurodegeneration, infections, cancer, and oxidative stress-related conditions. p62 deficiency is associated with a shorter lifespan, elevated oxidative stress, synaptic deficiencies, and memory impairment. By interacting with GATA4, p62 promotes selective autophagic degradation, inhibiting cellular senescence.
In the dermis, fibroblasts regulate collagen expression and maintain skin integrity. However, senescent fibroblasts contribute to dermal thinning, increased wrinkle formation, and skin sagging. Keratinocytes also play a pivotal role in shaping the senescent skin microenvironment, including the maintenance of the dermal-epidermal junction and the secretion of senescence-associated secretory phenotype (SASP) factors. Notably, senescent keratinocytes exhibit enrichment of SASP components, including proinflammatory cytokines and proteases. The consequent decline in cellular and tissue regenerative potential is implicated in the progression of skin aging. However, the precise mechanisms through which p62 regulates keratinocytes in skin aging are unknown.
In this study, we investigate the function of p62 and potential mechanisms in skin aging and cellular senescence. We identified p62 as a negative regulator in skin aging and senescent keratinocytes. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of USP7 during senescence induction by orchestrating its degradation through specific binding interactions. Importantly, this study provides the first time, to our knowledge, that p62 plays a critical role and regulates specific mechanisms in skin aging and cellular senescence.
100 Teams in the XPRIZE Healthspan Competition
https://www.fightaging.org/archives/2025/05/100-teams-in-the-xprize-healthspan-competition/
One of the challenges inherent in developing an industry of medical development aimed at the treatment of aging is that present regulatory structure and investment culture actively discourage any attempt to quantify effects on life span. While aging clocks are interesting, they cannot yet be relied upon, and no-one is willing to fund the lengthy studies needed to assess the effects of any given therapy on long term health the old-fashioned way, by waiting and watching. Aging is not yet considered a treatable medical condition by regulators, and so developers are forced by investors into optimizing their approaches to therapy for specific age-related conditions, as that is the fastest path to market.
The XPRIZE Healthspan competition aims to encourage more efforts to assess effects on health span and longevity, but the same problems apply here also. The prize organizers have chosen to ask competitors to assess before and after functional assays of immune function, cognitive capacity, and muscle mass and strength, and this may or may not prove to be a good way forward. To pick one example, is mechanically removing severe, artery-narrowing atherosclerotic plaque actually rejuvenation? If only a few accessible plaques were limiting overall blood flow, then removing them will likely improve cognition, cardiovascular function, and muscle function just by restoring blood flow to these tissues. But I think it is hard to argue that we learned anything by doing this, or advanced the field meaningfully.
As today's article notes, there are a lot of teams entered into the contest. We can certainly debate how many of those are actually working on ways to treat aging, depending on one's definition of the term. Nonetheless, it is good to see enthusiasm and activity channeled into a path that will likely help to raise the profile of the industry and research community focused on aging; research prizes are a proven way to generate more support for a field. That said, at the end of the day the assays chosen for success in the prize competition are like aging clocks in that they still have to be validated against life span and health span the old-fashioned way, and separately for every type of therapy one wants to measure. There is all too little certainty in short-term measures of aging at the present time.
Global competition enters clinical phase as selected teams work to restore immune, cognitive and muscular function in older adults.
The race to improve how long we live well has entered a new phase. XPRIZE Healthspan, the seven-year, 101 million global competition announced in late 2023, has unveiled its first cohort of semifinalists - 100 teams from 58 countries tasked with developing therapies to extend the years we spend in good health. The prize sets a clear goal: to restore muscular, cognitive, and immune function by a minimum of ten years in adults aged 50 to 80, within a 12-month timeframe. It's a challenging mandate, yet one that neatly reflects the evolving ethos of longevity science - less about aspirational immortality, more about physiological capacity and quality of life.
From over 600 registrants, the XPRIZE judging panel has selected a strikingly diverse range of interventions. BioAge Labs is focusing on inflammation and metabolic dysfunction via NLRP3 inhibition; Longeveron Inc is trialing a mesenchymal stem cell therapy for age-related frailty; Timeline continues to develop its Urolithin A-based mitophagy activator. Other teams, such as NUS Academy for Healthy Longevity and Cyclarity Therapeutics, are deploying multi-modal or precision geroscience strategies, while firms like Rejuvenate Bio are turning to gene therapy and AI-guided systems biology.
XPRIZE Healthspan Qualified Teams Book 2025
The Semifinalists in the 101M XPRIZE Healthspan competition have shown exceptional promise in developing therapies aimed at restoring muscle strength, cognitive abilities, and immune function in individuals aged 50-80. In our recently released Qualified Team Lookbook, you can explore the innovations of the Top 100 Qualified Teams. These teams are not just advancing science - they're building a future of health and opportunity for all. And remember, it's not too late to enter the competition with your idea!
γδ T cells are Involved in the Clearance of Senescent Cells
https://www.fightaging.org/archives/2025/05/%ce%b3%ce%b4-t-cells-are-involved-in-the-clearance-of-senescent-cells/
Senescent cells accumulate with age in large part because the capacity of the immune system to destroy these cells diminishes in late life. Lingering senescent cells disrupt tissue structure and function via their pro-growth, pro-inflammatory secretions. The more senescent cells present in the body, the worse the outcome. Many approaches to the selective destruction of senescent cells are under development, but a greater understanding of the role of the immune system in the natural clearance of senescent cells may open further doors to more effective classes of therapy. The ideal therapy is one that enhances the ability of the immune system to clear undesirable senescent cells, while allowing the short-term existence of senescent cells in response to injury, potentially cancerous tissue, and so forth, scenarios in which senescent cells are beneficial.
In today's open access preprint paper, researchers discuss the role of γδ T cells in the clearance of senescent cells, noting that γδ T cells react to the presence of senescent cells. Interestingly, past research has shown that a subset of γδ T cells become inflammatory in visceral fat tissue, and contribute to the harmful chronic inflammation generated by excess visceral fat. We also know that excess visceral fat produces senescent cells at an accelerated pace, one of the ways in which it can provoke inflammation throughout the body. Joining the dots here, one might speculate that continual generation of senescent cells in sufficient numbers in visceral fat tissue causes the γδ T cell response to become maladaptive, part of the problem rather than part of the solution.
γδ T Cells Target and Ablate Senescent Cells in Aging and Alleviate Pulmonary Fibrosis
A variety of physiological and pathological stimuli elicit the cellular senescence response. Immune cells are known to execute surveillance of infected, cancerous, and senescent cells, and yet senescent cells accumulate with age and drive inflammation and age-related disease. Understanding the roles of different immune cells in senescent cell surveillance could enable the development of immunotherapies against biological aging and age-related disease.
Here, we report the role of human gamma delta (γδ) T cells in eliminating senescent cells. Human donor Vγ9vδ2 T cells selectively remove senescent cells of different cell types and modes of induction while sparing healthy cells, with parallel findings in mouse cells. We find that senescent cells express high levels of multiple γδ T cell ligands, including cell-surface BTN3A1. Individually blocking NKG2D or γδ T cell receptor of γδ T cells only partially reduces Vγ9vδ2 T cell cytotoxicity, evidencing their versatility in senescence removal. γδ T cells expand in response to the induction of a mouse model of idiopathic pulmonary fibrosis (IPF), accompanied by the emergence of senescent cells, and colocalize with senescent cells in lung tissue from patients with IPF. Finally, we show that adoptive cell transfer of γδ T cells into an IPF mouse model reduces the number of p21-expressing senescent cells in affected lung tissue and improves outcomes.
γδ T cells or modalities that activate their surveillance activity present a potent approach for removing senescent cells and their attendant contribution to aging and disease.
A Complex Relationship Between Transposable Elements and Aging
https://www.fightaging.org/archives/2025/05/a-complex-relationship-between-transposable-elements-and-aging/
A sizable fraction of any mammalian genome is the made up of transposable elements, largely the debris of ancient viral infections, sometimes repurposed, sometimes of dubious benefit. Many of these sequences retain the ability to hijack the machinery of gene expression to copy themselves, or to generate particles that are sufficiently virus-like to provoke an innate immune reaction. In youth, transposable elements are suppressed. Regions of the genome containing transposable elements are folded away, given epigenetic decorations that ensure that these regions are inaccessible to the protein machinery that carries out transcription of sequences into RNA. The epigenetic changes that occur with age alter this situation for the worse, and transposable element sequences are unfolded to become accessible and active. This is thought to cause inflammation and genetic damage at the very least, contributing in some yet to be established degree to degenerative aging.
In today's open access review paper, researchers discuss what is known of the relationship between transposable element activity and aging. It is by no means straightforward. Transposable element activity doesn't seem to be a root cause of aging, in that it is downstream of epigenetic changes characteristic of aging and will not emerge absent those changes. But one can argue for a range of possibly bidirectional interactions between transposable element activation and other mechanisms and outcomes in aging. Any disruptive influence on cells that results in epigenetic dysregulation to expose transposable elements may in turn be accelerated by transposable element activity, particularly via inflammatory signaling resulting from innate immune reactions.
Exploring the relationship of transposable elements and ageing: causes and consequences
Modern theories of ageing, which seek to explain its underlying mechanisms, are divided into two main categories: the error/damage and the programmed perspective. The error/damage model proposes that ageing results primarily from the accumulation of cellular and molecular damage over time. This theory emphasises that environmental factors, lifestyle choices, and metabolic processes contribute to this damage. In contrast, the programmed model views ageing as an inherent and essential part of the life cycle, driven by genetic and hormonal mechanisms rather than simply being a consequence of accumulated damage over time.
Advances in whole-genome sequencing techniques have enabled the study of the genetic mechanisms involved in ageing. Among various genomic components, transposable element (TE) effects have been repeatedly linked to ageing due to their capacity to generate mutations with potential to disrupt normal cellular functions. TEs are repetitive DNA sequences capable of moving (transpose) within the genome, which are commonly classified into two main classes based on their mechanism of transposition. Class I elements, or retrotransposons, transpose via an RNA intermediate through a "copy and paste" mechanism. In contrast, Class II elements, or DNA transposons, move using a DNA intermediate and typically follow a "cut and paste" mechanism.
To capture the diversity within these broad categories, TEs are further classified in subclasses, orders, and superfamilies based on mechanistic and enzymatic criteria. TEs are present in virtually all eukaryotic and prokaryotic genomes, and they typically represent a considerable fraction of the genomes, although their abundance is highly variable from one species to another. Due to their mobile and repetitive nature, TEs are a source of genomic variation. The DNA breaks and insertions associated with transposition events lead to obvious alterations to the genome. The consequences of TE expression and mobilisation can also have widespread effects, altering gene expression and structure, chromosome dynamics, as well as the epigenetic landscape of the genome.
The idea that TEs can contribute to ageing processes through mutations (associated with the error/damage theory of ageing) was first proposed in the 1980s. Building up on the same idea, the transposon ageing model, introduced in 1990, postulates that an exponential increase of TE copy number with time could eventually kill the cell or organism by inactivating essential genes. Indeed, the activation of TEs has been demonstrated to affect lifespan associated with DNA damage in several organisms like fruit flies and mice. Similarly, TE activation has been recently associated with neurodegenerative, autoimmune, and cancer diseases which can in turn affect organismal lifespan.
To mitigate detrimental TE-related effects, TE activity (expression and/or transposition) is normally repressed by epigenetic mechanisms that can involve DNA methylation, histone modifications and/or production of small RNAs. Ageing disrupts these TE silencing mechanisms, increasing their activity. Examples of that have been documented in several organisms, where TE expression and sometimes TE transposition increased with age in different somatic tissues. In this review, we explore current literature demonstrating that TE activity can be associated with both the causes and consequences of ageing, leading to a more complex hypothesis regarding the role of TEs in ageing processes.
Hearing Loss Correlates with Increased Risk of Cognitive Decline
https://www.fightaging.org/archives/2025/05/hearing-loss-correlates-with-increased-risk-of-cognitive-decline/
It is well established that hearing loss and cognitive decline correlate with one another. There is some debate over causation, the degree to which hearing loss might contribute to cognitive decline versus both outcomes arising from the same underlying mechanisms of cell and tissue damage that drive aging. Recent studies strongly suggest that loss of hearing does accelerate cognitive decline, but this doesn't rule out shared contributions to both conditions from underlying processes or a bidirectional relationship of mutual causation.
Hearing loss (HL) of moderate or higher grades is common in older adults with increasing prevalence as people age, rising from 12% at the age of 60 years to over 58% at 90 years. HL in midlife is one of the main potentially modifiable risk factors for dementia. It is estimated that 7% of dementia cases globally could be avoided if this risk factor was eliminated.
Participants from the Brazilian Longitudinal Study of Adult Health were evaluated in three study waves (2008-10, 2012-14, and 2017-19). HL was defined as pure-tone audiometry above 25 dB in the better ear. Cognitive performance was evaluated with six tests related to memory, verbal fluency, and trail-making tests. A global cognitive z-score was derived from these tests. The association between HL and cognitive decline was evaluated with linear mixed-effects models adjusted for sociodemographic, lifestyle, and clinical factors.
Of 805 participants (mean age 51 ± 9 years), 62 had HL. During follow-up, HL was associated with faster global cognitive decline (β = -0.012). In conclusion, HL was significantly associated with a faster rate of global cognitive decline after a median follow-up of eight years in a sample of middle-income country.
A Deeper Look at TP53 in the Determination of Species Life Span
https://www.fightaging.org/archives/2025/05/a-deeper-look-at-tp53-in-the-determination-of-species-life-span/
The tumor suppressor protein p53, encoded by the gene TP53, is thought to be a component of the trade-off between tissue maintenance and cancer risk that contributes to species life span. Too much p53 activity and cancer risk declines but life span shortens as tissue maintenance is also suppressed. To little p53 activity and life span increases, but so does cancer risk - eventually to the point of cutting short that extended life. Evolution comes to some balance for any given niche, but perhaps there is something to be learned from other species that could inform possible approaches to the control of cancer in our own species.
Several molecular mechanisms have been purported to regulate aging and influence lifespan - many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes and induces tumor-suppressive processes such as DNA repair, apoptosis, and cellular senescence. In a context-dependent manner, its DNA-repair mechanism enhances longevity while aberrant apoptosis and cellular senescence accelerate aging.
Genotype-phenotype correlation studies that have sought to map observed differences in lifespan across species to differences in the sequence and structure of p53 ortholog have largely focused on the DNA-binding domain (DBD). For closely related p53 orthologs, those of longer-lived species possess unique mutations in their DBD that have been hypothesized to enhance their longevity-regulating interactome. Residues 180-192, which compose the L2 region of the DBD in human p53, are most highly correlated with longevity.
Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) domains are largely unexplored. To address this, we developed a Relative Evolutionary Scoring (RES) workflow to comprehensively investigate the changes in full-length p53 structure across organisms of various taxonomic orders and observed average lifespan. Using the Sorting Intolerant From Tolerant (SIFT) mutation prediction tool and the results from yeast-based functional assays, we characterized the effect of found RES-predicted longevity-associated residues (RPLARs) on p53 function and tumor-suppressive pathways.
Our findings reveal that while most longevity-associated residues are found in the DNA-binding domain, critical residues also exist in other p53 domains. Mutational functional experiments and protein interaction predictions suggest these residues may play a vital role in p53 stability and its interactions with other proteins involved in the induction of senescence. This work broadens our understanding of the mechanisms undergirding dysregulated p53 tumor suppression and its link to accelerated aging.
Inflammatory Immune Cells in Cerebral Small Vessel Disease
https://www.fightaging.org/archives/2025/05/inflammatory-immune-cells-in-cerebral-small-vessel-disease/
Chronic inflammation is a major component of aging, disruptive to tissue structure and function. Researchers here review some of what is known of the immune system dysfunction associated with cerebral small vessel disease, noting various measures reflective of inflammation. A number of lines of evidence point to inflammation of the vascular endothelium, the inner lining of blood vessels, as important in the development of vascular conditions such as atherosclerosis and small vessel disease. One should expect sustained inflammation to be disruptive to all of the structures and functions of vascular tissue, however, including the all-important blood-brain barrier that lines blood vessels in the brain.
Cerebral small vessel disease (cSVD) refers to all pathologies of the brain's arterioles, capillaries, and venules. cSVD is highly prevalent with ageing and is diagnosed by its characteristic neuroimaging features. Emerging evidence suggests that circulating immune cells play an important role in cSVD's pathology. However, the specific immune cell populations involved remain poorly understood. This systematic review synthesizes current evidence on circulating immune cells in cSVD and their associations with cSVD features. A systematic search was conducted and a total of 18 studies were included, all studies investigating the association between peripheral immune cells and imaging features of cSVD. Data was extracted on study design, immune cells and cSVD measures, and outcomes.
Pro-inflammatory monocytes were associated with the severity and progression of cSVD over time. The neutrophil-to-lymphocyte ratio (NLR) showed positive associations with white matter hyperintensities (WMH) and enlarged perivascular spaces. The monocyte-to-HDL ratio (MHR) demonstrated a stronger association than the NLR with WMH, lacunes, and cerebral microbleeds. The lymphocyte-to-monocyte ratio (LMR) was linked to slower WMH progression and lower cSVD prevalence. Key findings highlight a role for pro-inflammatory circulating monocytes, NLR, MHR, and LMR in cSVD patients. These derived ratios serve as more reliable disease predictors than individual blood counts, showing potential as innovative diagnostic and prognostic markers. However, the reviewed studies predominantly employed cross-sectional and retrospective designs, suggesting the need for large-scale, prospective investigations to determine the role of these inflammatory markers in cSVD's pathogenesis.
Investigating a Methionine Restriction Mimetic Compound
https://www.fightaging.org/archives/2025/05/investigating-a-methionine-restriction-mimetic-compound/
A sizable portion of the health benefits (and life extension in short-lived species) resulting from the practice of calorie restriction is triggered by sensing of levels of specific amino acids. Methionine is one of the more important such amino acids, and researchers have demonstrated that low-methionine diets can produce some fraction of the benefits of calorie restriction without reducing calorie intake, at least in rodents. Just as there are calorie restriction mimetics, molecules that trigger some of the same biochemical responses to calorie restriction, there should in principle be methionine restriction mimetics. Researchers here discuss one such methionine restriction mimetic, though note that nowadays everything in this part of the field is filtered through the lens of treating obesity, regardless of possible benefits to people of normal weight, because obesity has become the primary focus of the pharmaceutical industry.
Sulfur amino acid restriction (SAAR), lowering the dietary concentration of sulfur amino acids methionine and cysteine, induces strong anti-obesity effects in rodents. Due to difficulties in formulating the SAAR diet for human consumption, its translation is challenging. Since our previous studies suggest a mechanistic role for low glutathione (GSH) in SAAR-induced anti-obesity effects, we investigated if the pharmacological lowering of GSH recapitulates the lean phenotype in mice on a sulfur amino acid-replete diet.
Male obese C57BL6/NTac mice were fed high-fat diets with (a) 0.86% methionine (CD), (b) 0.12% methionine (SAAR), © SAAR diet supplemented with a GSH biosynthetic precursor, (d) N-acetylcysteine in water (NAC), and (e) CD supplemented with a GSH biosynthetic inhibitor, DL-buthionine-(S, R)-sulfoximine in water (BSO). The SAAR diet lowered hepatic GSH but increased Nrf2, Phgdh, and serine. These molecular changes culminated in lower hepatic lipid droplet frequency, epididymal fat depot weights, and body fat mass; NAC reversed all these changes.
BSO mice exhibited all SAAR-induced changes, with two notable differences, i.e., a smaller effect size than that of the SAAR diet and a higher predilection for molecular changes in kidneys than in the liver. Metabolomics data indicate that BSO and the SAAR diet induce similar changes in the kidney. Unaltered plasma aspartate and alanine transaminases and cystatin-C indicate that long-term continuous administration of BSO is safe. Data demonstrate that BSO recapitulates the SAAR-induced anti-obesity effects and that GSH plays a mechanistic role. BSO dose-response studies in animals and pilot studies in humans to combat obesity are highly warranted.
Machine Learning Applied to Polypharmacology to Slow Aging
https://www.fightaging.org/archives/2025/05/machine-learning-applied-to-polypharmacology-to-slow-aging/
One of the tasks in which machine learning and related techniques excel is finding patterns in very large data sets and extrapolating those patterns to predict as yet undiscovered members. The outcome of combinations of known small molecule drugs and drug candidates is one such data set. There is very little known in certainty about polypharmacology, as research and development groups operate under incentives that strongly discourage assessment of combination treatments. Where researchers have looked into combinations of small molecules in the context of slowing aging, they have found that the typical outcome is that any two compounds that individually alter metabolism to modestly slow aging produce no benefit or a mild harm when combined. This is a vast space of possibilities, little concrete knowledge, and maybe some useful outcomes hidden in the dross - and that is exactly the sort of challenge in which machine learning can be used accelerate the pace of discovery. That said, at the end of the day we are talking about effect sizes that are, at best, on a par with that of exercise. This isn't the path to radical life extension.
The genetic foundation of lifespan is becoming increasingly well-understood, but the optimal strategies for designing interventions to extend it remain unclear. Small molecule drugs, the mainstay of the pharmaceutical industry, act by modulating the activity of gene products - proteins, herein referred to as targets. Standard drug-discovery practice dictates that therapeutic compounds should be highly specific to a single target. However, closer inspection of FDA-approved drugs reveals that some of the most efficacious drugs bind multiple targets simultaneously and that, in some instances, more specific analogs are less efficacious. These findings suggest polypharmacology may improve efficacy for some complex indications.
The largest unbiased longevity screen of the Library of Pharmacologically Active Compounds (LOPAC), particularly FDA-approved drugs, identified a significant cluster of compounds that extend lifespan by modulating neuroendocrine and neurotransmitter systems. We observed that most inhibitors of G-protein coupled receptors (GPCRs) bind multiple structurally related targets, suggesting that polypharmacological binding increases their efficacy in extending lifespan. To test this notion, we used statistical and machine learning tools, specifically graph neural networks (GNNs), to identify geroprotector compounds that simultaneously bind multiple biogenic amine receptors and then evaluated their efficacy on the lifespan of Caenorhabditis elegans.
Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to all geroprotectors recorded in the DrugAge database. Thus, our study reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.
Synaptic Spread versus Selective Vulnerability Hypotheses of Neurodegenerative Disease
https://www.fightaging.org/archives/2025/05/synaptic-spread-versus-selective-vulnerability-hypotheses-of-neurodegenerative-disease/
The authors of this open access paper provide an overview of two viewpoints on the onset and progression of neurodegenerative conditions. The biochemistry of the brain is exceptionally complex, and its dysfunction is also complex. It is clear that the aggregation of a few forms of altered protein is important in neurodegeneration, but exactly how and why it is important remains an active area of research. There are points of consensus, points of debate, and this landscape shifts over time as new evidence emerges. The absence of curative therapies for neurodegenerative conditions is a symptom of the inability to determine the critical mechanisms driving dysfunction, distinguishing them from the many interacting consequences of those mechanisms and other changes associated with degenerative aging.
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneering researchers have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases.
The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation.
Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.
Therapeutic Peptide Amphiphiles Prevent Misfolded Amyloid-β from Aggregating
https://www.fightaging.org/archives/2025/05/therapeutic-peptide-amphiphiles-prevent-misfolded-amyloid-%ce%b2-from-aggregating/
Researchers here outline an interesting approach to trapping misfolded amyloid-β before it can aggregate and disrupt the biochemistry of the brain. Without the ability to aggregate into solid structures, the misfolded amyloid-β will break down or be cleared without causing harm. It remains to be seen as to how well this does in practice, but it is certainly the case that safer, cheaper alternatives to the present anti-amyloid immunotherapies are much needed. It appears that amyloid-β is important only in the long lead in to Alzheimer's disease, and thus therapies are most effectively deployed very early and broadly, in a large fraction of the population. The cost and side-effect profile of present immunotherapies is not well suited to this sort of use case.
Most neurodegenerative conditions are characterized by the accumulation of misfolded proteins in the brain, leading to the progressive loss of neurons. To tackle this challenge, researchers turned to a class of peptide amphiphiles that contain modified chains of amino acids. Peptide amphiphiles are already used in well-known pharmaceuticals. "Trehalose is naturally occurring in plants, fungi, and insects. It protects them from changing temperatures, especially dehydration and freezing. Others have discovered trehalose can protect many biological macromolecules, including proteins. So, we wanted to see if we could use it to stabilize misfolded proteins."
When added to water, the peptide amphiphiles self-assembled into nanofibers coated with trehalose. Surprisingly, the trehalose destabilized the nanofibers. Although it seems counterintuitive, this decreased stability exhibited a beneficial effect. Unstable assemblies of molecules are very reactive. Searching for stability, the nanofibers bonded to amyloid-beta proteins, a key culprit implicated in Alzheimer's disease. But the nanofibers didn't just stop the amyloid-beta proteins from clumping together. The nanofibers fully incorporated the proteins into their own fibrous structures - permanently trapping them into stable filaments.
"Then, it's no longer a peptide amphiphile fiber anymore, but a new hybrid structure comprising both the peptide amphiphile and the amyloid-beta protein. That means the nasty amyloid-beta proteins, which would have formed amyloid fibers, are trapped. They can no longer penetrate the neurons and kill them. It's like a clean-up crew for misfolded proteins. This is a novel mechanism to tackle progression of neurodegenerative diseases, such as Alzheimer's, at an earlier stage. Current therapies rely on the production of antibodies for well-formed amyloid fibers."
Phenylacetic Acid Produced by Gut Microbes Harms the Vascular Endothelium
https://www.fightaging.org/archives/2025/05/phenylacetic-acid-produced-by-gut-microbes-harms-the-vascular-endothelium/
The balance of microbial populations making up the gut microbiome shifts with age. Inflammatory species and those generating harmful metabolites increase in number at the expense of species that generate beneficial metabolites. This is why approaches that rejuvenate the gut microbiome, forcing it back into a more youthful balance of populations, produce significant gains in health and life span in animal studies conducted to date. Here, researchers focus on just one aspect of gut microbiome aging, identifying a specific microbial metabolite that harms the vascular endothelium by provoke cellular senescence. The endothelium is in the inner lining of blood vessels. Damage and dysfunction in the endothelium is one of the early contributing causes of a range of vascular dysfunction, from the development of atherosclerotic lesions to leakage of the blood-brain barrier.
Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos).
We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H2O2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.
A Recipe to Produce Hematopoietic Stem Cells from Embryonic Stem Cells
https://www.fightaging.org/archives/2025/05/a-recipe-to-produce-hematopoietic-stem-cells-from-embryonic-stem-cells/
The hematopoietic cell populations in bone marrow deteriorate with age, negatively affecting the production of immune cells and red blood cells. Given the importance of immune system dysfunction in aging, restoring the hematopoietic populations to youthful competence is thought important. A number of lines of research focus on this goal, one of which is replacement, meaning the delivery of a functional population of hematopoietic stem cells into the bone marrow with the support needed for these cells to survive and engraft. This requires the ability to reliably and cost-effectively generate hematopoietic stem cells from induced pluripotent stem cells made from a tissue sample provided by the recipient. Most of the other capabilities needed to establish this form of therapy exist, but making hematopoietic stem cells remains a challenge. Here, researchers propose a specific approach.
Hematopoietic Stem Cells (HSCs) possess the ability to long-term reconstitute all the blood lineages and generate all blood cell types. As such, the in vitro generation of HSCs remains a central goal in regenerative medicine. Despite many efforts and recent advancements in the field, there is still no robust, reproducible and efficient protocol for generating bona-fide HSCs in vitro. This suggests that certain regulatory elements have yet to be uncovered.
Here, we present a novel and unbiased approach to identifying endogenous components to specify HSCs from pluripotent stem cells. We performed a genome-wide CRISPR activator screening during mesodermal differentiation from mouse embryonic stem cells (mESCs). Following in vitro differentiation, mesodermal KDR+ precursors were transplanted into primary and secondary immunodeficient NSG mice. This approach led to the identification of seven genes (Spata2, Aass, Dctd, Eif4enif1, Guca1a, Eya2, Net1) that, when activated during mesoderm specification, induce the generation of hematopoietic stem and progenitor cells (HSPCs). These cells are capable of serial engraftment and multilineage output (erythroid, myeloid, T lymphoid, and B lymphoid) in vivo.
Single-cell RNA sequencing further revealed that activating these seven genes biases the embryoid bodies towards intraembryonic development, instead of extraembryonic, increasing the number of mesodermal progenitors that can generate HSCs. Our findings underscore the importance of differentiation during the first germ layer specification to generate definitive blood stem cells.
An Example of Proteomic Correlations with Aging
https://www.fightaging.org/archives/2025/05/an-example-of-proteomic-correlations-with-aging/
The past twenty years of work on an increasingly diverse set of aging clocks has comprehensively demonstrated that analysis of any sufficiently complex database of biological data will find correlations with age. Aging causes changes, driven by the accumulation of forms of cell and tissue damage. Since that damage is the same for everyone, even given individual variations in pace of aging there will be any number of specific age-related changes in biological data that run in much the same way in near all individuals. In an era in which obtaining and analyzing data costs little, we should expect to see a steady supply of papers such as the one noted here, in which researchers identify ever more specific age-related changes.
This study analyzed data from 51,904 UK Biobank participants to explore the association between 2,923 plasma proteins and nine aging-related phenotypes, including PhenoAge, KDM-Biological Age, healthspan, parental lifespan, frailty, and longevity. Protein levels were measured using proteomics. We utilized the DE-SWAN method to detect and measure the nonlinear alterations in plasma proteome during the process of biological aging. Mendelian randomization was applied to assess causal relationships, and a phenome-wide association study (PheWAS) explored the broader health impacts of these proteins.
We identified 227 proteins significantly associated with aging, with the pathway of inflammation and regeneration being notably implicated. Our findings revealed fluctuating patterns in the plasma proteome during biological aging in middle-aged adults, pinpointing specific peaks of biological age-related changes at 41, 60, and 67 years, alongside distinct age-related protein change patterns across various organs. Furthermore, Mendelian randomization further supported the causal association between plasma levels of CXCL13, DPY30, FURIN, IGFBP4, SHISA5, and aging, underscoring the significance of these drug targets. These five proteins have broad-ranging effects. The PheWAS analysis of proteins associated with aging highlighted their crucial roles in vital biological processes, particularly in overall mortality, health maintenance, and cardiovascular health. Moreover, proteins can serve as mediators in healthy lifestyle and aging processes.
View the full article at FightAging
