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- Expansion of the Montana Right to Try Law Passes
- Mechanisms of Germline Stem Cell Decline in the Aging of the Testes in Flies
- A High Level Tour of the Metabolism of Long-Lived Individuals
- Building an Aging Clock from Microglial Transcriptomics
- Arguing for Clinical Trials of Exercise Conditioned Plasma
- NAD Deficiency Impairs CAR-T Cells Derived from Older Adults
- The Aging of the Gut Microbiome from a DNA Damage and Telomere Erosion Perspective
- Regulators of Detoxification Genes Extend Life Span in Nematode Worms
- Time Restricted Feeding Improves the Gut Microbiome and Slows Aging in Flies
- Klotho Gene Therapy in Adult Mice Produces a 20% Increase in Life Span
- Loss of Histone Lactylation in Muscle Aging
- Phase Angle Measure of Muscle Quality Correlates with Dementia Risk
- YTHDF2 Downregulation is Protective in the Aging Retinas of Mice
- The Aging Brain is More Vulnerable to Amyloid-β Toxicity
- Altos Labs Broadens Scope to Senotherapeutics via Acquisition
Expansion of the Montana Right to Try Law Passes
https://www.fightaging.org/archives/2025/05/expansion-of-the-montana-right-to-try-law-passes/
Montana state regulators now allow any drug candidate that has passed a phase 1 safety trial to be provided to patients. This is a step in the right direction of allowing patients and developers greater freedom to figure out how to cost-effectively generate human data and bring promising therapies to the clinic. It allows patients to choose their own level of risk tolerance. That said, it remains the case that guiding a novel therapy through even a phase 1 clinical trial requires a great deal of time and funding, even if conducting the trial in Australia, where local authorities require only partial compliance with the very burdensome Good Manufacturing Practice rules, and where centralized government authority is replaced with a competing market of institutional review boards and hospitals specialized in running clinical trials.
It is hard to have a rational discussion about how much cost and effort is actually required for reasonable safety, even as the cost and effort required by the FDA and equivalent regulators has increased dramatically over time. Yet most institutions and individuals react poorly to the idea that present standard practices are far more than is needed to assure a high degree of safety for most drugs. Propose any reduction in requirements and additional testing and alarm bells start to ring. This is how Good Manufacturing Practice ratchets into ever greater cost and complexity over the years, far past what is actually good practice, and certainly far more costly and burdensome.
The first US hub for experimental medical treatments is coming
A bill that allows medical clinics to sell unproven treatments has been passed in Montana. Under the legislation, doctors can apply for a license to open an experimental treatment clinic and recommend and sell therapies not approved by the Food and Drug Administration (FDA) to their patients. Once it's signed by the governor, the law will be the most expansive in the country in allowing access to drugs that have not been fully tested. The bill allows for any drug produced in the state to be sold in it, providing it has been through phase I clinical trials-the initial, generally small, first-in-human studies that are designed to check that a new treatment is not harmful. These trials do not determine if the drug is effective.
The bill essentially expands on existing Right to Try legislation in the state. But while that law was originally designed to allow terminally ill people to access experimental drugs, the new bill was drafted and lobbied for by people interested in extending human lifespans - a group of longevity enthusiasts that includes scientists, libertarians, and influencers. These longevity enthusiasts are hoping Montana will serve as a test bed for opening up access to experimental drugs. Ultimately, they hope that the new law will enable people to try unproven drugs that might help them live longer, make it easier for Americans to try experimental treatments without having to travel abroad, and potentially turn Montana into a medical tourism hub.
Mechanisms of Germline Stem Cell Decline in the Aging of the Testes in Flies
https://www.fightaging.org/archives/2025/05/mechanisms-of-germline-stem-cell-decline-in-the-aging-of-the-testes-in-flies/
You might recall a recent article implicating impaired ketogenesis of supporting Leydig cells in the age-related functional decline of the testes in mice. Today's open access preprint presents a different perspective on this functional decline, in flies as opposed to a mammalian species. Rather than aspects of cell metabolism, the authors focus on genes that regulate germline stem cell quality in the testes. These cells influence tissue function in more ways than simply producing daughter cells; their signaling is also important.
Stem cell populations lose function with age in a number of broadly similar ways, even if each population is meaningfully different from one another in specific mechanisms. Stem cells can become negatively influenced by the signaling environment, as age-related damage accumulates in the supporting cells of their stem cell niche. Stem cells can become less active while still retaining their function in principle. The population size can decline. Mutational damage can create stem cells that generate damaged daughter cells. And so forth. In this case, changes in gene expression that take place with age, possibly caused by changes in supporting cells, can produce malfunctioning stem cells that replicate more readily to outcompete their more functional peers. Restoring expression of target genes can reverse this issue, and restore lost function to the testes.
Age-related declines in niche self-renewal factors controls testis aging and spermatogonial stem cell competition through Hairless, Imp, and Chinmo
Adult organs rely on tissue stem cells for lifelong maintenance. These stem cells typically reside in specialized microenvironments termed niches, which provide short-range signals essential for preserving stemness. However, as organisms age, niche functionality declines, resulting changes in secretion of soluble factors and in biophysical properties of the microenvironment. The age-dependent decline in niche function reduces both stem cell activity and overall stem cell numbers, leading to age-related organ dysfunction. In humans, the decline in fertility in older men is due in part to the dysfunction of Sertoli and Leydig cells - key components of the spermatogonial stem cell (SSC) niche.
Competition among adult stem cells often occurs with aging and results from extrinsic and intrinsic events. The age-altered microenvironment can exert different selective forces on resident stem cells, and stem cells can sustain age-dependent mutations that could impart a selection advantage. Stem cell competition is implicated in a range of human pathologies. In the male germline, paternal age effect (PAE) disorders arise from de novo mutations in aging SSCs that confer a growth or competitive advantage, leading to clonal expansion and an increased proportion of mutant cells in the seminiferous tubules. These "selfish" mutations pose serious risks to offspring. Despite their clinical importance, in vivo models for PAE are limited, and the phenomenon of stem cell competition in the germline remains underexplored.
Using the Drosophila testis, we identify a regulatory axis in which age-related decline of niche signals (bone morphogenetic proteins, BMPs) lead to upregulation of the co-repressor Hairless, which downregulates the RNA-binding protein Imp in aged germline stem cells (GSCs). Reduced Imp causes loss of Chinmo, a key factor in GSC aging and competition. Reduced Chinmo causes ectopic Perlecan secretion which accumulates in the testis lumen and causes GSC loss. Aging of the testis is reversed by increasing BMPs in the niche, or by overexpressing Imp or depleting Hairless in GSCs. Furthermore, GSC clones with reduced Imp or increased Hairless are more competitive, expelling wild-type neighbors and monopolizing the niche. Thus, BMPs regulate testicular niche aging through the Hairless-Imp-Chinmo axis and "winning" GSCs usurp these aging mechanisms.
A High Level Tour of the Metabolism of Long-Lived Individuals
https://www.fightaging.org/archives/2025/05/a-high-level-tour-of-the-metabolism-of-long-lived-individuals/
Over the past 20 years, a large amount of data has been generated to cover the genetics, epigenetics, transcriptomics, proteomics, and the many varied aspects of the metabolism of long-lived individuals. Very little has been found when it comes to genetic variants associated with longevity - or rather every study produces associations, and then those association near all fail to replicate. The few genetic associations with longevity that hold up on multiple study populations and appear otherwise robust have small effect sizes.
Metabolism and immune function are perhaps more interesting, however. Long-lived individuals are long-lived in large part because they have a less degraded, more functional metabolism and immune system. Otherwise they would already be dead. It isn't clear whether the wealth of data pointing to this less impacted function of metabolism and immune system will at the end of the day provide novel, useful answers to the question of why some people achieve this outcome while others do not.
Clearly lifestyle is important, but there remains a substantial variation in outcomes between individuals with similarly healthy lifestyles. It is possible that this variation is driven by thousands of individually tiny contributions, summing to a different aggregate effect for each person, in which case there will be little of use to be found in the biochemistry of long-lived individuals when it comes to a basis for the creation of therapies to slow aging.
[Publicity Materials] Factors involved in human healthy aging: insights from longevity individuals
Long-lived individuals (LLIs), defined as individuals surviving beyond 90 years, exhibit distinct characteristics such as reduced morbidity, delayed onset of chronic diseases, and preserved physiological functions. Key nuclear genomic variants include APOE ε2 (protective against cardiovascular disease and Alzheimer's), FOXO3A (linked to oxidative stress resistance and DNA repair), and SIRT6 (involved in genome maintenance). Mitochondrial haplogroups like J and D are associated with reduced oxidative stress, while telomere maintenance genes (hTERT, TERC) ensure chromosome stability. However, genome-wide association studies (GWAS) highlight APOE and FOXO3A as the most consistently linked genes across populations, underscoring their pivotal roles.
Epigenetic mechanisms bridge genetics and environment. DNA methylation patterns in LLIs show delayed age-related methylation loss, particularly in heterochromatin regions, which may stabilize genome integrity. Noncoding RNAs, such as miR-363* and lncRNAs THBS1-IT1/THBS1-AS1, regulate cellular senescence and gene expression, contributing to healthy aging. These epigenetic signatures correlate with younger biological age and reduced disease risk in LLIs and their offspring.
Metabolic profiles in LLIs are characterized by favorable lipid metabolism (low LDL cholesterol, high HDL), reduced insulin resistance, and enhanced antioxidant capacity. Endocrine factors like low thyroid hormone levels and preserved sex hormones (estradiol in females, testosterone in males) play protective roles.
Immune system alterations in LLIs include reduced chronic inflammation ("inflammaging") and preserved immune cell function. Centenarians exhibit lower IL-6 levels, higher TGF-β and IL-10 (anti-inflammatory cytokines), and maintained T-cell proliferation and natural killer cell activity. The balance between pro-inflammatory Th17 cells and regulatory T cells (Tregs) shifts toward anti-inflammatory states, contributing to disease resistance. Environmental and lifestyle factors are equally critical. Gut microbiota in LLIs features increased diversity and enrichment of health-promoting taxa like Akkermansia muciniphila and Bifidobacterium, which enhance gut barrier function and produce anti-aging metabolites.
[Paper] Factors involved in human healthy aging: insights from longevity individuals
The quest to decipher the determinants of human longevity has intensified with the rise in global life expectancy. Long-lived individuals (LLIs), who exceed the average life expectancy while delaying age-related diseases, serve as a unique model for studying human healthy aging and longevity. Longevity is a complex phenotype influenced by both genetic and non-genetic factors. This review paper delves into the genetic, epigenetic, metabolic, immune, and environmental factors underpinning the phenomenon of human longevity, with a particular focus on LLIs, such as centenarians. By integrating findings from human longevity studies, this review highlights a diverse array of factors influencing longevity, ranging from genetic polymorphisms and epigenetic modifications to the impacts of diet and physical activity. As life expectancy grows, understanding these factors is crucial for developing strategies that promote a healthier and longer life.
Building an Aging Clock from Microglial Transcriptomics
https://www.fightaging.org/archives/2025/05/building-an-aging-clock-from-microglial-transcriptomics/
Any sufficiently complex set of biological data can be used to produce an aging clock via machine learning approaches, generating some combination of values that reflects biological age. This is possible because the burden of damage and dysfunction associated with aging produces characteristic changes in biological data. Novel clocks are published by the research community at a fair pace these days, such as the clock reported in today's open access paper. It was built from transcriptomic data derived from microglia, innate immune cells of the brain. It is a research tool, impractical for medical use given the difficulty of obtaining brain-resident cells from a living individual.
The existence of a clock doesn't tell us anything of the way in which the components of the clock relate to specific forms of damage and dysfunction, only that they may be correlated. A clock could in principle be based on measures that are only sensitive to some of the mechanisms or outcomes of aging - it is impossible to know, given the way the development process works, and the inability to point to any one omics measure, such as level of a specific transcript, and describe accurately how it relates to aging. Thus one cannot trust a clock to accurately assess potential age-slowing and rejuvenation therapies until it has been calibrated against those therapies. This will take some time, and while the growing body of clock data from various studies is very interesting, this calibration has yet to happen in a comprehensive way for any of the clocks developed to date.
Microglia Single-Cell RNA-Seq Enables Robust and Applicable Markers of Biological Aging
"Biological aging clocks" - composite molecular markers thought to capture an individual's biological age-have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA-sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets in humans and mice, we develop and compare computational approaches for generating transcriptome-wide summaries from microglia to establish robust and applicable aging clocks.
Our results reveal that unsupervised, frequency-based summarization approaches, which encode distributions of cells across molecular subtypes, strike a balance in accuracy, interpretability, and computational efficiency. Notably, our computationally derived microglia markers achieve strong accuracy in predicting chronological age across three diverse single-cell datasets, suggesting that microglia exhibit characteristic changes in gene expression during aging and development that can be computationally summarized to create robust markers of biological aging.
We further extrapolate and demonstrate the applicability of single-cell-based microglia clocks to readily available bulk RNA-seq data with an environmental input (early life stress), indicating the potential for broad utility of our models across genomic modalities and for testing hypotheses about how environmental inputs affect brain age. Such single-cell-derived markers can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.
Arguing for Clinical Trials of Exercise Conditioned Plasma
https://www.fightaging.org/archives/2025/05/arguing-for-clinical-trials-of-exercise-conditioned-plasma/
In the context of aging and age-related disease, forms of plasma transfusion remain therapies in search of conclusive proof that the benefits are worth it. Efforts focusing on transfer of young donor plasma into old individuals conducted over the past decade or so have so far failed to produce convincing results in clinical trials. The blood products industry is a large one, and the larger entities in that industry appear to view this as a discovery problem, that somewhere in the fractionation of donor blood there is a way to produce a product that will be modestly useful for some aspects of aging. Looking at the lengthy history of research to establish the production of medical products from donor blood, this may be a reasonable expectation. So far the results have been disappointing, however.
This is the context in which researchers here write an editorial to argue for the assessment of plasma from individuals who are fit and have recently exercised. Physical activity produces beneficial effects throughout the body in large part through altered secretion of signal molecules and vesicles carried in blood. One might reasonably argue that plasma from a fit young donor fresh from the gym could be more beneficial to the recipient than plasma from a sedentary young donor fresh from a bed. Effect sizes and proof matter, however, and thus the need for more data and more rigorous data.
Is it time for exercise-conditioned plasma to enter human trials?
Skeletal muscle contraction during an acute bout of exercise elicits a complex array of molecular responses in multiple organ systems. Such molecular signals continue to persist, after the exercise and thus the long-term accumulation of such exercise sessions culminate in systemic adaptations that extend beyond the musculoskeletal system - remodeling of organ systems occur and improvement in healthspan. Acute exercise mobilizes thousands of proteins and peptides, mRNA, extracellular vesicles (EVs), and non-coding RNA systemically, transporting them to distant sites, and exert modulatory effects on the organs, including brain, adipose tissue, liver, etc.
Recent studies in pre-clinical mouse models reveal promising evidence that plasma obtained after exercise training directly improves physiological outcomes in non-exercised recipients. Transfused plasma from exercised rats improved neuronal viability, decreased cell atrophy and increased neurogenesis by three-fold in transgenic Alzheimer's Disease (AD) rat recipients. Furthermore, exercised young (three-month old) murine plasma administered intravenously to old (18-month-old) mice resulted in increased proliferation of hippocampal neurons. Exciting work on plasmapheresis is being pioneered in the United States of America (USA) and Norway. In the former, young male donors provided 1 unit (~250mL) of fresh frozen plasma (FFP) to patients with Alzheimer's disease in a once per week infusion, followed by a 6-week washout period and crossover with saline treatment. The primary endpoints were safety, tolerability and feasibility of the intervention - all of which were met at the conclusion of the trial. In the latter, the ongoing study involved blood plasma obtained from young, healthy and well-trained (aerobically fit) individuals and transfused intravenously to older adults with Alzheimer's disease at intervals of 3 months.
Such recent investigations have given a glimpse of a novel translational application of exercise-induced adaptations for chronic disease management, particularly in oncology and neurology. The putative molecular mechanisms that underlie the therapeutic effects of exercise-induced plasma transfusion therapy provide a foundation for their potential translational use in cancer, cardiovascular diseases, and neurodegenerative diseases. Furthermore, there is an opportunity to translate the benefits of exercise-induced plasma for bedridden or paralyzed patients who are unable or intolerant to exercise training. In conclusion, we believe it is time for early-phase clinical trials to test exercise-conditioned plasma for different chronic diseases.
NAD Deficiency Impairs CAR-T Cells Derived from Older Adults
https://www.fightaging.org/archives/2025/05/nad-deficiency-impairs-car-t-cells-derived-from-older-adults/
Nicotinamide adenine dinucleotide (NAD) is involved in mitochondrial metabolism. Levels decline with age and there has been some interest in finding ways to increase NAD in mitochondria via various approaches, largely using supplements derived from niacin, such as nicotinamide riboside and nicotinamide mononucleotide. These do not appear to work all that well, based on the history of clinical trials conducted to date. Nonetheless, researchers here suggest low NAD is an important determinant of the relative lack of effectiveness of CAR-T therapies targeting cancer in older people. Chimeric antigen receptor (CAR) T cells are produced from T cells taken from the patient, engineered to add features that allow them to target the patient's cancer cells, expanded in culture, and returned to the patient. To the degree that the patient's T cells are less effective, CAR-T therapy is less effective.
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy.
Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. We used the small molecule 78c to specifically block the NAD-degrading activity of CD38, and we combined it with nicotinamide mononucleotide (NMN) supplementation. We observed that, according to the previous data, NMN alone was not sufficient to increase NAD levels in aged T cells. However, when combined with the CD38 inhibitor 78c, NAD levels were restored to levels seen in younger controls. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.
The Aging of the Gut Microbiome from a DNA Damage and Telomere Erosion Perspective
https://www.fightaging.org/archives/2025/05/the-aging-of-the-gut-microbiome-from-a-dna-damage-and-telomere-erosion-perspective/
Researchers here focus specifically on DNA damage and telomere erosion as hallmarks of aging, and discuss mechanisms by which changes in the microbial populations of the body (primarily the gut microbiome) can indirectly influence these outcomes. Unsurprisingly, inflammation is high on the list. With age, beneficial microbial species decline in number to be replaced by an expanded pool of species capable of provoking continual, unresolved inflammatory reactions as they interact with tissues and the immune system. Evidence suggests that this is an important contribution to the state of low-grade inflammation that is characteristic of older individuals, and thus to degenerative aging, disruptive to tissue structure and function.
Aging is not a singular event but a complex interaction of numerous inherent and external factors that together shape the timing and nature of the process. Among these factors, the human microbiome has emerged as an important influence on host physiology and health outcomes. Dysbiosis, or imbalances in the microbiome, is linked to age-related conditions such as cardiovascular diseases (CVDs), neurodegenerative diseases (NDs), and metabolic syndromes.
DNA repair mechanisms and cell cycle checkpoints protect genetic material, ensuring its stability across cell generations. However, internal and external factors continuously threaten this stability by causing DNA damage. An important factor in cellular aging is the progressive shortening of telomeres, repetitive DNA sequences found at the ends of chromosomes. Telomeres protect chromosomal ends, preventing them from being mistaken for DNA breaks and maintaining genomic stability. However, with each cell division, telomeres shorten because DNA polymerase cannot fully replicate the lagging strand. As a result, telomeres act as a molecular timer, restricting the ability of cells to proliferate and leading to replicative senescence. Understanding how the human microbiome, genomic stability, and telomere shortening are interconnected is crucial to uncovering the mechanisms of aging and developing strategies for healthy aging.
This review examines how microbiome dynamics influence aging by triggering inflammation, oxidative stress, immune dysregulation, and metabolic dysfunction, all of which affect two primary hallmarks of aging: genomic instability and telomere attrition. Understanding these interactions is essential for developing targeted interventions to restore microbiome balance and promote healthy aging, offering potential treatments to extend healthspan and alleviate aging-related diseases. The convergence of microbiome and aging research promises transformative insights and new avenues for improving global population well-being.
Regulators of Detoxification Genes Extend Life Span in Nematode Worms
https://www.fightaging.org/archives/2025/05/regulators-of-detoxification-genes-extend-life-span-in-nematode-worms/
Researchers here note that the stress response to the presence of toxic molecules can, like other stress responses, be upregulated to slow aging in short-lived species such as the nematode worms used in this study. Detoxification is arguably not as well studied as the response to heat shock or low nutrient availability. Like those items, upregulation of the detoxification response will likely only produce a usefully large slowing of aging in short-lived species. As species life span increases, the effects of the increased operation of stress response mechanisms remain similar in the short term, but the degree of slowed aging over the long term diminishes. Mice live as much as 40% longer when calorie intake is limited, but humans likely gain only a few years from the long term practice of calorie restriction.
Recently, increasing evidence shows that the expression of detoxification genes is enhanced in long-lived animals. The increase in the expression of detoxification genes was identified in several long-lived mice. For example, in genetic long-lived growth hormone-releasing hormone receptor knockout Little mice and growth hormone deficient Ames dwarf mice, the livers' detoxification genes were increased and showed more resistance to liver toxins. Similar observation was found in the pituitary abnormal Snell dwarf mice and growth hormone receptor knockout mice. A recent study has found that the transcription levels of detoxification enzymes, cytochrome P450s (Cyps) and glutathione-S-transferases (Gsts), were increased in the livers of mice with lifespan-extending interventions. Enhancing detoxification functions is a common transcriptome marker of all long-lived mice, suggesting that the upregulation of detoxification enzymes may be a potential anti-aging therapy.
Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr-/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.
Time Restricted Feeding Improves the Gut Microbiome and Slows Aging in Flies
https://www.fightaging.org/archives/2025/05/time-restricted-feeding-improves-the-gut-microbiome-and-slows-aging-in-flies/
Flies are interesting in that their aging process appears very centered around intestinal function. Possibly related is the point that flies do not appear to as reliably exhibit slowed aging and improved health in response to reduced nutrient intake as is the case in other laboratory species; studies are hit and miss. Touching on another related topic, research into the gut microbiome, its age-related changes, and effects on aging have expanded considerably in recent years. Little of this has focused on flies, however. So while one might suspect that results in flies are not all that relevant to mammals, and there is in any case a growing amount of data on the aging of the gut microbiome and approaches to its rejuvenation in mammalian species, it is nonetheless interesting to see efforts to fill in this blank spot.
Time-restricted feeding (TRF), a dietary intervention involving daily fasting periods, has been associated with metabolic benefits; however, its long-term physiological impact remains unclear. Using Drosophila melanogaster as a model, we investigated the effects of a 16:8 TRF regimen on lifespan, reproductive output, gut health, and microbiota composition. TRF significantly extended lifespan, even when applied only during early adulthood. Notably, this longevity benefit occurred without compromising reproductive fitness, as measured by female fecundity in life's most crucial reproductive phase.
TRF promoted gut homeostasis in aged flies by reducing intestinal stem cell proliferation and enhancing epithelial barrier integrity. Furthermore, TRF induced a shift in microbiota composition, increasing the prevalence of gram-negative bacterial taxa. These results show that even short-term TRF interventions at a young age can have long-term physiological benefits. Metabolic reprogramming or increased autophagy are the most likely mechanisms mediating the health-promoting effects of this type of nutritional intervention. TRF is an effective, non-invasive strategy for promoting healthy longevity without significant adverse effects on other aspects of life.
Klotho Gene Therapy in Adult Mice Produces a 20% Increase in Life Span
https://www.fightaging.org/archives/2025/05/klotho-gene-therapy-in-adult-mice-produces-a-20-increase-in-life-span/
Researchers here report a 20% increase in life span for adult mice given a gene therapy to express the circulating factor klotho. Evidence to date suggests that increased circulating klotho has minimal side-effects, and is wholly beneficial for at least cognitive function and kidney health. It remains unclear as to whether the more general benefits to health observed in animal models are downstream of improved kidney function, or are the result of the direct interaction between circulating klotho and cells in other tissues. Regardless, this is an encouraging study for those groups presently working on bringing klotho gene therapies to the clinic, or that are already providing such therapies via medical tourism.
Aging is a major risk factor for pathologies including sarcopenia, osteoporosis, and cognitive decline, which bring suffering, disability, and elevated economic and social costs. Therefore, new therapies are needed to achieve healthy aging. The protein Klotho (KL) has emerged as a promising anti-aging molecule due to its pleiotropic actions modulating insulin, insulin-like growth factor-1, and Wnt signaling pathways and reducing inflammatory and oxidative stress. Here, we explored the anti-aging potential of the secreted isoform of this protein on the non-pathological aging progression of wild-type mice.
The delivery of an adeno-associated virus serotype 9 (AAV9) coding for secreted KL (s-KL) efficiently increased the concentration of s-KL in serum, resulting in a 20% increase in lifespan. AAV9 vectors were delivered through a combination of intracerebroventricular (ICV) and intravenous (IV) injections, enabling efficient transduction of both the central nervous system and peripheral tissues. Notably, KL treatment improved physical fitness, related to a reduction in muscle fibrosis and an increase in muscular regenerative capacity. KL treatment also improved bone microstructural parameters associated with osteoporosis. Finally, s-KL-treated mice exhibited increased cellular markers of adult neurogenesis and immune response, with transcriptomic analysis revealing induced phagocytosis and immune cell activity in the aged hippocampus.
These results show the potential of elevating s-KL expression to simultaneously reduce the age-associated degeneration in multiple organs, increasing both life and health span.
Loss of Histone Lactylation in Muscle Aging
https://www.fightaging.org/archives/2025/05/loss-of-histone-lactylation-in-muscle-aging/
It is one thing to point to a mechanism, show it declines with age, and suggest it might contribute to aging. It is quite another to develop an understanding of where this mechanism stands in terms of its relative importance in degenerative aging, and how it relates to other mechanisms. Here, researchers consider a form of histone modification, one type of epigenetic alteration that changes the structure of packaged DNA in the cell nucleus, and thus changes which genes can be accessed in order to manufacture proteins. This in turn changes cell behavior. But what causes the histone modification in the first place? Cells contain feedback loops piled upon feedback loops, creating dynamic links between environment, control of protein manufacture, activity of the manufactured proteins, and so forth. It is very challenging to identify specific chains of cause and consequence and then weigh their significance against all other relevant chains of cause and consequence, not all of which are well mapped.
Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. This study shows that histone lactylation, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation and lactyl-CoA levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways. Furthermore, the modulation of enzymes crucial for histone lactylation, leads to reduced histone lactylation and accelerated cellular senescence.
Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Modulating the enzymes can also lead to the loss of histone lactylation in skeletal muscle, downregulating DNA repair and proteostasis pathways, and accelerating muscle aging. Running exercise increases histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways. This study highlights the significant roles of histone lactylation in modulating cellular senescence as well as muscle aging, providing a promising avenue for antiaging intervention via metabolic manipulation.
Phase Angle Measure of Muscle Quality Correlates with Dementia Risk
https://www.fightaging.org/archives/2025/05/phase-angle-measure-of-muscle-quality-correlates-with-dementia-risk/
Researchers have established a relationship in old individuals between the age-related loss of muscle mass and strength leading to sarcopenia and risk of dementia, but have not yet established good measures to quantify the early development of these pathologies in middle aged individuals. Phase angle is a measure of muscle quality derived from electrical impedance of muscle tissue, and here researchers provide evidence for phase angle to be a useful tool in assessing the early stages of muscle decline and cognitive decline. Early detection of the consequences of degenerative aging can allow better management of the decline at this point in time, and later will be an indication of the need for earlier use of rejuvenation therapies.
Sarcopenia is a condition characterized by the progressive loss of skeletal muscle mass and function. Gowing evidence has highlighted the novel significance of the phase angle (PhA) in the diagnosis of sarcopenia. PhA is an indicator of cellular health that reflects intracellular and extracellular fluid status, cellular nutritional status, cell membrane integrity and cell function. PhA and handgrip strength (HGS) were reported to be associated with malnutrition, a risk factor for sarcopenia, but PhA proved to be a more sensitive indicator than HGS. Other studies have shown that PhA is lower in individuals with sarcopenia than in those without sarcopenia. In a previous study, we revealed that PhA is an index of muscle quality and is useful for detecting sarcopenia. These findings suggest that muscle quality, as well as muscle mass, strength and physical performance, would be valuable indices for the diagnosis of sarcopenia.
This was a cross-sectional study involving 263 participants (163 men with a median age of 60 years and 100 women with a median age of 58 years) who underwent a general health examination. Sarcopenia-related indices included appendicular skeletal muscle mass (ASM)/height^2, ASM/body mass index, handgrip strength (HGS), HGS/upper extremity skeletal muscle mass and phase angle (PhA). We examined the associations between these indices and cognitive function using the Japanese version of the Montreal Cognitive Assessment (MoCA-J).
Higher PhA, an indicator of muscle quality, was associated with a lower risk of mild cognitive impairment (MCI) in women (adjusted odds ratio = 0.28), whereas the other sarcopenia-related indices showed no significant association with MCI in both sexes. The PhA of women was positively associated with the MoCA-J scores (β = 0.27). Moreover, the PhA of women showed a positive correlation with cognitive subdomains, including memory (r = 0.22), which is one of the earliest manifestations of cognitive impairment. The PhA in men was also positively correlated with memory.
YTHDF2 Downregulation is Protective in the Aging Retinas of Mice
https://www.fightaging.org/archives/2025/05/ythdf2-downregulation-is-protective-in-the-aging-retinas-of-mice/
Researchers here uncover a protective mechanism that helps retinal cells resist stresses. It is observed to slow the development of conditions such as glaucoma, but also to slow the more general age-related declines in retinal function. Whether this is a suitable basis for the production of useful therapies remains to be seen. Slowing the progression of age-related loss of function is a poor substitute for repair and rejuvenation. So if funding is to be directed to the production of therapies, one would hope that priority is given to methods that repair damage rather than methods that slow the consequences of damage.
The retina, as the fundamental structural tissue to encode and transmit visual signals into the brain, is organized by diverse cell types mediating the signal transduction cooperatively. The degenerations in the aging retina are associated with such diseases as the progressive degeneration of photoreceptors in aging-related macular degeneration and retinal ganglion cells (RGCs) degeneration in glaucoma. In addition, disease-free vision decline is also relevant to structural and physiological changes in the retina, including RGC dendrite shrinking, retinal pigment epithelium degeneration, and photoreceptor dysfunction.
Previously we discovered that the m6A reader YTHDF2 negatively regulates dendrite development and injury of RGCs. The expansion of RGC dendrite arbors and more synapses in the inner plexiform layer after conditional knockout (cKO) of Ythdf2 in the retina modestly improve the visual acuity of mice in an optomotor assay. In the glaucoma models, the m6A writers METTL3 and WTAP, and its reader YTHDF2, are upregulated, and the loss-of-function of YTHDF2 has a neuroprotective role. However, it remains unknown whether m6A modification and its reader YTHDF2 regulate the degeneration of RGCs in the aged retinas.
Here, we show that conditional ablation of Ythdf2 protects the retina from RGC dendrite shrinking and vision loss in aged mice. Additionally, we identify Hspa12a and Islr2 as the potential YTHDF2 target mRNAs mediating these effects. Together, our results indicate that the m6A reader YTHDF2 regulates retinal degeneration caused by aging, which might provide important therapeutic potential for developing new treatment approaches against aging-related vision loss.
The Aging Brain is More Vulnerable to Amyloid-β Toxicity
https://www.fightaging.org/archives/2025/05/the-aging-brain-is-more-vulnerable-to-amyloid-%ce%b2-toxicity/
Researchers here demonstrate that old mice are far more vulnerable than young mice to pathology resulting from the introduction of amyloid-β aggregates into brain tissue. Amyloid-β misfolds to form aggregates in the aging brain, and this is thought to be the cause of Alzheimer's disease. Looking at the results here, one might think that this difference between young and old mice is centered around the aging of the immune system. The aged immune system is both more inflammatory and less capable, and the introduction of toxic molecules is thus more likely to provoke a sustained maladative and ineffective response.
Aging is the primary risk factor for Alzheimer's disease (AD), and the aging brain shares many characteristics with the early stages of AD. This study investigates the interplay between aging and amyloid-beta (Aβ) induced pathology. We developed an AD-like in vivo model, using the stereotactic injection of Aβ1-42 oligomers into the hippocampi of aged mice. Cognitive impairments were assessed using a Y maze. Immunohistochemical and protein analyses were conducted to evaluate neuronal survival, synaptic function and number, levels of tau hyperphosphorylation, microglial activation, autophagy, and mitochondrial function.
We compared baseline aging effects in young adult (3 months) and aged (16-18 months) healthy mice. We found that aged mice displayed significant deficits in working memory, synaptic density and neurogenesis, and an increased basal inflammation. In response to acute injury to the hippocampus with Aβ oligomer injection, aged mice suffered sustained deficits, including impaired cognitive function, further reduced neurogenesis and synaptic density, increased microglial activation, astrogliosis, mitochondrial stress, and lysosomal burden. Furthermore, in the weeks following injury, the aged mice show increased amyloid accumulation, microglial activation and phosphorylated tau propagation, expanding from the injection site to adjacent hippocampal regions.
In contrast, the young adult mice exhibited only acute effects without long-term progression of pathology or neurodegeneration. We conclude that the aging brain environment increases susceptibility to an acute Aβ injury, creating fertile soil for the progression of AD, whereas younger brains are able to overcome this injury. The processes of aging should be considered as an integral factor in the development of the disease. Targeting aging mechanisms may provide new strategies for AD prevention and treatment, as well as for other neurodegenerative diseases.
Altos Labs Broadens Scope to Senotherapeutics via Acquisition
https://www.fightaging.org/archives/2025/05/altos-labs-broadens-scope-to-senotherapeutics-via-acquisition/
Altos Labs was founded with an enormous amount of capital in order to work on reprogramming as an approach to rejuvenation. They recently acquired a senotherapeutics company, Dorian Therapeutics. Given that we're in the second year of a bad market for biotech fundraising, one might speculate that this was an acquihire. A company in an investor's portfolio runs out of runway, the investor wants to avoid an outright loss, and that overlaps with another portfolio company's desire to rapidly obtain an experienced team. There may or may not be strong-arming on the part of the investor to make it happen. That said, this may also indicate investor pressure for Altos Labs to do something other than run the long-term development programs needed to bring reprogramming therapies to the clinic. Quicker wins and a quicker exit for those investors is ever a plausible goal. In terms of outcomes that could be good or it could be bad. It depends on the choices made, but it is certainly the case that investor pressure for faster returns is the root of a great many evils in the broader biotech and pharmaceuticals industry.
Longevity behemoth Altos Labs has acquired senotherapeutics startup Dorian Therapeutics in a landmark deal in the emerging cellular rejuvenation space. The financial terms of the acquisition were not disclosed. Stanford University spinout Dorian is focused on targeting cellular senescence, the process by which aging or damaged cells cease dividing and accumulate in tissues, contributing to age-related diseases and diminished regenerative capacity. The company has been developing small-molecule "senoblockers" designed to neutralize the harmful effects of senescent cells while reactivating the body's natural repair mechanisms.
While the companies are taking different scientific approaches, there are clearly synergies. Altos Labs launched in 2022 with a whopping $3 billion in funding to advance cellular rejuvenation programming aimed at restoring the function of cells, tissues and organs. Dorian's senoblockers target epigenetic regulators to reduce senescent cell burden and enhance stem cell function, effectively reawakening youthful gene expression and tissue regeneration pathways. Dorian's technology modulates chromatin accessibility to orchestrate cellular programs disrupted in aging and disease, with broad potential applications in age-related conditions. Its lead candidates have shown promising preclinical efficacy in models of lung fibrosis and osteoarthritis.
View the full article at FightAging
