Fight Aging!

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.

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.

Link: https://longevity.technology/news/altos-labs-snaps-up-dorian-therapeutics/

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.

Link: https://doi.org/10.3389/fnagi.2025.1569181

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.

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.

Link: https://doi.org/10.1111/acel.70107

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.

Link: https://doi.org/10.1002/jcsm.13820

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.

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.

Link: https://doi.org/10.1002/advs.202412747

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.

Link: https://doi.org/10.1016/j.ymthe.2025.02.030

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.

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.

Link: https://doi.org/10.1096/fj.202500875R

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.

Link: https://doi.org/10.1016/j.apsb.2025.01.006

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.

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.

Link: http://dx.doi.org/10.14218/ERHM.2024.00045

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.

Link: https://doi.org/10.1038/s43018-025-00982-7

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.

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.

Link: https://doi.org/10.1016/j.jare.2025.05.004

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.

Link: https://doi.org/10.1182/blood.2024027742

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.

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.

Link: https://doi.org/10.1038/s43587-025-00864-8

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."

Link: https://news.northwestern.edu/stories/2025/05/sugar-coated-nanotherapy-dramatically-improves-neuron-survival-in-alzheimers-model/

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!

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.

Link: https://doi.org/10.3389/fnagi.2024.1370580

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.

Link: https://doi.org/10.1111/acel.70060

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.

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), (c) 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.

Link: https://doi.org/10.18632/aging.206237

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.

Link: https://doi.org/10.1007/s10522-025-10250-x

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.

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.

Link: https://doi.org/10.1371/journal.pcbi.1012382

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.

Link: https://doi.org/10.1177/13872877251315043

The blood-brain barrier consists of specialized cells that line blood vessels passing through the brain. These cells collectively permit only certain molecules to pass to and from the brain, maintaining the distinct biochemistry and cell populations of the central nervous system versus the rest of the body. Where the blood-brain barrier leaks, the result is inflammation and dysfunction in brain tissue as, a reaction to the presence of unexpected and unwanted molecules and cells. Unfortunately the blood-brain barrier declines and malfunctions with age, as is the case for all complex biological systems. This is likely an important contribution to the development of neurodegenerative conditions.

In today's open access paper, researchers discuss the role of hypoxia in producing blood-brain barrier dysfunction. While a local lack of oxygen will induce leakage of the blood-brain barrier at any age, older individuals are both more vulnerable and more likely to suffer conditions and states of aging that provoke hypoxia on a regular basis. Greater blood-brain barrier leakage in transiently hypoxic individuals may be an important mechanism in the link between a number of hypoxia-inducing conditions and increased risk of neurodegenerative conditions.

Defining the hypoxic thresholds that trigger blood-brain barrier disruption: the effect of age

We recently demonstrated that exposure to chronic mild hypoxia (CMH; 8% O2) in young (2 months old) mice triggers a cerebrovascular remodeling response that includes endothelial proliferation and low levels of transient blood-brain barrier (BBB) disruption that is accompanied by microglial activation and aggregation around leaky blood vessels. Strikingly, the extent of hypoxia-induced BBB disruption is greatly amplified (5-10-fold) in aged (20 months old) mice. As hypoxia is a common component of many age-related diseases including chronic obstructive pulmonary disease (COPD), asthma, ischemic heart disease, heart failure, and sleep apnea, it follows that in the elderly population, hypoxic events could trigger BBB breakdown, culminating in neuronal dysfunction, neurodegeneration, and vascular dementia. Consistent with this idea, several studies have demonstrated increased dementia risk in people who suffer from hypoxia-inducing conditions such as sleep apnea and COPD.

What hypoxic level is sufficient to trigger vascular remodeling and BBB breakdown, and how does age influence the hypoxic threshold that triggers BBB disruption? At what age do cerebral blood vessels become more susceptible to hypoxia-induced disruption? In this study, we addressed these fundamental questions by first exposing young (2 months old) and aged (20 months old) mice to a range of oxygen levels from normoxia (21% O2) to marked hypoxia (8% O2) to define the hypoxic thresholds that triggers vascular remodeling and BBB disruption at the two different ages. Next, we investigated at what specific age mice become more susceptible to hypoxia, by comparing mice of 8 different ages (from 2 months to 23 months) to a fixed (8% O2) level of hypoxia.

Analysis of brain sections demonstrated that the thresholds required to trigger hypoxia-induced BBB disruption (CD31/fibrinogen) and endothelial proliferation (CD31/Ki67) were much lower in aged mice (15% O2) compared to young (13% O2). Hypoxia-induced endothelial proliferation was relatively constant across the age range, but advanced age strongly enhanced the degree of BBB disruption (4-6-fold greater in 23 months vs. 2 months old). While the BBB became more vulnerable to hypoxic disruption at 12-15 months, a large step-up also occurred at the surprisingly young age 2-6 months. Our data demonstrates that the aged BBB is far more sensitive to hypoxia-induced BBB disruption than the young and define the hypoxic thresholds that trigger hypoxia-induced BBB disruption in young and aged mice. This information has translational implications for people exposed to hypoxia and for those living with hypoxia-associated conditions such as asthma, emphysema, ischemic heart disease, and apnea.

The composition of the gut microbiome has been shown to change with age, undergoing a loss of beneficial microbes in favor of inflammatory microbes that contribute to the chronic inflammation of aging and onset and progression of age-related conditions. Researchers have comprehensively demonstrated in animal models that introducing a young microbiome into an old animal via fecal microbiota transplantation produces a lasting rejuvenation of the gut microbiome and corresponding improvements in measures of health. Here, researchers show that these benefits include an improvement in memory function in old animals.

While transplanting the fecal microbiota from young to aged rodents has been extensively studied (that is, young FMT [yFMT]), its mechanism of alleviating working memory decline has not been fully elucidated. In this report, we aimed to investigate the effect of yFMT on the working memory of aged recipient rats performing delayed match-to-position (DMTP) tasks and the associated cellular and molecular mechanisms.

The results revealed that yFMT mitigated the decline in DMTP task performance of aged recipients. This improvement was associated with a reshaped gut microbiota and increased levels of brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 1, and synaptophysin, enhancing synaptic formation and transmission. The remodeling of the gut microbiome influenced peripheral circulation and the hippocampus and medial prefrontal cortex by regulating the Th17/Treg ratio and microglial polarization. Ultimately, interleukin-4 and interleukin-17 emerged as potential key molecules driving the beneficial effects of FMT.

These observations provide new insights into the gut-brain axis, emphasizing the connection between the gut and brain through the circulation system, and suggest an immunological mechanism that may help reverse age-related declines in the gut microbiota.

Link: https://doi.org/10.1016/j.neures.2025.04.005

The consensus on air pollution is that it increases late life mortality, largely via an increase in chronic inflammation in exposed tissues in the lung. Researchers here propose that uptake of iron from inhaled particulate matter can contribute to the age-related increase of iron that takes place in the brain, and thus cause pathology. The researchers demonstrate that this introduction of iron from airborne pollutants into the brain can occur in mice, but the question (as usual) is whether in humans this has an effect size large enough to be important versus the inflammatory consequences of air pollution.

Both excess brain iron (Fe) and air pollution (AP) exposures are associated with increased risk for multiple neurodegenerative disorders. Fe is a redox-active metal that is abundant in AP and even further elevated in U.S. subway systems. Exposures to AP and associated contaminants, such as Fe, are lifelong and could therefore contribute to elevated brain Fe observed in neurodegenerative diseases, particularly via nasal olfactory uptake of ultrafine particle AP. These studies tested the hypotheses that exogenously generated Fe oxide nanoparticles could reach the brain following inhalational exposures and produce neurotoxic effects consistent with neurodegenerative diseases and disorders in adult C57/Bl6J mice exposed by inhalation to Fe nanoparticles at a concentration similar to those found in underground subway systems (~150 µg/m3) for 20 days.

Inhaled Fe oxide nanoparticles appeared to lead to olfactory bulb uptake. Alzheimer's disease (AD) like characteristics were seen in Fe-exposed females including increased olfactory bulb diffusivity, impaired memory, and increased accumulation of total and phosphorylated tau, with total hippocampal tau levels significantly correlated with increased errors in the radial arm maze. Fe-exposed males showed increased volume of the substantia nigra pars compacta, a region critical to the motor impairments seen in Parkinson's disease (PD), in conjunction with reduced volume of the trigeminal nerve and optic tract and chiasm.

Link: https://doi.org/10.1186/s12989-025-00622-z

Stem cell therapies have expanded in use over the last 30 years, and are now widespread. Substituting extracellular vesicles for the stem cells is a more recent innovation, but also now widely used in the medical tourism industry. These treatments have shown effects on aging and longevity in animal studies, but we have no idea whether this is the case in humans, and we are in no danger of finding out any time soon. Even short clinical trials are expensive, while trials large enough and long enough to assess effects on life span are prohibitively expensive. There is as yet no generally accepted and trusted measure of biological age one might apply to patients before and after a treatment. The existing aging clocks will produce their results, but those results have yet to be calibrated against real-world outcomes for life span.

One is only left with the reasonable hypothesis that reducing chronic inflammation and encouraging tissue maintenance via this class of therapy will slow the progression of aging to some degree. How much of a degree? No-one knows. One pessimistic view of the field of rejuvenation biotechnology as a whole is that the recent history of stem cell medicine is a preview of the next 30 years of efforts to treat aging, in that (a) useful therapies will slowly spread into widespread clinical use, but (b) we will have no concrete measure as to how effective these therapies are when it comes to slowing or reversing aging.

With all of this in mind, today's open access paper provides a discussion of stem cell therapies and extracellular vesicle therapies from the point of view of the treatment of aging, rather than the treatment of specific conditions per se. As the authors point out, there is ample data to characterize the safety of these treatments and the beneficial suppression of inflammation produced by these treatments, but next to nothing can be said about how the observed effects on life span in animal models translate to humans.

Mesenchymal stem cells and their derivatives as potential longevity-promoting tools

Mesenchymal stem cells (MSCs) represent a distinct population of mesenchymal stromal cells, which (i) are able to adhere to plastic surfaces, (ii) express specific cell surface markers (CD73, CD90, and CD105, but not CD14, CD34, CD45, and HLA-DR), (iii) and are able to differentiate into osteogenic, chondrogenic, or adipogenic cell lineages in vitro. It should be noted that MSC isolation yields heterogeneous, non-clonal cultures of stromal cells, including stem cells with diverse multipotent potential, committed progenitors, and differentiated cells. MSCs are found in virtually all organs of the adult organism, examined thus far. A rapidly growing body of evidence indicates the beneficial effects of systemic administration of MSCs or MSC-derived extracellular vesicles (EVs) in various pathological conditions, including age-related diseases (ARDs). For example, the systemic administration of bone marrow-derived MSCs or MSC-derived EVs from young rodents increased hippocampal neurogenesis and improved cognitive function in aged animals.

Systemic administration of MSCs and stem cell/blood-derived EVs modified the omics profiles of various organs of aged rodents towards the young ones. The application of EVs appears to be even more beneficial than MSCs. Remarkably, over 70% of microRNAs, which are over-presented in ESC-derived EVs, were found to target longevity-associated genes. Along with MSCs, other types of stem cells were reported to display healthspan- and lifespan-extending effects. Pluripotent Muse cells, a specific subpopulation of MSCs, which possess a number of unique features, could be particularly relevant for promoting healthspan. The rejuvenation potential of MSCs, EVs, and Muse cells warrants further investigation in both animal models and clinical trials, using aging clocks for biological age determination as one of the endpoints.

Longevity is the most general and integrative parameter for evaluating the therapeutic effects of any interventions. Another integrative parameter directly related to life expectancy is biological age. Recently, its determination has become possible, using various biological aging clocks. However, to date, a comprehensive analysis of the impact of MSCs/MSC-derived EVs on longevity, biological age, and aging phenotypes has not been conducted. With this in mind, in this review, we primarily focus on the effects of MSC or EV administration on the lifespan of wild-type or progeroid animals. Along with the health- and lifespan-extending effects, we discuss their putative mechanisms as well as the impact on biological age and aging omics signatures.

Nucleoside reverse transcriptase inhibitors (NTRIs) were developed to treat HIV infection, interfering in the ability of the virus to replicate. Researchers here present epidemiological evidence for this class of drug to slow the onset of Alzheimer's disease. The researchers focus on reduced inflammation as a driving mechanism, but it seems plausible that this outcome occurs because NTRI's interfere in harmful transposable element activities. Transposable elements such as retrotransposons are largely the genetic remnants of ancient viral infections. They make up a sizable fraction of the genome. These sequences are suppressed in youth, but with age and the epigenetic changes characteristic of aging, transposable elements become active, duplicate themselves in the genome to cause mutational damage, create particles that sufficiently resemble viruses to trigger innate immune responses, and cause other harms.

NRTIs, or nucleoside reverse transcriptase inhibitors, are used to prevent the HIV virus from replicating inside the body. Researchers previously determined that the drugs can also prevent the activation of inflammasomes, important agents of our immune system. These proteins have been implicated in the development of Alzheimer's disease, so researchers wanted to see if patients taking the inflammasome-blocking drugs were less likely to develop Alzheimer's.

To do that, they reviewed 24 years of patient data contained in the U.S. Veterans Health Administration Database - made up heavily of men - and 14 years of data in the MarketScan database of commercially insured patients, which offers a broader representation of the population. They looked for patients who were at least 50 years old and were taking medications for either HIV or hepatitis B, another disease treated with NRTIs. They excluded patients with a previous Alzheimer's diagnosis.

In total, the researchers identified more than 270,000 patients who met the study criteria and then analyzed how many went on to develop Alzheimer's. Even after adjusting for factors that might cloud the results, such as whether patients had pre-existing medical conditions, the researchers determined that the reduction in Alzheimer's risk among patients on NRTIs was "significant and substantial." The researchers note that patients taking other types of HIV medications did not show the same reduction in Alzheimer's risk as those on NRTIs. Based on that, they say that NRTIs warrant clinical testing to determine their ability to ward off Alzheimer's.

Link: https://www.eurekalert.org/news-releases/1083000

It seems likely that the next century will see the engineering of new humans to have genetic alterations that have been identified as wholly beneficial. It is a lot easier to edit the genomes in an embryo than it is to adjust all of the cells in an adult in the same way, due to the issues of delivery of suitable genetic medicine to all cells in all tissues. One interesting class of beneficial gene variants are those associated with what is known as natural short sleep, a phenomenon in which a rare few human lineages need very little sleep, as little as a few hours a night. More time spent awake in a lifetime is somewhat analogous to living for longer. So far ADRB1 variants and DEC2 variants have been identified. Here, researchers show that SIK3 is another gene in which variants can produce the need for very little sleep.

Sleep is an essential component of our daily life. A mutation in human salt induced kinase 3 (hSIK3), which is critical for regulating sleep duration and depth in rodents, is associated with natural short sleep (NSS), a condition characterized by reduced daily sleep duration in human subjects. This NSS hSIK3-N783Y mutation results in diminished kinase activity in vitro.

In a mouse model, the presence of the NSS hSIK3-N783Y mutation leads to a decrease in sleep time and an increase in electroencephalogram delta power. At the phosphoproteomic level, the SIK3-N783Y mutation induces substantial changes predominantly at synaptic sites. Bioinformatic analysis has identified several sleep-related kinase alterations triggered by the SIK3-N783Y mutation, including changes in protein kinase A and mitogen-activated protein kinase. These findings underscore the conserved function of SIK3 as a critical gene in human sleep regulation and provide insights into the kinase regulatory network governing sleep.

Link: https://doi.org/10.1073/pnas.2500356122

It is an ugly market for biotech companies seeking funding, and this has been the case for going on two years now. In this environment companies can only survive for so long. Smaller biotech companies have been fading into oblivion left and right in this past year as investors remained very risk averse. UNITY Biotechnology, developing senolytic therapies to clear senescent cells from aged tissues, is now one of the higher profile companies to run out of funding. While demonstrating some success in recent clinical trials, clearly the company hasn't achieved a glowing enough success to convince investors to continue to back further progress towards the clinic.

UNITY has pioneered the local rather than systemic use of senolytic drugs, and on the whole their results suggest that this is not a viable approach in most circumstances; it doesn't play to the strengths of senolytic drugs. Senescent cells cause issues via their inflammatory secretions, and while a nearby cell will in principle produce a larger effect with its secretions than a distant cell will, the body is large in comparison to any single organ, and there are many times more distant senescent cells than local senescent cells.

Senolytics company announces full 36-week data from ASPIRE trial and considers partnerships, mergers, or even winding down

Longevity focused biotech company UNITY Biotechnology has released complete 36-week data from its Phase 2b ASPIRE clinical study, along with a corporate update reflecting a significant shift in its direction. The company revealed it is restructuring its operations to conserve capital and pursue strategic alternatives for its pipeline programs, with a focus on reducing operational expenses and seeking external partners or transactions to advance its programs. As part of the shift, it appears UNITY will lay off its entire workforce, retaining some consulting agreements to manage the closeout of the ASPIRE study and provide continuity during the transition. Key executives, including its CEO, CFO and Chief Legal Officer, will transition to advisory roles to support the strategic review process.

Today's complete results from the trial reveal that the company's lead senolytic therapy, UBX1325, achieved vision improvements comparable to the current standard of care (aflibercept) in patients with advanced diabetic macular edema (DME) who had experienced suboptimal benefit from prior anti-VEGF therapies. At week 36, UBX1325 was statistically non-inferior to aflibercept in improving Best-Corrected Visual Acuity (BCVA), which it also achieved across most time points in the study. However, as previously reported, the trial did not meet its primary endpoint - non-inferiority in BCVA at the average of weeks 20 and 24. "Even at week 24, we met non-inferiority, so it's a very, very narrow technical definition. Having run a lot of trials, when a study doesn't work, it's rarely just one small measure falling short while everything else looks good. But that's exactly what happened in our case."

Proteins can undergo a large range of post-translational modifications, usually the addition of one or more molecules. This changes the interactions of the protein and its role in cellular biochemistry, and thus post-translational modification is an important aspect of the way in which protein machinery functions in the cell. Acetylation is one such modification, the addition of an acetyl group. Here, researchers assess the acetylome, amounts of all aceltyated proteins in tissues, in search of correlations with species longevity.

Despite extensive studies at the genomic, transcriptomic, and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals.

Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair, and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.

Link: https://doi.org/10.1038/s41467-025-58762-x

Researchers have found that genetic engineering to reduce expression of HDAC11 favorably changes the metabolism of muscle tissue in mice regardless of age. In older mice this alteration slows the well known loss of muscle mass and strength and improves muscle regeneration. Interestingly, HDAC11 inhibitor small molecules have been identified by the cancer research community, so the next step is to assess the ability of these drugs to improve muscle function in old mice.

Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function, and globally improves muscle performance in young mice.

Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed.

HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.

Link: https://doi.org/10.1007/s11357-025-01611-y

While not yet rising to the level of definitive proof and quantification of risk, a fair-sized body of evidence suggests that persistent viral infection by herpesviruses and the like can drive the onset and progression of age-related disease. This work is largely focused on the brain and neurodegenerative conditions, but if the primary mediating mechanism is increased chronic inflammation, one could imagine that viral infection is important in the progression of aging more generally. With advancing age, the immune system reacts in increasingly maladaptive ways to rising levels of biochemical damage and altered cell behaviors. Constant, unresolved inflammatory signaling - and the reactions of cells to that signaling - is damaging to tissue structure and function.

Today's open access paper discusses the present consensus view of the role of viral infection on brain aging. As the authors point out, inflammation may be important, but a range of other mechanisms are likely involved. As is usually the case for any aspect of aging, it is one thing to list involved mechanisms, but quite another to know their relative importance. The research community is fairly good at identifying mechanisms. Understanding which of those underlying mechanisms are more versus less important to any specific outcome is vital to the effective development of therapies, but unfortunately it is very challenging in practice to discover this information by any means other than trial and error. Thus trial and error remains the order of the day in the development of therapies.

Neurotropic Viruses as Acute and Insidious Drivers of Aging

In the central nervous system, neurotropic viruses are a major stressor and, therefore, a major driver of aging. Epidemiological studies of multiple large biobanks have shown that patients with a history of neurological viral infection are thirty times more likely to develop a neurodegenerative disease. In addition to the pressures of viral proteins during active infection, acute and chronic viral infections disrupt the homeostasis of the cell. This occurs throughout life, with acute causes of neurodegeneration (e.g., hemorrhagic or ischemic stroke, traumatic brain injury) and chronic conditions (e.g., viral latency, metabolic disease) compounding, often synergistically.

Here, we define aging, outline the impact viruses have on the brain, and identify the overlapping pathways of viral pathogenesis and age-related neurodegeneration. Previously proposed "Hallmarks of Aging" range in number but can be generally described by three categories: altered proteostasis, genomic compromise, and senescence. Neurotropic viruses manipulate each of these categories, driving rapid neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD), and more progressive neurodegenerative conditions like Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD).

Through our contextualization of myriad basic science papers, we offer explanations for premature aging via viral induction of common stress response pathways. Viruses induce many stresses: dysregulated homeostasis by exogenous viral proteins and overwhelmed protein quality control mechanisms, DNA damage through direct integration and epigenetic manipulation, immune-mediated oxidative stress and immune exhaustion, and general energy theft that is amplified in an aging system. Overall, this highlights the long-term importance of vaccines and antivirals in addition to their acute benefits.

The protein α-synuclein becomes prion-like when it misfolds, capable of encouraging other α-synuclein molecules to misfold the same way and assemble into solid deposits that are disruptive to cell biochemistry. This is the pathology that drives Parkinson's disease and other synucleinopathies, as α-synuclein spreads throughout the brain. Cellular biochemistry is complex and incompletely understood, and mapping the ways in which various forms of protein aggregate in fact cause harm remains an active area of research. Researchers here provide evidence for α-synuclein aggregation to alter lipid metabolism in the brain in ways that are likely harmful.

The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson's disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine.

In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species.

Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy.

Link: https://doi.org/10.1038/s41531-025-00960-x

As noted in this article, progress towards ways to significantly extend the healthy human life span continues to be slower than desired. Further, most of the approaches to the problem are little better than exercise. One can't conjure extra decades and a reversal of aging using calorie restriction mimetic drugs. That part of the field focused on therapies that can only modestly slow aging must atrophy in favor of more viable classes of therapy, those capable of much greater repair of aged tissue, addressing the known causes of aging in order to allow youthful metabolism and tissue maintenance to reemerge.

The rise of longevity biotechnology is a modern crusade to unlock the secrets of extended life. Billions of dollars have poured into startups, research labs, and bold promises of reversing aging. We have made progress: we know that human life, and especially the lives of lab animals, can be stretched impressively. Yet despite all our high-tech tools, no cutting-edge intervention, whether cellular reprogramming with Yamanaka factors or advanced drug cocktails, has outperformed rapamycin or caloric restriction in animal models, whether tested alone or in combination.

The longevity field projects a contradictory message. On one hand, it claims we are close to developing a drug against aging; on the other, it acknowledges that we still lack a shared understanding of what aging actually is. We are like early aviators tinkering with wings and engines, achieving powered flight through trial and error. Drugs that mimic the effects of caloric restriction, like rapamycin and metformin, are our first creaky airplanes: promising, but still crude.

The ambition to truly defeat aging is not just about building better airplanes; it's about realizing that no airplane, no matter how refined, can reach the moon. To get there, humanity needed rockets, which are based on entirely different principles. Similarly, halting aging will demand not just incremental improvements, but a deep, principled mastery of the fundamental mechanics that drive the aging process.

Link: https://www.lifespan.io/news/playing-the-long-game-towards-radical-life-extension/

Researchers interested in the comparative biology of aging have focused much of their efforts on the search for genetic differences that correlate with species life span. This can be higher or lower expression in directly homologous genes, but also differences in the number of genes in a family relating to a specific function, and differences in gene sequences. As one might expect, well established genetic differences involve genes associated with mechanisms relevant to aging and life span, such as DNA repair, tumor suppression, regenerative capacity, and antioxidant mechanisms.

In today's open access paper, researchers describe a more comprehensive search for differences between mammalian species, and find that genetic differences are more related to immune system function and brain size relative to body size than they are to body size alone. This is interesting; as you might recall, body size and metabolic rate correlates decently well with species longevity. Bigger animals tend to live longer than smaller animals, and exhibit a slower metabolism. The outliers are extreme, however, such as naked mole rats that live nine times as long as similarly sized mice and tiny bats that live for decades. The outliers show there is no necessary dependency on body size, and that the real mechanisms are elsewhere. That one of those mechanisms is the state of the immune system will keep researchers busy for a while: it is a very complex, incompletely understood part of mammalian biology.

Maximum lifespan and brain size in mammals are associated with gene family size expansion related to immune system functions

Mammals exhibit high diversity in their maximum lifespan potential (MLSP, the age at death (longevity) of the longest-lived individual ever recorded in a species), ranging from less than a year in some shrew species to over a hundred years in humans and up to two hundred in bowhead whales. Unlike average lifespan, which reflects both intrinsic and extrinsic factors such as the risk of predation and resource availability, MLSP is assumed to reflect a species' inherent longevity limit and is widely available used in comparative studies focused on life history trade-offs and the genomic determinants of longevity.

Identifying the overarching genomic signatures associated with the evolution of MLSP can provide insights into the evolution of key life history traits and variations in longevity between individuals in a species. Comparative studies have linked MLSP variations to changes in gene expression profiles. Genes associated with MLSP in these studies were enriched in DNA repair, defence response, cell cycle, and immunological process related terms. Genes such as PMS2 (DNA repair), PNMA1 (cell fate determination), and OGDHL (reactive oxygen species regulation) show positive correlation with MLSP across mammalian tissues. BCL7B, which inhibits carcinogenesis through Wnt pathway regulation, and GATM, associated with oxidative stress protection, are prominently linked to increased lifespan. These molecular signatures collectively enhance cellular maintenance and stress resistance mechanisms that appear critical for extended longevity.

Here, we use a comparative genomics approach to identify genomic signatures associated with the evolution of MLSP across mammals. We examine whether MLSP variations correlate with gene family sizes (of protein-coding genes) in 46 fully sequenced mammalian species. We found significant gene family size expansions associated with maximum lifespan potential and relative brain size but not in gestation time, age of sexual maturity, and body mass in 46 mammalian species. Extended lifespan is associated with expanding gene families enriched in immune system functions. Our results suggest an association between gene duplication in immune-related gene families and the evolution of longer lifespans in mammals.

Measurable early signs of aging are interesting because they can serve as an easier platform for the development of therapies: there are more patients, and the patients are more physically robust. Here, researchers show that wear and tear damage to cartilage can be seen as early as the 30s, particularly in people who are overweight. Cartilage damage remains a challenge for the medical community, though a range of efforts are underway to develop and assess regenerative therapies to address this issue. That younger people might be candidates for those therapies can only increase the incentives for developers.

Mild structural changes visible in knee MRI scans are already common among adults in their thirties - even in those without knee pain or other symptoms. A study found signs of joint damage in more than half of the 33-year-old participants. A high body mass index emerged as the most common factor associated with these changes. The participants were part of the Northern Finland Birth Cohort 1986, with 297 individuals undergoing knee imaging. Each participant received a comprehensive health examination, provided blood samples, and underwent a magnetic resonance imaging scan of the knee. Their average age was 33.7 years.

The most common findings were minor articular cartilage defects, particularly between the kneecap and thighbone, observed in over half of those imaged. Cartilage defects were also found in the joint between the shinbone and thighbone in about a quarter of participants. In addition, small bone spurs, or osteophytes, were detected in more than half of the group, although these were generally small. Researchers identified a higher body mass index as the clearest factor linked to the MRI findings. Although most participants were asymptomatic, the findings suggest that structural changes in joints can occur before clear symptoms develop. The researchers stress the need for longitudinal studies to determine which factors predict the progression of these changes later in life.

Link: https://www.oulu.fi/en/news/early-structural-changes-knees-common-age-30-often-without-symptoms

The value of lower levels of physical activity has been one of the major themes of the past twenty years of research into the effects of exercise on long-term health. The advent of low-cost wearable accelerometer devices has enabled researchers to rigorously quantify differences for lesser amounts of physical activity, in order to get a much better look at the lower end of the dose-response curve for exercise. That leads to studies such as the one noted here, in which researchers assess the impact of small amounts of high intensity exercise on brain aging.

Endurance training and good fitness can reduce the risk of dementia and promote healthy brain aging. Even small amounts of physical activity may be enough to protect the aging brain, researchers recently concluded. A new paper evaluated evidence from both animal and human studies, and shows how physical activity affects inflammation, blood flow, immune function, brain plasticity and the release of protective molecules in the blood - processes that weaken with age and contribute to the development of neurodegenerative diseases.

Today, the recommendation is at least 150 minutes of moderate or 75 minutes of high intensity per week. The researchers point out that exercising much less than what the current recommendations recommend can provide great benefits - as long as the intensity of the training is high. "We believe it's time for health authorities to provide clearer advice on how important exercise is for the brain. Our review shows that even small doses of high-intensity activity - equivalent to brisk walking where you can't sing - can reduce the risk of dementia by up to 40 per cent."

Link: https://norwegianscitechnews.com/2025/04/exercise-helps-improve-how-our-brain-ages/

Primary aging derives from mechanisms inherent to our biology, such as the damaging mechanisms listed in the Strategies for Engineered Negligible Senescence (SENS) view of aging. Secondary aging derives from lifestyle choices (such as diet and exercise) and environmental exposures (such as particulate air pollution or persistent viral infections), harmful factors that can interact with the mechanisms of primary aging to accelerate the path to loss of function, age-related disease, and mortality. Epidemiological studies suggest that many people are losing at least a few years of life to poor choices, poor luck, or poor living circumstances.

Today's open access paper offers a high level tour of some of the major categories of environmental pollution. While extensive data indicates air pollution is harmful and increases the incidence of age-related diseases, data is somewhat lacking for many other areas of potential concern. Exposure to microplastic and nanoplastic particles, for example, may turn out to be as harmful as air pollution, but the few existing studies are by no means enough to say in certainty one way or another. Those studies can only collectively suggest that it would be wise to gather enough data to be sure.

Environmental Health Is Overlooked in Longevity Research

Environmental pollutants constitute an often-overlooked factor in the aging process. The mechanistic insights presented in this manuscript provide a snapshot of how specific classes of pollutants - including heavy metals, particulate matter, and endocrine-disrupting chemicals - induce oxidative stress through multiple pathways. These pollutants disrupt redox balance, impair mitochondrial function, and damage critical biomolecules such as DNA, proteins, and lipids, ultimately affects epigenetic aging. The cumulative impact of these events has significant implications for the overall trajectory of organismal aging. Epidemiological evidence linking pollutant exposure to cardiovascular, neurodegenerative, and oncologic outcomes further supports the concept that environmental health is an integral component of the longevity equation. In a recent study comparing genetic and environmental influences for 22 major diseases, polygenic risk scores explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points.

Environmental factors are estimated by the World Health Organization (WHO) to account for approximately 25% of the total burden of disease globally, which translates into a substantial loss of healthy life years on a population level. Using a back-of-the-envelope calculation based on WHO metrics, one can approximate that environmental exposures result in loss of several years of good health over the lifespan. This environmental burden is quantified using Disability-Adjusted Life Years (DALYs), which represent the total number of years lost due to ill health, disability, or premature death. WHO estimates that approximately 1.7 million DALYs are lost annually in France due to environmental factors.

To translate this population-level burden into an individual context, we can estimate annual per capita loss by dividing the annual 1.7 million DALYs by France's population of approximately 66 million which yields an average loss of about 0.0258 DALYs per person per year. Since one DALY equates to one lost year of healthy life, this corresponds to roughly 9.4 days of healthy life lost per person each year. Over an average lifespan of 80 years, this annual loss accumulates to approximately 2.1 years of healthy life lost per individual due to environmental exposures. This estimation reaches 3-4 years for the most polluted countries like China. This calculation does not take into account interindividual variations and it is likely that individuals who are exposed to pollution levels orders of magnitude higher than others will suffer in proportion.

Researchers here note recent progress towards assessment of the burden of misfolded α-synuclein in a living brain via contrast imaging. This would provide a way to reliably diagnose Parkinson's disease in advance of symptoms. Unlike imaging for the protein aggregates associated with Alzheimer's disease, this is not an established capability. It seems likely that imaging approaches will fade in importance in the years ahead, however, as blood assays with a much lower cost are now demonstrated to be able to detect neurodegenerative diseases in their earliest stages.

The abnormal accumulation of α-synuclein protein is a defining pathological feature of several neurodegenerative conditions collectively known as synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Until recently, confirming the presence of these protein aggregates required post-mortem examination, severely limiting early diagnosis and treatment monitoring capabilities.

A recent paper meticulously reviews recent advances in positron emission tomography (PET) tracer development, with special attention to promising candidates that have shown effectiveness in both laboratory and clinical settings. The researchers highlight tracers such as [18F]F-0502B, [18F]C05-05, and [18F]ACI-12589, which have demonstrated encouraging results in distinguishing patients with synucleinopathies from healthy controls.

One particularly significant breakthrough came when [18F]C05-05 successfully visualized synucleinopathies in ten patients meeting clinical diagnostic criteria for Parkinson's disease or dementia with Lewy bodies. This tracer showed increased binding in the midbrain - an area commonly affected by Lewy body pathologies - and this binding correlated well with the severity of motor symptoms.

Despite these developments, several challenges that remain in developing optimal α-synuclein PET tracers. The heterogeneous distribution and conformation of α-synuclein aggregates across different synucleinopathies, along with the relatively low density of these pathological features, complicate the development of universally effective imaging agents.

Link: https://www.eurekalert.org/news-releases/1081920

The extracellular matrix is a complex structure of molecules generated and maintained by cells to support themselves and determine the physical properties of a tissue, such as load-bearing capacity or elasticity. The extracellular matrix changes with age in ways that are not fully explored, but which harm cells and tissue function. Comparatively little effort is focused on finding ways to repair the aged extracellular matrix, in part because it seems a hard problem. There are few points of intervention that can be as simple as the one noted here, where delivering a novel substitute molecule allows it to be incorporated into the matrix to improve matters. In most cases, providing the raw materials is not enough; there are issues of cell activities, problematic alterations to existing structures, or toxic debris from chemical interactions in the matrix, to pick a few of the many issues.

Intervertebral disc degeneration (IDD) accounts for nearly half of the cases of low back pain (LBP), a leading cause of disability worldwide. The progression of IDD is characterized by decreased intervertebral disc height and water content in the nucleus pulposus (NP) tissue which lies in the center of the intervertebral disc and is surrounded by annulus fibrosus (AF).

A key change to the NP tissue along IDD development is the increasing loss of glycosaminoglycan (GAG) polysaccharides. GAGs are a main component of the gel-like extracellular matrix (ECM) that maintains the morphology and phenotypes of NP cells (NPCs). Although replenishing GAGs has emerged as a promising strategy, its efficacy remains unclear, with hardly any clinical success achieved. Recent findings have raised questions that the NP tissue under degeneration is maintained as a catabolic microenvironment by the elevated presence of enzymes that can degrade native GAGs. An alternative approach is to implant a biomaterial substitute of GAGs - serving as a glue to the damaged ECM of NP. This glue material should avoid recognition by the enzymes in the pathological niche, and meanwhile, mimic native GAGs in exerting specific bioactivities to support NPC functionality.

Accordingly, we synthesize a glucomannan octanoate (GMOC) with robust resistance to ECM-cleaving enzymes. GMOC injected into the degenerated intervertebral disc leads to NP tissue regeneration in a rat and a rabbit model, which represent two clinical scenarios of pre-surgical intervention and post-surgical regeneration of IDD, respectively. In summary, we report enriching the ECM with a glycan glue as a mechanism to promote NP regeneration for IDD treatment.

Link: https://doi.org/10.1038/s41467-025-58946-5

The Strategies for Engineered Negligible Senescence (SENS) was the original attempt to produce a list of important mechanisms in aging, created in an era in which the aging research community leadership was actively hostile towards the concept of treating aging as a medical condition. A great deal of patient advocacy and hard work was required to create the much more receptive research community that exists today, in which the treatment of aging is accepted as a legitimate goal, and the inflamed discussion has moved on to how exactly one should go about it. In this more receptive environment, SENS was followed by other lists of mechanisms: the Hallmarks of Aging, echoing the much earlier Hallmarks of Cancer, and the Seven Pillars of Aging.

To my eyes the important difference between SENS and the hallmarks of aging is that SENS was framed as a call to action from the very start. It attempts to list the root causes of aging, conceptualizing aging as an accumulation of specific well-established forms of cell and tissue damage, points at which intervention will plausibly produce rejuvenation - and rejuvenation is the goal, the point of the exercise, to eliminate age-related suffering and death. The hallmarks of aging is just a list, attempting to be scientifically neutral. One can use both as starting points for directions in research and development of means to treat aging, but SENS was from the beginning intended to be used that way, and its creation was biased towards achieving the greatest expectation of extended healthy life span given viable therapies.

SENS vs. the hallmarks of aging: competing visions, shared challenges

In response to the complexity of aging, a range of pluralistic frameworks have emerged to address its challenges. Two particularly relevant proposals in this regard are Strategies for Engineered Negligible Senescence (SENS), which advocates repairing accumulated damage in the body to reverse its effects, and the Hallmarks of Aging (HoA), which identifies and classifies the key biological processes driving age-related decline. Given their prominent roles, both SENS and the HoA are the subject of ongoing debate and scrutiny. SENS has been criticized regarding the burden of proof, an epistemological principle stipulating that those who propose a novel hypothesis must provide robust evidence to substantiate it. The HoA has also faced considerable criticism, particularly for lacking a clear framework to prioritize therapeutic targets.

We contend that, despite their divergences, a comparative analysis of the conceptual and methodological foundations of SENS and the HoA is both feasible and valuable. There are several considerations that support the relevance of such analysis. First, SENS and the HoA rest on a remarkably similar theoretical foundation: both conceptualize aging as a multifactorial phenomenon driven by interconnected biological mechanisms, primarily at the cellular and molecular levels. Second, both proposals have played a pivotal role in shaping the idea that aging is a plastic process - one that, in principle, can be modulated through biotechnological interventions - insofar as it is conceived as amenable to targeted manipulation. Third, while sharing the overarching goal of addressing aging, SENS and the HoA have engaged in a form of intellectual and material competition, seeking to influence the conceptual direction and the allocation of recourses in aging research. Finally, both proposals have achieved sustained prominence.

SENS adopts an explicitly interventionist stance rooted in a technological solutionist perspective, framing aging as a technical problem that necessitates practical solutions rather than a deeper theoretical understanding. It does not provide a strict definition of aging, as its main focus is on the effectiveness of treatments rather than conceptual debates. It argues that a precise definition of aging is unnecessary from a biomedical perspective, emphasizing the importance of focusing on the repair and prevention of accumulated damage. From this standpoint, semantic debates are not only unproductive but also delay the development of effective interventions.

The HoA explicitly defines aging, as its approach necessitates a clear conceptualization to integrate and systematize the existing body of biological knowledge. Aging is described as a "progressive deterioration of physiological integrity, leading to impaired function and increased vulnerability to death". Unlike SENS, which emphasizes intervention over definition, the HoA regards a precise understanding of aging as essential for identifying the key biological processes that underlie its progression.

This paper seeks to contribute to a deeper understanding of the core principles and assumptions underpinning SENS and the HoA. We consider that previous literature has not sufficiently addressed the conceptual and methodological foundations of these proposals. Addressing these dimensions is essential not only for a more nuanced understanding of the frameworks themselves but also for a more accurate evaluation of their theoretical and practical contributions.

The blood-brain barrier consists of specialized cells that line blood vessels passing through the central nervous system, only selectively allowing passage of molecules and cells between the circulation and the brain. Dysfunction of the blood-brain barrier allows unwanted molecules and cells into the brain, where they cause chronic inflammation and become an important contribution to the onset and progression of neurodegenerative conditions. While blood-brain barrier dysfunction appears early in the aging of the brain, and thus seems a good candidate for the position of primary causative mechanism, many studies - such as the one noted here - suggest that other pathologies associated with neurodegenerative conditions can cause blood-brain barrier dysfunction.

Problems with blood vessels in the brain are recognized as some of the earliest changes that can lead to memory loss and other symptoms in Alzheimer's disease and other forms of dementia. These problems generally center around the neurovascular unit - a group of different cell types, including blood vessel cells, support cells, and neurons - that work together to keep the brain healthy. This system helps regulate blood flow in the brain, controls how nutrients and energy are delivered, and helps protect the brain from inflammation and harmful substances.

Until now, scientists did not fully understand what tau protein aggregates were doing at the brain's blood vessels. To uncover the mystery, researchers ran a series of experiments in vitro using a cell model that mimics the brain's protective barrier. When they exposed the cells to protofibrillar tau - a form of tau that appears early in Alzheimer's disease - they discovered that it weakened the barrier, making it more "leaky" and less able to protect the brain. The researchers also found that right after exposure to protofibrillar tau, brain blood vessel cells quickly changed how they make energy. This shift triggered inflammation and weakened the protective barrier, suggesting these damaging changes happen very early in the disease process.

Link: https://www.templehealth.org/about/news/scientists-at-the-lewis-katz-school-of-medicine-at-temple-university-uncover-how-tau-protein-weakens-the-brains-vascular-defenses-in-alzheimers-disease

Hematopoietic stem cells in the bone marrow generate red blood cells and immune cells. Immune cells can be roughly divided into myeloid lineages of the innate immune system and lymphoid lineages of the adaptive immune system. With advancing age, the generation of myeloid cells becomes favored over lymphoid cells, and this is one source of dysfunction in the aged immune system. Here, researchers find a signature of age-related dysfunction in hematopoietic cells that favor myeloid cell production. This could be a first step towards targeting these malfunctioning hematopoietic cells in order to restore a more balanced generation of immune cells and thus improve immune function in older individuals.

Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging-associated proteins or reporter systems of aged HSC signature genes.

Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis.

The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.

Link: https://doi.org/10.1182/blood.2024025776

TDP-43 is one of the few proteins capable of becoming altered in ways that allow it to form solid aggregates. Like many of the other examples, it is involved in the onset and progression of neurodegenerative conditions. This form of pathology in the brain was a more recent discovery than, for example, the involvement of amyloid-β and tau in Alzheimer's disease or α-synuclein in Parkinson's disease. It was only a few years ago that researchers clearly defined limbic-predominant age-related TDP-43 encephalopathy (LATE) as a novel form of neurodegenerative condition. Separately, TDP-43 also appears important in amyotrophic lateral sclerosis (ALS). As research into TDP-43 aggregation broadens, it appears likely that it causes neurodegenerative pathology to some degree in a large fraction of the older population.

In today's open access paper, researchers report on one of the ways in which TDP-43 aggregation can cause harm to the brain. Problems start because aggregation depletes TDP-43 in the cell nucleus, where it serves useful functions. This depletion alters cell behavior in pathological ways. When this happens in cells making up the blood-brain barrier, it causes the blood-brain barrier to leak. Normally the blood-brain barrier prevents unwanted cells and molecules from passing from the circulation into the brain. Leakage produces persistent inflammatory reactions to those unwanted cells and molecules in brain tissue, and this chronic inflammation is disruptive to brain function.

Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects

Loss of nuclear TDP-43 (TAR DNA-binding protein 43) is a common feature in a wide range of neurodegenerative diseases. These include Alzheimer's disease (AD), limbic-predominant age-related TDP-43 encephalopathy, and amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Across these diseases, a common feature is aggregation of ubiquitinated TDP-43 in the cytosol and nuclear loss of TDP-43 in neurons. The identification of familial FTD mutations in TDP-43 that exacerbate this process highlights TDP-43 dysfunction as a driver in disease progression. Mechanistically, the reduced nuclear levels of TDP-43 are associated with impaired nuclear splicing functions. In a dose-dependent manner, the loss of nuclear TDP-43 results in the aberrant inclusion of exonic junctions into transcripts, often leading to transcript destabilization and degeneration through nonsense-mediated mRNA decay. In neurons, the loss of specific transcripts alters the expression of proteins critical for axonal projection, which is thought to contribute to the progression of motor neuron deficits in ALS.

Early in the course of neurodegenerative diseases, increased flux across the blood-brain barrier (BBB) is detected. BBB leakage alone can exacerbate neurodegenerative changes in animal models. While not all the subsequent consequences of BBB leakage are fully understood, fibrin deposition has been linked to reactive changes in brain microglia. The BBB is part of a complex neurovascular unit comprising endothelial cells (ECs) lining the lumen of vessels, an underlying basement membrane, associated pericytes, astrocytes, and perivascular fibroblasts. Although each of these components contributes to the barrier, it is the ECs that provide the functional barrier.

Here, we show that TDP-43 has a critical function in the maintenance of the BBB. We recently identified reduced nuclear TDP-43 in capillary ECs of donors with ALS-FTD. Because BBB permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 and that this leads to loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phosphorylated Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.

A growing body of work has found correlations between selenium deficiency and suggestions of accelerated aging: increased epigenetic age, increased mortality, increased incidence of age-related disease. Selenium is incorporated into a range of proteins called selenoproteins, and it is possible to argue that too little selenium, leading to a lower production of these proteins, impairs functions relevant to aging, such as antioxidant capacity and immune system activities. As is usually the case in these matters, there is correlation and inference, but no concrete data on which of these proteins and mechanisms are more versus less important.

In this study, we analyzed the association between serum biomarkers, namely total serum selenium, selenoprotein P (SELENOP), the selenocysteine-containing glutathione peroxidase 3 (GPx3), and biological age measured by epigenetic clocks in 865 participants of the observational Berlin Aging Study II. Lower values in all three selenium biomarkers were associated with an increased pace of aging measured with the DunedinPACE clock. Our analyses do not allow to draw any conclusions on cause-effect relationships between selenium levels and accelerated biological aging. However, our results corroborate recent findings on aging phenotypes assessed by other clinical and phenotypic outcomes that show an association between selenium biomarkers and mortality.

In a recent prospective study with ~17 years of follow-up, serum concentrations of the selenium transporter SELENOP were inversely associated with all-cause and cardiovascular mortality, independent of biologically relevant confounders. In line with this finding, serum selenium was inversely associated with mortality and incident heart failure in the Dutch PREVEND study comprising ~6000 individuals. Similar results were observed in other recent large prospective European studies for all-cause mortality as well as cardiovascular outcomes. Besides all-cause mortality and cardiovascular outcomes, serum selenium biomarkers were shown to be inversely associated with prognosis in several cancer entities. Moreover, an effect of selenium levels on epigenetic age is also biologically plausible since changes in the methylome in dependence to the selenium levels in rodents, cell-lines (human, mouse) and human tissue are well established.

Link: https://doi.org/10.1186/s13148-025-01863-7

The immune system of the brain is distinct from that of the rest of the body, at least to a first approximation. Given improved tools and more research, scientists are finding that immune cells from the body do find their way into the brain. This seems to occur to a limited degree normally, in young people, but becomes more pronounced in later life. This is likely due to increasing dysfunction of the blood-brain barrier, specialized cells that line blood vessels that pass through the brain and collectively determine which cells and molecules are allowed to pass to and from the brain. When the barrier leaks, allowing unwanted cells and molecules to enter the brain, the result is usually harmful persistent inflammation in the nearby brain tissue.

Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment derived from the yolk sac that resists seeding with cells derived from adult hematopoiesis occurring in the bone marrow. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles.

Unlike yolk-sac-derived microglia in the brain, due to their derivation from hematopoietic stem cells MoMΦs are exposed to somatic mutations that are associated with age-related clonal hematopoiesis. Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human clonal hematopoiesis variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with clonal hematopoiesis, can cause brain pathology.

Link: https://doi.org/10.1016/j.celrep.2025.115609

Animal study data makes it very clear that senescent cells are actively involved in producing the age-related dysfunction that leads to disease and mortality. Senescent cells grow in number with age and generate signaling, the senescence-associated secretory phenotype, that disrupts tissue structure and function. Selectively destroying senescent cells via the use of senolytic therapies removes this influence to produce a profound and rapid reversal of many measurable aspects of aging in mice. Some of these therapies are used by a growing number of patients with access to anti-aging physicians, and human trials have taken place to produce promising early results. Nonetheless we are still some way from a good enough understanding of dosing in humans and enough rigorous human data to convince the world that this is as impressive as it appears to be in the laboratory.

Clearance of senescent cells should help to, at the very least, slow the progression towards neurodegenerative conditions, such as the prevalent mild cognitive impairment in older individuals. In today's open access materials, researchers report on the ability to correlate circulating markers of the burden of senescent cells with the risk of mild cognitive impairment. Beyond the point that more ways to assess the risk of neurodegeneration improve the ability to prevent such conditions via early intervention, this adds to the body of evidence to suggest that presently available senolytic therapies with a good safety profile, such as intermittent treatment with the dasatinib and quercetin combination, should be widely used as preventative medicine in the older population.

Plasma senescence associated secretory proteins: A new link to mild cognitive impairment

Cellular senescence is widely acknowledged hallmark of aging that has been implicated in the progression of several age associated disorders. The secretome of senescent cells, termed as senescence associated secretory phenotype (SASP), consists of a number of inflammatory cytokines as well as growth factors and proteases that can lead to paracrine disruption of normal tissue structure and function and propagate senescence in neighboring cells. Moreover, many SASP molecules have been identified as potential biomarkers of aging and associated traits. In cases of age associated neurodegenerative diseases that can lead to dementia or cognitive impairment, increased senescence has been observed in multiple cell types in brain.

Mild cognitive impairment (MCI) is defined as a condition defined by cognitive impairment with minimal impairment of daily activities. It is observed in about 10-20% of individuals over 65 years of age and about 10% of individuals with MCI can progress to dementia every year. There are few potential plasma biomarkers that have been reported, particularly senescence-associated protein biomarkers. Therefore, there is a need to identify new robust potential plasma biomarkers that can be applied clinically for diagnosis of MCI.

A new study explored the connection between cellular senescence and MCI by analyzing the plasma levels of certain SASP markers to predict risk of MCI among older adults. The study is based on the data from the Lifestyle Interventions for Elders (LIFE), a large cohort study designed to assess the effects of physical activity and health education on mobility in sedentary older adults. The authors assessed a panel of 27 SASPs that were previously identified as markers associated with mobility disability. Among these, higher plasma levels of myeloperoxidase (MPO) and Membrane metalloprotease-7 (MMP7) and reduced levels of MMP1 reportedly led to increased risk of MCI in older adults. Importantly, MPO and MMP7 were longitudinally associated with future MCI (24 months later), underscoring their predictive potential. These markers had been previously reported to be associated with different neurological disorders including Alzheimer's disease. However, the current study points to a potential mechanistic connection with cellular senescence and SASP as players in development of MCI. If certain cases of MCI are driven by cellular senescence, a possibility that needs to be further explored, then senotherapeutic interventions may offer a novel therapeutic opportunity.

People with excess visceral fat tissue suffer more age-related disease, develop those conditions earlier, and exhibit a higher mortality risk. But is this accelerated aging, an increased burden of the defined forms of damage and dysfunction that drive aging, or is it a different set of damaging processes? There is a fair amount of evidence to suggest that being overweight does literally accelerate aging, such as the fact that greater amounts of visceral fat produce a greater burden of senescent cells, and studies such as the one noted here that correlate higher aging clock measures with the amount of visceral fat. But this isn't a concretely answered question.

Cardiometabolic multimorbidity (CMM), as one of the most prevalent and representative multimorbidity forms, is characterized by the coexistence of at least two cardiometabolic diseases (CMD), typically including coronary heart disease (CHD), type 2 diabetes (T2DM), and stroke. Obesity is widely recognized as a significant risk factor for CMM. A growing consensus holds that the accumulation of visceral adipose tissue is more deleterious to health than the expansion of subcutaneous adipose tissue. The body roundness index (BRI) is a novel anthropometric measure that integrates height and waist circumference (WC) to characterize body shape. Compared to the traditional body mass index (BMI), it provides a more accurate reflection of visceral fat distribution.

Using data from the UK Biobank, a nationwide cohort study was conducted using the available baseline BRI measurement. Biological aging was assessed using the Klemera-Doubal method for biological age and the phenotypic age algorithms. The association between the BRI and CMM was estimated using the Cox proportional hazards regression model, while the roles of biological aging were examined through interaction and mediation analyses.

During a median follow-up of 14.52 years, 6,156 cases of CMM were identified. A significant association was observed between the BRI and CMM. The hazard ratio (HR) for CMM was 3.72 for individuals in the highest quartile compared with those in the lowest quartile of the BRI. More importantly, the BRI demonstrated superior predictive performance relative to body mass index. Furthermore, the BRI exhibited additive interactions with accelerated biological aging on the risk of CMM, and accelerated biological aging partially mediated the association between the BRI and CMM. These findings provide evidence for the application of the BRI as a novel and readily accessible screening tool associated with CMM, suggesting that the effective management of visceral fat and biological aging deceleration may hold promise for reducing CMM risk.

Link: https://doi.org/10.3390/nu17081397

Researchers here show that the distribution of microbial populations in the nasal microbiome correlates with mild cognitive impairment and age-related loss of sense of smell. Both of these are manifestations of neurodegenerative processes that degrade function in the central nervous system. While we know that age-related changes in the gut microbiome are probably influential on age-related conditions via, at the very least, provoking increased chronic inflammation. But is the nasal microbiome large enough to have the same sort of effect on the function of parts of the brain? It seems more plausible that both nasal microbiome and neurodegeneration are influenced by the state of the aging immune system. Either way, more research is needed if a concrete answer is wanted.

Emerging evidence has highlighted that olfactory dysfunction, a common feature of aging, is increasingly linked to cognitive decline in older adults. However, research on the underlying mechanism, particularly the role of nasal microbiome, remains limited. In this study, we investigated the associations between olfactory function, the nasal microbiome, and cognition among 510 older adults with an average age of 77.9 years. Olfactory function was assessed using the brief Chinese Smell Identification Test, and cognitive assessments were conducted via the Mini-Mental State Examination and the Revised Hasegawa Dementia Scale. Nasal microbiome profiles were generated through 16S rRNA gene sequencing.

We observed that olfactory dysfunction (i.e., hyposmia) was associated with a higher richness of nasal bacteria, and such observation was replicated in an external dataset. A total of 18 nasal bacterial genera were identified to be associated with olfactory function, with eight genera such as Acidovorax and Morganella being enriched in the hyposmic group. A composite microbial index of nasal olfactory function significantly improved the reclassification accuracy of traditional risk model in distinguishing hyposmic from normosmic participants. Furthermore, participants with a nasal biotype dominated by Corynebacterium had a lower prevalence of mild cognitive impairment compared to those dominated by Dolosigranulum or Moraxella.

Our findings suggested that the nasal microbiome may play a role in the association of olfactory function with cognition in older adults, providing new insights into the microbial mechanisms underlying hyposmia and cognitive decline.

Link: https://doi.org/10.1038/s41398-025-03346-y

Senescent cells accumulate with age in tissues throughout the body. Senescent cells are created throughout life, largely because somatic cells reach the Hayflick limit on replication, but also as a result of various stresses. In youth, newly created senescent cells are cleared rapidly by the immune system. In later life, that capability declines, and senescent cells begin to linger as a result. While senescent cells never make up more than a tiny fraction of all cells in a tissue, they energetically produce inflammatory signaling, in what is known as the senescence-associated secretory phenotype (SASP). It is this signaling that causes harm when sustained over time, disruptive to cell and tissue function, and a contributing cause of age-related conditions.

There are a few different approaches to the problem of senescent cells. Firstly one can try to selectively destroy senescent cells via the use of senolytic therapies. This is the most well developed and most easily implemented approach, and has the largest set of animal and human data to suggest that it will be beneficial. In mice, certainly, it produces by far the largest and most rapid reversal of specific age-related conditions so far observed. The second approach is to prevent cells from becoming senescent, and thus allow the immune system to catch up and reduce the burden of lingering senescent cells. Therapies that upregulate autophagy, such as mTOR inhibitors, are the best example of this strategy.

The third approach is to interfere in the ability of senescent cells to generate the SASP. This is likely the most challenging of the options on the table, as it requires a much greater understanding than presently exists of the regulation of the SASP and its most important component molecules. Further, what is known of the SASP suggests that both it and its regulation are very complex. Any one protein or protein interaction target is unlikely to address more than a modest fraction of the overall problem. It seems doubtful that SASP modulation could be more effective than clearance of senescent cells, which obviously reduces the SASP quite readily, to the degree to which it reduces the burden of senescence.

SASP Modulation for Cellular Rejuvenation and Tissue Homeostasis: Therapeutic Strategies and Molecular Insights

Modulation of the SASP has gained attention as a therapeutic strategy for combating age-related diseases, tissue degeneration, and cancer progression. While preclinical studies show promise, clinical translation remains limited due to the heterogeneous and context-specific nature of SASP, as well as its complex crosstalk with immune pathways. Addressing these challenges requires integrated efforts in molecular biology, pharmacology, and computational sciences to develop targeted, tissue-specific therapies.

The SASP is not a uniform signature but varies depending on cell type, senescence trigger, tissue environment, and duration. While core components like IL-6, IL-8, and CXCL1 are commonly expressed, others such as extracellular vesicle-derived microRNAs and long non-coding RNAs show high tissue specificity. This molecular diversity complicates biomarker discovery and universal therapy design. Advances in single-cell RNA sequencing and spatial transcriptomics have enhanced our understanding of SASP heterogeneity, although technical limitations persist. Machine learning tools capable of integrating multi-omic datasets may help create personalized approaches for SASP modulation.

Therapeutically, SASP displays both beneficial and detrimental roles depending on context. Acute SASP promotes regeneration, wound healing, and embryonic development, but chronic SASP contributes to inflammaging, fibrosis, and cancer. For instance, senescent fibroblasts secrete pro-angiogenic factors, aiding repair while also facilitating tumor growth and immune evasion in epithelial tissues. Mitochondrial dysfunction, particularly via the cGAS-STING pathway, may drive chronic SASP and associated inflammation, yet targeting mitochondria raises concerns over the long-term effects on metabolic integrity.

The immune system is both influenced by and responsive to the SASP. Early SASP supports immune recruitment through cytokines like IL-6 and CXCL2, promoting senescent cell clearance. However, a persistent SASP can drive immune exhaustion and chronic inflammation, suppressing anti-tumor responses through elevated levels of IL-6 and TGF-β. Immunotherapies such as PD-1/PD-L1 inhibitors offer partial success but require a deeper understanding of SASP-immune dynamics to improve consistency and efficacy.

Translating preclinical findings into clinical applications presents further obstacles. Murine models often fail to replicate human senescence biology due to species-specific differences in SASP and immune responses. Emerging platforms such as humanized organoid systems and grafts of patient-derived aged tissues offer better fidelity but are hampered by inconsistent induction methods and limited standardization. Collaborative research frameworks and harmonized protocols will be essential for achieving reproducible clinical outcomes.

The authors of this review paper have a positive view of the future of regenerative medicine built on the ability to generate induced pluripotent stem cells from any patient cell sample. That should be tempered by a realistic expectation on timelines. At this point almost two decades have passed since the discovery of the first approach to reprogramming adult cells into induced pluripotent stem cells, but relatively little progress has been made on bringing therapies into even initial clinical trials. Perhaps the biggest challenge is that working with cells is very expensive and very challenging, far more so than development of small molecule drugs. Higher costs means fewer programs, slower progress.

Aging-related diseases often involve the dysfunction or loss of specific cell types, leading to organ and tissue degeneration. Due to their "young" characteristics, induced pluripotent stem cells (iPSCs) offer a promising solution by enabling the reprogramming of adult cells into a pluripotent state, which can then be directed to differentiate into various cell types needed to replace damaged or dysfunctional cells and thus make a difference in aged bodies. In addition, the advent of iPSCs has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells.

Despite the promising potential of iPSC technology, several challenges remain to be addressed before its full therapeutic potential can be realized. These include ensuring the safety and stability of iPSC-derived cells, overcoming potential immune rejection issues, and refining differentiation protocols to produce fully functional and mature cell types. Additionally, establishing robust protocols for large-scale production and rigorous quality control will be essential for the successful clinical translation of iPSC-based therapies. The field of iPSC-based cell therapy is advancing rapidly, with genetic engineering and cellular manipulation techniques significantly enhancing the functionality and therapeutic potential of iPSC-derived cells. As research progresses, the integration of cutting-edge iPSC technology with discoveries in aging biology promises to revolutionize treatments for aging-related diseases.

Beyond merely treating aging symptoms, iPSCs offer the transformative potential to intervene in fundamental aging processes, ushering in a new paradigm of regenerative medicine focused on extending both lifespan and healthspan. As these technologies advance, it is crucial to maintain a focus on ethical considerations and regulatory frameworks to ensure that these groundbreaking therapies are developed responsibly and equitably.

Link: https://doi.org/10.3390/cells14080619

One of the less frequently discussed aspects of aging, perhaps because it is seen as a less critical function, is the progressive loss of the sense of smell. When arising from the underlying cell and tissue damage of aging, this can be considered a form of neurodegeneration. Strategies in the development of regenerative medicine that are aimed at regrowth of neurons and axonal connections between neurons are applicable to this form of age-related dysfunction, and here find a review of some of this ongoing work.

Olfactory loss impacts more than 12% of the population and increases with aging. Multiple conditions can cause loss of smell (hyposmia or anosmia), including post-viral damage from COVID-19 or influenza, head injuries, sinusitis, or neurodegenerative conditions such as Alzheimer's or Parkinson's disease. While treatments including surgery, anti-inflammatories or olfactory training may be of benefit in specific cases, there is an unmet need for effective therapies for many common causes of olfactory dysfunction, especially those thought to be due to damage to the olfactory neurons that have failed to recover spontaneously.

Broadly, regenerative medicine approaches may exert a therapeutic effect by (a) delivering signals to endogenous cells in a damaged tissue that promote a necessary process that has been inhibited or blocked, such as cell division or differentiation; or (b) delivering exogenous cells capable of engrafting appropriately into the damaged tissue and functioning as stem or progenitor cells that can divide and differentiate appropriately.

In either scenario, the organ system must be capable of integrating the newly regenerated cells properly. For instance, a newly produced olfactory sensory neuron in the olfactory epithelium (OE) of the nose must extend an axon through the cribriform plate, enter the central nervous system, and establish a synapse at an appropriate glomerulus in the olfactory bulb of the brain. Because the OE continually produces new olfactory neurons from resident stem cells as needed throughout life, evidence suggests that the presence of local guidance cues and a permissive microenvironment may support repair.

Link: https://doi.org/10.21053/ceo.2025-00065

A number of proteins in the body are capable of misfolding or otherwise becoming altered in ways that allow the formation of aggregates, solid clumps that precipitate from solution to cause harm to the normal function of cells. Those harms might be direct, or result from a surrounding biochemistry of interactions with the aggregates that generates damaging molecules, or be driven by a maladaptive inflammatory response to the presence of the protein aggregates. Much of the research related to protein aggregates is focused on the aging brain and neurodegenerative conditions, as these are largely characterized by the formation of various forms of protein aggregate, such as amyloid-β, tau, and α-synuclein.

TDP-43 is a more recent addition to the established list of protein aggregates, with its own Alzheimer's-like condition called limbic-predominant age-related TDP-43 encephalopathy (LATE). As research into TDP-43 aggregation progresses, it is becoming clear that it is a common form of pathology, perhaps often misdiagnosed as Alzheimer's disease. TDP-43 aggregation is also important in amyotrophic lateral sclerosis (ALS) and potentially other conditions. Generally, one should expect all forms of protein aggregation to be present in the aging brain; the various named conditions develop when one or more of these protein aggregates pass the threshold needed to produce outright, evident pathology. Even prior to this, they cause harm, however. Protein aggregation should be treated as a form of damage, and therapies developed to minimize it as best possible.

Neurodegenerative disease ALS: Cellular repair system could prevent protein aggregation

In amyotrophic lateral sclerosis (ALS), poorly soluble protein aggregates accumulate in motor neurons. Among other proteins, these aggregates consist of TDP-43, which plays various critical roles in cellular RNA metabolism. While in healthy cells TDP-43 is mainly found in soluble form in the cell nucleus, in ALS patients it forms poorly soluble aggregates that mainly accumulate outside the cell nucleus. This means that TDP-43 loses its functionality, as well as ultimately leading to the death of the motor neurons.

Researchers exposed cells to stress, for example by increasing the temperature or using a chemical substance. As a result, some TDP-43 was released from the cell nucleus into the cytosol, where it accumulated in so-called stress granules. "The formation of such stress granules is a normal process and serves the cell as a temporary protective space for proteins so that they are immediately available to the cell once the stress has subsided. However, if TDP-43 is mutated, as it is in the cells of many ALS patients, the stress granules persist, increasingly solidify and ultimately damage the neurons."

The scientists successfully prevented TDP-43 from leaving the cell nucleus under stress by linking it with the cell's "roadside assistance" - a protein called SUMO - which directed TDP-43 to a cellular "mechanic", the so-called nuclear bodies. As a result, TDP-43 remains soluble, and the nuclear bodies - like a mechanic - ensure that harmful forms of TDP-43 are restored or broken down by the cellular recycling system. Insoluble protein aggregates that damage or even kill cells would therefore be prevented from forming in the first place. The team of researchers is now looking for future drug candidates in the form of chemical compounds that bring SUMO and TDP-43 together.

Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks

The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control.

We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation-ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO-ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.

Coping with the damage and dysfunction of aging imposes a staggering cost. The funds dedicated to aging research are tiny compared to the funds spent on coping with the consequences of aging, and it is still the case that little of the activity taking place in the field of aging research is focused on establishing ways to slow or reverse aging. When looking a the consequences of aging category by category, the costs remain huge. Here, for example, find an estimate of the yearly costs imposed by the various forms of dementia in the United States alone.

The total economic burden of Alzheimer's disease and related dementias in the United States will reach $781 billion this year according to a newly developed model produced as a part of the U.S. Cost of Dementia Project. An estimated 5.6 million Americans are living with dementia this year, including 5 million who are 65 and older. Medical and long-term care for patients with dementia will cost the United States $232 billion this year, including $52 billion paid out of pocket by patients and their families. More than two-thirds of the total cost of care is paid for by Medicare ($106 billion) and Medicaid ($58 billion).

Dementia's societal costs are even more staggering, the model reveals. The largest share stems from a factor often not measured in other cost estimates: The significant decline in quality of life for patients ($302 billion) and care partners ($6 billion). Lost earnings among friends and family who forego work to provide care - another measure often not captured by other estimates - total $8.2 billion. Care partners provide 6.8 billion hours of unpaid care, valued at $233 billion.

Link: https://mann.usc.edu/news/u-s-dementia-costs-to-exceed-780-billion-this-year-usc-led-research-finds/

Senescent cells accumulate with age to cause cell and tissue dysfunction, and their clearance via varied forms of senolytic treatment has been shown to produce rapid rejuvenation in animal studies. Human clinical trials have provided initially promising results. Senescent cells also serve useful purposes in regeneration from injury and suppression of cancer, when present for only a short time. Researchers here assess changes in epigenetic age produced by senolytic treatment in aged and injured muscle tissue, and note that clearance of senescent cells actually aids regeneration in old mice. The senolytic in question inhibits p53-MDM2 binding, not as well studied as BCL2 family inhibitors in the context of clearance of senescent cells, though well explored in the context of cancer.

Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl2-induced regeneration versus non-injured). Young injured mice (5-6 months) without senolytics were comparators.

DNAmAGE was decelerated by up to 68% after injury in aged muscle. DNAmAGE was modestly but further significantly decelerated by injury recovery with senolytics. ~1/4 of measured CpGs were altered by injury then recovery regardless of senolytics in aged muscle. Specific methylation changes caused by senolytics included differential regulation of Col, Hdac, Hox, and Wnt genes, which likely contributed to improved regeneration. Altered extracellular matrix remodeling using histological analysis aligned with the methylomic findings with senolytics.

Without senolytics, regeneration had a contrasting effect in young mice and tended not to influence or modestly accelerate DNAmAGE. Comparing young to old injury recovery without senolytics using methylome-transcriptome integration, we found a more coordinated molecular profile in young mice and differential regulation of genes implicated in muscle stem cell performance: Axin2, Egr1, Fzd4, Meg3, and Spry1. Muscle injury and senescent cells affect DNAmAGE and aging influences the transcriptomic-methylomic landscape after resident stem cell-driven tissue reformation. Our data have implications for understanding muscle plasticity with aging and developing therapies aimed at collagen remodeling and senescence.

Link: https://doi.org/10.1111/acel.70068

Mutational damage to nuclear DNA occurs constantly throughout life, and is suspected to contribute to degenerative aging in ways other than risk of cancer. But most mutational damage occurs in somatic cells with few replications left before the Hayflick limit, and in DNA sequences that are not used in that cell type. So how can this damage cause significant disruption of metabolism? One recent idea is that repeated activation of DNA repair processes can deplete factors necessary to maintain correct DNA structure and gene expression, producing detrimental epigenetic changes characteristic of aging. Separately, perhaps only some mutations are meaningfully harmful, those that occur in stem cells. A mutated stem cell will spread that mutation throughout a tissue as it creates a steady supply of mutated daughter somatic cells. Over time, tissues will develop a patchwork of different combinations of mutations that originally occurred in specific stem cells, creating what is known as somatic mosaicism.

Clonal hematopoiesis of indeterminate potential (CHIP) is one of the better researched manifestations of somatic mosaicism, occurring in the hematopoietic cell populations in bone marrow responsible for generating immune cells. It is known to be a risk factor for leukemia, and also correlates with other conditions, possibly because of an increased propensity for chronic inflammation on the part of the immune system as its somatic mosaicism grows. In today's open access paper, researchers report on a specific connection between the aging gut microbiome and CHIP, showing that one specific metabolite produced by microbial populations can promote the expansion of populations of potentially harmful mutated hematopoietic cells, raising the risk of a resulting leukemia.

Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1

Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary.

Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-d-glycero-β-d-manno-heptose (ADP-heptose), a metabolic specific to Gram-negative bacteria, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation.

Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.

Many disparate aspects of aging correlate with one another, emerging from the same underlying processes of cell and tissue damage. Similarly, any one specific form of age-related damage will tend to correlate with outcomes in aging regardless of whether it makes a sizable contribution to those outcomes. There are so many bidirectional connections between forms of damage, and between consequent dysfunction and forms of damage, that excess in any one aspect of aging tends to drag along the others. Nonetheless, there are cases in which one can reasonably speculate about causation in a narrow sense of one mechanism and one outcome, as the contribution is likely large enough to consider in isolation. Here is one of them, the link between levels of the metabolic waste of advanced glycation endproducts and their relation to physical frailty.

Advanced glycation endproducts (AGEs) form non-enzymatic cross-links with proteins, thereby altering the structure of extracellular matrix proteins comprising muscles and skeletal tissues. These structural changes negatively affect tissue stiffness and elasticity. Consequently, the altered physical properties of musculoskeletal tissues reduce force transmission from the muscle fibers, resulting in a decline in muscle strength and function. Additionally, AGEs bind to the receptor for AGEs (RAGE), promoting inflammatory responses and oxidative stress, which contribute to muscle cell dysfunction and the aging of muscle cells. However, AGEs accumulation is likely a consequence rather than the initial trigger of oxidative stress and inflammation. Minor but chronic oxidative stress and proinflammatory conditions create a favorable environment for the formation of AGEs, nitrosylated proteins, and lipids, which in turn propagate oxidative damage through radical chain reactions. This bidirectional relationship between oxidative stress and AGEs suggests a reinforcing cycle rather than a one-way causative mechanism

This cross-sectional correlational study included 552 community-dwelling older adults. AGE accumulation was assessed using skin autofluorescence (SAF) measured using an AGE reader. Mobility decline factors were evaluated using the sit-to-stand (STS), gait speed (4 m walk tests), single-leg stance (SLS), and Timed Up and Go (TUG) tests. A comparison of the physical function across the quartile groups revealed that the group with the highest SAF values exhibited a general decline in STS, gait speed, SLS, and TUG performance when compared with the other groups. Spearman's correlation analysis revealed that the SAF-AGEs demonstrated significant negative correlations with STS, gait speed, and SLS. Additionally, TUG showed a significant positive correlation. In conclusion, this study has demonstrated that higher SAF values were associated with decreased lower-limb strength, gait speed, and balance, thereby suggesting that SAF may be a useful screening tool for predicting mobility decline in older adults.

Link: https://doi.org/10.3390/healthcare13060613

Senolytic drugs capable of selectively destroying senescent cells in aged tissues are probably the most immediately promising of present efforts to treat aging as a medical condition. It is unfortunate that so little work presently takes place to rigorously evaluate the well established low-cost generic drug and supplement senolytics in human patients, as the animal studies suggest that they could be very beneficial. Unfortunately the high costs of running clinical trials ensure that low cost treatments receive little attention from the biotech and pharmaceutical industry. The dasatinib and quercetin combination is at least demonstrated to reduce the burden of senescent cells in humans, and is prescribed off-label by some anti-aging physicians, but large clinical trials are needed to be able to say in certainty that human use produces some degree of rejuvenation.

Aging is a multifactorial process driven by various intrinsic and extrinsic factors, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These factors are closely related to organismal aging, and research has shown that inducing them can accelerate aging, while intervening in them can slow down, halt, or even reverse the aging process.

Among these factors, cellular senescence is a key contributor to organismal aging. Targeting senescent cells (SCs) holds promise for developing novel and practical anti-aging therapies. Cellular senescence is an irreversible state of cell cycle arrest caused by various factors, such as DNA damage and telomere shortening. Additionally, the process whereby immune system function gradually declines or becomes dysregulated with human aging is known as immunosenescence. Although considerable variability in aging exists among individuals, the aging process generally involves chronic inflammation, tissue homeostasis disorders, and dysfunction of the immune system and organ functions, readily causing cardiovascular, metabolic, autoimmune, and neurodegenerative diseases associated with aging.

Existing research indicates that transplanting SCs into young mice induces bodily dysfunction, while transplanting them into aged mice exacerbates aging and increases the risk of death. This suggests that SCs accelerate organismal aging. The specific reason is that SCs release the senescence-associated secretory phenotype (SASP) into the tissue, promoting chronic inflammation and inducing senescence in surrounding tissue cells and immune cells. SCs and chronic inflammation interact and crosstalk, forming a vicious cycle of inflammation and aging. Therefore, in-depth research into the key characteristics and underlying mechanisms of cellular senescence, immunosenescence, and inflammation, identifying drug intervention targets, and developing targeted interventions can help mitigate aging and aging-related diseases, thereby promoting healthy aging in the elderly.

Link: https://doi.org/10.3390/cells14070499