Fight Aging!

The reduced intake of protein is what triggers many of the beneficial changes in cell behavior that result from calorie restriction. One of the many outcomes of calorie restriction is that some white fat tissue transitions to become beige fat via an increase the number of brown fat cells present in the tissue. Brown fat cells are involved in thermogenesis and, on balance, a greater proportion of brown fat in the body leads to incrementally better metabolic health and modestly slowed aging. Interestingly, activity in specific microbial species of the gut microbiome is necessary for the browning of white fat to take place in response to reduced protein intake, suggesting possible paths to the production of novel therapies that induce fat browning.

Interactions between diet and the gut microbiota are fundamental to metabolic health, shaping energy balance and disease susceptibility. However, the underlying mechanisms by which dietary and microbial factors converge to regulate host physiology remain unclear. Here we show that protein availability profoundly modulates the functional landscape of the gut microbiota and promotes remodelling of white adipose tissue (WAT). Specifically, low-protein diets (LPDs) robustly induce signature genes of browning in WAT to a similar extent to that seen in response to classical stimuli, such as cold exposure or β-adrenergic receptor activation.

LPD-mediated browning was markedly diminished in germ-free mice, and this defect was rescued by colonization with defined bacterial consortia made up of strains that were isolated and down-selected from the faeces of either LPD-fed mice or healthy human volunteers with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-confirmed brown- or beige-fat activity. Microbiota-induced browning was mediated both by bile acids driving the activation of the farnesoid X receptor (FXR) in adipose progenitor cells, and by nrfA-encoding commensal-derived ammonia driving the expression of fibroblast growth factor 21 (FGF21) in hepatocytes. The bile acid-FXR and ammonia-FGF21 axes both have non-redundant, essential roles in promoting WAT browning.

These findings highlight a mechanistic link between diet, gut microbial metabolism and adipose tissue remodelling, uncovering microbiota-dependent pathways by which the host responds to dietary cues.

Link: https://doi.org/10.1038/s41586-026-10205-3

Any sufficiently complex set of data that changes with age can be used to produce an aging clock, given a database of measures from people of various ages. Machine learning is applied to discover algorithmic combinations of that data that predict age. This is thought to produce outcomes that reflect biological age; a person with a predicted age higher than chronological age has a greater burden of damage and dysfunction. No clock is fully understood, in the sense that it is unknown at the time of creation as to how exactly the clock will react to a higher or lower burden of any one specific form of cell and tissue damage or consequent dysfunction in aging. This makes clocks hard to use in the way that we would like to use them, to speed up the process of evaluating potential rejuvenation therapies by providing a rapid, low cost measure of the efficacy of a given treatment.

Biological age reflects the current state of the body, considering the aspects of lifestyle, environment, and hereditary component. Currently there is no universal formula for determining it, but there are markers that can be used to calculate it. This study aims to develop and compare two models for calculating biological age based on laboratory blood tests and composition of gut microbiota.

The biochemical model of biological age uses 7 indicators and is gender-specific (general - cystatin-C, IGF-1, DHEAS, only for females - homocysteine, urea, glucose, zonulin, only for males - HbA1c, NT-proBNP, free testosterone, hs-CRP). The microbial model requires the input of percentages of 45 bacterial species as indicators of the gut microbiota. Both methods demonstrate high predictive accuracy (mean absolute error ~ 6 years, R-squared > 0.8) and the degree of agreement of assessments both with each other and with PhenoAge (correlation > 0.89).

Among the selected 45 gut bacterial species, 16 were positively associated with age. Of these, 3 species (Muribaculum intestinale, Ruminococcus albus, Ruminococcus champanellensis) can be considered "beneficial," as they are involved in acetate production, carbohydrate fermentation, and support overall microbiota and metabolic health. However, 5 other species (Catabacter hongkongensis, Clostridium saudiense, Desulfovibrio desulfuricans, Holdemanella biformis, Howardella ureilytica) are potentially pathogenic and may cause infections or contribute to inflammatory bowel disease (IBS) involving an immune component. The remaining 8 positively associated species can be classified as neutral, as they produce acetate, butyrate, and propionate, and modulate metabolic pathways.

The majority of microorganisms (29 species) exhibited a negative correlation with age, meaning their abundance decreases in older age. Among these, 7 species (Anaerobutyricum hallii, Butyricicoccus pullicaecorum, Clostridium leptum, Coprococcus comes, Eubacterium rectale, Fusicatenibacter saccharivorans, Lachnospiraceae bacterium Choco86) can be considered beneficial. They are responsible for synthesizing or fermenting various substances, support barrier function, exert anti-inflammatory effects, and reduce the risk of metabolic disorders. Conversely, only 5 species (Blautia obeum, Blautia producta, Dialister invisus, Enterocloster bolteae, Sutterella wadsworthensis) are potentially pathogenic, potentially contributing to obesity, IBS, and negatively impacting mental health. Most of the remaining age-negatively correlated species can be classified as neutral; they produce and ferment substances but under certain conditions may cause gastrointestinal disorders and metabolic disturbances.

The bacterial species used in the model collectively reflect an age-related decline in protective and metabolic functions, an increase in pro-inflammatory potential, and a disruption and impoverishment of metabolic networks.

Link: https://doi.org/10.18632/aging.206360

It is by now clear that alterations to the composition and activities of the gut microbiome affect function in the rest of the body, including the brain. The composition of the gut microbiome changes with age, a growth in populations that provoke chronic inflammation via metabolites or direct interaction with tissues, versus a reduction in the size of populations that generate beneficial metabolites that are required for normal tissue function. The research community has started to identify specific microbial species and specific metabolites associated with specific age-related conditions, and in some cases have already demonstrated the ability to restore lost function in animal studies via interventions that alter microbial population size or metabolite levels.

This research will continue. The most plausible near term interventions to emerge into widespread use are those involving probiotics. The existing probiotics industry will most likely develop a range of new products as the evidence for benefits in animal studies emerges, and do so well in advance of large human studies of efficacy. Another potentially important approach is the use of fecal microbiota transplantation from a young donor to an aged recipient, as this approach has been demonstrated to produce lasting restoration of a more youthful composition of the gut microbiome following one course of treatment, and significant health benefits in animal models. There are caveats, such as how to screen for species that can be problematic when introduced to an older individual, but these caveats seem unlikely to provoke a replacement of fecal microbiota transplantation initiatives with efforts to develop far more complex probiotic mixtures than can currently be manufactured - synthetic microbiomes in essence.

Gut-brain axis in health and brain disease

The gut-brain axis is a complex, bidirectional network of communication systems that integrates neural, endocrine, and immune pathways, as well as metabolic processes, to regulate homeostasis and maintain physiological and cognitive equilibrium. Central to this axis is the gut microbiota, which exerts a profound influence on brain function through microbial metabolites, including short-chain fatty acids, tryptophan metabolites, and bile acids. Disruption of this microbial balance, known as dysbiosis, has been implicated in the onset and progression of major neuropsychiatric and neurodegenerative disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD).

Probiotics, which are "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host," have shown considerable promise in improving mental health symptoms. Findings suggest that specific species within the Lactobacillus and Bifidobacterium genera exert the most significant impact on alleviating mental health symptoms, particularly those associated with anxiety and depressive disorders. Furthermore, studies suggest that probiotics may enhance cognitive function and potentially slow the progression of AD. In addition, they have been shown to reduce neuroinflammation and influence both blood-brain barrier integrity and neurotransmitter regulation in PD.

Fecal microbiota transplantation (FMT) is a clinical procedure in which fecal material from a healthy donor is introduced into a recipient to help reestablish a balanced and healthy gut microbiota. The primary goal of FMT is to directly alter the recipient's gut microbial composition, thereby conferring a health benefit. This approach has gained recognition for its effectiveness in treating recurrent Clostridium difficile infections. However, its potential applications extend to a range of other conditions, including those affecting the gut-brain axis. By restoring microbial balance in the gut, FMT may lead to improvements in both gastrointestinal and brain health.

Emerging studies have focused on the application of FMT as a potential treatment for various neurodegenerative diseases. For example, preclinical studies conducted in mouse models of PD have shown that FMT from healthy donors can lead to improvements in motor function and a reduction in neuroinflammation, suggesting a promising therapeutic avenue. Animal studies in models of AD have yielded varied results, with some showing improvements in behavioral measures and reductions in amyloid plaques and neuroinflammation following FMT. Although several clinical trials have been completed, ongoing studies continue to investigate the efficacy and safety of FMT in various neurological conditions. For example, clinical studies examining the effects of FMT in patients with PD and MS have shown improvements in both motor and non-motor symptoms.

In summary, early results for FMT are encouraging, but the variability in outcomes and the overall limited data underscore the need for more rigorous and extensive clinical trials. Further clinical trials are crucial for identifying the specific conditions and patient populations that are most likely to benefit from FMT. Likewise, the current body of data on the use of FMT for treating most neurodegenerative disorders remains limited. To definitively establish the efficacy and safety of FMT in this context, large-scale, well-controlled clinical trials are necessary.

Can neurodegenerative conditions be effectively treated by only changing the behavior of cells in the brain? That is an interesting question, particularly given the sizable research focus placed on epigenetic reprogramming in recent years. On the one hand there are clearly issues that occur outside cells, such as formation of aggregates or chemical changes in the extracellular matrix. There are other issues inside cells that no amount of altered cell behavior can fix, such as mutational damage to nuclear DNA. On the other hand, a variety of approaches that focus on altering epigenetic control of nuclear DNA structure and gene expression have led to improved function in animal models of neurodegenerative conditions, such as the example shown here.

Emerging evidence implicates epigenetic dysregulation as a central contributor to the pathogenesis of neurodegenerative diseases. Unlike irreversible genetic mutations, epigenetic marks such as histone methylation are dynamic and potentially reversible, making them attractive therapeutic targets. In particular, two histone methyltransferases (HMTs), GLP (EHMT1) and G9a (EHMT2), have attracted increasing attention due to their role in catalyzing the dimethylation of histone H3 at lysine 9 (H3K9me2), a repressive mark associated with transcriptional silencing. G9a/GLP-mediated epigenetic repression has been shown to influence critical processes such as neuronal development, synaptic plasticity, and memory consolidation.

Intriguingly, an aberrant upregulation of G9a activity has been linked to increased oxidative stress, neuroinflammation, and neuronal dysfunction, which are hallmarks of Alzheimer's disease (AD) and other neurodegenerative conditions. However, translating G9a inhibition into a viable therapeutic strategy has proven to be difficult. Most known G9a inhibitors, including BIX-01294, UNC0638, and A-366, suffer from poor selectivity, high cytotoxicity, and inadequate blood-brain barrier (BBB) permeability, which are limitations that are less critical in oncology but represent major obstacles for central nervous system (CNS) applications. Consequently, the therapeutic potential of G9a inhibition in neurodegeneration remains largely untapped.

Here, we report the discovery and characterization of FLAV-27, a brain-penetrant, subnanomolar inhibitor of G9a with exceptional selectivity for G9a over the closely related GLP and other methyltransferases. Unlike previously reported G9a inhibitors, FLAV-27 exhibits favorable CNS drug-like properties, including excellent BBB permeability and a strong safety profile. FLAV-27 reduces amyloid beta (Aβ) and phosphorylated tau aggregation and restores neuritic complexity in vitro. In Caenorhabditis elegans, it improves mobility, lifespan, and mitochondrial respiration. In mouse models of both late-onset AD (SAMP8) and early-onset AD (5xFAD), FLAV-27 rescues memory performance, social behavior, and synaptic structure.

Link: https://doi.org/10.1016/j.ymthe.2025.12.038

Here, researchers review what is known of the aging of heart muscle, and what might be done about it. The heart is more vital to life than any other specific muscle tissue, and thus the panoply of late life dysfunctions and other manifestations of aging are well studied in this organ. Connecting the underlying mechanisms of aging to observed changes in function remains a work in progress, and will likely only advance significantly as therapies to address specific mechanisms of aging are developed and deployed. Consider the accelerated pace at which the understanding of cellular senescence in aging has advanced since the the first senolytic drugs were demonstrated in animal studies fifteen years ago, for example.

The heart, a vital organ, works without interruption and constantly adjusts to the ever-changing demands on our body. It adapts to physiological and pathological changes, including exercise and emotional state, as well as metabolic, respiratory, and vascular abnormalities. The pumping action of the heart is determined by the health of the myocardium, which undergoes changes with ageing that are both under-investigated and incompletely understood, potentially impacting our approach to pathological conditions. Here, the alterations in cellular, tissue, and gross physiological function of the heart with age are discussed.

At the molecular level, non-coding RNAs influence cellular senescence, and extracellular vesicles induce fibrosis through matrix remodelling. Mitochondrial dysfunction and altered fatty acid oxidation reduce cellular energetics, whilst accumulation of reactive oxygen species and steatosis, as well as telomere shortening coupled with reduced autophagy, limit the myocardium's regenerative capability. Loss of cardiomyocytes, combined with senescence, requires compensatory hypertrophy, inducing myocardial stiffness and altered muscle function. In addition to these direct alterations in myocardial characteristics with ageing, other factors that can affect the myocardium indirectly are addressed, including valve calcification, resulting in regurgitation and/or stenosis; vascular abnormalities, reducing compliance and exacerbating hypertension; fibrosis leading to cardiac arrhythmias; and autonomic dysregulation, reducing cardiac adaptability.

Finally, potential modulation of cardiac ageing is discussed whilst also addressing which senescent modifications should be considered as ageing-related physiological changes of the myocardium. A better understanding of myocardial ageing will differentiate physiological changes from early, preventable, and reversible pathological changes, consequently helping to optimize management of individuals with or at risk of myocardial disease by taking into account diverse trajectories of myocardial ageing.

Link: https://doi.org/10.1093/eurheartj/ehag095

Lipid metabolism is a complex area of study. Any given lipid can be transformed into scores of other molecules with quite different properties, and the scientific community's understanding of what each of these lipid products is doing in our biology is far from complete. Even just looking at cholesterol alone quickly becomes a sizable undertaking; if you were under the impression that researchers know exactly what every modified form of cholesterol or transformed product of cholesterol does in detail, you may be surprised to see just how much is left to catalog, map, and comprehend. Cellular biochemistry is very complicated, and there are only so many researchers and only so much time.

So science tends to proceed by establishing points of focus on specific molecules or specific interactions, and incrementally mapping nearby molecules and interactions. The further away from these points of focus one moves, the less complete the understanding. One of the scientific programs first started in the SENS Research Foundation has led to a growing point of focus on 7-ketocholesterol and its effects. 7-ketocholesterol is a oxidized form of cholesterol known to be toxic and thought to have no useful purpose in metabolism. Evidence points to a role for 7-ketocholesterol in atherosclerosis and a range of other conditions, and thus a company, Cyclarity Therapeutics, was formed to develop therapies to clear 7-ketocholesterol from tissues. That program is currently in its early clinical stages.

The scientific process doesn't stop at "7-ketocholesterol is toxic, and thus we should clear it from tissues to improve health", however. 7-ketocholesterol exists in the sizable space of alterations to cholesterol and products of cholesterol. Many of the transformations that can be applied to cholesterol can also be applied to 7-ketocholesterol. Do researchers have a good idea as to what these further derivatives of 7-ketocholesterol are doing to cells? Not really, but the point of focus established on 7-ketocholesterol will expand slowly to these products and their effects.

Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease

Cholesterol is a vital lipid molecule essential for cellular structure and function. Oxidation of cholesterol leads to the formation of biologically active oxidized cholesterols known as oxysterols. Among oxysterols, 7-ketocholesterol (7KC) is a key product, primarily formed by oxidation at the C7 position of the cholesterol molecule. 7KC is notably elevated in conditions such as hypercholesterolemia and within atherosclerotic lesions, often at higher concentrations than other oxysterols. Growing research highlights 7KC's significant involvement in the development and progression of a wide array of diseases and aging cells, where it is widely recognized for its cytotoxic, pro-inflammatory, and pro-apoptotic properties, positioning it as a critical factor in pathophysiology.

While 7KC has traditionally been studied as an end-product of cholesterol oxidation, increasing evidence suggests that it also serves as a precursor or co-product in the generation of more structurally complex oxysterols bearing multiple oxidative modifications. Among these, double-substituted oxysterols such as 7-keto-25-hydroxycholesterol (7-keto-25-OHC) and 7-keto-27-hydroxycholesterol (7-keto-27-OHC) represent an underexplored but potentially significant class of downstream metabolites.

The presence of both a C7 ketone and a side-chain hydroxyl group profoundly alters sterol polarity, membrane partitioning, and reactivity. Compared with mono-substituted oxysterols, double-substituted species are expected to exhibit reduced membrane affinity, enhanced aqueous solubility, and increased accessibility to intracellular targets. These physicochemical properties may influence their transport, cellular distribution, and rate of further metabolism or clearance. Moreover, the coexistence of two oxidative modifications may amplify biological activity, either through additive effects or through the emergence of distinct signaling properties not observed with single modifications. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.

In recent years, researchers have noted that circular RNAs accumulate in cells in old age. It has been unclear as to whether this is only a marker of dysfunction or a change that in and of itself causes further downstream issues. The fastest way to obtain an answer to this sort of question is to repair the problem and see what happens. Researchers here identify that levels of RNASEK, a protein responsible for breaking down circular RNA, decline with age, allowing circular RNA levels to rise. Forcing increased expression of RNASEK slows aging and extends life, which strongly suggests that circular RNAs are harmful in some way. The researchers suggest that harms result from circular RNA aggregation in the cell, but further research is needed on this topic.

Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. Using Caenorhabditis elegans, a short-lived roundworm widely used in aging research, researchers first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.

Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.

The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. When RNASEK is deficient and circular RNA accumulates, "stress granules" form abnormally inside the cell, which can impair cellular functions and accelerate aging. RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=59490

The thymus, a small organ near the heart, is important to the function of the adaptive immune system. Thymocytes migrate from bone marrow to the thymus where they mature into T cells. The thymus atrophies with age, and the loss of active thymic tissue reduces the pace at which new T cells are produced. This leads to an adaptive immune system that, lacking sufficient replacements, is ever more populated with senescent, exhausted, and malfunctioning T cells. That this is an important contribution to the loss of immune function that occurs in later life is illustrated by the data presented here, in which researchers correlate degree of thymic atrophy with mortality and incidence of age-related disease in a large human study population.

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581).

In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex, and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity, and physical activity.

Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Link: https://doi.org/10.1038/s41586-026-10242-y

Aging clocks are produced from machine learning strategies applied to databases of biological data, typically omics data of various sorts, obtained from people of various ages. Patterns that change with age can be identified and an algorithm defined to take any other person's data and predict their age based on comparisons to the reference database. Whether the predicted age is higher or lower than chronological age says something about the individual's biological age, the accumulation of damage and dysfunction in tissues and systems.

The biggest challenge in using these clocks is that the method of production tells us nothing about how exactly the data used in the algorithm is connected to particular processes or dysfunctions of aging. Thus it is hard to trust the outcome, particularly if the intent is to use clock measures to assess potential interventions that might slow or reverse aspects of aging. The clock may underestimate outcomes, overestimate outcomes, or just produce completely irrelevant results for any specific individual, and we have no good way of knowing which of these is the case.

This issue is well understood by the research community, and there are a number of different approaches that might be taken to improve the situation. Researchers have, for example, built clocks based on clinical measures such as blood counts and inflammatory cytokine levels rather than omics data. This is still not ideal, as the details of the connection between clinical measures and mechanisms of aging remain somewhat nebulous in most cases, but one can at least theorize on what is going on under the hood to a greater degree. Another, much harder approach is to start over and develop the means of building new omics clocks that are, from the ground up, manufactured with the intent of providing greater insight into underlying mechanisms. That work continues, but research groups are producing incremental progress along the way, such as the interpretable clock reported in today's open access paper.

DeepStrataAge: an interpretable deep-learning clock that reveals stage- and sex-divergent DNA methylation aging dynamics

Aging is the strongest risk factor for chronic diseases such as cardiovascular disease, Alzheimer's, and cancer. DNA methylation (DNAm) clocks offer a promising measure of biological age, but most rely on linear models that miss non-linear dynamics and CpG interactions. To address this, we developed a deep neural network (DNN)-based DNAm clock trained on 29,167 samples profiled on Illumina EPIC v1.0 and v2.0 arrays. Using 12,234 CpGs selected through sex- and age-stratified correlations, our model achieved high accuracy (1.89 years) and outperformed published deep learning and elastic net based epigenetic clocks in a separate validation cohort.

Using Shapley Additive Explanations (SHAP), we further uncovered phase-structured, wave-like dynamics in age-influential CpGs: an early-life module, a midlife transition, and late-life remodeling, with distinct timings by sex. These epigenetic waves cohere with non-linear, multi-omic "aging waves" reported in proteomics and longitudinal omics. SHAP further enabled interpretable CpG attribution, revealing structured, sex-specific aging phases: early-life male clocks involved developmental pathways, while female clocks emphasized cytoskeletal regulation; late-life divergence included immune activation in males and transcriptional remodeling in females. Our framework thus unites accuracy with mechanistic interpretability, revealing sex-specific windows when molecular aging reconfigures most rapidly.

The gut microbiome changes in composition with age in ways that harm tissue function and provoke chronic inflammation. Among the potential causes of this shift in composition is the age-related dysfunction of the immune system, allowing growth in microbial populations that should be kept in check. Researchers here work in fruit flies to identify a regulatory interaction that can be targeted to restore some of that lost immune function. It remains to be seen as to how applicable this is to the analogous situation in the mammalian immune system and gut microbiome, but one can hope.

The maintenance of immune homeostasis is critical for tissue health and longevity, yet the regulatory mechanisms linking immune modulation to aging remain poorly understood. Here we found that the transcription factor cAMP response element-binding protein (CREB), activated by JNK signaling in aging guts, transcriptionally suppresses peptidoglycan recognition protein SC2 (PGRP-SC2) - a homolog of mammalian anti-inflammatory PGLYRP1-4 with amidase activity. 16S rRNA sequencing revealed that CREB modulates not only microbial load but also microbiota composition. Elevated CREB activity decreased the Firmicutes/Bacteroidetes (F/B) ratio - a hallmark of age-associated dysbiosis in animals.

Genetic enhancement of PGRP-SC2 rescues age-related gut hyperplasia, microbiota imbalance, and lifespan shortening induced by overactivation of CREB or its coactivator CRTC. Notably, CREB's regulation of PGRP-SC2 operates independently of canonical immune pathways such as Imd/Relish, revealing a previously unrecognized layer of immune modulation. Our findings establish CREB as a central player in age-associated immune dysregulation and propose targeting the CREB-PGRP-SC2 axis as a potential therapeutic strategy for mitigating gut aging and its systemic consequences.

Link: https://doi.org/10.1038/s41420-026-02955-w

Quality of sleep tends to decline with age for reasons both physical and neurological; sleep apnea is a concern for many older people. A broad body of literature connects sleep issues with risk of neurodegenerative conditions. Thus researchers can plausibly expect to take sleep assessment data from a population of people at various ages, and employ machine learning strategies to develop an aging clock derived from that data. Any sufficiently complex data set that changes with age can be used in this way. Researchers here report on an implementation of this approach to measuring the aging of the brain, and produce an aging clock that can predict dementia risk based on sleep electroencephalography results recorded during a sleep study.

Sleep disturbances are increasingly recognized as early indicators and potential modifiable risk factors for dementia. However, the macrolevel sleep architecture has shown inconsistent associations with cognitive impairment and incident dementia. These broad sleep metrics do not fully capture the complex and multidimensional nature of sleep physiology. In contrast, the microstructure of sleep electroencephalography (EEG) directly reflects the neural processes with explicit functional implications. To capture these complex patterns, we developed a sleep EEG-based brain age using a novel, interpretable machine learning approach that integrates multiple age-dependent EEG microstructures into a single agelike number. The difference between brain age and chronological age is termed the brain age index (BAI).

For this individual participant data meta-analysis, sleep study data from 5 community-based longitudinal cohorts were pooled. These cohorts included the Multi-Ethnic Study of Atherosclerosis (MESA; 2010-2013), the Atherosclerosis Risk in Communities (ARIC) study (1987-1989), the Framingham Heart Study-Offspring Study (FHS-OS; 1995-1998), the Osteoporotic Fractures in Men Study (MrOS; 2003-2005), and the Study of Osteoporotic Fractures (SOF; 2002-2004). This meta-analysis included 7,105 participants.

The median time to dementia was 4.8 years in the MESA cohort (n = 119 [6.6%]), 16.9 years in the ARIC cohort (n = 354 [19.7%]), 13.1 years in the FHS-OS cohort (n = 59 [9.6%]), 3.6 years in the MrOS cohort (n = 470 [17.8%]), and 4.6 years in the SOF cohort (n = 86 [34.3%]). Across the cohorts, each 10-year increase in BAI was associated with a 39% higher risk of incident dementia (hazard ratio [HR] 1.39) after adjustment for covariates. These associations remained after additional adjustment for comorbidities and apnea-hypopnea index scores (HR 1.31) and apolipoprotein E ε4 (HR 1.22), and they were consistent across sex and age groups.

Link: https://doi.org/10.1001/jamanetworkopen.2026.1521

Researchers have identified many contributing issues leading to the characteristic loss of muscle mass and strength that takes place with age. Arguably the central problems are (a) the disruptions of cell behavior caused by chronic inflammation, (b) damage to neuromuscular junctions, depriving muscle tissue of signals it relies upon for normal maintenance to take place, and (c) loss of muscle stem cell activity, and thus a reduced supply of somatic muscle cells to replace losses. These central problems likely interact with one another, but in principle could be addressed distinctly to produce benefits in patients.

Past studies have shown, rather convincingly, that muscle stem cells in older individuals retain their function when moved from an old environment to a young environment. The problem is not so much damage to these cell populations, but rather their growing lack of activity. Stem cells spend most of their time quiescent, only activating to produce daughter somatic cells when needed. With age, activation of stem cells diminishes for reasons that are only partially explored, and may differ considerably in their details from tissue to tissue. In principle, a greater knowledge and control over stem cell activation could be employed to reduce the age-related loss of muscle tissue, but that requires progress in uncovering specifics of the regulatory systems involved that might be targeted by novel therapeutics.

MG53 in Early Skeletal Muscle Stem Cell Activation: Implications for Aged Muscle Regeneration

Skeletal muscle regeneration declines with age despite the persistence of satellite cells (muscle stem cells, MuSCs), suggesting that regenerative impairment reflects functional dysregulation rather than MuSC depletion. Increasing evidence identifies early MuSC activation during the immediate post-injury period as a stress-sensitive, rate-limiting transition that is particularly vulnerable in aged muscle. Aged MuSCs exhibit elevated stress responses and reduced membrane remodeling capacity, accompanied by weakened activation-associated transcriptional induction. In contrast, proliferative and differentiation programs remain largely intact once activation is successfully initiated.

These findings underscore that impaired coordination during early activation contributes to long-term regenerative decline in aging. Within this framework, MG53 (tripartite motif-containing protein 72, TRIM72), a muscle-enriched TRIM family E3 ubiquitin ligase originally identified as a mediator of sarcolemmal membrane repair, may also function as a stress-responsive regulator that stabilizes the early activation environment. Rather than directly determining cell fate, MG53 is proposed to facilitate activation by mitigating stress-associated membrane disruption and maintaining programmatic coordination under age-related physiological constraints.

However, direct experimental evidence defining the role of MG53 in the early activation of aged MuSCs remains limited. Current data primarily support its functions in membrane stabilization, oxidative stress mitigation, and inflammatory modulation. Whether these stress-buffering properties directly influence the early activation transition in aging muscle has not yet been formally tested. In this review, we suggest that MG53 may contribute to the regulation of early MuSC activation under conditions of elevated cellular stress in aged muscle. Clarifying this potential role represents an important direction for future mechanistic investigation.

It has been fifteen years since the first compelling demonstration of clearance of senescent cells in mice. That study paved the way for the transformation of the research community into one convinced of the relevance of cellular senescence to degenerative aging. It also helped to change the culture of aging research more generally, one of the important contributions to a shift in attitudes that has led to a research and development community that understands the treatment of aging as a medical condition to be a practical, desirable goal. Here, discuss the role of cellular senescence in muscle aging specifically; how it contributes to harm and lost function, and what might be done about it.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation.

Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Link: https://doi.org/10.3803/EnM.2025.2816

There is a reasonable consensus in the research community on the broad categories of issue that lead to and are associated with the aging of the immune system. One can start by dividing immune aging into immunosenescence, a loss of capacity, versus inflammaging, a continual state of unresolved inflammatory signaling, and look at the various contributions to each state, for example. This paper is chiefly interesting for the attempt to propose classes of intervention to address immune aging based on the categorization of issues provided. This would not have been the case twenty years ago; the paper would have outlined what was known of immune aging and possible causes and then stopped. It is a reminder that we now live in an era in which the treatment of aging as a medical condition is widely accepted as an aspirational goal for the life sciences.

Immune aging is best understood not as a collection of isolated defects, but as a complex, interconnected reconfiguration of immune and tissue networks that alters how the body responds to internal and external stressors. Aging causes coordinated changes in innate and adaptive immunity, metabolic pathways, and inter-organ communication, creating a web of interactions whose emergent properties differ fundamentally from those of younger systems. Therapeutic targeting of immune aging aims to rebalance dysregulated inflammatory networks, restore immune adaptability, and improve tissue repair capacity. Current approaches range from mechanistically targeted pharmacological agents to regenerative, metabolic, lifestyle, and precision strategies. Evidence strength varies considerably, with some interventions supported by early clinical data and others remaining primarily experimental.

Interventions directed at fundamental drivers of immune aging, including chronic inflammatory signaling and cellular senescence, represent the most mechanistically advanced therapeutic class. Modulation of the mechanistic target of rapamycin (mTOR) pathway - through agents such as rapamycin and its analogs - has been shown to recalibrate immune metabolism, attenuate excessive inflammatory signaling, mitigate components of the senescence-associated secretory phenotype (SASP), and enhance antiviral responses in older adults, with early-phase clinical trials providing supportive evidence of immunological benefit. However, potential risks include metabolic dysregulation, impaired wound healing, and dose-dependent immunosuppression, emphasizing the need for intermittent or low-dose regimens.

Targeting intracellular inflammatory signaling represents a complementary strategy to rebalance immune network activity. Inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) can restore macrophage functionality, enhance efferocytosis, and promote pro-resolving phenotypes in aging models. While mechanistically attractive, long-term systemic kinase inhibition may carry risks related to host defense impairment and unintended metabolic effects.

Cellular and regenerative interventions aim to restore immune architecture and adaptive capacity. Mesenchymal stem cells (MSCs)-based therapies exhibit immunomodulatory and tissue-repair properties, with encouraging preclinical and early clinical data suggesting benefits for inflammatory dysregulation and impaired regeneration. However, heterogeneity in cell preparations, uncertain durability of effects, and potential tumor-promoting signals remain key concerns. Reconstitution of adaptive immune output through thymic and hematopoietic rejuvenation represents an emerging but strategically important avenue. Beyond IL-7 supplementation, several molecular regulators are under investigation. Forkhead box N1 (FOXN1)-associated pathways, keratinocyte growth factor (KGF), and fibroblast growth factor (FGF) 21 contribute to thymic epithelial integrity and naive T-cell production, with preclinical evidence indicating delayed thymic involution and improved immune function.

Modulation of the gut microbiome through dietary fiber, prebiotics, probiotics, and microbiome-directed therapies can influence systemic inflammation and immune regulation. Diets rich in fiber and prebiotics, targeted probiotic supplementation, and microbiome-directed interventions can enhance gut barrier integrity, promote beneficial microbial taxa, and reduce translocation-induced inflammaging, thereby influencing systemic immune function and inflammatory set points. Improvements in barrier integrity and microbial metabolite production may reduce translocation-driven inflammatory activation. While mechanistically promising and supported by observational studies, variability between individuals and limited standardized clinical trials currently restrict therapeutic generalization.

Link: https://doi.org/10.3390/cells15050414

Myostatin is a circulating inhibitor of muscle growth. It has been an area of research interest for some time, long enough for myostatin loss of function mutants to have been identified or engineered in a range of mammalian species: mice, dogs, cows, and so forth. Complete loss of function in the myostatin gene throughout life is accompanied by exceptional muscle growth and strength, alongside a lesser amount of visceral fat tissue. All told it seems a benefit with little to no downside.

Since muscle mass and strength is lost with advancing age, there have been efforts to develop therapies based on inhibition of myostatin, such as via monoclonal antibodies. The popularity of GLP-1 receptor agonist drugs that produce loss of muscle mass in addition to visceral fat tissue by reducing calorie intake has resulted in an even greater pharmaceutical industry interest in developing ways to avoid this loss of muscle.

There are many possible points of intervention beyond direct inhibition of myostatin expression, circulating levels, or activity. One possibility presently in clinical trials is the inhibition of myostatin receptors. Another example is the upregulation of follistatin, a circulating molecule that acts in opposition to myostatin, and comes with a similar body of work in mouse studies, where genetic engineering or gene therapies have produced heavily muscled mice. A number of therapies claim to improve follistatin levels, and follistatin gene therapies are now used to some degree in the medical tourism industry. Data on human efficacy is thin to non-existent, however.

Meanwhile, research into myostatin continues as the range of possible muscle growth therapies expands. Today's open access paper is a very interesting tour of what can be learned from the very large genetic databases that now exist. Only the one convincing human myostatin mutant with very evident effects is known to the scientific community, but these large databases allow the discovery of other individuals with mutations that produce a weaker loss of function in the myostatin gene. Since genetic data is coupled with a large amount of other health data in the UK Biobank, one can actually map mutation to muscle strength and other characteristics known to be affected by myostatin.

Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity

Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health.

Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%.

Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.