Longevity Papers

During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of Alu-driven molecular changes remains to be conducted, and Alu's potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an AluJb transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that Alu transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.

Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs. We identified 119 genetic loci associated with organ aging, including 27 shared across multiple organs, and prioritized 554 risk genes involved in organ-relevant biological pathways, such as T cell-mediated immunity in immune aging. Causal inference analyses indicated that accelerated heart and muscle aging increase the risk of heart failure, whereas kidney aging contributes to hypertension. Moreover, smoking initiation was positively linked to the aging of the lung, intestine, kidney, and stomach. These findings establish a genetic foundation for understanding organ-specific aging and provide insights for promoting healthy longevity.

Age-related diseases often show sex differences, yet their molecular bases remain unclear. Mouse models suggest that aging disrupts X chromosome inactivation (XCI) in females. Here, we test whether this phenomenon extends to humans by analyzing allele-specific gene expression derived from: i) bulk RNAseq data from three females with non-mosaic XCI; and ii) single cell RNAseq data from the immune cells of hundreds of females. We find that age-dependent escape from XCI also occurs in human females, particularly among: i) genes at the distal (Xq) end of the X chromosome; and ii) those involved in sister chromatid cohesion, gene regulation, and glutamate signaling. These findings implicate reactivation of the inactive X in human female-specific aging processes and highlight potential mechanisms underlying sex-biased outcomes in age-related diseases.

Local brain age (LBA) is a regional metric of brain aging that offers a spatially resolved alternative to global brain age, but whose genetic basis is unexplored. This study reports the first genome-wide association study of cortical LBA, as estimated by a deep neural network from the T

Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.

Cellular senescence contributes to age-related neurodegeneration, yet its manifestation varies across brain cell types and senescence-inducing stressors. Here, we investigated senescence hallmarks in five human brain cell lines - astrocytes, endothelial cells, microglia, oligodendrocytes, and dopaminergic-like neurons - using chronic 5-Bromodeoxyuridine treatment and validated our findings in primary cells and alternative toxin-induced models. Principal component analysis and transcriptional network inference identified both common and cell-type-specific senescence-associated transcriptional regulators (SATRs). Functional studies of TFAP4, a key SATR, revealed its role in modulating senescence phenotypes in a cell-type-dependent manner, with decreased TFAP4 expression observed in Parkinson's Disease patient tissue and in vivo models. These results delineate distinct senescence profiles across brain cell types and highlight transcriptional regulators that may underlie senescence heterogeneity, offering insights into targeted therapeutic strategies for neurodegenerative diseases.

Biological aging clocks capture heterogeneous rates of aging in individuals and transform current medical practice toward translational preventive medicine. Here, we developed a clinical aging clock based on routine blood biochemistry markers from 59,741 healthy samples in a Southeast Asian cohort. We established a novel correction method to address the systematic skew in predictions from first-generation clocks. This correction improved the accuracy of age-acceleration predictions for disease risks and enhanced interpretability for disease-driven and organ-specific aging processes without relying on mortality data. Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed NHE1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits HDAC activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.

Enrichment analysis is a cornerstone of \"omics\" data interpretation, enabling researchers to connect analysis results to biological processes and generate testable hypotheses. While well-established tools exist for transcriptomics and other omics layers, the development of robust enrichment resources for metabolomics remains comparatively limited. To address this gap, we developed hypeR-GEM, a methodology and associated R package that adapts gene set enrichment analysis to metabolomics. hypeR-GEM leverages genome-scale metabolic models (GEMs) to infer reaction-based links between metabolites and enzyme-coding genes, enabling the mapping of metabolite signatures to gene signatures and their subsequent annotation via gene set enrichment analysis. We validated hypeR-GEM using paired metabolomics-proteomics and metabolomics-transcriptomics datasets by assessing whether genes mapped from metabolites significantly overlapped with differentially expressed proteins or transcripts. We further evaluated whether pathways enriched via hypeR-GEM-mapped genes corresponded to those derived from paired proteomic or transcriptomic data. In most datasets analyzed, both the predicted enzyme-coding genes and the associated enriched pathways showed significant concordance with independently derived omics signatures, supporting the utility and robustness of hypeR-GEM. Finally, we applied hypeR-GEM to the analysis of age-associated metabolic signatures from the New England Centenarian Study. The results revealed consistent enrichment of lipid-related pathways, aligning with the well-established role of lipid metabolism in aging, and highlighted additional pathways not captured in the metabolites\' annotation, demonstrating hypeR-GEM\'s practical utility in a real-world use case.

Cross-sectional brain age models have demonstrated high accuracy and reliability for predicting chronological age based on structural brain features derived from single MRI scans. However, these models cannot separate baseline variation from true aging-related changes or noise. Longitudinal models address this limitation by predicting inter-scan intervals from paired MRI scans, controlling for baseline factors through repeated measurements. Using OASIS-3 data, we compare a cross-sectional 3D CNN against three longitudinal architectures for predicting inter-scan intervals: LILAC (Siamese neural network), LILAC+ (enhanced Siamese network with multi-layer perceptron), and AM (variational autoencoder). Longitudinal models substantially outperformed the cross-sectional approach, with LILAC+ achieving best performance (MSE = 1.97 years^2, MAE = 0.99 years, r = 0.86, R^2 = 0.71). Our results suggest that direct modeling of longitudinal change is more effective at capturing individual aging trajectories than deriving intervals from cross-sectional predictions.

Senescent cells are characterized by the expression of the cell cycle inhibitor and biomarker of aging, p16INK4A, and the capacity to modify the microenvironment through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in physiological and pathological conditions, including aging. In spite of this, fibroblasts ectopically expressing p16INK4A do not release a SASP nor communicate with the microenvironment. Here, we find that human primary fibroblasts expressing p16INK4A release more small extracellular vesicles (sEV) as part of the SASP than proliferating cells. In addition, we show that sEV isolated from p16INK4A cells are able to mediate paracrine senescence by inducing a growth arrest and DNA damage response in proliferating cells albeit not stimulating the expression of IL-8. Furthermore, we show the transmission of paracrine senescence via sEV is conserved in two cellular models of ageing: expression of progerin, mimicking an accelerated form of ageing, and inducing telomere shortening using a dominant negative mutant. Importantly, sEV isolated from fibroblasts derived from old donors also induce paracrine senescence in fibroblasts derived from young donors. In conclusion, our data indicate that sEV released by senescent and aging cells are an important mechanism of intercellular communication and could potentially explain tissue dysfunction in aging.

The human utricle is a vestibular organ essential for balance, a function that declines with age. With the aging population projected to double to 2 billion by 2050 and no pharmaceutical or biological treatments available, balance disorders represent a significant unmet medical need. The utricle is composed of sensory and non-sensory cells, which are closely related. Non-sensory cells have limited capacity to regenerate sensory cells and, therefore, are a relevant therapeutic target. In this work, we profile the cellular and transcriptional landscape of the adult human utricle and its early response to ototoxic damage using bulk and single-cell RNA-sequencing of patient-derived samples. We identify six transcriptionally distinct non-sensory cell types, including a previously uncharacterized supporting cell-like population, demonstrating utricular heterogeneity. Following aminoglycoside-induced damage, we detect early transcriptional changes consistent with a capacity to respond to ototoxic damage within 24 hours and potentially initiate a regenerative response via an early-responding cell population, providing a foundation for regenerative strategies for balance recovery.

Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using SUCNR1

Organ shortage remains a major barrier in treating end-stage organ failure, with many patients dying while waiting or becoming medically unfit by the time an organ is offered. A substantial number of organs, particularly from older donors, remain unused due to concerns over age-related decline in quality. This review highlights emerging strategies to rejuvenate and optimize such organs by mitigating ischemia-reperfusion injury and reducing age-related immunogenicity. Advances in organ preservation, perfusion technologies, and novel therapies - including senotherapeutics, anti-inflammatory agents, and stem cell treatments - show promise in improving graft viability and bridging the gap between organ supply and demand.

DNA methylation-based aging clocks capture biological aging processes and may improve cardiovascular risk prognostication. However, evidence about epigenetic aging clocks, incident outcomes, and interactions with clinical biomarkers such as coronary artery calcium (CAC) in diverse cohorts are limited.

Background: Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a key contributor to aging-associated skeletal muscle degeneration and dysfunction. However, the interactive effects of aging, sex, and exercise modality on ferroptosis regulatory markers at the histological, protein, and gene expression levels remain poorly understood. Methods: Male (n = 23) and female (n = 23) mice aged 7 (young) and 17 (aged) months were assigned to sedentary control, voluntary wheel running, or forced treadmill exercise. Ferroptosis in the quadriceps muscle was assessed using histological markers (e.g., fibrosis, Fe3+; accumulation, 4-HNE, MDA), protein-level markers (e.g., GPX4, SLC7A11, p-AMPK, MDA, GSH/GSSG), and gene expression markers (e.g., SLC7A11, GSS, ACSL4, POR). Results: Aging significantly elevated histological indicators of ferroptosis, fibrosis, lipid peroxidation, and iron overload, regardless of sex. At the protein and gene levels, sex-dependent differences were evident: aged females exhibited lower MDA and GSSG levels and upregulation of antioxidant-related genes, compared with aged males. Both exercise interventions modulated ferroptosis markers, with forced exercise exerting more pronounced effects than voluntary exercise. Notably, aged females demonstrated the most substantial reductions in ferroptosis-related markers in response to forced exercise, indicating a significant sex-by-exercise interaction. Conclusion: Aging markedly increases ferroptosis-related changes in skeletal muscle, with partial sex-specific differences at the molecular level. Forced exercise provides more robust regulatory effect against ferroptosis than voluntary exercise, especially in aged females. These findings underscore the therapeutic potential of sex-specific, targeted exercise interventions for mitigating ferroptosis-mediated muscle deterioration during aging.

Three categories of explanations exist for why we age: mechanistic theories, which omit reference to evolutionary forces; weakening force of selection theories, which posit that barriers exist that prevent evolutionary forces from optimising fitness in ageing; and optimisation theories, which posit that evolutionary forces actually select for ageing under the constraints that exist due to limited energy and other resources. We now have a broad data set of observed features of ageing against which these categories of theories can be tested, including results of interventions like caloric restriction, features of long-lived organisms, the existence of mortality rate plateaus, longevity of eusocial insect queens, and the malleability of lifespan. Optimisation theories are the only ones that fit all the observed data. Moreover, this category of theory makes a very ordinary claim, consistent with significant other data: evolution by natural selection is operating in ageing. It is actually quite extraordinary, either implicitly or explicitly, to claim that natural selection fails to operate, as the other categories of theories do. A key prediction of optimisation theories that differs from other theories is that mutations that extend lifespan should generally reduce fitness under natural conditions. Contrary to some suggestions in the literature, to date the available evidence supports this prediction. Optimisation theories have several implications, including that lifespan should be relatively easy to manipulate by tapping into existing biological mechanisms, and that the geroscience hypothesis, which states that intervention on the rate of ageing should also modulate the incidence of age-related diseases, is likely to be correct.

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67-90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53-94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.

Liver aging is characterized by pathological features including lipid deposition, exacerbated chronic inflammation, and increased cell death. Although exercise intervention has been proven effective in delaying liver aging, its fundamental biochemical mechanism remains unclear. This study utilized a naturally aged mouse model and an in vitro cellular senescence system to reveal, for the first time, the cascade mechanism by which β-hydroxybutyrate (β-HB), a core protective mediator induced by aerobic exercise, delays liver aging through regulating the macrophage-hepatocyte crosstalk. Within the aging microenvironment, disturbance of mitochondrial homeostasis results in the cytosolic release of mtDNA, which activates the cGAS-STING signaling pathway and drives macrophage polarization towards the pro-inflammatory M1 phenotype. M1 macrophages subsequently indirectly induce hepatocyte lipid metabolic dysregulation and initiate PANoptosis. Aerobic exercise stimulates the production of endogenous β-HB, which protects mitochondrial function, inhibits the activation of the cGAS-STING pathway in macrophages, facilitates macrophages transformation into the anti-inflammatory M2 phenotype, and ultimately indirectly ameliorates hepatocyte lipid deposition and PANoptosis. Additionally, exogenous β-HB administration efficiently mimics the endogenous ketogenic effect of aerobic exercise, restoring mitochondrial homeostasis, mitigating inflammation, and reducing PANoptosis levels in the liver of aged mice. This study elucidates the molecular mechanisms by which exercise-induced endogenous β-HB confers hepatoprotection. We establish β-HB as an exercise mimetic, exerting its protective effects on the aging liver through targeted inhibition of the innate immune hub STING. These findings provide a robust theoretical and experimental foundation for the translational application of β-HB in clinical nutritional strategies for aging intervention.

The hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, synchronizing peripheral clocks through oscillations in core clock genes and proteins. Circadian disruption contributes to immunosenescence, aging, and neurodegenerative disorders such as Parkinson's disease (PD). Previous work from our group demonstrated age-related changes in circadian rhythms of clock genes, protein levels, and serotonin metabolism in the SCN and substantia nigra (SN) of male Wistar rats. This study examined the age of onset for circadian misalignment in clock (rBmal1, rCry1, rCry2, rPer1, rPer2), immune (rCox2, rIl1β, rIl4, rTgfβ1), and PD-associated (rLrrk2, rPark2, rPark7, rSnca) genes in SCN and SN. Male Wistar rats aged 3 (adult), 12 (middle-aged), and 24 (aged) months were studied. In SCN, rPark2 decreased and rSnca increased in 12 months and 24 months, while rCry1 and rPer2 were elevated in 12 months. Rhythmicity of rTgfβ1 declined in 24 months. In SN, rBmal1 rhythmicity was abolished in 24 months, while rPark2 lost rhythmicity in 12 months and 24 months. rSnca and rIl1β were elevated in 24 months. Misalignments in rCry1, rPer2, rIl4, rIl1β, rTgfβ1, and rLrrk2 in SCN, and rCry2, rIl4, rLrrk2, rPark2, and rSnca in SN appeared by middle age. A ketogenic diet intervention (KDI) resulted in modulation of rhythmic expression of rPer2, rSnca, rCry1, rTgfβ1, and rPark2 in SCN and improved rPark2, rSnca, and rIl1β in SN. These findings indicate that translationally, circadian misalignment in PD-related genes emerges early, suggesting its potential as a biomarker for preclinical PD. Moreover, dietary strategies such as KDI highlight promising non-pharmacological approaches to preserve circadian integrity, delay neurodegeneration, and guide personalized interventions in at-risk individuals.

Sleep is a universal behavior that is critical for brain function and physiological homeostasis. While growing epidemiological and experimental evidence suggests reduced sleep quality is associated with negative health outcomes, the causal relationship between sleep loss and reduced longevity remains poorly understood. Here, we examine sleep across the lifespan and its relationship to longevity in Drosophila melanogaster. We examined the associations between numerous components of sleep at different life stages to longevity. Early life sleep, but not middle and late-life sleep, was positively associated with longevity. Age-dependent changes in sleep were consistent but accelerated, when flies are housed under stressful conditions including nutrient and temperature stress. Further, pharmacological restoration of sleep in the first 10 days of life, but not at later time points, increases longevity. Together, this work provides a systematic investigation of how different components of sleep impact longevity and suggests early life sleep may be particularly important in promoting sleep across the lifespan.

Many biological processes, including cellular senescence, manifest as diverse phenotypes that vary across cell types and conditions. In the absence of single, definitive markers, researchers often rely on the expression of sets of genes to identify these complex states. However, there are multiple ways to summarise gene set expression into quantitative metrics (i.e., signatures), each with its own strengths and limitations, and we know of no consensual framework to systematically evaluate their performance across datasets. We therefore developed markeR (https://bioconductor.org/packages/markeR), an open-source, modular R package that evaluates gene sets as phenotypic markers using various scoring and enrichment-based approaches. markeR generates interpretable metrics and intuitive visualisations that enable benchmarking of gene signatures and exploration of their associations with chosen study variables. As a case study, we applied markeR to 9 published senescence-related gene sets across 25 RNA-seq datasets, covering 6 human cell types and 12 senescence-inducing conditions. There was wide variability in gene set performance, as some signatures (e.g., SenMayo) were robust senescence markers across contexts, while others (e.g., those from MSigDB), performed poorly as such. We also used markeR to analyse gene expression in 49 GTEx tissues, revealing tissue- and age-related differences in senescence-associated signals. Together, these findings emphasise the difficulty of characterising molecular phenotypes and demonstrate the potential of markeR in facilitating the systematic evaluation of gene sets in various biological contexts.

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions (LODmax [≥]3.0) at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci. Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-b; signaling (Serpine1, Dab2, Igfbp7), whereas skin senescence is dominated by keratinization and barrier homeostasis modules (Krt10, Lor, Sbsn). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm-1) that robustly marks p21+ senescent cells. To unify these layers, we develop a machine learning derived multimodal barcode that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ. In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10, Lor, Sbsn, Sfn, and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.

The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately, rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumor risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.

Cellular senescence, a state of irreversible growth arrest, is characterized by various phenotypic changes, including altered mitochondrial function. While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca2+) homeostasis. We find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca2+ uptake, thereby preventing Ca2+ overload and apoptosis. Disrupting this interaction using the BH3 mimetic ABT-263 or Bcl-xL targeting siRNA increases mitochondrial Ca2+ uptake, leading to apoptosis and blocking the formation of senescent cells. These findings uncover a previously unrecognized role of the Bcl-xL VDAC1 axis in regulating mitochondrial Ca2+ dynamics during the onset of senescence. Our work provides mechanistic insight into how senescent cells evade apoptosis, highlighting potential therapeutic targets for selectively eliminating them in cancer and age-related diseases.

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in

Testosterone treatment increases muscle mass, maximal voluntary muscle-strength, aerobic capacity, and some measures of physical function. Activational and epigenetic mechanisms by which androgens improve muscle mass and physical performance and how to apply these anabolic effects to treat functional limitations associated with aging and disease remain incompletely understood. Testosterone treatment induces hypertrophy of type 1 and 2 muscle fibers, and increases muscle progenitor cell numbers by promoting differentiation of mesenchymal progenitor cells into myogenic lineage by an androgen receptor (AR)-mediated pathway. Liganded AR binds to β-catenin, translocates into nucleus where it binds TCF4 and upregulates follistatin that blocks signaling through TGFβ-pathway to promote myogenesis and inhibit adipogenesis. Testosterone increases myoblast proliferation by stimulating polyamine biosynthesis. Stimulation of GH and IGF-1 secretion, intramuscular IGF1-receptor, and muscle protein synthesis, and inhibition of muscle atrophy genes further contribute to testosterone's anabolic effects. Testosterone improves muscle bioenergetics by increasing erythrocytes, oxygen availability, tissue blood flow, and mitochondrial mass and quality. Testosterone increases blood flow by nongenomic mechanisms involving NO production, and calcium and potassium channels in vascular smooth muscle. The conversion of testosterone to 5α-dihydrotestosterone is not required for mediating its anabolic effects. Mechanisms of testosterone's sexually-dimorphic epigenetic and tissue-specific activational effects; and roles of α-keto reductase and steroid 5α-reductase, one-carbon and polyamine metabolism in testosterone's actions remain poorly understood. Strategies to translate testosterone-induced muscle mass and strength gains into patient-important improvements in functional performance and health outcomes are needed to enable its clinical applications to treat functional limitations associated with aging and disease.

During a lifetime, normal cells accumulate thousands of changes in their genome sequence. These changes, termed somatic mutations, have mostly been studied in the context of cancer, but their presence in normal tissues is ubiquitous and widespread. Somatic mutation accompanies the aging process and is influenced by genetic and environmental factors. Differently from gene expression or imaging data, which fluctuate over time, somatic variants are non-reversible marks in the genome and accumulate over time. This property can be exploited to track the history of a cell, from conception to old age, providing information that cannot be acquired via classical histological tissue inspection nor other types of omics data. Mutations can track embryonic development, measure how clones compete in a tissue over time, or report the mutational processes active in cells and tissues throughout life. We discuss selected examples and emphasize how somatic mutation analysis can enable expanding applications at the service of physiology and cell biology, as well as a deeper understanding of the aging process.