Longevity Papers

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPR

Social isolation and loneliness (SIL) are increasingly recognized as potent determinants of cognitive decline in aging and Alzheimer's disease-related dementias (ADRD). Yet, despite their prevalence, the neurobiological pathways through which SIL accelerates brain aging remain incompletely understood, and effective interventions are scarce. This narrative review synthesizes human and animal research to present a translational framework linking SIL to brain aging across cognitive-affective, socio-behavioral, physiological, and neural domains. Converging evidence indicates that SIL and cognitive impairment constitute a self-reinforcing loop: isolation amplifies age-related deficits in cognitive control, emotional regulation, and stress resilience, while these impairments heighten social threat sensitivity and blunt social reward, perpetuating isolation. Cross-species findings implicate interconnected neural networks, including the prefrontal and insular cortices, hippocampus, and associated reward and stress-regulatory systems, as critical hubs mediating this loop. Large-scale human neuroimaging consortia reveal convergent neural signatures of SIL within these networks, supported by mechanistic findings from animal models that identify shared molecular cascades involving neuroinflammation, glucocorticoid imbalance, myelin disruption, and dysregulated oxytocin and dopaminergic signaling. Importantly, evidence from animal resocialization paradigms and human multimodal interventions demonstrates that SIL-related neural and behavioral alterations are partially reversible, highlighting enduring plasticity in the aging brain. Together, these findings define SIL and cognitive decline as a dynamic, mutually reinforcing cycle that accelerates brain aging through convergent molecular and circuit mechanisms. Targeting these pathways, by enhancing cognitive control, modulating reward systems, reducing stress reactivity, and strengthening social connectedness, offers a promising translational route to preserve resilience and cognitive vitality across the lifespan.

Constant monitoring and fine-tuning of internal body status to maintain energy homeostasis despite changing physiological needs and environmental conditions are essential brain functions. Hypothalamic tanycytes - specialized ependymoglial cells at the interface between the blood and the brain - play crucial roles in this regulation through mechanisms as diverse as sensing and responding to circulating nutrients and metabolic hormones, gating their access or shuttling them into the brain, modulating hypothalamic neuronal function and neuroendocrine communication with peripheral organs, and generating new regulatory neurons. We summarize these mechanisms and emphasize striking recent discoveries that extend beyond energy balance to reproduction and even cognitive aging. These highlight the need for a deeper understanding of the physiological and pathological roles of these unique cells.

Forgetting is a critical component of memory, but its molecular regulation - particularly with age - is not well understood. Epigenetic modifications are a candidate for this regulation and may further drive age-related behavioral decline, as they are dramatically altered in the aging brain. We found that multiple components of the SET1/COMPASS complex, a conserved histone methyltransferase complex associated with active gene transcription, are upregulated with age in the C. elegans nervous system. Neuronal knockdown of the SET1/COMPASS components improves memory in young adult animals and slows memory decline in old animals. By pharmacological and genetic inhibition, optogenetics, and neuronal mRNA and chromatin profiling, we demonstrate that SET1/COMPASS-mediated active transcription promotes forgetting. SET1/COMPASS regulates the de novo activity-dependent transcription and release of a neuropeptidergic signal from the AWC olfactory sensory neuron, which erases the associative memory trace in downstream motor neurons, resulting in forgetting. We further found that increased SET1/COMPASS-dependent chromatin accessibility at these gene loci with age primes these loci for transcription, resulting in accelerated forgetting. Our results reveal the role of active gene transcription in the regulation of forgetting and altered SET1/COMPASS- mediated gene transcription as a mechanism of cognitive decline, implicating increased expression of COMPASS components as a driver of increased forgetting in the aging brain. This mechanism may offer a new target for slowing loss of cognitive function with age.

While existing studies have linked declines in intrinsic capacity (IC) to adverse health outcomes, the role of potentially modifiable lifestyle factors in this pathway, especially sedentary behavior, remains critically underexplored. Using data from the Beijing Longitudinal Disability Survey in Community Elderly (BLINDSCE) cohort (2023-2024), this study investigated both cross-sectional and 1-year longitudinal associations between sedentary time and IC in community-dwelling older adults. Of the 2044 participants (≥ 65 years) enrolled at baseline, 1576 completed 1-year follow-up assessments through face-to-face interviews. Multivariable linear regression analyses revealed that each additional hour of daily sedentary time was associated with a 1.18-point lower baseline IC score (95% CI: -1.38, -0.98) and an accelerated 0.48-point greater IC decline over 1 year (95% CI: -0.72, -0.24). Exposure-response analyses showed a linear relationship between sedentary time and 1-year IC change. Significant interaction effects were observed between sedentary time and baseline IC level, moderate-to-vigorous physical activity (MVPA), and daily internet use. These findings provide empirical support for reducing sedentary behavior, ensuring adequate MVPA, promoting moderate digital engagement, and implementing IC-stratified interventions to promote healthy aging-thereby operationalizing the WHO Integrated Care for Older People (ICOPE) framework through actionable public health measures.

Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (T

Age and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years.

Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA 3222401L13Rik as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog ENSG00000272070. We found that 3222401L13Rik is expressed in both astrocytes and microglia and increases with age. Knockdown of 3222401L13Rik in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFalpha, and increased phagocytic activity. RNA sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog ENSG00000272070 showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, 3222401L13Rik interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, ENSG00000272070 expression was significantly reduced in postmortem Alzheimer\'s disease (AD) brains, and AD-associated genes were enriched among 3222401L13Rik-regulated targets. Together, our results identify 3222401L13Rik/ENSG00000272070 as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests 3222401L13Rik as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases.

Evidence has demonstrated established associations and causal links between gut microbiota and host aging, with microbiota-targeted dietary interventions potentially mitigating age-related decline. In addition, current formulations considering comprehensive and balanced nutritional needs of the elderly are very few. Therefore, we developed a Novel Formulated Food for the Elderly (NFFE) that is enriched with prebiotics (fructooligosaccharide (FOS) and edible fungal β-glucans) targeting gut microbiota and addresses complete and specific nutritional requirements of the elderly. After an 8-week intervention in a randomized self-controlled trial, age-related physiological decline in participants was significantly mitigated. Notably, NFFE selectively enriched short-chain fatty acid (SCFA)-producing bacteria (Bifidobacterium ↑42 % and Ruminococcus ↑35 %). Interaction network analysis identified three functional microbial groups within the prebiotic metabolic pathway, revealing a fine metabolic relay among the three microbial guilds/groups, characterized by a flow of step-by-step degradation of prebiotics from microbes of Group 1, via microbes within Group 2, finally to those of Group 3. Notably, inter-individual variability in response was observed following NFFE intervention, and we identified two distinct host responder groups: high responders (HR, 50 %) and low responders (LR, 50 %) with the baseline characteristics of these two groups varying. HR group exhibited more significant improvements in aging-related physiological parameters, with enrichment of Ruminococcus 1 and Faecalibacterium in baseline microbiota, taxa known to degrade NFFE-derived prebiotics. These findings position NFFE as a promising dietary intervention against age-related decline via gut-microbiota modulation and comprehensive nutritional supplementation. The baseline-microbiota-dependent heterogeneity in response underscores the necessity of developing personalized formulations in future diet intervention trials.

Millions worldwide suffer from sleep problems and dementia, yet effective treatments and predictions remain elusive. As populations age, these issues become increasingly critical for public health. While strong associations between sleep quality, cognitive functioning, and mortality are well-documented, the mechanisms underlying sleep's role in cognitive status and life expectancy (LE) across different cognitive states remain unclear. This study used multistate life tables and data from the Health and Retirement Study (2002-2020, N = 20,683), to quantify long-term associations between sleep and cognition/mortality for older adults. Our results show that poorer sleep quality is linked to 1.0 to 2.4 fewer years of total LE and LE with normal cognition for men and women. This study highlights the complex interplay between sleep, cognitive aging, and gender and underscores the importance of addressing sleep issues to promote healthy cognitive aging with important implications for public health policies and interventions targeting cognitive decline and dementia.

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multi-omic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR at puberty disrupts this balance, precipitating premature cell-cycle entry, skewed divisions toward symmetric differentiation, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

Aging is marked by the accumulation of cells expressing the cyclin-dependent kinase inhibitor p16Ink4a. These p16⁺ cells, largely senescent, contribute to inflammation and tissue dysfunction. While eliminating p16⁺ cells improves healthspan, sex-specific differences in their burden and clearance remain unclear. Through combined transcriptomic, proteomic, and functional analyses, we reveal distinct sex-dependent dynamics of p16⁺ cells during aging. Female mice accumulate significantly more p16⁺ cells across multiple tissues, particularly in the liver. In the p16-3MR model, selective ablation of these cells enhances grip strength, promotes skin regeneration, and reduces liver damage exclusively in females. Multi-omics profiling shows that p16⁺ cell removal shifts female liver expression toward youthful, health-associated profiles, marked by improved mitochondrial activity and reduced inflammatory signaling-molecular patterns resembling those induced by longevity interventions such as calorie restriction, rapamycin, and acarbose. Integrative analysis of our and independent datasets identifies a conserved transcriptional network involving Srm, Cd36, and Lrrfip1, suggesting shared mitochondrial-immune regulatory mechanisms. Overall, our findings establish p16⁺ cells as critical yet heterogeneous drivers of tissue aging, uncover sex-specific differences in their abundance and senolytic responsiveness, and support the development of precision senotherapeutics that consider sex as a key biological variable in aging and rejuvenation.

Mutations in carboxyl ester lipase (CEL) cause maturity-onset diabetes of the young type 8 (MODY8), yet the mechanism linking exocrine CEL deficiency to β-cell failure remains unclear. Here, we demonstrate that a truncating CEL mutant (MUT-CEL, c.538 + 16C > T) is aberrantly internalized by β-cells, where it forms cytotoxic aggregates that resist degradation. These aggregates induce endoplasmic reticulum stress, trigger a sustained unfolded protein response, and drive β-cells into a senescent state characterized by cell cycle arrest and loss of identity markers. Crucially, we identify cyclin-dependent kinase 4 (CDK4) dysfunction as a central mediator of this lipotoxicity induced senescence. Restoration of CDK4 activity rescues β-cell proliferation and function in vitro and in vivo, revealing a targetable pathway to mitigate β-cell demise in MODY8.

Cellular senescence is emerging as one of the leading underlying mechanisms of ageing. Senescent cells are observed in most tissues and organs with advancing age, which augments tissue dysfunction and inflammatory disorders. Extracellular vesicles (EVs) are nanoscale sacs released by almost all cells, which carry cell-type dependent molecular cargo that can exhibit pharmacological effects in recipient cells. Since senescence represents a global phenomenon in an organism, and EVs are released by various cell types, this review attempts to delineate their intricate interactions in regulating various facets of cellular senescence and age-related diseases, as well as potential diagnostic avenues, research gaps, and challenges. EVs released by senescent cells are biophysically different and can not only promote bystander senescence in healthier cells but can also accelerate the development of age-dependent chronic disorders by promoting a pro-tumorigenic and pro-inflammatory environment. Conversely, EVs isolated from healthy cells, typically stem cells, can suppress senescence, promote inflammatory homeostasis, and improve lifespan in vivo. Novel non-mammalian sources of EVs, including the gut microbiota and dietary plants, are also being recognised with potentially senescence-modulatory effects. A previously unknown role of EVs in modulating immune cell response during senescence is also developing, and EVs-based biomarkers are identified with the aim of early prediction and diagnosis of senescence. However, several challenges remain at the technical and translational end of EVs, and future research should focus on the identification of EVs in senescent cell subtypes and immune cells, understanding non-mammalian sources of EVs in modulating senescence, and establishing the safety of EVs to fully comprehend their pathological, therapeutic, and diagnostic potential in regulating cellular senescence.

Telomeres are key biomarkers of cellular ageing, yet their dynamics remain poorly studied in tropical and short-lived bat species. Here, we present the first investigation of telomere length across age in Molossus molossus, a tropical bat historically categorised as the shortest-lived bat on record. Through a multi-year mark-recapture study in Gamboa, Panama, we sampled 492 individuals (n = 317 females, 175 males) and documented a female M. molossus surviving to at least 13 years of age, more than doubling the previously reported maximum lifespan of 5.6 years. Across the population, relative telomere length (rTL) showed no overall decline with age. However, sex-specific models revealed clear divergence: males tended to have longer rTL than females but showed significant age-related shortening, whereas females exhibited stable rTL across the observed age range. The pattern of telomere stability in females aligns closely with results observed in long-lived bats of the Myotis genus while male-specific attrition suggests differential physiological and life-history costs between the sexes. Overall, the findings here challenge previous assumptions about the lifespan and ageing biology of M. molossus, demonstrate that telomere maintenance is not limited to temperate bats and reinforce the value of long-term field studies for understanding ageing processes in the wild.

Shorter leukocyte telomere length (LTL) is associated with aging-related cardiovascular diseases, but its relationship with heart failure with preserved ejection fraction (HFpEF) in high-risk Chinese patients with hypertension under 65 years remains unclear. In this observational prospective study, we investigated 646 patients with hypertension aged < 65 years with diabetes, coronary heart disease (CHD), or ≥ 3 cardiovascular risk factors. Baseline assessments included clinical evaluation, measurement of aging markers (LTL and mitochondrial DNA copy number) and echocardiography. Participants underwent scheduled quarterly follow-up for 5 years, with documentation of major adverse cardiovascular events (MACEs), including cardiovascular mortality, myocardial infarction, ischemia-driven revascularization, stroke and heart failure hospitalization. At the final follow-up visit, the evaluation for HFpEF was performed through echocardiography and plasma B-type natriuretic peptide (BNP) measurement. Participants were stratified by LTL tertiles: long (> 79.89; n = 216), mid (58.49-79.89; n = 214), and short (< 58.49; n = 216). Compared with the long and mid LTL groups, the short LTL group had a higher prevalence of male, smoking, hyperlipidemia, diabetes, and CHD, along with elevated blood pressure and fasting blood glucose, but lower mitochondrial DNA copy number (all P < 0.05). At 5-year follow-up, HFpEF prevalence increased with shorter LTL (15.7%,11.2% and 7.9% across LTL tertiles, p = 0.037). Multivariable logistic regression analysis identified shorter LTL as an independent predictor of HFpEF (adjusted OR 2.087, 95% CI: 1.017, 4.280, p = 0.045), in addition to CHD, uric acid, and C-reactive protein. Compared with the long LTL group, both the short (adjusted hazard ratio [HR] 1.953, 95% CI 1.259-3.028; P = 0.003) and mid LTL groups (adjusted HR 1.581, 95% CI: 1.015-2.464, P = 0.043) showed a significantly increased risk of 5-year MACE. In conclusion, shorter LTL independently predicts HFpEF development and adverse cardiovascular outcomes in high-risk Chinese patients with hypertension under 65 years, suggesting telomere biology may contribute to HFpEF pathogenesis and clinical outcomes in this population.

Background: Ageing is accompanied by progressive declines in skeletal muscle mass and strength, culminating in sarcopenia, a condition that contributes to frailty, multimorbidity, and mortality. Age-related changes to mitochondria lead to oxidative damage and dysfunction and are proposed to occur early in the trajectory of sarcopenia, supporting the candidacy of mitochondrial-protective therapies. Here, we test the efficacy of mitochondrial uncoupler BAM15 in age-dependent sarcopenic mouse models. Methods: Male and female MitoQC mice aged 24 months received either standard chow or chow supplemented with BAM15 (0.033% mg/g) ad libitum for eight weeks (n=13-14/group). Young (3-month-old) mice served as reference controls (n=8/group). Muscle mitochondrial respiration was assessed in permeabilized fibres, and contractile function was measured in isolated extensor digitorum longus and soleus muscles. Mitophagy was quantified by immunofluorescence confocal microscopy. Data were analyzed using one- or two-way ANOVA followed by Dunnett or Bonferroni multiple comparison tests. Results: Aged male and female mice exhibited reduced gastrocnemius muscle mass relative to body mass compared with young controls (p<0.05; ~18% and ~32% loss, respectively). BAM15 did not alter muscle size but reversed the age-related loss of contractile function in EDL muscles, to that of the young reference controls in both sexes (p<0.05; ~33% in males, ~16% in females). In male mice, BAM15 improved mitochondrial efficiency, evidenced by restoration of Complex I-linked respiration and decreased proton leak (~52% improvement; p<0.05), and normalized protein levels of oxidative stress marker 4-HNE, without changes in mitophagy or mitochondrial content. In females, BAM15 did not improve mitochondrial parameters, which may be, in part, due to aged female muscle exhibiting unchanged Complex I leak and 4-HNE protein abundance, alongside lower complex I subunit (NDUFB8) protein abundance. Conclusions: BAM15 improved skeletal muscle mitochondrial efficiency and contractile function in aged male mice, supporting the potential of mitochondrial uncoupling as a therapeutic strategy for sarcopenia.

Coronary artery disease (CAD) remains a major cause of morbidity and mortality. Caloric restriction promotes cardiovascular health but is difficult to sustain. Spermidine, a naturally occurring polyamine and caloric-restriction mimetic, has been linked to improved longevity in epidemiological studies and shown to enhance autophagy, mitochondrial function, and cardiovascular ageing in preclinical models. This trial will investigate whether high-dose spermidine improves cardiac remodelling, exercise capacity, muscle mass, and systemic inflammation in elderly patients with CAD.

Cellular senescence is a state that contributes to tissue patterning during development and tissue repair, but which becomes misregulated in ageing and disease. The senescence-associated secretory phenotype (SASP) mediates many of the context-dependent effects, yet its molecular composition and evolutionary origins remain incompletely understood. Here, we characterize the SASP signature of developmental senescent cells and find that it is enriched for genes encoding major developmental signaling pathways. Integrative analyses of in vitro and in vivo transcriptomes reveal that senescent cells across diverse contexts consistently activate these developmental programs, with key morphogens constituting conserved SASP components. Functionally, we show that the SASP is sufficient to induce the expression of central developmental genes and transcription factors across multiple cell types. These findings show that senescent cells resemble developmental signaling centers and uncover developmental signaling reactivation as an evolutionarily conserved feature of senescence, providing conceptual insight into its physiological functions and its pathological impact during ageing.

Sleep is typically viewed through a brain-centric lens, with little known about the role of the periphery. Here, we identify a sleep function for peripheral macrophage-like cells (hemocytes) in the Drosophila circulation, showing that hemocytes track to the brain during sleep and take up lipids accumulated in cortex glia due to wake-associated oxidative damage. Through a screen of phagocytic receptors expressed in hemocytes, we discovered that knockdown of eater, a member of the Nimrod receptor family, reduces sleep. Loss of eater also disrupts hemocyte adhesion to the brain and lipid uptake, which results in increased brain levels of Acetyl CoA and acetylated proteins, including mitochondrial proteins PGC1 and DRP1. Dysregulation of mitochondria, reflected in high oxidation and reduced NAD+, is accompanied by impaired memory and lifespan. Thus, peripheral blood cells, which we suggest are precursors of mammalian microglia, perform a daily function of sleep to maintain brain function and fitness.

Type 2 diabetes mellitus (DM) is closely associated with cellular senescence (SnC), a state of irreversible cell cycle arrest marked by functional decline. Preventing cellular senescence in already diagnosed DM patients is crucial for limiting disease progression and the onset of co-morbidities. The relationship between oxidative stress, DNA damage, and telomere shortening provides a mechanistic framework for elucidating the role of cellular senescence in the pathogenesis and progression of type 2 DM. This senescence-driven model of metabolic dysfunction not only accounts for impaired β-cell function and insulin resistance but also for the systemic complications observed in DM patients. The accumulation of senescent cells, particularly in metabolically active tissues such as adipose tissue, is increasingly recognized as both a cause and consequence of the chronic inflammatory environment that characterizes diabetes. Evidence from in vitro and preclinical studies highlight the detrimental effects of the senescence associated secretory phenotype, reinforcing tissue damage through paracrine and autocrine signalling mechanisms. Despite its complexity, approaches targeting the senescent phenotype offers a promising avenue for adjunct therapies. Senotherapeutics, such as senomorphic agents that protect cells from cytotoxic damage and mitigate oxidative stress, can potentially protect against disease onset, whereas senolytic agents have the potential to eliminate senescent cells to limit metabolic disease progression mitigating complications, and ultimately improving patient outcomes. There is, however, an urgent need to translate the preclinical findings into clinical trials to assess the safety, efficacy, and long-term effects of senotherapeutic agents.

DNA damage is a key driver of aging, contributing to epigenetic erosion, senescence, and chronic inflammation. However, genoprotective strategies to counteract aging remain intangible. Here we show that FOXM1 repression during aging accounts for a global transcriptional shutdown of DNA repair genes and the accrual of DNA damage. Restored FOXM1 activity in aged cells reduces DNA damage and epigenetic alterations driving senescence. Mechanistically, FOXM1 drives the transcription of DNA repair genes, which prevents the DNA damage-driven degradation of the G9a methyltransferase and subsequent loss of H3K9me2 at the nuclear periphery. Remarkably, we show that amendment of the H3K9me2 guidepost for peripheral heterochromatin by FOXM1 induction in aged cells inactivates enhancers of the AP-1-driven senescence and inflammation program. These findings establish FOXM1 as an age-reversal factor capable of restoring (epi)genetic integrity to inhibit the senescence enhancer landscape, offering a promising therapeutic avenue to address the fundamental causes of aging.

The extent to which somatic mitochondrial DNA (mtDNA) mutations are subject to selection is a fundamental question relevant to development, mitochondrial disease, cancer, and aging. Recently a study from the Sudmant laboratory that used an advanced, high fidelity mutational analysis reported that somatic mutations in protein-coding genes exhibit signatures of negative selection. This report came as surprise as several other studies including those that used same technology reported either lack of selection or positive (destructive) selection on somatic mutations. We hypothesized that these discrepancies may stem, in part, from the inclusion of germline mutations in addition to somatic ones, which could bias selection analyses due to the high synonymity of the latter. To test this, we reanalyzed the Sudmant dataset by separating mutations into germline (defined as shared between related animals) and somatic (not shared between tissues of an animal). We then employed a cumulative curve approach to assess selection without bias. Our analysis reveals that, indeed, an apparent purifying selection signal is driven by an admixture of synonymous germline mutations and disappears upon their removal. The remaining somatic mutations for most part show overall dynamics consistent with neutral drift. However, mutations at higher mutant fractions show positive selection trend, most compatible with a low proportion of mutations experiencing positive selection. While we do not exclude rare or context-specific selection events, our results argue against pervasive somatic selection and highlight the importance of rigorous stratification when interpreting mtDNA mutational patterns.

In many organisms, aging is a clear risk factor for chromosome missegregation, the main source of aneuploidy. Here, we report that old yeast cells lose chromosomes by partitioning them asymmetrically to their daughter cells together with the pre-existing (old) spindle pole body (SPB, centrosome equivalent in yeast). Strikingly, remodelling of the nuclear pore complex (NPC) and the displacement of its nuclear basket triggered these asymmetric chromosome segregation events. Simultaneously, nuclear basket displacement caused unspliced pre-mRNAs to leak into the cytoplasm. We show that removing the introns of three genes involved in chromosome segregation was sufficient to fully suppress chromosome loss in old cells. Promoting pre-mRNA leakage in young cells also caused asymmetric chromosome partitioning and loss through the same three introns. Therefore, we propose that basket displacement from NPCs and its consequences for pre-mRNA quality control are key triggers of aging phenotypes such as aneuploidy.

Sarcopenia, the age-related decline in muscle mass, strength and function, is characterized by impaired muscle homeostasis, reduced regenerative potential of muscle stem cells (MuSCs) and increased fibrosis. Here we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the polycomb-deficient Ezh2

Sarcopenia and atherosclerosis are prevalent age-related conditions increasingly recognized as interconnected through shared immune-mediated pathways. This review elucidates how "inflammaging" driven by dysregulated immune responses. Key age-related mechanisms include macrophage polarization imbalance, T/B cell dysregulation, and activation of pro-inflammatory signaling pathways. These processes promote oxidative stress, insulin resistance, creating a vicious cycle that exacerbates muscle and vascular decline. Emerging therapeutic strategies offering potential for dual-benefit interventions. Understanding these immune interactions provides a foundation for integrated approaches to mitigate sarcopenia and atherosclerosis in aging.

The senescence of alveolar epithelial cells plays a central role in the pathogenesis of idiopathic pulmonary fibrosis, a disease currently lacking specific therapeutic approaches. Luteoloside, a flavonoid glycoside compound found in plants such as those from the Asteraceae and Fabaceae families, has various biological activities. This study aimed to explore the anti-senescence and anti-fibrotic effects of luteoloside in experimental pulmonary fibrosis and investigate its underlying molecular mechanisms. Our results indicated that luteoloside attenuated bleomycin-induced pulmonary fibrosis, oxidative stress, and lung senescence in mice. Immunofluorescence analysis revealed that luteoloside reduced AEC senescence, as indicated by decreased P21 expression in SPC⁺ epithelial cells. In vitro, luteoloside removed bleomycin- and oxidative stress-induced AEC senescence and mitochondrial dysfunction. Mechanistically, we proved through the inhibition effect of EX527 that luteoloside's protective effects were mediated through SIRT1. This study provides new insights into the mechanisms through which luteoloside modulates cellular senescence and pulmonary fibrosis, offering potential pathways for the development of novel therapeutic strategies.

The generation and maintenance of immunity is a dynamic process that is dependent on age

DunedinPACE quantifies the pace of biological aging. No study has examined its association with cardiorespiratory fitness (CRF). Additionally, the physiologically relevant CRF thresholds associated with slow aging remain unclear. The purpose of this study was to investigate the association between CRF and the pace of epigenetic aging, as measured by DunedinPACE, and to identify a CRF threshold indicative of slower biological aging. Here, we analyzed data of 144 older men (aged 65-72 years) enrolled in the WASEDA'S Health Study to examine the association of CRF (VO₂/kg at peak and ventilatory threshold (VT)), physical fitness, anthropometric parameters, and nutritional intake with epigenetic aging. Epigenetic aging was assessed using DunedinPACE derived from blood DNA methylation profiles. We performed Pearson's and partial correlation analyses adjusted for age, smoking status, and drinking status, followed by receiver operating characteristic (ROC) curve analyses with bootstrapped optimal cutoff determination. In the unadjusted analyses, VO₂/kg at peak (r =  - 0.17, p = 0.041) and VT (r =  - 0.17, p = 0.046) were inversely associated with DunedinPACE, and VO₂/kg at peak showed a significant association even in the adjusted models (r =  - 0.16, p = 0.046). The ROC curve analysis revealed a potential threshold of VO₂/kg at peak (26.2 mL/kg/min) for differentiating individuals with slower biological aging, supported by bootstrap distributions of optimal cutoff points and Youden's index. This study suggests that higher CRF is associated with a slower pace of epigenetic aging, as measured using DunedinPACE. The identified VO₂peak threshold may provide a biomarker-based fitness target to support healthy aging in older adults.

Small vessel disease (SVD) impacts healthy aging of organs across the body, yet its contributions to adverse brain aging remain poorly defined. Here we show thromboinflammation, a core feature of SVD, as a driver of adverse brain aging. We identify cerebrospinal fluid fibrinogen as a marker of brain thromboinflammation and screen neurovascular biosignatures mediating its impact on synaptic vulnerability along the full spectrum of brain aging from cognitively typical, amyloid-negative to cognitively impaired, amyloid-positive older adults. We identified 53 proteins mediating the effect of fibrinogen on synaptic markers in 1,655 donors from three independent cohorts. Single-cell transcriptomic mapping revealed mediator enrichment in neurovascular unit cells. Pathway analysis demonstrated dysregulation of angiogenesis, fibrosis, and immune signaling. Vascular and microglial-enriched biosignatures associated with compromised white matter integrity. These findings implicate thromboinflammation as an early, amyloid-independent pathway to neurodegeneration and tauopathy, establishing vascular health as fundamental to preserving brain healthspan.

Autophagy and cellular senescence are intimately linked processes that play pivotal roles in renal homeostasis, aging, and disease progression. Autophagy preserves intracellular integrity by degrading damaged organelles, misfolded proteins, and metabolic waste through lysosomal pathways, thereby maintaining energy balance and delaying senescence. However, with advancing age or persistent stress, autophagic activity declines, leading to the accumulation of senescent cells, mitochondrial dysfunction, and chronic inflammation. In the kidney, a metabolically demanding organ, this imbalance contributes to the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI). Senescent cells secrete a senescence-associated secretory phenotype, which amplifies inflammation, fibrosis, and tissue remodeling. The bidirectional interplay between impaired autophagy and cellular senescence exacerbates renal tubular atrophy, glomerulosclerosis, and interstitial fibrosis, thereby promoting CKD progression and maladaptive repair following AKI. Emerging therapeutic strategies, including autophagy activators, senolytics, antioxidants, and stem cell based interventions, have shown promise in restoring cellular homeostasis and delaying renal aging. Nonetheless, challenges remain in achieving cell type specific modulation while avoiding the deleterious effects of excessive activation. This review highlights recent advances in understanding the mechanistic interplay between autophagy and senescence in renal physiology and disease, outlines their contributions to CKD and AKI, and explores evolving therapeutic strategies aimed at restoring autophagic flux and eliminating senescent cells. Targeting the autophagy senescence axis represents a compelling avenue for precision therapy in kidney disease and may redefine future approaches in nephrology.

Alpha-1 antitrypsin (AAT) deficiency in younger people is well characterized, but the effects of elevated AAT levels in older age are unclear. We examined the effect of elevated AAT levels and mortality in a longitudinal cohort of older adults, alongside high-sensitivity C-reactive protein (hs-CRP) levels. This post hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) trial included 11,879 adults aged ≥ 70 years without prior cardiovascular disease, dementia or life-limiting illness at enrolment. Cox proportional hazard models estimated adjusted hazard ratios (aHRs) for all-cause and cause-specific mortality (cancer, cardiovascular and other) over a median follow-up of 10.9 years. AAT and hs-CRP were analyzed in deciles, comparing the highest decile to the middle 80% as reference. Median (IQR) levels of AAT and hs-CRP in the top decile were 1.69 (1.65-1.78) g/L and 10.40 (7.97-15.53) mg/L, respectively. Individuals in highest AAT decile had a 53% higher likelihood of mortality during follow-up (aHR 1.53, 95% CI 1.28-1.65). Risk of cancer, cardiovascular and 'other' deaths were all elevated. The associations remained significant after excluding participants with elevated hs-CRP. Participants in the highest hs-CRP decile had a 32% higher likelihood of mortality (aHR 1.32, 95% CI 1.18-1.48). Elevated hs-CRP was associated with cancer and 'other' mortality but not cardiovascular mortality. Elevated AAT is a robust predictor of mortality in older adults, independent of hs-CRP, and may reflect subtle, age-related changes in systemic inflammation. These findings support the potential utility of AAT as a biomarker of biological ageing and mortality risk.

Rationale: Chronic Obstructive Pulmonary Disease (COPD) is considered an aging-associated disease but can have its origin early in life. Chronological age is an imprecise measure of biological aging. To accurately measure biological age and age acceleration, different generations of epigenetic clocks have been developed. Objective: To evaluate the role of epigenetic age acceleration in COPD across adulthood, COPD severity and smoking status and in adults younger than 50 years. Methods: First-, second- and third-generation epigenetic clocks were used to estimate biological aging, telomere length and pace of aging in two cohorts (Lifelines COPD&Control DNA cohort and a Spanish COPD cohort). The association between age acceleration and FEV1%pred, FEV1/FVC and COPD was evaluated. In those clocks with significant associations, the effect of COPD severity, smoking status as well as the mediating role of age acceleration on the association between smoking and lung function levels was assessed. Finally, we investigated if these associations were already present in early adulthood. Results: Age acceleration estimated by second- and third-, but not first-, generation clocks was associated with FEV1%pred, FEV1/FVC and COPD in both cohorts. Associations were strongest in severe COPD cases and current smokers and age acceleration mediated the association between smoking and lung function levels. Importantly, these associations were already present in early adulthood. Conclusion: Epigenetic clock-derived age acceleration relates to lower lung function and COPD and mediated smoking-related lung impairment. As these associations already exist in early adulthood, age acceleration holds potential as tool to identify smokers susceptible to COPD at early age, potentially enabling preventive strategies.

Ageing brings about various biochemical, structural and mechanical alterations within tissues, profoundly impacting cellular behaviour and function. One of the hallmark changes observed with ageing is an increase in cellular microenvironment stiffness, a biomechanical property influenced by intrinsic factors within the cell and extrinsic factors from the surrounding extracellular matrix (ECM). This shift in ECM stiffness has been implicated in the development and progression of several age-related diseases, but the exact molecular mechanisms underlying different organ tissues remain to be fully elucidated. This review examines the lung and ovaries, two organ tissues with distinct functions but interconnected by similar timing of changes in ECM stiffness with age. We discuss common pathways and factors that drive changes in the ECM stiffness of these organs. Such insights may pave the way for innovative treatments addressing the root causes of age-related diseases, ultimately enhancing the ageing population's health span and quality of life.

Respiratory virus infections have been presenting significant global public health challenges. The virulence of SARS-CoV-2 and seasonal influenza largely relies on triggering abnormal host immune responses, particularly the production of a cytokine storm, which is notably increased in elderly patients. However, as the mechanisms underlying this age-associated exacerbation remain unclear, we investigated the role of the aging tissue microenvironment in promoting inflammation associated with viral infection. Our research, based on clinical samples, cellular experiments, and mouse models, provides evidence that the aging lung microenvironment induces severe inflammatory responses and leads to tissue damage, with senescent cells playing a crucial role in this process. Further mechanistic insights reveal that elevated levels of downstream inflammatory factors result from a significant and robust activation of the NF-κB pathway. This increase is attributed to the accumulation of reactive oxygen species in senescent cells and subsequent reduced expression of PDLIM2, an E3 ubiquitin ligase regulating P65 degradation. Finally, restoring PDLIM2 significantly inhibits viral infection-mediated inflammatory responses and organ damage in the aging body. Therefore, this study offers a novel perspective by elucidating the molecular mechanism and exploring the therapeutic potential behind viral infection-related inflammatory responses, particularly the mechanism accelerating inflammatory storms in elderly patients post-infection.

Mast cells (MCs) are innate immune cells primarily located in the papillary layer of the dermis that play a crucial role in the skin immune response by secreting mediators and recruiting effector cells. Increasing laboratory and clinical evidence indicates that MCs are not only passive participants but also key regulators of skin aging. MCs act as sensors and amplifiers of aging-related signals, integrating various stimuli, including the nature of the triggering factor, microenvironmental cues such as senescence-associated secretory phenotype (SASP) factors, and specific activation pathways. Upon activation, MCs release diverse mediators that engage signalling pathways including Fc epsilon RI (FcεRI), c-KIT, Toll-like receptors (TLRs) and Mas-related G-protein-coupled receptor X2 (MRGPRX2) thereby eliciting broad target cell responses. MCs engage in pathological crosstalk with fibroblasts, keratinocytes, melanocytes and immune cells, establishing self-perpetuating feedback loops that amplify aging-related processes. Collectively, these findings highlight the dual and context-dependent roles of MCs as not only protectors but also accelerators of skin aging, positioning them as promising therapeutic targets. The use of novel MC stabilisers such as ketotifen or luteolin, as well as phototherapy and other treatments, shows potential in mitigating skin aging and may offer valuable insights into novel therapeutic targets. Nonetheless, additional studies are required to dissect the underlying mechanisms and optimise targeted therapies to facilitate the development of precision medicine strategies.

Aging research has primarily focused on adult aging clocks, leaving a critical gap in understanding a biological clock across the full life cycle, particularly during infancy and childhood. Here we introduce LifeClock, a biological clock model that predicts biological age across all life stages using routine electronic health records and laboratory test data. To enhance individualized predictions, we integrated virtual patient representations from 24,633,025 heterogeneous longitudinal clinical visits across 9,680,764 individuals and projected them into a latent space. Our approach leverages EHRFormer, a time-series transformer-based model, to analyze developmental and aging dynamics with high precision and develop accurate biological age clocks spanning infancy to old age. Our findings reveal distinct biological clock patterns across different life stages. The pediatric clock is strongly associated with children's development and accurately predicts current and future risks of major pediatric diseases, including malnutrition, growth and developmental abnormalities. The adult clock is strongly associated with aging and accurately predicts current and future risks of major age-related diseases, such as diabetes, renal failure, stroke and cardiovascular diseases. This work therefore distinguishes pediatric development from adult aging, establishing a novel framework to advance precision health by leveraging routine clinical data across the entire lifespan.

Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) and poly (ADP-ribose) polymerase 1 (PARP1) are closely linked to aging and aging-related disorders. However, the underlying mechanisms of AHR-PARP1 axis-mediated DNA repair in countering aging remain largely unknown. In this study, it is found that both aged humans and mice exhibit marked intestinal aging, characterized by gut dysbiosis and dysfunction and DNA damage, compared to their young counterparts. Intriguingly, it is discovered that intestinal AHR activation by indole-3-acetic acid (IAA), which is derived from Lactobacillus salivarius rather than host cells, effectively mitigates intestinal aging by regulating DNA-damage responses. Mechanistically, activated AHR by IAA interacts with PARP1, potentiating PARP1 activity and the polymerization of poly (ADP-ribose) (PARylation) by binding to its promoter. This interaction enhances intestinal barrier function and suppresses inflammation and cell senescence. Finally, the interplay between AHR and PARP1 is confirmed by in vivo and in vitro experiments, including intestine-specific Ahr knockout mice, Ahr and Parp1 knockdown, and Parp1 overexpression in enterocytes. These findings provide a potential intervention strategy targeting AHR-PARP1 axis to mitigate age-related intestinal dysfunction.

This study critically reevaluates the utility of brain-age models within the context of detecting neurological and psychiatric disorders, challenging the conventional emphasis on maximizing chronological age prediction accuracy. Our analysis of T1 MRI data from 46,381 UK Biobank participants reveals that simpler machine learning models, and notably those with excessive regularization, demonstrate superior sensitivity to disease-relevant changes compared to their more complex counterparts, despite being less accurate in chronological age prediction. This counterintuitive discovery suggests that models traditionally deemed inferior might, in fact, offer a more meaningful biomarker for brain health by capturing variations pertinent to disease states. These findings challenge the assumption that accuracy-optimized brain-age models serve as useful normative models of brain aging. Optimizing for age accuracy appears misaligned with normative aims: it drives models to rely on low-variance aging features and to deemphasize higher-variance signals that are more informative about brain health and disease. Consequently, we propose a recalibration of focus towards models that, while less accurate in conventional terms, yield brain-age gaps with larger patient-control effect sizes, offering greater utility in early disease detection and understanding the multifaceted nature of brain aging.

Preserving genomic integrity is crucial for the accurate transmission of genetic information across generations, as well as for preventing precocious ageing. The DNA Damage Response (DDR) safeguards the genome from genotoxic stress through a coordinated system of sensors, relay proteins, and repair mechanisms. Since DNA repair is an energy-intensive activity, the process is tightly regulated and coordinated with various metabolic pathways. The nutrient-sensing insulin/IGF signalling (IIS) pathway has been extensively studied for its role in ageing and lifespan regulation in C. elegans through its downstream FOXO transcription factor DAF-16. However, there is limited understanding of its involvement in maintaining genomic integrity through the regulation of the DDR. In this study, we demonstrate the role of DAF-16/FOXO in preserving genome integrity by activating the expression of DDR repair genes in C. elegans. Activated DAF-16/FOXO directly binds to the promoter of DDR genes under conditions of low IIS, ensuring that their expression is maintained at a higher level, which is crucial for prompt DNA damage repair. Interestingly, we find that DAF-16 functions both cell autonomously as well as non-autonomously to support DNA integrity. We also determine that the DAF-16(d/f) isoform, but not the DAF-16(a) isoform, is essential for maintaining germline genome integrity. Furthermore, DAF-16 activation enhances the DDR primarily through the canonical DDR components and, to a lesser extent, via apoptosis-mediated clearance of damaged cells. Overall, our study highlights a new role for DAF-16/FOXO in the DDR and the preservation of genome integrity.

Variations in age-related lung function decline are associated with genetic and environmental factors. The genetic variants contributing to this decline remain largely unknown, limiting the understanding of individual susceptibility and potential interventions. This study aims to uncover the genetic factors associated with lung function decline, using the Lifelines cohort study. Longitudinal data covering 3 visits and approximately 15 years follow up from 165,138 individuals were available. Genotyping and longitudinal spirometry data were present for 24,749 subjects aged 25 or older at baseline. A three-step approach was used. First, lung function change over time was estimated using a linear-mixed effect model. Second, a genome-wide association study for the estimated change was conducted, adjusting for age, sex, smoking load and the first 10 principal components. Third, single nucleotide polymorphisms (SNPs) with p-value<1x10-5 were analysed using a linear-mixed effect model. Selected SNPs were tested in two independent cohorts (N=1,376 and N=27,249), followed by meta-analysis. Among the included individuals, 19,722 had spirometry at two timepoints and 5,027 at three, with median [IQR] follow-up of 8.1 [4.4, 10.4] and 12.1 [11, 13.6] years, respectively. We identified 67 variants suggestively associated with lung function decline (p<1x10-5). Rs150094594, was significant (P=0.007) in a replication cohort with consistent effect direction. This intergenic variant, not previously reported, reached genome-wide significance in the meta-analysis (rs150094594:T, {beta}(SE): 15.9(2.7) ml/year, p-value=3.9x10-9). This study shows a role of genetics in lung function decline, emphasizing the importance of exploring the interplay between genetic and environmental factors.

The heart uses various nutrient sources for energy production, primarily favoring fatty acid oxidation. Although ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging.

The senescent microenvironment, defined as the cellular environment surrounding senescent cells, plays a pivotal role in tissue degenerative diseases by promoting inflammation, disrupting extracellular matrix homeostasis, and inducing senescence in neighboring healthy cells. By analyzing the etiology of the senescent microenvironment in intervertebral disc degeneration (IVDD), senescence-associated secretory phenotype (SASP)-positive nucleus pulposus cells (NPCs) and pro-inflammatory macrophages were considered the most likely primary contributors to this pathological microenvironment. Inspired by these findings, we developed an on-demand collaborative delivery system that concurrently suppresses the SASP in senescent NPCs and reprograms macrophages to attenuate intervertebral disc degeneration. Mechanistically, this delivery system collaboratively reshaped the senescent microenvironment by sustainably releasing interleukin-37 (IL-37) to inhibit SASP progression via the NF-κB pathway and delivering itaconate to macrophages through PLGA nanoparticles to activate the Nrf2 pathway. Notably, this on-demand collaborative delivery system reduced senescence in NPCs from 55.44 ± 2.95% to 5.54 ± 1.35%, achieving a 90% reduction, confirming its efficacy in modulating the senescent microenvironment. Consequently, based on the pathological mechanism, this study proposes a targeted microsphere strategy for senescent microenvironment reconstruction, thereby offering a potential therapeutic avenue for degenerative tissue repair.

Skeletal muscle aging is associated with oxidative stress and mitochondrial dysfunction. Peroxiredoxins (PRDXs), particularly PRDX3 and PRDX5, are antioxidant enzymes that are uniquely localized to mitochondria. While PRDX3 has been reported to play a role in maintaining mitochondrial function in muscle, the specific function of PRDX5 in muscle remains unclear. This study investigated the role of PRDX5 in mitochondrial function, myonuclear distribution and muscle aging.

Cardiac biological aging results in vascular, structural, and electrical changes that account for age-related cardiovascular disease. Using techniques such as deep neural networks, Artificial Intelligence (AI) based analysis of signals such as ECGs and echocardiograms has revealed that patients age at different rates, and that differences between AI-estimated age and chronological age ("age gaps") are associated with long-term survival. However, so far, cardiac biological aging has focused on single modality estimation and in addition has not yet been evaluated using coronary angiograms. In this study, we first developed a cardiac age estimation model using coronary angiograms. Then, in a group of 1,345 patients who had an echocardiogram and ECG within one month of their angiogram, we examined how patient survival was associated with age gaps in each modality in isolation (using previously developed models for echocardiograms and ECGs) and then across the three modalities combined. For the average across the three modalities, we observed a hazard ratio (HR) of 2.24 (95% confidence interval: 1.71-2.92) per unit increase in the age gap, which was a marked increase compared to each modality on its own (HR of 1.63, 1.54, and 1.24 for angiograms, echocardiograms, and ECGs respectively). This result demonstrates that the predictive value of AI-estimated cardiac age compounds with additional inputs. While angiograms are not practical for routine monitoring, they serve as proof of concept that richer vascular imaging can enhance biological age prediction. As interventions targeting aging emerge, we will need objective tools to measure their impact. Multi-modal cardiac age may provide a scalable, interpretable marker of cardiovascular aging and possibly even rejuvenation.

Decreased telomerase expression, telomere shortening, senescence-associated markers, and inflammation have all been independently observed in the ageing brain and associated with disease. However, causality between limited telomerase expression and brain senescence and neuro-inflammation in the natural ageing setting is yet to be established. Here, we address these questions using the zebrafish as an ageing model. Akin to humans, zebrafish display premature ageing and death in the absence of telomerase and telomere shortening is a driver of cellular senescence. Our work shows for the first time that telomerase deficiency (tert

Cellular senescence is traditionally viewed as a terminal state of cell-cycle arrest accompanied by widespread molecular remodeling, yet its underlying regulatory logic and progression remain poorly understood. Here, we combined quantitative phase microscopy and normalized Raman imaging with quantitative proteomic and phosphoproteomic profiling to examine human RPE1 cells undergoing doxorubicin-induced senescence. Senescent cells did not reach a steady state but instead exhibited sustained, unbounded growth over a 12 day period, marked by a continuous rise in dry mass and volume coupled with declining mass density. Time resolved proteomics revealed extensive and asynchronous remodeling across organelles, with lysosomal, ER, and Golgi proteins increasing in abundance, whereas nuclear and mitochondrial proteins declined, indicating large scale reorganization of cellular composition. Phosphoproteomic inference linked these structural shifts to regulatory signaling, confirming the expected downregulation of CDK activity while revealing coordinated activation of stress and DNA damage responsive kinases such as CAMK2D, DNAPK, and MARK family members. Together, these integrated data depict senescence as a dynamic, actively regulated state, maintained through coordinated remodeling of proteome composition and signaling activity rather than passive arrest. Our findings highlight how combining quantitative biophysical measurements with multi-layered molecular profiling exposes the regulatory architecture that sustains the senescent phenotype and its loss of internal homeostasis.

A loss of proteostasis is a primary hallmark of ageing that has emerged from mechanistic studies in model organisms, but little is currently known about changes to proteostasis in the muscle of older humans. We used stable isotope labelling (deuterium oxide; D2O) in vivo, and peptide mass spectrometry of muscle samples to investigate differences in proteome dynamics between the muscle of younger (28 {+/-} 5 y; n=4) and older (69 {+/-} 3 y; n=4) men during either habitual activity or resistance exercise training. We quantified the abundance of 1787 proteins and the turnover rate of 1046 proteins in bi-lateral samples of vastus lateralis (n=32 samples total) taken before and after a 15-day program including 5 sessions of unilateral leg-press exercise (3 sets of 10 repetitions at 90% of 10 RM). Our protein abundance profiling revealed a stoichiometric imbalance within the proteostasis network in aged skeletal muscle, including subunits of eIF3, subunits of 40S and 60S ribosomal proteins. The rate of bulk, mixed-protein synthesis was not different between younger and older men, but most ribosomal proteins were less abundant in the muscle of older participants, suggesting ribosomes in older muscle may exhibit increased translational efficiency to maintain similar levels of protein turnover compared to ribosomes in younger muscle. Resistance exercise partially restored age-related disruptions to the proteostasis network. In older skeletal muscle, resistance exercise specifically increased the absolute turnover rate (ATR) of mixed mitochondrial proteins, with increased fractional turnover rate (FTR) of prohibitin 1 (PHB1) and profilin-1 (PROF1), and increased abundance of prohibitin 2 (PHB2). These adaptations may suggest resistance exercise promotes mitochondrial proteostasis by facilitating the synthesis and maintenance of key mitochondrial proteins. Thus, our Dynamic Proteome Profiling data provide an impetus for further exploration of the role of proteostasis in maintaining skeletal muscle quality and supports resistance exercise as a potential therapeutic strategy to promote healthy skeletal muscle ageing in humans.

Postmenopausal osteoporosis (PMOP) manifests as a systemic skeletal disorder arising from disrupted bone metabolic equilibrium, characterized by a marked reduction in bone mineral density and compromised microarchitectural integrity, ultimately leading to increased bone fragility and greater fracture susceptibility. Current delivery therapeutic strategies frequently fail to address mitochondrial dysfunction arising from estrogen depletion and senescence-associated processes. We developed a multifunctional coacervate system, in which peptide coacervates were used to encapsulate estradiol (E2) and subsequently coated by a metal-phenolic network (MPN), capable of concurrently modulating mitochondrial function and reconstructing bone homeostasis. The MPN-coated coacervates demonstrate microenvironment-responsive degradation within osteoporotic bone tissue. In ovariectomized aged mouse models, intravenous injection of these coacervates significantly increased bone volume in both the femur and vertebrae while mitigating side effects on the uterus. This unique therapeutic paradigm establishes a bidirectional regulatory mechanism that provides a promising strategy for comprehensive osteoporosis management.

Aging is characterized by a coordinated functional decline across multiple organs. While cell-autonomous mechanisms contribute to local aging phenotypes, the systemic synchronicity of aging suggests a major role for cell non-autonomous drivers. Emerging evidence implicates the hypothalamus-a central regulator of neuroendocrine and homeostatic functions-as a potential source of circulating pro-geronic signals. A hallmark of brain aging is the accumulation of senescent cells, particularly in microglia and brain microvascular endothelial cells, including within the hypothalamus, which contributes to a heightened state of neuroinflammation and altered systemic signaling. Here, we tested the hypothesis that brain senescence and its associated inflammatory milieu promote peripheral aging by reshaping the systemic environment. To model this, we employed targeted whole-brain irradiation (WBI) in young mice-a well-established method to induce widespread brain cellular senescence and neuroinflammation, mimicking changes seen in natural aging. Two months after WBI, we performed transcriptomic profiling of the heart to evaluate remote, cell non-autonomous effects. Cardiac RNA sequencing revealed a striking overlap in gene expression changes between WBI-treated young mice and naturally aged controls. Notably, several gene sets associated with fundamental cellular and molecular mechanisms of aging were concordantly dysregulated in both groups, with strong enrichment for pathways related to mitochondrial metabolism, immune activation, interferon signaling, and extracellular matrix remodeling. These findings demonstrate that localized brain senescence is sufficient to induce aging-like transcriptomic remodeling in peripheral organs, likely mediated by circulating factors. Our findings establish brain senescence as a key orchestrator of systemic aging-a mechanism that may contribute to accelerated aging trajectories in individuals with lifestyle-associated increased brain senescence and neuroinflammation, as well as in cancer survivors exposed to senescence-inducing treatments such as whole-brain irradiation.