Longevity Papers

Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.

Drosophila has long served as a powerful model for investigating locomotor behavior, and geotaxis assays have generated valuable insights into genetics, aging, and neurobiology. Nonetheless, their use can be constrained by subjective scoring, modest throughput, and challenges in reproducibility. To complement and extend these classical approaches, we developed and validated an integrated hardware-software platform that enables automated, high-resolution locomotor analysis across 12 vials in parallel. The system integrates 3D-printed mechanical components, Raspberry Pi-based video acquisition, and programmable environmental controls to ensure standardized conditions. A deep learning pipeline segments vials with near-perfect accuracy (IoU > 0.95), while computer vision algorithms quantify climbing trajectories, velocity, and positional zone occupancy at 60 frames per second. The end-to-end workflow converts raw video into time-resolved metrics, supports sex-specific aggregation, and incorporates advanced statistical analyses, including Linear Mixed Effects regression, harmonic mean p-values, and Mann-Whitney U tests. Relative to manual scoring, this automated pipeline yields 2.8-fold faster processing and nearly 800-fold higher data density. Application of the platform uncovered reproducible phenotypes of multiple genotypes. For example, a circadian mutant known as ClockOut, males displayed progressive climbing deficits with age, whereas females-maintained age-resilient trajectories. Moreover, male ClockOut exhibited a reduced performance compared to age-matched control (w1118), however, female ClockOut showed subtle reduction in performance. Additionally, glial-specific knockdown of PolG, encoding the DNA polymerase gamma catalytic subunit, revealed striking sex-dimorphic aging patterns: females outperformed controls at older age, while males exhibited marked decline. To promote broad adoption, a user-friendly Python interface (Tkinter GUI) enables accessibility independent of computational expertise. Collectively, this standardized, high-throughput framework advances the resolution of genotype-, age-, and sex-dependent locomotor dynamics, offering new opportunities in aging, circadian biology, and neurodegeneration research.

Brain aging involves synapse decline, with astrocytes playing a key role in synapse homeostasis. However, the impact of astrocyte senescence on synaptic dysfunction and cognitive decline remains unclear. Here, we identified a hallmark of aging astrocytes Senescent Astrocytic Deposits (SAD) observed at aged rodents, macaques, and human hippocampal astrocytic processes that is associated with tripartite synapse dysfunction and memory decline. Laser capture microdissection-coupled mass spectrometry (LCM-MS), spatial transcriptome analysis and 3D electron microscopy revealed that SAD are abnormal protein deposits at the processes of ApoE-high expression astrocyte subtype and associated with dysfunctional tripartite synapses. Using a transgenic mouse (Nrbf2 knockout) with accelerated SAD formation as a tool for genetic manipulation, we clearly demonstrated that age-dependent defect of phagocytosis at maturation stage in astrocytic drives SAD accumulation, synaptic injury and cognitive deficits. Collectively, our findings establish SAD as a mechanistic link between astrocyte senescence and synaptic damage, underscoring the critical role of astrocytic phagocytic function in preserving synaptic homeostasis and cognitive function during aging.

Age-associated changes in intestinal permeability and function have not been studied in domestic cats, leaving a key factor in the relationship between age and digestive health in cats unexplored. Due to factors not currently understood, mature and senior cats may experience a loss of fat and protein digestibility, along with a loss of body weight (BW), impacting lifespan and quality of life. Therefore, to establish the relationship between age and intestinal health, intestinal permeability and absorptive capacity were quantified in young and senior cats using a differential sugar absorption test (SAT) on cat plasma. A solution containing four different sized sugars was orally administered to 36 healthy mixed-breed domestic shorthair cats (male (n = 21) and female (n = 15)) split into two groups by age, young 2.40 ± 0.758 (n = 21) and senior 11.23 ± 1.896 (n = 15) years (mean ± SD). Blood was collected before and again 3 h after dosage and plasma was analysed using liquid chromatography mass-spectrometry (LC-MS). Intestinal permeability was higher (p = 0.004) in senior cats than young cats, and was not affected by sex (p = 0.288), sampling date (p = 0.652), or BW (p = 0.951). Absorptive capacity was higher (p = 0.033) in male cats than females, and was not affected by age class (p = 0.440), sampling date (p = 0.580), or BW (p = 0.652). In conclusion, intestinal permeability was higher in older cats and suggests age-related changes in intestinal barrier structure and function. These findings highlight the need to further consider increased intestinal permeability as a cause of reduced nutrient digestibility in older cats, offering a new target for interventions to enhance their health and well-being.

To determine whether exercise of higher intensity can elicit greater improvements in body composition among older adults, given that body composition is implicated in the progression of chronic disease.

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.

We present an optimised luminometric method for measuring muscle mitochondrial ATP production rate (MAPR), adapted to a 96-well microplate format. The enhanced assay enables quantification of ATP production from 12 or more substrate combinations within 15 min, using only 10 μL of isolated mitochondria. The method demonstrates high accuracy and precision, with a validated measurement range of 0.3-70 nmol/min/L. To support clinical interpretation, a reference dataset was established from 92 individuals aged seven months to 79 years. All these individuals were referred for muscle biopsy but were subsequently deemed unlikely to have a mitochondrial disorder following comprehensive clinical evaluation. An overview of the current version of our assays for oxidative phosphorylation (OXPHOS) enzymes is also provided. As proof of concept, we present three patients carrying pathogenic variants in mitochondrial DNA (ATP6 and MT-TL1) and the nuclear PDHA1 gene. All exhibited decreased MAPR with one or more substrates, along with additional clinical, biochemical, and morphological features consistent with mitochondrial disease. Furthermore, we illustrate the age-dependent development of MAPR in muscle across the human lifespan, demonstrating a 60-80 % higher maximal capacity for oxidative ATP production in adults compared with young children. In contrast, MAPR supported by fatty acid-derived substrates remains unchanged over the same period. In conclusion, the improved MAPR assay offers a robust and efficient tool for assessing mitochondrial function in both clinical diagnostics and research. Its high-throughput format and reliable performance make it particularly well-suited for the investigation of suspected mitochondrial disorders.

Dendritic arbors are essential for neuronal computation and signal propagation, yet large-scale single-neuron morphology studies remain challenging. Here we present a systems biology approach, termed 'dendritome mapping', to profile the dendritic morphology of genetically defined single neurons in mice, unveiling striatal medium spiny neuron (MSN) morphological territories and aging-associated or disease-associated alterations. We generated 3,762 three-dimensional-reconstructed and reference-atlas-mapped striatal D1-type and D2-type MSNs, revealing distinct impacts of D1/D2 genotypes and striatal locations on MSN morphology. To analyze dendritic variation at a finer resolution than known anatomical landmarks permit, we assigned MSNs to latticed cubic boxes within the reference brain atlas, summarized a morphometric representation ('eigen-morph') for each box and clustered boxes with shared morphometry. This identified six modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found that aging confers dendritic atrophy in both D1-MSNs and D2-MSNs, whereas Huntington's disease mice exhibit MSN-type and regional-specific defects.

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.

As humans age, the aorta stiffens, diminishing its essential shock absorber function. This increased stiffness transmits higher pressures to downstream vessels in the kidney, brain, and heart, contributing to hypertension and end-organ damage. Although multiple mechanisms involving extracellular matrix (ECM) remodeling and vascular smooth muscle cell (VSMC) contributions to aortic stiffness have been described, additional molecular players likely remain uncharacterized. Dystrophin (DYS) and the dystrophin-associated proteins (DAPs) are cytoskeletal stabilizers known for protecting skeletal muscle cells from contraction-induced damage but are poorly characterized in VSMCs. Loss of DYS has been linked to myocardial stiffness and carotid artery abnormalities. Here, we investigated the function of DYS in biomechanical properties of the mouse aorta. We demonstrated by immunofluorescence that DYS and DAPs are expressed and colocalize in freshly dissociated murine VSMCs. The mdx model, a known dystrophin knockout mouse model, was used to investigate the consequences of lack of dystrophin expression on aortic geometry and biomechanics. In mdx mice, we observed decreased aortic wall thickness but no significant difference in diameter compared to wild-type (WT) mice. This significant difference in aortic geometry is directly related to ex vivo stress and stiffness. We measured aortic stiffness by high-frequency small-amplitude sinusoidal length perturbation and determined dystrophin is essential to maintain normal stiffness and stress at baseline. This suggests that extracellular matrix components in the mdx aorta are contributing to the increased stress and stiffness at baseline. We also determined that DYS is not required to maintain normal stress and stiffness due to the contractile response to depolarization by high K + or alpha-agonist, phenylephrine-induced contraction. Finally, we revealed by Western blot that DYS and alpha-sarcoglycan, a DAP, expression is decreased in aged vascular smooth muscle. Previous studies show that matrix metalloproteinase-2 (MMP2) can degrade DYS in cardiac tissue and that MMP2 activity increases with age in vascular tissue. While we did not directly assess MMP2 in this study, we propose its role as a hypothesis for future exploration. In summary, this study identifies a novel role for DYS in maintaining aortic mechanical integrity and presents evidence that aging diminishes DYS and DAP protein expression in VSMCs.

Lifelong learning is essential for active aging, yet interactive learning remains underexplored in older adults. Using fNIRS-based hyperscanning, this study investigated instructor-learner neural interactions in older learners during a concept learning task. Study 1 compared passive and active learning approaches in younger and older learners, while Study 2 compared intergenerational (younger instructors) versus intragenerational (older instructors) learning among older learners, using the more effective approach from Study 1. Older adults performed better with passive learning (Study 1) and when taught by younger instructors (Study 2). Passive learning increased frontopolar interpersonal neural synchronization (INS), while intergenerational learning enhanced INS in both frontopolar and dorsolateral prefrontal regions. Intersubject representational similarity analysis (IS-RSA) showed that learners with similar performance exhibited greater neural similarity in the frontopolar cortex. These findings reveal the neural basis of interactive learning in aging and offer practical guidance for optimizing educational practices in older populations.

Aging affects oral health and skeletal muscle, but the associations between oral diseases and possible sarcopenia remain understudied, especially in low-income regions. Thus, the study aimed to explore this relationship and potential mediating pathways.

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.

Global aging presents significant socioeconomic and health challenges, particularly for older adults who face an increased risk of chronic diseases and reduced physical activity levels. Although physical activity is crucial for maintaining health, most older adults do not meet the recommended guidelines. Gamification and mobile health (mHealth) technologies offer innovative solutions to motivate physical activity; however, research focusing on older adults is limited, especially regarding the effectiveness and sustainability of such interventions.

As research has shown that participation in leisure activities (LAs) is closely related to health outcomes in later life, we explored the associations between dynamic changes in LAs and disability in activities of daily living (ADL) in older people.

This study investigates the association of parental clinical manifestations with newborn telomere biology and immune senescence markers, utilising 204 parent-newborn triads in Karachi, Pakistan. The demographic data collection was followed by quantification of telomere length (TL) using quantitative PCR, while Sanger sequencing was performed to analyse variants in telomerase genes [Telomere Reverse Component (TERC) and Telomerase Reverse Transcriptase (TERT)]. Moreover, flow cytometry was used to analyse immune senescence markers CD57 and Killer cell lectin-like receptor G1 (KLRG1).

It is well established that the composition of the human microbiome changes with age; however, limited research has explored the association between the oral microbiome and aging, as well as its potential for age prediction. In this study, we investigated the correlation between the oral microbiome and age by analyzing samples from 150 individuals across a wide age range (6-78 years). The observed species richness and Chao1 index significantly increased with age. Permutational multivariate analysis of variance (PERMANOVA), using both Bray-Curtis and Jaccard distances, identified age as a major factor influencing microbial variation. After a comprehensive comparison of four different oral microbiome data processing approaches, we then developed an ensemble model based on binarized oral microbial data, incorporating an eXtreme Gradient Boosting (XGBoost) algorithm with 32 classifiers. This ensemble model achieved a mean absolute error (MAE) of 7.20 years in the independent validation set (

Skeletal muscle remodeling affects muscle functionality, quality and mass. The protein density is an important determinant of muscle quality, that can be readily assessed, but which is rarely reported. This study assessed how muscle protein density responds to challenges such as exercise, injury, immobilization and disease, and associated this with measures of lean mass, radiodensity, functionality and damage. The protein density was determined in human muscle biopsies from older adults (65-83 years) and young males (18-35 years), and in murine muscles. The protein density was compared between challenged conditions (disease, injury, eccentric exercise, immobilization) and a control condition, and/or associated with i) measures of muscle volume and radiodensity (via computed tomography), ii) molecular measures of damage and iii) measures of strength. Protein density correlated with upper leg lean mass (r=0.4468; p=0.0371) and radiodensity (r=0.5085; p=0.0157) in older adults. Eccentric exercise decreased the protein density with 9% (p=0.0248) in young adults, which correlated with decreases in strength (r>0.79; p<0.01). In murine disease and injury models, muscle loss (-12%; -90%; p<0.01) was accompanied by a loss of protein density (-3; -21%), in a muscle- and time-dependent way. Interestingly, the immobilization-induced muscle loss (-16%; p=0.0069) was accompanied by a higher protein density (+8%; p=0.0293) compared to the non-immobilized leg. In conclusion, muscle protein density associates with muscle mass and muscle function. Muscle protein density can be a valuable biomarker that provides more insights into the mechanisms that underlie muscle adaptations due to disease, aging, injury and exercise.

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.

Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth

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

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, chronic hyperglycemia, and pancreatic β-cell dysfunction, driven in part by cellular senescence and chronic inflammation. The sirtuin 1 (SIRT1) and mechanistic target of rapamycin (mTOR) pathways play critical roles in regulating cellular metabolism, stress responses, and aging, making them key targets for mitigating β-cell senescence and T2DM progression. SIRT1, a NAD + -dependent deacetylase, enhances insulin secretion, reduces oxidative stress, and suppresses inflammation by modulating transcription factors such as NF-κB and PGC-1α. Conversely, mTOR signaling, when hyperactivated, promotes cellular senescence and metabolic dysfunction. Exercise has emerged as a potent non-pharmacological intervention. It upregulates SIRT1 activity through increased NAD⁺ levels and AMP-activated protein kinase (AMPK) activation, while also downregulating excessive mTOR signaling. These effects enhance autophagy, reduce oxidative stress, and improve mitochondrial function, thereby preserving β-cell mass and function. Preclinical and clinical studies demonstrated that exercise-induced SIRT1 activation and mTOR inhibition mitigate β-cell senescence, improve glucose homeostasis, and reduce the risk of T2DM. Pharmacological strategies targeting SIRT1 activation and mTOR inhibition, such as NAD + boosters and rapamycin analogs, show promise in preclinical models but require further clinical validation. Understanding the interplay between the SIRT1 and mTOR pathways offers novel therapeutic avenues for preserving β-cell function, preventing T2DM, and promoting healthy aging. Future research should focus on optimizing exercise regimens and developing targeted interventions to harness the synergistic benefits of SIRT1 activation and mTOR inhibition in metabolic health.

To assess associations between blood nicotinamide adenine dinucleotide (NAD) levels and laboratory parameters at baseline and after 60 days of nicotinamide mononucleotide (NMN) supplementation. Post hoc analysis of a randomized, double-blind, clinical trial of daily NMN (300, 600, or 900 mg) or placebo in healthy middle-aged participants. Among the 80 participants (49.4 ± 6.8 year), the baseline NAD was 7.21 [5.5, 10.6] nM. Every 1 nM higher baseline NAD level was associated with 0.24% (95%CI: 0.05-0.44) higher lymphocytes, - 0.36% (95% CI: - 0.57 to - 0.14) lower neutrophils, 0.023% (95% CI: 0.011-0.036) higher triglycerides, - 0.009% (95% CI: - 0.015 to - 0.003) lower high-density lipoprotein, 0.02% (95% CI: 0.004-0.035) higher alanine transaminase, 0.01% (95% CI: 0.0003-0.021) aspartate transaminase. Every 1 nM increase in the NAD level was associated with an increase in hemoglobin of 0.027% (95% CI: 0.01-0.045), red blood cells (RBC) of 0.025% (95% CI: 0.009-0.042), mean corpuscular hemoglobin concentration of 0.016 g/dL (95% CI: 0.008-0.025), and uric acid of 0.02% (95%CI: 0.003-0.038). Higher baseline NAD levels are associated with inflammatory, lipid, and liver profiles. NMN-induced increases in blood NAD are associated with an increase in RBC parameters, potentially indicating enhanced oxygen-carrying capacity.

This work develops a biophysical theory in which a bioelectric field V(x,t) and a cortical stress field sigma(x,t) are weakly and reciprocally coupled. Because the mechanical sector includes an inertial-viscoelastic element, the coupled system supports two underdamped normal modes whose interference defines a measurable slow cadence f_slow = (omega_{+,r} - omega_{-,r}) / (2 pi). Sampling the dynamics at the neutral moment (the recurring near-symmetric crossing between the two sectors) produces an even circle map (mod pi) for the slow phase, with effective forcing Omega and coupling K2. Both Omega and K2 can be computed a priori from directly measurable electrical and mechanical properties of the tissue (membrane time constant tau_m, cortical stiffness kappa, viscosity eta, effective areal inertia rho_eff, diffusion constants D_V and D_sigma, and weak electromechanical gains gamma, beta_R, beta_I), without arbitrary integer fitting. Helical quantization then appears as a mode-locking problem: the canonical B-DNA rotation number n ~ 10.5 corresponds to the high-order lock rho_pi = 2/21, whose center in this even (mod pi) convention is Omega_{2/21} = pi * (2/21) ~ 0.2992 rad. We define a functional order parameter Lambda as the cross-spectral coherence C_{Vsigma}(f_slow) between V and sigma at f_slow. We hypothesize that high Lambda inside the 2/21 tongue is associated with more stable spindle orientation and cortical anchoring during division, constraining chromatin torsion and supporting controlled proliferation and differentiation. Drifting out of that tongue suggests two generic failure modes: (i) persistent unlocking with low Lambda and elevated spindle-angle dispersion (dysregulated proliferation and abnormal division geometry), and (ii) over-locked, low-plasticity states with a rigid slow cadence (aging-like overlock/drift). The model yields three preregisterable and falsifiable predictions. (P1) Homeostatic epithelia exhibit a shared narrow slow-band cadence in both V and sigma, together with a coherence peak Lambda = C_{Vsigma}(f_slow). (P2) The point (Omega, K2), obtained from those directly measurable properties together with neutral-moment stroboscopy, lies inside the 2/21 Arnold tongue while avoiding broad low-order tongues. (P3) A weak, frequency-specific electrical or mechanical drive at f_slow is predicted to increase Lambda and reduce spindle-angle dispersion, whereas a matched off-resonant control should not. This study provides analytical bounds, a numerical sandbox, and preregistered analysis code, enabling direct experimental falsification using combined optical electrophysiology and mechanical readouts.

Experiments on yeast show that the nuclear pore complex has a central role in the loss of chromosomes associated with aging.

Aging is a time-dependent decline in physiological function that reduces quality of life. In traditional Chinese medicine (TCM), aging is viewed as "deficiency" complicated by blood stasis and qi stagnation. "Kang Shuai Lao Pian" (KSLP) is a Ming Dynasty herbal formula widely used to repenish qi, nourish yin, calm the heart, and tranquilize the mind.

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.

In people living with HIV (PLWH), persistent viral replication and antiretroviral therapy (ART)-associated toxicity contribute to T cell exhaustion, characterised by significant metabolic reprogramming that negatively impacts cellular function and longevity. Understanding the metabolic dysregulation in exhausted T cells could unveil novel therapeutic strategies to rejuvenate immune responses in PLWH. This study investigated the prevalence and metabolic gene expression profiles of exhausted CD8

Osteosarcopenia, characterised by concurrent bone loss and muscle atrophy, presents a significant challenge in aging populations, particularly in postmenopausal women. The current therapeutic options potentially treat bone and muscle loss independently, highlighting the importance of an integrated approach. This study aimed to investigate the effects of branched-chain amino acid (BCAA) supplementation on muscle and bone health using ovariectomised (OVX) mice, a model for postmenopausal osteoporosis and sarcopenia.

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.

Aging is a primary risk factor driving the increased prevalence of cardiovascular diseases, significantly contributing to global mortality and healthcare burdens. Aging-related alterations, including genomic instability, telomere shortening, and loss of proteostasis, underpin the pathogenesis of numerous cardiovascular conditions such as heart failure, arrhythmia, cardiomyopathy, myocardial infarction, and atherosclerosis. Recent insights into molecular and cellular mechanisms highlight the roles of senescence, inflammation, mitochondrial dysfunction, and metabolic disturbances in cardiovascular aging. Cellular and vascular senescence further accelerates the development of aging-related cardiovascular diseases. Emerging therapeutic strategies targeting these pathways, such as metabolic regulators, senolytic agents, antioxidants, stem cell-derived exosomes, and natural bioactive compounds, offer promising avenues for mitigating aging-related cardiovascular pathology.

Epigenetic clocks, based on DNA methylation profiles at CpG sites, are widely recognized as reliable biomarkers of biological aging. However, common single-nucleotide polymorphisms (cSNPs), genomic variants that can overlap CpG sites, may affect DNA methylation profiles in ways that potentially interfere with the accuracy of epigenetic clocks. Moreover, because the prevalence of cSNPs varies across populations, such cSNP-CpG overlaps may differentially affect the age predictions of epigenetic clocks in diverse cohorts. Here, we present the first systematic cross-ancestry evaluation of cSNP robustness in the epigenetic clock, examining how cSNP-CpG overlaps affect the performance of epigenetic clocks across nine major genomic ancestry groups. We employed three complementary strategies: (a) testing whether cSNP-CpG overlaps are overrepresented in established epigenetic clocks or particular populations, (b) evaluating whether overlapping CpG sites correspond to the most influential aging predictors within clock models, and (c) simulating the effects of cSNP-associated methylation changes on predicted biological age. Our findings indicate that cSNP-CpG overlaps are not enriched among the CpG sites used in current epigenetic clocks, nor do they tend to involve the most influential sites. Furthermore, our simulation analysis revealed that current epigenetic clocks appear robust to cSNP-related methylation variations. Our findings underscore the overall stability of current epigenetic clocks, even in the presence of population-specific cSNP-CpG overlaps that are known to affect DNA methylation levels.

Influenza remains a major threat to human health, especially for the elderly. Aging leads to substantial changes to lung function, gut microbiota, and white adipose tissue (WAT)-a key endocrine organ regulating energy balance and lipid metabolism. In the current study, we performed a multi-omics analysis to investigate how influenza impacts the gut-lung-adipose tissue axis differently with age at days 2, 4, 7, 14, and 28 post-infection (dpi). Compared to young-adult mice, aged mice experienced worse disease outcomes following infection, along with distinct WAT alterations, including impaired browning, heightened inflammation, and reduced innate immune cell recruitment. Age-related differences were also evidenced in infection-driven shifts in gut microbiota. Akkermansia levels rose only in young mice from 4 dpi, while Faecalibaculum and Muribaculum expanded exclusively in aged mice at 7 dpi, the only timepoint at which their abundance correlated with lung pathology. Serum metabolomics at 7 dpi also revealed age-dependent metabolic responses to infection. Compared to their non-infected counterparts, young mice had lower levels of p-Cresol-sulfate and Indoxyl-sulfate alongside higher triglycerides, whereas aged mice showed disrupted glycerophospholipid metabolism. By pinpointing specific gut bacteria as potential probiotics and identifying lipid pathways associated with disease progression, these findings could lead to the development of targeted, age-specific strategies to mitigate influenza severity in the elderly.

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.

Amid global aging, frailty significantly threatens the health of middle-aged and older women. This study is the first to explore the association between reproductive factors (age at first livebirth, number of biological children, reproductive period, age at menopause, age at menarche, and history of abortion) and frailty among middle-aged and elderly Chinese women.

The long-term impact of professional endurance sports on frailty and fall risk in older age remains underexplored. This study examined frailty, physical activity (PA), and health outcomes in older men with and without a history of professional endurance sports. We assessed 200 men aged 60-85 years, 100 former professional endurance athletes (For-A) with ≥ 5 years of competitive experience and 100 age-matched non-athletes (Non-A). Frailty was evaluated using the Frailty Assessment Screening Tool (FAST), PA with the International PA Questionnaire-Short Form, quality of life (QoL) perception via self-report, and falls/hospitalizations via examination. Group differences were tested with Independent t-tests, Mann-Whitney U, and chi-square, while ANCOVA and logistic regression were employed to adjust for current PA. For-A showed lower frailty prevalence (24% vs. 68%, p = 0.001), higher PA (2385 vs. 299 MET-min/week, p = 0.001), better QoL (median 7 vs. 5, p = 0.001), fewer falls (OR = 0.023, 95% CI [0.004, 0.127], p < 0.001), and a non-significant reduction in hospitalizations (OR = 0.414, 95% CI [0.142, 1.202], p = 0.105) in the past year compared to Non-A. Frailty (p = 0.003) and falls (p < 0.001) remained significantly lower in For-A after adjustment for current PA (p = 0.003), but hospitalization differences attenuated. Early-life endurance training is associated with reduced frailty and potentially lower fall risk. While psychological health and hospitalization outcomes appear more dependent on current activity, the potential benefits for mobility, physical performance, continence, and memory suggest the importance of structured youth sports in supporting healthy and resilient aging. Longitudinal studies with diverse populations and objective measures are needed to confirm causality.

Across the evolutionary spectrum, sexual interactions can significantly influence the physiology and somatic aging in various species. In Caenorhabditis, male pheromones, sperm, and seminal fluid shorten the lifespan of hermaphrodites through different mechanisms. However, the specific male seminal fluid proteins responsible for this effect remain unidentified. Here, we find that several of the previously observed physiological changes in mated hermaphrodites require a newly-identified seminal fluid protein. SFP-1 is packaged into secretory vesicles via the phospholipid scramblases ANOH-1 and ANOH-2 in male seminal vesicles, and after mating taken up by intestinal cells via endocytosis. Within these intestinal cells, the NTF2-like domain of SFP-1 interacts with and activates the transcription factor SKN-1, which induces post-mating somatic fat depletion and lifespan reduction. Together, these results define how a male seminal-fluid protein can trigger mating-induced physiological changes in sexual interactions.

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.

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remain unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble Tumor Necrosis Factor (TNF) receptor-II) were available from first- and second-trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offspring's diffusion-weighted MRI data (mean age of offspring at imaging = 59 y; 51% male). We estimated the relationship between each biomarker and region-of-interest's neurite density. Higher first-trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the Cornu Ammonis 3, Cornu Ammonis 4, dentate gyrus, and subiculum subfields. In addition, higher second-trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding the risk of aging-related cognitive changes.

Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 in vulnerable neurons may accompany the primary neuropathology of various neurodegenerative diseases, or represent the hallmark of others, such as amyotrophic lateral sclerosis. Aging is the major risk factor for neurodegeneration, and sufficient to induce accumulation of TDP-43 in chronic cytoplasmic stress granules possibly further maturing to irreversible aggregates. Reduced expression of Fragile X protein (FXP) family members (FMR1, FXR1 and FXR2) in vulnerable neurons is associated with neurodegeneration, and loss of each individual FXP induces overlapping and unique aging-related phenotypes in HAP1 and SH-SY5Y cell models. Therefore, we analyzed consequences of FXP loss on TDP-43 cytoplasmic mislocalization and stress granule formation in fibroblast-like HAP1 FXP knockout cells. FXP loss induced nuclear pore pathology, and passive egress of proteins and RNA was evident upon loss of FXR1 or FXR2. Cytoplasmic mislocalization of TDP-43 was restricted to FXR1 knockout cells upon impairment of nuclear import, and cytoplasmic TDP-43 induced spontaneous stress granules exclusively in FXR2 knockout cells. In contrast, loss of FMR1 had no effect on nucleocytoplasmic exchange or TDP-43. Hence, reduced expression of FXR1 and FXR2 in aging and neurodegeneration may contribute to TDP-43 pathology.

Background: Human aging increases the reliance on vision for walking balance due to age-related declines in proprioceptive and vestibular function. Regular physical activity (PA) may reduce the reliance on visual input during walking. This study examined whether PA levels modulate age-related responses to perturbations of the optic flow that is crucial in the control of human locomotion. Methods: Sixty active and inactive younger (YA and YI: 23.3+/-3.91 y) and older adults (OA and OI: 68.3+/-3.98 y; n=15 for each group) walked on a treadmill in front of a virtual hallway. The walking protocol consisted of 3-minute walking without, and 8-minute with mediolateral optic flow perturbation. Sacrum and heel marker positions and ground reaction forces were recorded. Power spectral density (PSD) of the mediolateral sacrum position and gait parameters were analyzed. Results: The PSD increased more in OA compared to OI adults (p=0.041) while YA and YI adults did not differ. Mean (and variability of) step width and mediolateral margin of stability increased irrespective of age and PA (all p<0.001). During the 8-minute perturbation, OA adults demonstrated greater decreases in PSD than the OI adults (p=0.039). Additionally, the variability in the mediolateral margin of stability reduced more in YA and OA adults compared to YI and OI adults (p=0.048). Conclusion: Higher PA levels in OA adults were associated with stronger immediate responses in body sway to optic flow perturbations compared to older inactive and younger adults. This may support the beneficial effects of physical activity on age-related visual dependency during gait.