Longevity Papers

Global population aging intensifies "inflammaging," a bidirectional link between chronic inflammation and aging-related pathology. Among them, S100A8/A9 forms a positive feedback loop of "aging-inflammation". Here, we systematically review the structure and function of S100A8/A9, including extracellularly promoting leukocyte adhesion and myeloid-derived suppressor cell aggregation, and intracellularly regulating NOD-like receptor protein 3 inflammasome, arachidonic acid metabolism, autophagy, and apoptosis. This review systematically examines system-specific roles of S100A8/A9: in tumors, it fosters immunosuppression and chemoresistance; in the nervous system, it fuels neuroinflammation and neuronal injury via neutrophil extracellular traps and ferroptosis; in the cardiovascular system, it accelerates endothelial aging and plaque instability; in metabolism, it drives adipose dysfunction and insulin resistance; and in muscle, it induces atrophy and frailty. Disease activity, S100A8/A9 expression levels, chemotherapy resistance, and poor prognosis can be used as biomarkers for early diagnosis, risk stratification, and imaging tracing. Accumulating evidence demonstrates robust correlations between elevated S100A8/A9 expression, therapeutic resistance, and adverse clinical outcomes, establishing its utility as a diagnostic biomarker for disease stratification and molecular imaging. Targeting the S100A8/A9-Toll-like receptor 4 axis or neutralizing S100A9 strategies have shown potential in animal models to reduce inflammation and delay disease progression. In conclusion, S100A8/A9 is a core molecule connecting aging, inflammation, and multi-system lesions. Interventions targeting its pathway are expected to provide new strategies for extending healthy lifespans and a theoretical basis for novel and practical anti-aging strategies.

Advances in mass spectrometry and analytical platforms now allow precise qualitative and quantitative profiling of diverse intracellular molecules. The glycome was long considered technically difficult to analyze, and its biological roles remained poorly understood, but recent high-throughput glycomic technologies have greatly simplified its characterization. As a result, new glycan functions are being uncovered, underscoring the importance of using multiple model organisms to dissect the biological roles of the glycome. Caenorhabditis elegans serves as a robust model system for examining the complex interactions between glycosylation, aging, and neurological function. This microscopic nematode provides distinct experimental benefits for elucidating the regulatory role of glycan modifications on lifespan and neural circuit modulation, mechanisms that are conserved across metazoans. This review summarizes current evidence on the roles of the glycome in regulating neuronal function and aging in humans and compares these findings with glycomic features in C. elegans to highlight the advantages of C. elegans as an efficient model system for glycome research.

Lonp1 is the main mitochondrial matrix protease responsible for maintaining mitochondrial proteostasis through the degradation of damaged or misfolded proteins. Although impaired Lonp1 expression or activity has been linked to mitochondrial dysfunction and oxidative stress in peripheral tissues and non-neuronal cells, its role in the brain, and particularly in hippocampal function, remains unexplored. Here, we provide the first in vivo evidence that Lonp1 activity is a critical regulator of mitochondrial redox homeostasis, synaptic integrity, and learning in the hippocampus. We administered the Lonp1 inhibitor Sesamin intranasally to 4-month-old adult Senescent-Acelerated Mouse Prone 8 (SAMP8) mice for 6 weeks. Subsequently, we conducted cognitive tests to assess hippocampal-dependent learning and memory. We also examined Lonp1 proteolytic activity using the FITC-Casein assay, performed Golgi staining to evaluate dendritic spines, and used fluorescent and luminescent probes to investigate mitochondrial function. Interestingly, we selectively impaired Lonp1 function at an early stage of age-related brain vulnerability. Lonp1 inhibition led to the accumulation of mitochondrial Lonp1 substrates and a marked reduction in mitochondrial bioenergetic capacity, as reflected by decreased ATP production and a robust increase in mitochondrial reactive oxygen species (ROS). These redox alterations were accompanied by selective synaptic remodeling, characterized by a reduction in thin dendritic spines without changes in total spine density, and by impaired hippocampus-dependent learning, while memory retention remained preserved. Thus, our findings identify Lonp1 as a previously unrecognized regulator of mitochondrial redox balance and synaptic structure in the hippocampus. Importantly, Lonp1 inhibition recapitulates key features of brain aging, linking defective mitochondrial proteostasis to ROS-driven synaptic vulnerability and cognitive dysfunction. This study establishes Lonp1-dependent mitochondrial quality control as a central node connecting redox dysregulation to synaptic failure and highlights Lonp1 as a novel target for strategies aimed at preserving mitochondrial and cognitive function during aging.

Caloric restriction (CR) has demonstrated benefits in improving individual biomarkers and longevity, but its organ-specific systemic effects remain unclear. We aimed to quantify the effects of long-term CR on longitudinal changes in organ-specific biological age across multiple physiological systems.

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), a nitrogen-containing heterocyclic amine, mainly enters the human body through thermally processed foods and is recognized as a dietary organic pollutant. Although current toxicological studies have focused on the direct health effects of IQ, its pro-gerontic potential remains unknown. In this study, we evaluated the efficacy of a novel synbiotic composed of Lacticaseibacillus rhamnosus NKU FL1-11 and galacto-oligosaccharides against IQ-triggered aging in zebrafish. Multi-biochemical and behavioral analyses revealed that the synbiotic ameliorated IQ-induced locomotor deficits, reduced systemic SA-β-Gal activity, decreased aging markers (Cleaved Caspase3, p16, p21, and p53), enhanced tissue stemness (PCNA), and mitigated fibrosis (α-SMA) and histopathological damage across gonadal, intestinal, renal, and hepatic tissues. Interestingly, we found the synbiotic bidirectionally modulated β-glucuronidase activity, enhancing it in the intestine while suppressing it in the liver, thereby affecting enterohepatic circulation. Gut microbiota remodeling was central to this protection, marked by increased abundance of Cetobacterium, which was linked to elevated production of α-ketoglutaric acid and other organic acids. Mechanistically, the synbiotic suppressed PI3K-AKT/mTOR overactivation and restored FoxO1 expression, a signaling axis essential for its benefits, as confirmed by inhibition assays. Correlation analysis underscored a critical microbiota-metabolite-enterohepatic circulation-signaling axis in mediating the mitigation of IQ-triggered aging and the risk of aging-related disease. These results elucidate the pro-gerontic effects of IQ and reveal the multi-target anti-aging mechanisms of the synbiotic, supporting its potential as a synbiotic product against aging-related phenotypes and providing valuable theoretical insights into the risk management of IQ. Understanding its mechanisms and long-term effects will require further study.

MicroRNA-128-3p (miR-128-3p) has emerged as a crucial regulator of the aging process and age-associated disorders. Recent research highlights the vital role of miR-128-3p in osteoclast (OC) differentiation and the progression of osteoporosis following ovariectomy. Nonetheless, the mechanism by which miR-128-3p influences osteoblast (OB)-mediated bone formation and contributes to bone loss associated with aging is poorly understood. The present investigation began with an analysis of human bone samples, in which we observed that the age-related miR-128-3p increase was negatively correlated with bone formation. In addition, miR-128-3p expression decreased during OB differentiation. Next, we found that OB miR-128-3p conditional deletion (cKO, miR-128-3p

As global life expectancy rises, understanding predictors of survival in extreme old age is crucial. Body mass index (BMI) is a widely used proxy for adiposity and nutritional status. In adults, a BMI between 18.5 and 24.9 kg/m

Human aging is marked by progressive reorganization of large-scale functional brain networks; these brain network changes have been linked to cognitive decline and disease vulnerability. Conversely, while mice have served as powerful models for understanding the molecular and cellular changes that occur over the lifespan, an absence of precise characterization of age-related changes in large-scale functional brain network organization has limited cross-species translational insights. Here, using densely sampled resting-state functional MRI data acquired cross-sectionally and longitudinally in awake mice over a broad range of adulthood (n = 82; 3 to 20 mo), we describe organizational features and age-related alterations of the mouse's functional connectome. Mouse resting-state functional connectivity recapitulates known functional circuits, demonstrating the organizational validity of these signals. Graph theoretic analysis applied to functional connectivity reveals that mice exhibit modular architectures of functional brain network organization and that increasing age is associated with decreasing system segregation, indicative of network dedifferentiation analogous to observations in humans. Notably, mouse resting-state brain networks are more segregated than those of humans [determined using data from the Human Connectome Project and its developmental- and aging-counterparts (n = 1,179; 18 to 90 y)], attributable to mice exhibiting a diminished contribution of long-range functional relationships that integrate distributed systems. Mice also exhibit slower rates of age-related decline in brain network organization relative to humans, highlighting important species differences in functional brain network organization and trajectories of brain network aging. These findings establish a model of large-scale functional brain network aging in mice and provide a translational bridge across species and spatial scales of analysis.

Biological aging varies substantially among older adults and may shape vulnerability to frailty beyond chronological age. We conducted a cross-sectional study of 928 socially engaged elderly men to examine the associations among phenotypic age (PhenoAge) acceleration, frailty-related traits, and circulating metabolites. PhenoAge acceleration, calculated from routine clinical biomarkers, was consistently associated with greater frailty severity, particularly among the old-old and those with lower physical activity. Targeted metabolomic profiling identified serum tryptophan as inversely associated with both PhenoAge acceleration and frailty-related phenotypes. Mediation analyses suggested that tryptophan statistically accounted for part of the association between biological aging and frailty. These patterns were further supported by age-matched sensitivity analyses and an independent external cohort. Together, our findings highlight the close linkage between biological aging, metabolic profiles, and frailty-related traits in actively aging populations and support the potential utility of integrating routine aging metrics with metabolic indicators to inform future longitudinal studies of healthy aging.

Male reproductive aging is a complex physiological process characterized by progressive deterioration in spermatogenesis, hormonal imbalance, and increased susceptibility to infertility and genetic disorders. This review comprehensively summarizes the pivotal molecular mechanisms underlying testicular aging, with emphasis on mitochondrial dysfunction, oxidative stress, DNA damage, autophagy impairment, chronic inflammation, cellular senescence, and dysregulated apoptosis. Accumulating evidence indicates that age-related declines in Sertoli and Leydig cell function disrupt the blood-testis barrier (BTB), impair steroidogenesis, and compromise germ cell support, ultimately leading to reduced sperm quantity and quality. Furthermore, we highlight emerging therapeutic strategies targeting these pathways, including antioxidant agents, DNA repair enhancers, autophagy modulators, and anti-inflammatory compounds. This review provides a mechanistic framework for understanding male reproductive aging and identifies promising targets for intervention to delay testicular aging and preserve fertility in aging men.

The aging of the global population is linked to an increase in age-related diseases. The kidneys undergo both structural and functional declines with age, and aging is a significant risk factor for kidney diseases. Mitochondrial dysfunction is recognized as a crucial factor affecting kidney aging. Although the importance of disrupted mitochondrial homeostasis in renal aging has gained increasing attention, the associations and causal mechanisms have not been systematically summarized.

Gait is increasingly recognized as a vital sign, yet current approaches treat it as a symptom of specific pathologies rather than a systemic biomarker. We developed a gait foundation model for 3D skeletal motion from 3,414 deeply phenotyped adults, recorded via a depth camera during five motor tasks. Learned embeddings outperformed engineered features, predicting age (Pearson r = 0.69), BMI (r = 0.90), and visceral adipose tissue area (r = 0.82). Embeddings significantly predicted 1,980 of 3,210 phenotypic targets; after adjustment for age, BMI, VAT, and height, gait provided independent gains in all 18 body systems in males and 17 of 18 in females, and improved prediction of clinical diagnoses and medication use. Anatomical ablation revealed that legs dominated metabolic and frailty predictions while torso encoded sleep and lifestyle phenotypes. These findings establish gait as an independent multi-system biosignal, motivating translation to consumer-grade video and its integration as a scalable, passive vital sign.

The integration of environmental cues into cellular programs is crucial for cell function. Yet, how this integration is modulated due to cellular aging remains unclear. We propose that the 3D chromatin organization filters these signals and investigated how age-related chromatin changes in human dermal fibroblasts affect responses to mechanical tension and TGF-β. Young fibroblasts exhibited synergistic gene expression enhancement in response to combined stimuli, a response that was markedly blunted or divergent in aged cells. These distinct outcomes correlated with significant age-related differences in chromatin accessibility. We identified the AP-1 complex and other transcription factors with age-specific activity as pivotal in remodeling chromatin and orchestrating these divergent mechanochemical responses during cellular aging. We validated that disrupting AP-1 activity inhibits fibroblast activation by preventing JUNB recruitment to the transcription machinery. Our findings establish chromatin as a key integrator of mechanochemical signals and characterize the age-related alterations to this integration that modify the cellular responsiveness of aged cells, highlighting AP-1 and its network as potential therapeutic targets against age-related decline.

Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPR

Cardiovascular diseases remain the leading cause of global mortality, and early risk stratification is critical for improving prognosis. Artificial intelligence-derived electrocardiography (AI-ECG) provides a promising approach to derive cardiac biological age as a non-invasive digital biomarker. This study developed an AI-ECG framework based on the ECGFounder foundation model to quantify cardiac biological aging and predict cardiovascular risk. A total of 67,824 ECGs from 63,512 UK Biobank participants were included. The model was trained on the development cohort (n = 26,871), comprising healthy individuals, and evaluated in an independent clinical evaluation cohort (n = 40,953). The AI-ECG Age Gap was assessed for its association with MACCE and other secondary outcomes using Cox models. The model demonstrated good agreement between predicted and chronological age in the development cohort (r = 0.646; MAE = 4.61 years). In the clinical cohort, after adjusting for clinical comorbidities, each 1-year increase in the age gap was associated with a significant 13 percent higher risk of (HR = 1.13, 95 percent CI: 1.11-1.14) Individuals with an overestimated age gap (> 6 years) exhibited substantially elevated risks of MACCE (HR = 4.51) and other major cardiovascular outcomes, whereas those with an underestimated age gap (< -6 years) showed a significantly lower risk of MACCE (HR = 0.46) alongside protective effects across other outcomes. The AI-ECG age gap effectively quantifies occult accelerated cardiac aging. As a non-invasive digital biomarker, it exhibits immense potential for cardiovascular risk stratification in broad populations.

Clonal hematopoiesis of indeterminant potential (CHIP) is an age-related phenomenon associated with increased risk of hematologic malignancy. Preclinical studies have shown that infection is a driver of CHIP; clinical studies in people living with HIV suggest a relationship between chronic infection and CHIP, but the association between infection frequency and incident CHIP in the general population remains unknown. We leveraged the atherosclerosis risk in communities study to design a closed prospective cohort study. CHIP was determined based on whole-exome sequencing at 2 time points 20 years apart. Included were 3,367 individuals without cancer or CHIP at time 1 and without hematologic malignancy by time 2. The 3,367 study participants had an average age of 55.3 years at time 1; 59.1% were women, 40.9% were men; 24% were Black, and 76% were White. Documented infection was assessed from routinely collected hospital discharge summaries. Frequency was categorized as no documented infection, 1 infection, 2 infections, or ≥3 infections. Of the participants, 19.7% had incident CH, 6.9% had large CHIP, and 5.2% had large non-DNMT3A CHIP. Participants with ≥3 documented infections had an increased odds of incident CHIP (odds ratios [OR] 1.41, p = 0.03), especially large CHIP (OR 1.83, p = 0.008) and large non-DNMT3A CHIP (OR 1.81; p = 0.02). To our knowledge, this study is the first to demonstrate an association between infection and incident CHIP in a general population, highlighting a modifiable risk factor for CHIP. Further work is required to describe the mutation-specific impact underlying this observed relationship.

Cell cycle progression presents a fundamental challenge to epigenome integrity, particularly due to the need to reestablish post-translational histone modifications (PTMs) following DNA replication. Although proliferative and differentiating tissues exhibit markedly different cell cycle dynamics, how these differences shape the histone modification landscape in vivo remains largely unexplored. Here, we show that levels of H3K27ac, H3K27me3, and H3K9me3 are tightly linked to cell cycle dynamics in the Drosophila wing imaginal disc. We demonstrate that both physiological and pathological elongation of the cell cycle led to an accumulation of H3K9me3 and H3K27me3, whereas cell cycle acceleration reduces their levels. In contrast, H3K27ac exhibits the opposite pattern: levels decrease in arrested cells and increase with faster cycling. Genome-wide CUT&Tag analysis reveals that these changes predominantly affect genomic loci already modified in normally proliferating tissue. Importantly, the regulation of methylation levels at H3K9 and H3K27 is not solely mediated by the cell cycle machinery but reflects a metabolically guided process in which the rate of methylation is coupled to the rate of cell proliferation through metabolic activity, including signaling via the Insulin/PI3K/Akt pathway. Our study thus reveals key principles for understanding histone methylation in proliferating, senescent, and differentiating cells. In contrast, H3K27 acetylation is regulated through a distinct, cell cycle-coupled mechanism. We find that CBP/Nejire-mediated acetylation of H3K27 peaks during early and late S-phase and is reversed by HDAC1, as cells exit replication. Together, our findings establish a robust link between cell cycle progression and histone modification dynamics, highlighting the necessity of maintaining balanced PTM levels under varying proliferative states. These insights have broad implications for our understanding of development, aging, and tumor growth.

Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and non-myogenic skeletal muscle cells to coordinate adaptation and repair, but the mechanisms underlying this decline are not fully understood. Growing evidence implicates cellular senescence, a stress response marked by irreversible cell-cycle arrest and pro-inflammatory signaling, as a key contributor to muscle pathology. In this review, we synthesize current insights into the molecular mechanisms that govern cellular senescence in skeletal muscle, its effects on myogenic and non-myogenic cell populations, and recent technologies that have clarified key aspects of senescence biology. We further explore emerging therapeutic strategies aimed at targeting senescent cells and discuss key knowledge gaps that must be addressed to advance our understanding of senescent myogenic and non-myogenic cells in skeletal muscle.

Recent findings have associated alveolar bone loss (ABL) with the presence of senescent cells. Aging and the accumulation of senescent cells are associated with a pro-inflammatory environment which may exacerbate tissue damage. Senolytics, such as dasatinib and quercetin (D&Q), eliminate senescent cells, offering potential therapeutic benefits. We evaluated the effects of D&Q on ABL during physiological aging and experimental periodontitis.

Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair, metabolism, or neural activity. Correlation analysis showed that the expression of an additional subset of 6 genes was associated with chronological aging. Among them, further analysis identified RAD23B as the most significant gene with a negative correlation of its mRNA and protein expression with age in the human hippocampus. Its expression was even lower in patients with Alzheimer's disease. RAD23B was mostly expressed in neurons and astrocytes, where studies in human primary cultures uncovered that it is required for cell survival and function. In summary, these results unravel dynamic gene expression changes that distinguish young from older adults and identify RAD23B as a putative biomarker and regulator of cell aging in the brain.

Natural killer (NK) cells are innate lymphocytes that provide rapid immune surveillance through the recognition and elimination of virally infected, malignant, and stressed cells. Beyond their established roles in host defense, accumulating evidence indicates that NK cells undergo profound age-associated remodeling affecting subset distribution, receptor balance, metabolic programming, and effector function. These changes, collectively referred to as NK immunosenescence, contribute to impaired clearance of senescent cells, dysregulated inflammation, and increased susceptibility to cancer, infection, and metabolic disease. In this review, we integrate current knowledge of NK cell aging into the emerging framework of longevity medicine. Rather than introducing NK cells as a newly identified determinant of aging, we synthesize evidence positioning them as key immune effectors whose functional state reflects and influences biological aging processes. We highlight how NK cells participate in senescence surveillance, tissue homeostasis, and immunometabolic regulation across organs, and how their dysfunction intersects with multiple hallmarks of aging. We further discuss the potential utility of NK-related phenotypic and functional metrics as complementary biomarkers of immune aging, while acknowledging current limitations in specificity and prognostic validation. Finally, we examine therapeutic strategies aimed at preserving or restoring NK competence, ranging from lifestyle and nutritional interventions to cytokine-based therapies, immune checkpoint modulation, and emerging cellular platforms. While many advanced NK-targeted approaches remain investigational-particularly outside oncology settings-we outline a translational roadmap linking NK biology to actionable interventions and measurable outcomes relevant to healthspan. By situating NK cells within a systems-level view of immune aging, this review frames them as a tractable component of precision longevity medicine rather than a singular regulator of aging.

Ribosomes are increasingly recognized as heterogeneous regulators of gene expression, yet how ribosomal protein paralogs interface with nutrient signaling remains poorly understood. In Saccharomyces cerevisiae, ribosomal protein gene expression is governed by duplicated gene pairs, many of which exhibit functional divergence despite high sequence identity. A central regulator of ribosome biogenesis and translational control is the Target of Rapamycin (TOR) pathway, which integrates nutrient signals to modulate growth, stress adaptation, and lifespan. Target of Rapamycin Complex 1 (TORC1) influences ribosome activity by phosphorylating ribosomal protein S6 (Rps6), a modification that links nutrient availability to translational output. Here, we investigated the functional divergence of the Rpl12 ribosomal stalk protein paralogs RPL12a and RPL12b and found that rpl12b{Delta} produces phenotypes consistent with reduced TOR activity, including decreased Rps6 phosphorylation, G2/M cell-cycle accumulation, and significant extension of chronological lifespan as compared to rpl12a{Delta} and wildtype strain. Multi-omics analyses further indicate translational and metabolic reprogramming consistent with activation of a stress-adaptive program associated with Gcn4. Importantly, loss of RPL12b also reduces levels of the ribosome preservation factor Stm1, a TORC1-regulated protein required for stabilization of 80S ribosomes under stress. This finding links ribosomal stalk composition to ribosome stability and nutrient-responsive signaling. Together, our results demonstrate that ribosomal paralog specialization provides an additional regulatory layer connecting translation, TOR signaling, and cellular longevity.

Vanadium compounds are promising metallodrug candidates, with well-documented antidiabetic, antitumor, and anti-Alzheimer's activities. In search for the long-term beneficial or adverse effects of antidiabetic vanadyl complexes, we serendipitously discovered that the vanadyl complexes VOp-dmada exerted pro-healthy aging effects across a diverse panel of model organisms, i.e., yeast, C. elegans, and SAMP8 mice. Furthermore, VOp-dmada attenuated replicative senescence in mouse embryonic fibroblasts and alleviated thymic epithelial cell aging while preserving thymic architecture and function in a mouse model of dexamethasone-induced acute thymic atrophy. Mechanistic investigations revealed that VOp-dmada improved the structural integrity and functional capacity of mitochondrial complex II. This effect was mediated by activation of the c-Myc/S-phase kinase-associated protein 2 (SKP2)/sirtuin 3 (SIRT3) signaling axis, which in turn upregulated succinate dehydrogenase subunit A (SDHA) expression. Thus, vanadyl complexes suppressed reactive oxygen species (ROS) generation at the source, disrupted the deleterious ROS-thioredoxin-interacting protein (TXNIP) vicious cycle, and ultimately decelerated the aging process. Our findings highlight the potential application of antidiabetic vanadium complexes in the treatment of other aging-related disorders and corroborate the chronic safety profile. Moreover, these results support the targeting of mitochondrial complex II function and integrity as a novel strategy for the discovery of pro-healthy aging agents.

Experimental evidence suggests that caffeine has the potential to reduce the risk of age-related eye diseases (AREDs). However, there is a lack of population-based evidence directly assessing whether long-term caffeine exposure benefits these conditions. In this study, we employ Mendelian randomization (MR) to evaluate the causal effects of long-term elevated plasma caffeine levels (PCL) on AREDs, including age-related macular degeneration (AMD), age-related cataract (ARC), and glaucoma.

Cells can be exposed to many different stimuli that induce a variety of stresses, such as oxidative stress and proteotoxic stress of the cytoplasm, endoplasmic reticulum or mitochondria. These types of stresses trigger conserved molecular pathways (e.g., heat shock response, unfolded protein response, and autophagy) that can restore cellular homeostasis. Dysfunction (deficiency or hyperactivity) of these pathways is associated with aging and pathologies such as neurodegenerative diseases, diabetes and cancer. The basic molecular machinery of these stress response pathways has been elucidated, but how these pathways interact remains a vibrant area of research. Here, we show that the heat shock transcription factor-1 (HSF-1), the master regulator of the heat shock response, is required for efficient activation of the endoplasmic reticulum unfolded protein response (UPR

Mesenchymal stem cells (MSCs) are adult stem cells able to self-renewal or differentiation into different cell types, including chondrocytes. N-Glycans are post-translational modifications of glycoproteins that contribute to vital cell functions. In this work, we examined the cell surface N-glycome of human MSCs isolated from bone marrow to identify biomarkers for chondrogenic differentiation. In addition, we investigated for the first time the N-glycome of MSCs upon dedifferentiation and aging. Cell surface glycoproteins were released by tryptic digestion, then N-glycans were enzymatically cleaved, purified, permethylated, and analyzed by MALDI-TOF-MS combined with exoglycosidase digestions. We were able to detect 68 signals, comprising paucimannose, high-mannose, hybrid, and complex-type N-glycans, as well as structures containing polylactosamine motifs. A statistically significant decrease in antennarity and galactosylation, accompanied by an increase in sialylation, was observed during chondrogenic differentiation. Comparison of MSCs at passage 3 and passage 8 revealed increased levels of paucimannosylation, hybrid-type glycans, and sialylation, together with decreased biantennarity, bigalactosylation, and core-fucosylated N-glycans. Dedifferentiated MSCs exhibited a stem cell-like N-glycosylation profile, although statistically significant differences were still detected. These data show that the N-glycosylation profile of MSCs may serve as an indicator of the differentiation stage, dedifferentiation, and aging for the quality control of MSCs.

Sarcopenia is a significant age-related hurdle in older adults due to immobilization, prolonged bed rest, loss of resilience, and diminished quality of life. Despite its high prevalence, there are no FDA-approved drugs for sarcopenia to date, underscoring the critical need to explore novel therapeutics. Here, we explore an active immunization strategy to suppress the activity of negative regulators of muscle growth, specifically myostatin and activin A. Importantly, our primary objective was to determine whether long-term MSTN/Act A inhibition can enhance muscle performance independently of hypertrophy, under conditions of impaired GH/IGF-1 signaling. Using a long-lived growth hormone (GH)-deficient murine model, we investigated whether myostatin and activin A immunization improves muscle strength, independently of changes in muscle mass. We showed that, while in the presence of GH, this immunization increases lean mass and grip strength improvement. Notably, in the GH-deficient mice, grip strength is independent of muscle mass gain. Myostatin inhibition modulated transcriptomic shift in the gastrocnemius muscle, allowing for remodeling of the skeletal muscle and an increase in energy expenditure. Consistent with these findings, aged mice subjected to the same immunization schedule exhibited improved grip strength, along with alterations in lipid metabolism within the gastrocnemius muscle. Altogether, these results suggest that this inhibition strategy alters the contractility of the skeletal muscle, allowing for enhanced performance and offering a promising therapeutic strategy for muscle wasting.

Intervertebral disc degeneration (IVDD) is a leading cause of low back and leg pain and is primarily driven by inflammation-induced apoptosis of nucleus pulposus (NP) cells. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) have shown strong therapeutic potential for degenerative diseases. Sirtuin 6 (SIRT6), a key regulator of aging and inflammation, has been closely associated with IVDD progression. Therefore, we hypothesized that BMSC-exos might alleviate IVDD by promoting SIRT6-mediated deacetylation of high mobility group box 1 (HMGB1), thereby suppressing inflammation.

Manual frailty index (FI) assessment in mice is a strong predictor of morbidity and mortality, and is frequently used in mechanistic and translational geroscience. However, it is labor-intensive, requires expert training, and is vulnerable to scorer variability. We previously developed a visual frailty index (vFI) that objectively predicts age and frailty using expert-defined, supervised behavioral features extracted from open-field videos. However, relying solely on human-defined features may miss subtle, latent behavioral signatures of aging. Here, we test whether unsupervised behavioral discovery using Keypoint-MoSeq (KPMS) could uncover these hidden signatures and improve the prediction of aging-related outcomes. Using a large dataset of isogenic C57BL/6J (B6J) and genetically diverse Diversity Outbred (DO) mice, we find that unsupervised features are highly predictive of chronological age, biological frailty, and the proportion of life lived. Notably, while supervised features overall outperformed unsupervised features in these tasks, combining both feature sets yielded the highest predictive accuracy across all outcomes. Despite these improvements, models trained on either feature set failed to generalize across strains, confirming that behavioral manifestations of aging are strongly population-specific. These findings demonstrate that supervised and unsupervised machine vision provide complementary information, establishing a highly sensitive, scalable, and non-invasive framework for objective and scalable geroscience in rodents.

Polysaccharides are natural macromolecules with diverse bioactivities and potential health benefits. It exhibits a broad spectrum of biological effects, with extensive research supporting their antioxidative, anti-inflammatory, immunomodulatory, and anti-aging properties. The study evaluated the aging-modulatory effects of Labisia pumila polysaccharides (LPP) using Caenorhabditis elegans (C. elegans) and Drosophila melanogaster (D. melanogaster) as model organisms. LPP treatment increased the lifespan of in both models, enhanced locomotor activity and improved stress tolerance under the variety stress conditions. The researches using C. elegans mutant strains suggested that these effects are associated with the conserved stress response pathways DAF-16 and SOD-3, indicating potential involvement in cellular defense mechanisms. Metabolomic profiling further indicated increased levels of antioxidant metabolites and altered energy metabolism pathways, suggesting improved cellular homeostasis. These effects align with hormesis, in which mild stress induced by LPP triggers endogenous protective mechanisms to enhance physiological resilience. Overall, the results show that LPP modulates aging through integrated changes at the behavioral, genetic, and metabolic levels, offering a mechanistic foundation for its potential use as a safe and effective natural agent in promoting healthy aging.

Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age-related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein-centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC-EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age-related PSC (ARC-PSC), compared with age-related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence-associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro-inflammatory milieu across PSC subtypes, with IL-17A uniquely elevated in ARC-PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL-17A, that activate NF-κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL-17A blockade disrupted this loop, attenuating senescence- and EMT-associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL-17A-NF-κB circuit that drives EMT and accelerates ARC-PSC progression, positioning ARC-PSC as a unique human context to study senescence-induced epithelial remodeling in aging tissues.

The increasing prevalence of obesity, diabetes, and other metabolic disorders is driving the application of sucralose in the food industry. However, its direct effects on the reproductive function have not been sufficiently investigated. Chronic sucralose consumption may induce ovarian aging, leading to ovarian dysfunction. This occurs in association with intestinal dysbiosis and disruption of intestinal tight junctions caused by prolonged intake of sucralose. These changes increase the production of lipopolysaccharide (LPS), which is derived from gram-negative bacteria, and facilitate its translocation into the systemic circulation. Circulating LPS binds to TLR4 in ovarian granulosa cells, activating the NF-κB signaling pathway. This activation triggers the nuclear translocation of the p65 subunit and increases the transcription of downstream inflammatory cytokines. Moreover, Baicalin methyl ester may serve as an early intervention strategy. It can significantly attenuate both intestinal and ovarian inflammatory damage induced by sucralose, primarily by inhibiting the TLR4/NF-κB pathway.

Introduction: The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes. Methods: We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort. Results: The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months. Discussion: Our findings support the potential of a deep learning-derived SASP Score as a biomarker for systemic cellular senescence burden. Our statistical approach can offer enhanced interpretability and cross-platform utility, providing a valuable tool for aging research and the evaluation of geroscience-guided interventions.

To improve senolytic efficacy and selectivity, we designed gemcitabine (Gem)-based galactoside prodrugs activated by senescence-associated β-galactosidase (SA-β-gal), bearing lysosome-targeting groups at the 3- and 5-positions of the self-immolative linker aromatic ring. This strategy avoids stereocenter formation and promotes faster, electron-donating-effect-driven drug release. Gal-dMor-Gem, with two morpholine groups, showed the strongest activity. Its senolytic index reached 16.1-56.7 across six senescent cell (SnC) models, a 2.8- to 3.7-fold improvement over the nontargeted SSK1. Gal-dMor-Gem released Gem faster and preferentially induced SnC apoptosis, as validated in a coculture model. Biodistribution studies confirmed its preferential accumulation and activation in senescent tissues. In senescent mice, Gal-dMor-Gem (0.5 mg/kg) surpassed SSK1 in restoring body weight, improving biochemical parameters, and reducing SA-β-gal, IL-6, and lamin B1 abnormalities in multiple organs. At 1.0 mg/kg, most markers returned to healthy levels. This work identifies Gal-dMor-Gem as a potent senolytic and highlights a generalizable strategy for developing targeted SA-β-gal-responsive prodrugs.

Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases. The role of ferroptosis in age-related HF remains unclear. Here, we show that aged rats exhibit impaired cardiac function accompanied by hallmark features of ferroptosis, including reduced glutathione peroxidase 4 (GPX4) expression and excessive lipid peroxidation. Consistently, cardiomyocyte-specific GPX4 knockout mice develop exacerbated cardiac ferroptosis and pronounced cardiac dysfunction. Iron overload further aggravates ferroptotic injury and cardiac dysfunction in aged rats, whereas pharmacological inhibition of ferroptosis markedly alleviates these effects. Conversely, cardiomyocyte-specific overexpression of GPX4 via rAAV9 attenuates ferroptosis and preserves cardiac function in D-galactose-induced aging mice. Proteomic analysis identifies hydroxyacyl-CoA dehydrogenase subunit A (HADHA) as a key protein markedly downregulated in aging hearts, particularly under iron overload. Mechanistically, HADHA deficiency induces mitochondrial dysfunction and excessive reactive oxygen species production, leading to glutathione depletion, GPX4 suppression, and subsequent ferroptosis. Accordingly, cardiomyocyte-specific knockdown of HADHA in young mice recapitulates ferroptosis-associated cardiac remodeling, which is reversed by ferrostatin-1 treatment. Furthermore, we identify SIRT1 (sirtuin 1) as an upstream regulator of HADHA during cardiac aging. Reduced SIRT1 expression in aging hearts suppresses HADHA transcription through inhibition of GATA4. Importantly, both cardiomyocyte-specific SIRT1 overexpression via rAAV9 in D-galactose-induced aging mice and pharmacological SIRT1 activation by resveratrol in aging rats restore HADHA expression, suppress ferroptosis, and protect against HF. Collectively, these findings establish ferroptosis as a critical contributor to age-related HF and identify the SIRT1-GATA4-HADHA axis as a potential therapeutic target.

How minute pathogenic signals trigger decisive immune responses is a fundamental question in biology. Classical signaling often relies on ATP-driven enzymatic cascades, but innate immunity frequently employs death fold domain (DFD) self-assembly. The energetic basis of this assembly is unknown. Here, we show that specific DFDs function as energy reservoirs through metastable supersaturation. Characterizing all 109 human DFDs, we identified sequence-encoded nucleation barriers specifically in the central adaptors of inflammatory signalosomes, allowing them to accumulate far above their saturation concentration while remaining soluble and poised for activation. We demonstrate that the inflammasome adaptor ASC is constitutively supersaturated in vivo, retaining energy that powers on-demand cell death. Swapping a non-supersaturable DFD in the apoptosome with a supersaturable one sensitized cells to sublethal stimuli. Mapping all DFD nucleating interactions revealed that supersaturated adaptors are triggered to polymerize specifically by other DFDs in their respective pathways, limiting potentially deleterious crosstalk. Across human cell types, adaptor supersaturation strongly correlates with cell turnover, implicating this thermodynamic principle in the trade-off between immunity and longevity. Profiling homologues from fish and sponge, we find nucleation barriers to be conserved across metazoa. These findings reveal DFD adaptors as biological phase change materials in thermal batteries to power cellular life-or-death decisions on demand.

Protein aging, stress, or metabolism can lead to the accumulation of numerous nonenzymatic chemical alterations that can threaten protein stability and function, particularly in long-lived proteins. Eukaryotic cells recognize these protein-damage events through repair and removal pathways, whose loss can lead to adverse effects and contribute to age-related disease pathogenesis. Here, we review recent advances in understanding the formation, repair, and removal mechanisms of posttranslational modifications arising from protein damage, including dehydroamino acids, early-stage glycation, isoaspartate, C-terminal cyclic imides, and C-terminal amides. We emphasize the emerging role of E3 ubiquitin ligases in facilitating the degradation of proteins bearing these modifications, highlight the approaches used to make these discoveries, and discuss the potential functions of these modifications beyond protein damage. Mounting evidence that protein-damage events influence cellular signaling and metabolism suggests the existence of vast undiscovered regulatory networks, creating opportunities to uncover tissue-specific repair mechanisms and their roles in development, aging, and stress responses across diverse biological contexts.

Aging causes a progressive loss of tissue homeostasis, with stem cell exhaustion as a major hallmark. Age-associated decline in organ function is widely perceived as emanating from progressive accumulation of cellular damage in adult tissues. However, whether aging trajectories are established early on during development remains an open question. Here, we demonstrate that genetic modulation of cellular aging pathways in larval adult midgut progenitors (AMPs), which serve as the precursors of adult intestinal stem cells and differentiated epithelial cells, dictates the long-term trajectory of intestinal aging in Drosophila. Accelerated cellular aging by genetic perturbation employing Toll or Imd pathway overactivation or elevation of reactive oxygen species (ROS) using ND42 (mitochondrial complex I) knockdown in the AMPs results in aberrant progenitor proliferation, skewed lineage allocation, epithelial barrier dysfunction, and genomic instability. These alterations are accompanied by marked destabilization of AMP islet architecture and widespread changes in age-related molecular signatures, as revealed by bulk transcriptomic analysis. In contrast, decelerated cellular aging mediated by Foxo or Atg8a overexpression results in a decrease in enteroendocrine population and the intestinal barrier remained unaffected. Intriguingly, early-life activation of immune and oxidative stress signaling manifested later in the adult gut as elevated enteroendocrine differentiation, highlighting lasting effects on intestinal regenerative capacity and lineage balance. Together, our findings demonstrate that cellular aging is tightly regulated early on in development and its perturbation can cause developmental disruption hampering adult gut homeostasis, establishing AMPs as key developmental determinants that regulate the trajectory of intestinal aging in Drosophila.

Aging is a universal phenomenon characterized by a progressive decline in physiological function. In this study, we applied a rigorous physical theory based on irreversible thermodynamics to analyze experimental data from Drosophila melanogaster. We establish a unifying principle: the functional thermodynamic efficiency loss parameter per cycle (α). This parameter is proportional to the specific entropy produced in a functional cycle relative to the total entropy produced until failure. By analyzing 61 values across various organs and functions, we identified a "quantized" behavior in functional aging. Furthermore, we determined the maximum energy dissipated per unit mass (μlmg) throughout the lifespan. These findings suggest a fundamental architecture in biological energy allocation. This thermodynamic approach offers a novel, quantitative method for evaluating aging and testing interventions, providing a solid alternative to traditional demographic biomarkers.

As the population ages, a rising mortality burden is attributed to deaths in older adults, particularly deaths from inflammation-related chronic non-communicable diseases. The synergism between aging and inflammation remains unclear. Here, we conducted a study to examine whether a decrease in leukocyte mitochondrial DNA copy number (mtDNA

This study evaluated the histological impact of long-term caloric restriction (CR) on liver and kidney aging, assessing fibrosis, metabolic overload, and senescence-associated readouts.

The aging brain is characterized by accumulation of senescent glia, chronic neuroinflammation, and vulnerability to neurodegeneration. While their co-occurrence is established, causal relationships remain poorly understood-a critical gap for developing mechanism-based therapies rather than symptomatic treatments. This review examines evidence for causality among glial senescence, neuroinflammation, and neurodegeneration using Bradford Hill criteria, longitudinal studies, genetic approaches, and senolytic trials. Glial senescence in astrocytes and microglia initiates neuroinflammatory cascades through the senescence-associated secretory phenotype (SASP), creating self-perpetuating cycles driving neuronal dysfunction. However, neuroinflammation also emerges as a primary event triggered by peripheral signals, blood-brain barrier breakdown, or pathogens, subsequently inducing glial senescence. Neuronal damage generates inflammatory signals activating glia, indicating bidirectional causality. Disease-specific patterns are heterogeneous: in Alzheimer's disease, early microglial activation may precede amyloid pathology, while in Parkinson's disease, gut-brain inflammation may initiate central pathology. Common feed-forward loops amplify initial insults-senescence, inflammation, or protein aggregation-transcending linear causality. We propose a framework recognizing critical temporal windows and tipping points, distinguishing reversible from irreversible stages. Anti-inflammatory and senolytic interventions show promise preventively or early but limited efficacy in advanced disease, emphasizing intervention timing. Outstanding questions include identifying earliest causal events, determining points of no return, and understanding genetic-environmental modification of causal pathways. Addressing these requires longitudinal multi-omics studies and interventional trials. Establishing causation beyond correlation enables precision medicine targeting root causes, offering hope for preventing age-related cognitive decline and neurodegeneration.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene, leading to the production of progerin, an aberrant and toxic form of lamin A. Due to its hydrophobic nature, progerin accumulates at the nuclear membrane, disrupting nuclear architecture, impairing cellular functions, and ultimately resulting in death around adolescence. Reducing progerin levels is considered the most effective strategy to improve disease progression. To date, small-molecule approaches have primarily targeted progerin upstream mechanisms to indirectly reduce its levels. In this study, we report the development of first-generation proteolysis targeting chimeras (PROTACs) designed to directly degrade progerin, establishing a novel therapeutic paradigm for HGPS. We identify UCM-18142 (compound 2) as the first PROTAC capable of selectively degrading progerin. Treatment with UCM-18142 results in significant improvements in cellular phenotype in both HGPS patient-derived cells and a murine model, including enhanced proliferation, reduced senescence markers, and normalization of nuclear and mitochondrial abnormalities. Additionally, transcriptomic analysis of treated human cells reveals the cellular pathways modulated by compound. Remarkably, PROTAC 2 reduces progerin levels in vivo, supporting the therapeutic potential of this direct-targeting approach and opening new avenues for intervention in HGPS and related laminopathies.

Brown adipose tissue (BAT) undergoes progressive age-related involution into white adipose tissue (WAT), yet the epigenetic mechanisms underlying BAT whitening remain unclear. This study investigates the transcriptomic dynamics of goat perirenal adipose tissue (PRAT) across four postnatal stages and profiles active histone modifications and chromatin accessibility in PRAT at postnatal day 1 (BAT) and day 90 (WAT). PRAT whitening coincides with reduced enrichment of active histone marks and decreased chromatin accessibility at genes involved in thermogenesis and mitochondrial function, critical for maintaining brown adipocyte identity. Integration of high-resolution PGC1A chromatin interaction mapping identifies two BAT-specific active enhancers, PGC1A-En1 and PGC1A-En2, which exhibit additive effects and are further activated under cold stimulation. Functional repression of PGC1A-En1 and/or PGC1A-En2 in goat brown adipocytes reduces PGC1A expression and impairs thermogenic capacity, highlighting the pivotal role of PGC1A-En1. Consistently, lentivirus-mediated repression of the conserved mouse Pgc1a-En1 in vivo decreases Pgc1a expression and attenuates cold-induced thermogenesis in BAT. Notably, the conserved PGC1A-hEn1 also functions as a critical regulatory element required for PGC1A expression and thermogenic activation in human brown adipocytes. These findings elucidate epigenetic mechanisms controlling BAT activity and identify conserved enhancer elements as potential therapeutic targets for metabolic disorders.

Telomere shortening is a hallmark of aging, yet telomere length (TL) varies considerably among individuals and is strongly influenced by inheritance. In mice, efficient mitochondrial function-characterized by low reactive oxygen species (ROS) production-is critical for telomere elongation during early embryogenesis. Since mitochondrial DNA (mtDNA) encodes several subunits of the electron transport chain, it may influence TL at birth by regulating mitochondrial function in utero. To explore the relationship between mtDNA and TL, we used a transmitochondrial cybrid approach, introducing mitochondria from donor platelets with varying telomere lengths into mtDNA-depleted cells. This revealed an inverse correlation between donor blood TL and mitochondrial ROS levels measured in the resulting cybrids. Under the specific conditions of cybrid formation, which involve a metabolic shift from glycolysis to oxidative phosphorylation, mtDNA variants associated with reduced complex I (CI) activity induced rapid telomere shortening, further implicating mitochondrial metabolism in TL regulation. Notably, this effect was prevented by antioxidant treatment and supplementation with NAD precursors, supporting a critical role for CI in sustaining PARP1 activity through maintenance of the NAD/NADH balance to preserve telomere integrity under acute oxidative stress. Collectively, these findings suggest that specific mtDNA variants may contribute to the maintenance of long telomeres in humans by enhancing mitochondrial fitness, thereby highlighting potential therapeutic opportunities for mitochondrial replacement strategies.

The human brain varies from person to person in ways that shape behaviors and vulnerabilities, yet the cellular and molecular bases for inter-individual variation are largely unknown. Here we describe an analysis of cellular and gene-expression variation in four key structures of the striatum complex, the caudate, putamen, nucleus accumbens, and internal capsule, as well as the prefrontal cortex, from single-nucleus RNA-seq analysis of 3.9 million nuclei from 178 adult brain donors. We found that people with more astrocytes in any one brain region tended to have this property in all brain regions sampled; the same was true of striatal interneurons, microglia, and oligodendrocyte precursor cells (OPCs). OPCs showed attrition with age, declining in numbers by approximately 40% between age 30 and age 80 in both gray matter and white matter regions. We identified thousands of age-associated (but few sex-associated) variations in gene expression; the vast majority of these effects of age were cell-type-specific. Aging most strongly affected gene expression in projection neurons, especially striatal medium spiny neurons (MSNs/SPNs), and had a much smaller effect on gene expression in interneurons. Individuals' ages could be predicted to within about five years based on RNA-expression patterns from any of the striatal cell types. Common genetic variants detectably affected the expression levels of some ten thousand genes; the great majority of these effects were cell-type-specific. These data will provide a foundation for exploring natural inter-individual variation, aging, and tissue-based studies of human brain vulnerabilities.

The nuclear receptor Nurr1 (NR4A2) is an essential transcription factor that governs the differentiation, maturation, and long-term maintenance of midbrain dopaminergic (mDA) neurons in the substantia nigra. Reduced Nurr1 expression has been closely linked to age-related dopaminergic neuronal loss and the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating Nurr1 expression and protein stability in the aging midbrain remain poorly understood. Here, we identify Janus kinase 2 (JAK2) as a previously unrecognized regulator of Nurr1 in mDA neurons. In the substantia nigra of aged mice (12 and 18 month old), JAK2 was robustly expressed in Nurr1 positive mDA neurons, whereas its expression was minimal in young adult mice. In SK-N-BE(2)C neuroblastoma cells, overexpression of JAK2 modestly enhanced Nurr1 transcriptional activity, while the constitutively active mutant JAK2V617F markedly increased it. Notably, this effect was not blocked by pharmacological inhibition of STAT, PI3K, or Akt signaling pathways, indicating that JAK2 regulates Nurr1 independently of canonical JAK/STAT or PI3K/Akt signaling. Mechanistically, JAK2 did not promote tyrosine phosphorylation of Nurr1 but instead physically interacted with Nurr1, leading to enhanced nuclear stability of the Nurr1 protein. Consistent with this mechanism, expression of JAK2V617F increased Nurr1 protein levels without altering its mRNA expression. Functionally, co-expression of JAK2V617F and Nurr1 attenuated oxidative stress induced cytotoxicity and reduced reactive oxygen species accumulation. Together, these findings reveal a phosphorylation independent mechanism by which JAK2 stabilizes Nurr1 protein and enhances its transcriptional activity. Our results further suggest that age associated induction of JAK2 in dopaminergic neurons may promote neuronal resilience by maintaining Nurr1 protein stability during aging.

Background Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and Analysis This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70+. Participants will be randomised to one of three arms (Metformin MR 1500mg, Fisetin 100mg or Spermidine 15mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-{beta}-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and Dissemination Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial Registration REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.

Aberrant accelerometry-derived circadian rest-activity rhythm (CRAR) is associated with an increased risk of cardiovascular disease (CVD), yet the potential sex differences in this association among middle-aged and elderly adults remain unclear. This study investigates sex-specific associations between CRAR, CVD, and mortality in a large, diverse U.S. population. We analyzed data from participants aged ≥45 y in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 who completed 7 d wrist actigraphy and had at least four valid 24-h accelerometer recordings. Parametric CRAR measures, including amplitude, mesor, pseudo-F, and acrophase, were derived using an extended cosinor model. Weighted multivariable logistic regression assessed the associations between CRAR measures and the prevalent CVD, while Cox regression models evaluated the associations of CRAR with all-cause and cardiovascular mortality. Among 4893 participants, those in the lowest quintile of CRAR amplitude had 64% higher odds of CVD than those in higher quintiles (95% CI, 1.11-2.43). Low amplitude and mesor were significantly linked to increased risks of all-cause and cardiovascular mortality. Associations between CRAR disruption and outcomes appeared stronger in women, with significant interactions observed for several cardiovascular outcomes. Maintaining a robust circadian rhythm may be important for cardiovascular health and longevity, particularly among women.

The question of whether aging should be classified as a disease has gained prominence in geroscience, fueled by advances in molecular biology and the aspiration to develop interventions that mitigate age-associated functional decline. However, evolutionary models describe aging as an emergent consequence of declining selection gradients and life-history trade-offs rather than as a deviation from species-typical function. Comparative data across taxa reveal substantial heterogeneity in aging trajectories, challenging the assumption of a uniform pathological pattern. At the molecular level, processes often described as "hallmarks of aging" reflect conserved regulatory mechanisms whose effects are context-dependent and do not consistently align with criteria used to define diseases. Likewise, epigenetic clocks capture molecular signatures that track biological aging and predict mortality risk, yet these biomarkers reflect time-dependent molecular remodeling rather than an underlying pathological process. While translational research aimed at extending healthspan has generated important advances, current empirical evidence does not support equating aging with disease in a strict biological sense. Even though the classification of aging is not relevant to the importance of investing in aging research to alleviate its burden, maintaining a clear conceptual distinction between time-dependent biological remodeling and pathological dysfunction may provide a more coherent basis for both scientific inquiry and therapeutic development.

While biomedical advancements have significantly extended human longevity, increased lifespan is frequently decoupled from healthspan, as these additional years are often accompanied by frailty and chronic morbidity. Frailty is characterized by a multisystem decline in physiological reserve, and renders individuals disproportionately vulnerable to adverse outcomes -including mortality- when faced with health stressors. Consequently, research into the biological mechanisms linking ageing to the onset of frailty is needed. The zebrafish is increasingly utilized as a model for human aging and frailty due to its high degree of genetic homology. With a short lifespan of approximately three years, zebrafish show several conserved senescent phenotypes, including cataracts, sarcopenia, spinal curvature, and motor decline. Crucially, as in humans, ageing in zebrafish is not strictly chronological; apparent biological age often diverges from calendar age, with physical condition indicating frailty status more accurately. We propose a frailty index designed to evaluate the divergence between successful ageing and frailty in zebrafish. By utilizing easily quantifiable phenotypic markers such as spinal curvature and Body Mass Index, this index provides a score that predicts frailty status as validated against expert assessment. Implementing this standardized metric will facilitate cross-laboratory comparisons and enhance the reproducibility of future zebrafish-based ageing research.

Understanding the intricate relationship between sex, age, and the oral microbiome is crucial for deciphering the onset and progression of numerous age-related oral and systemic diseases.

Mitochondrial dysfunction is widely considered a conserved hallmark of aging and has been linked to lifespan limitation across many species, including the budding yeast Saccharomyces cerevisiae. However, the widely used S288C laboratory background carries several polymorphisms that impair mitochondrial genome stability and function. Here, using a three-color reporter and single-cell microfluidics, we demonstrate how these mutations cause spontaneous transition to a state with severe mitochondrial deficiency characterized by low membrane potential, loss of heme biosynthesis, activation of iron regulon and morphological changes. Equally affecting young and old cells, this condition-dependent transition creates an apparent split in aging trajectories mimicking an age-dependent pathway. We further identify the BY allele of the MKT1 gene as a major genetic driver of this pathological mitochondrial state. Finally, we show that condition-dependent variation in petite formation contributes to lifespan differences in BY. Together, our results indicate that background-specific pathological defects can distort apparent aging trajectories and obscure genuine age-associated phenotypes.

Aging presents intensifying challenges including physical vulnerability, social isolation, and financial insecurity, predicted by biological age yet critically shaped by environmental context. This qualitative study explores how these vulnerabilities accumulate across World Health Organization (WHO)- age groups (Young-Old, Old-Old, and Oldest-Old) using in-depth narratives from thirty diverse older adults in urban Assam, India. Moving beyond purely biological understandings, the study adopts an integrated framework synthesizing Lawton's Ecological Model, Cumulative Disadvantage (CAD) Theory, and Active Aging. While health shifts with age, socio-spatial contexts critically shape lived experiences. Rapid urbanization and inadequate planning often 'manufacture dependency', turning neighbourhood environments into spaces of confinement, particularly for older women facing cumulative lifelong inequalities. However, findings indicate advancing age need not lead to inevitable decline where accessible infrastructure exists. The study advocates for inclusive urban planning to transform age-related challenges into opportunities for dignity and continued participation.