Longevity Papers

Interventions Testing Program identified rapamycin as a robust lifespan-extending agent at multiple testing sites and in both sexes, with particularly strong effects in females, making it a leading candidate in aging research. We used genetically heterogeneous UM-HET3 mice of both sexes to determine whether rapamycin can prevent or delay age-sensitive traits. Mice were supplemented with microencapsulated rapamycin at 14 ppm starting at 12 months of age. Chronic rapamycin supplementation prevented the age-related decline in motor function, with females benefiting more than males. We further determined that rapamycin attenuated the age-related increase in protein carbonyls, principally in the insoluble protein fraction of brain regions that subserve motor function. We also found increased protein expression of glial fibrillary acidic protein (GFAP) across several brain regions, surprisingly, rapamycin treatment further increased GFAP levels in the striatum of both sexes, however this increase is not supporting evidence for a decrease in oxidative stress. Age-related increase in ER stress has been reported to be associated with increased protein carbonyls. We observed that rapamycin reduced the expression of C/EBP homologous protein (CHOP), a marker of ER stress-mediated apoptosis, in the striatum region of female mice. Our data show a novel beneficial effect of rapamycin on age-related motor deficits that is not sex-specific and that these changes are associated with reduction in protein carbonyls in brain regions linked to motor function. Furthermore, our results are consistent with the idea that rapamycin's beneficial effects are mediated, at least in part, by reducing oxidative stress and ER stress-mediated apoptosis.

This study aims to elucidate whether silica (SiO₂) induces alveolar epithelial cell senescence through telomere shortening, and to explore the involvement of TERF1 and its subsequent activation of the cGAS-STING pathway in the development of pulmonary fibrosis.

The microbiota of intestinal origin has a significant impact on the aging process, affecting skin health and overall cell longevity. Aging is marked by physiological alterations, such as enhanced oxidative stress, which is intensified by external factors like UV radiation and environmental pollution. The gut microbiota profoundly influences immune functions and results in reduced inflammation, which contributes to the anti-aging process. The present review is an attempt to showcase the current studies on the gut-skin axis, investigating the impact of gut-derived metabolites, particularly short-chain fatty acids, postbiotics, synbiotics, and psychobiotics, on the function of skin barriers and the aging process. Dietary supplements, including prebiotics along with probiotics, have demonstrated significant potential in altering gut microbiota composition and, in turn, improving skin health. Future studies must focus on investigating the connection between gut microbiota and cellular senescence, the effectiveness of microbiota-targeted therapeutics, and the incorporation of targeted therapy to delay the aging process. Comprehending these processes may facilitate the development of novel ways to enhance healthy aging and alleviate age-related diseases through the gut-skin axis via microbiome regulation.

Brazil is rapidly aging with limited welfare infrastructure to support healthy aging, making spouses and adult children among the primary sources of support. Declining fertility and marital transitions may threaten older adults' health, raising a critical question: Are there gender differences in older Brazilians' mortality risks by partnership and parenthood status? We used baseline data from the Brazilian Longitudinal Study of Aging (ELSI-Brazil) of adults 50 and older (2015-2016), including 9412 participants with deaths linked to Brazil's Mortality Information System. Cox proportional hazard models assessed mortality by close kin availability: (1) partnered with children, (2) partnered childless, (3) unpartnered with children, and (4) unpartnered and childless, adjusting for demographic, early-life conditions, health, and social factors. For both men and women, lacking both traditional family ties presents the highest mortality risks, but for men, having children and lacking a partner also elevate mortality risks. We discuss these findings in the context of demographic and social changes in the availability of close kin and the potential opportunities to enhance survival among older adults in Brazil.

Macrophages serve as major defenders against pathogens, playing a crucial role in the initiation and modulation of immune responses. Age-related decline in macrophage functions is attributed to a complex network of cellular senescence and immunosenescence. The onset of cellular senescence is often a consequence of sustained oxidative stress, which is worsened by immunosenescence. Green tea catechin, epigallocatechin gallate (EGCG), has emerged as a promising candidate for promoting healthy aging by reducing cellular senescence and enhancing cytoprotective responses. However, its effectiveness in preventing oxidative stress-induced senescence and dysfunction in immune cells, particularly macrophages, remains less characterized. The present study explored the anti-senescence and cytoprotective effects of EGCG in the wake of oxidative stress-induced premature senescence in RAW 264.7 macrophages. Oxidative stress was induced in cells using repeated exposure to hydrogen peroxide (H

Aging and sarcopenia are associated with metabolic inflexibility. This study investigated the effects of resistance exercise (RE) and a high protein diet (PRO) on metabolic flexibility (the ability to adjust rates of substrate oxidation to changes in fuel availability) in older men.

Senescent cells have been implicated in the pathogenesis of metabolic dysfunction-associated liver disease (MASLD), which can negatively affect female fertility. Senolytic drugs are reported to eliminate senescent cells in various tissues, including the ovary. However, the efficacy of senolytic drugs in reducing liver damage and preserving fertility in female mice with MASLD remains unclear. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in reproductive aged female mice with MASLD. Three-month-old female mice were fed a standard chow (SD) or Western diet (WD) to induce MASLD until nine months of age. Starting at six months of age, mice were also randomized to receive senolytic treatment (Dasatinib + Quercetin, D + Q) or vehicle within each diet. We observed that mice fed the WD exhibited liver damage characteristic of MASLD, with increased liver size, triglyceride accumulation and fibrosis. These mice also exhibited increased liver senescence and inflammation. Senolytic treatment slightly reduced liver mass and modulated some liver senescence and inflammation related genes, suggesting limited efficacy in controlling WD-induced liver damage. Pregnancy rates were reduced in mice with MASLD and improved by senolytic treatment. Mice with MASLD had increased ovarian senescence, inflammation, and fibrosis, which was attenuated by senolytic treatment, despite having no effect on the ovarian follicle reserve. We conclude that senolytic treatment has potential for improving reproductive function in aged female mice with MASLD, despite limited impact in liver and systemic indicators.

Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urgently needed.

Age-associated sarcopenia and declining physical function in older women are connected to changes in hormones, inflammation, and disrupted protein metabolism. Myokines and cytokines play central roles in muscle atrophy. While both resistance exercise (RE) and essential amino acid (EAA) supplementation are promising interventions, limited randomized trials have assessed their combined effect in healthy elderly populations. Early targeted strategies may help delay sarcopenia and promote healthier aging.

Maintaining muscle health is a growing concern in aging populations, yet the role of eating frequency remains understudied. This study hypothesized that lower eating frequency, particularly infrequent breakfast consumption, is associated with poorer muscle health in older adults. This study examined the association between eating frequency and muscle outcomes among 3292 adults aged ≥50 years from the 2022-2023 Korea National Health and Nutrition Examination Survey. Meal frequency was categorized by weekly breakfast (0, 1-2, 3-4, 5-7/week), lunch and dinner (≤2, 3-4, 5-7/week), and grouped as ≤12, 13-14, or 15-21 meals/week. Muscle outcomes included the skeletal muscle index (SMI) and handgrip strength (HGS). Sex-stratified multivariable logistic regression models were adjusted for sociodemographic, health behaviors, and clinical and dietary intake. In men, skipping breakfast was associated with higher odds of combined low SMI/HGS (odds ratio [OR]: 2.02; 95% confidence interval [CI], 1.01-4.04). In women, it was associated with low SMI (OR: 1.90; 95% CI, 1.08-3.34). Men consuming 13 to 14 or ≤12 meals/week had higher odds of low SMI (OR: 4.74; 95% CI, 2.39-9.42 and OR: 1.96; 95% CI, 1.22-3.14, respectively) and combined low SMI/HGS (OR: 2.38; 95% CI, 1.11-5.13 and OR: 1.79; 95% CI, 1.07-3.01, respectively). Among women, consuming ≤12 meals/week was associated with low SMI (OR: 1.69; 95% CI, 1.18-2.42). These associations remained consistent in participants aged ≥65 years. No significant associations were found for lunch or dinner frequency. In conclusion, regular meal consumption, especially consistent breakfast intake, may help preserve muscle mass and strength in older adults.

Plasminogen activator inhibitor 1 (PAI-1) has well-described roles in cardiovascular disease states including clinical thrombosis, atherosclerosis, arteriosclerosis, and myocardial infarction. However, an evolving plethora of research associates PAI-1 with numerous other disease processes including inflammation and infection, diabetes, metabolic syndrome, neurodegeneration, and cancer. Aside from disease processes, PAI-1 has also recently been shown to be a key biomarker for aging with effects on skeletal muscle repair, cardiovascular health, and cellular senescence. This review provides a timely and comprehensive update of PAI-1's role in the pathogenesis of a diverse array of human diseases.

Intervertebral Disc Degeneration (IDD) is a common degenerative spinal disease and a leading cause of low back pain and disability. The senescence of nucleus pulposus cells (NPCs) is a central mechanism driving the pathological progression of IDD, though its regulatory mechanisms remain unclear. Bioinformatic analysis identified FGF21 as a key gene regulating NPCs senescence. In both human and rat degenerated intervertebral discs, FGF21 expression was significantly downregulated and closely associated with the upregulation of senescence markers (P16, P21, and P53) and clinical pathological features (age, symptom duration, and Pfirrmann grading). In vitro experiments demonstrated that FGF21 intervention significantly alleviated tert-butyl hydroperoxide (TBHP)-induced NPCs senescence and mitochondrial damage. Mechanistically, FGF21 upregulated SIRT1 and promoted the deacetylation of FOXO3 at lysine sites K241, K258, K289, and K568, thereby enhancing mitophagy and inhibiting NPCs senescence. In vivo, FGF21 treatment significantly improved disc height and histological scores in a rat IDD model, whereas SIRT1 knockdown attenuated these protective effects. In summary, FGF21 inhibits NPCs senescence and delays IDD progression by activating SIRT1-mediated FOXO3 deacetylation and enhancing PINK1-Parkin pathway-dependent mitophagy. Therefore, the FGF21-targeted SIRT1/FOXO3/PINK1/Parkin axis may represent a promising new therapeutic strategy for IDD.

We identified a new progeroid syndrome with severe neuropathy and intellectual deficits but its underlying cellular and molecular mechanism is unknown. Exome sequencing revealed a homozygous mutation in the IVNS1ABP gene, which encodes IVNS1ABP, an influenza virus non-structural protein-1 binding protein. To investigate disease mechanisms, we generated isogenic induced pluripotent stem cells (iPSCs) from patient fibroblasts and differentiated them into neural progenitor cells (NPCs). Mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited defective cytokinesis, increased DNA damage, and premature cellular senescence. Consistent with these findings, cerebral organoids showed early differentiation of NPCs into neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin / actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that mutant IVNS1ABP dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this progeroid neuropathy.

Companion dogs represent a valuable and emerging translational model for human aging, as they share the human environment, receive comparable medical care - yet have much shorter lifespans. Despite their potential, a validated set of canine biomarkers of aging has not yet been established. The OLD-DOG Project, launched in 2023 at the University of Padua's Veterinary Teaching Hospital, is a 30-month prospective study designed to identify and validate biomarkers of aging in companion dogs and to assess their predictive value for healthspan and lifespan, thereby evaluating the suitability of dogs as models for human aging research. A cohort of 209 privately owned dogs aged  ≥ 5 years was enrolled and underwent comprehensive evaluations every six months, including clinical examinations, physical fitness testing, blood and fecal sampling, and owner questionnaires. Collected data encompass physiological, biochemical, hematological, and behavioral parameters, as well as microbiota profiles, telomere length, and DNA methylation patterns. Surplus biological material is stored to establish a long-term biobank. Preliminary cross-sectional analyses have identified consistent age-related patterns across multiple domains, including hematological and biochemical indices, inflammatory markers, and measures of physical and cognitive performance. Ongoing longitudinal analyses aim to determine the predictive value of these candidate biomarkers for morbidity and mortality, as well as to assess the influence of environmental and lifestyle factors on aging trajectories. Ultimately, the project seeks to construct an integrative model of biological age in dogs, thereby strengthening their value as a robust translational model for human aging research.

In C. elegans, prolonged food deprivation during early larval development results in aging-like phenotypes that can be fully reversed upon refeeding, but it remains unknown whether and how this ability persists into later life stages. Here we subjected C. elegans of the last larval stage to starvation, driving them into adult reproductive diapause (ARD). During starvation, ARD worms exhibited a wide spectrum of aging-like phenotypes, including transcriptomic reprogramming accompanying cellular and functional declines. These phenotypes are largely restored within one day of refeeding, suggesting a rejuvenation effect. Time-series transcriptomics, proteomics, and follow-up analyses of the refeeding/rejuvenation process uncovered an intricate coordination between: (1) activation of the IRE-1 branch of UPRER (unfolded protein response of endoplasmic reticulum) to induce chaperone expression; (2) quiescence of the PEK-1 branch of UPRER to avoid translation suppression; (3) up-regulation of the translation machinery to boost protein synthesis. IRE-1, together with its downstream effector, XBP-1, play an essential role in boosting protein synthesis, which is required for complete rejuvenation from the ARD state. These findings indicate that coordination between a high protein synthesis activity and a high protein folding capacity is key to refeeding-associated rejuvenation.

The ability of cells to transmit information encoded in the genome, and its organization into chromatin across cell generations, is a cornerstone of eukaryotic life. Chromatin replication, the copying of the mammalian genome in its structural and functional chromatin context to maintain cell identity and fate, is fundamental to lifelong health and has important implications for cancer and aging. Here, we review the major breakthroughs in our understanding of chromatin dynamics during DNA replication, critical for genome and epigenome inheritance. We discuss how chromatin is disrupted at the replication fork and how the replication machinery ensures transmission of parental histones with their modifications to daughter DNA strands with high fidelity. We highlight how incorporation of new histones is integrated into this process to maintain chromatin integrity and functionality. Finally, we consider how these processes maintain gene expression programs and thus cellular identity and function across cell division throughout the organismal life span.

Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood cells maintaining the hematopoietic system. Age-related HSC dysfunction impacts all of hematopoiesis, with DNA methylation alterations in aged HSCs contributing to altered function. Growth Arrest and DNA Damage-inducible proteins (Gadd45a, Gadd45b, and Gadd45g) are expressed in HSC activation, and Gadd45b has been reported to induce DNA demethylation. Thus, we explored the relationship between Gadd45b, DNA methylation and age-related HSC changes. WGBS on HSCs from GADD45B knockout mice demonstrated young knockout HSCs have increased DNA methylation, with both unique and overlapping methylation changes compared to aged wild-type HSCs without reflecting aging transcriptional changes. Peripheral blood and bone marrow analysis, competitive transplants, and single-cell culture analyses showed no significant loss of functional potential in the aberrantly methylated GADD45B knockout HSCs. We concluded these altered methylation sites don't alter HSC potential. We generated a searchable HSC DNA methylation database incorporating available datasets and present a truncated list of methylation sites associated with changes in HSC function for prioritization to target for resetting the age-associated loss of HSC potential.

Cell senescence has been widely demonstrated to limit the osteogenic and odontogenic potential of human dental pulp stem cells (DPSCs). This study aimed to elucidate the regulatory mechanism by which E2F transcription factor 2 (E2F2) influences senescence and osteogenic differentiation in young DPSCs (yDPSCs). yDPSCs and old DPSCs (oDPSCs) were isolated and characterized by flow cytometry. The endogenous expression levels of E2F2, methyltransferase-like 3 (METTL3), and senescence- or osteogenesis-related markers were determined by qRT-PCR and Western blot. Senescence-associated β-galactosidase (SA-β-gal) staining was performed to assess cell senescence, while Alizarin Red S (ARS) and alkaline phosphatase (ALP) staining were used to evaluate the osteogenic differentiation capacity of yDPSCs. Dual-luciferase reporter and chromatin immunoprecipitation assays were conducted to confirm molecular interactions. Both yDPSCs and oDPSCs were positive for CD73 and CD105 and negative for HLA-DR. Compared with oDPSCs, yDPSCs exhibited stronger osteogenic differentiation potential and higher E2F2 expression. Knockdown of E2F2 increased the proportion of SA-β-gal-positive cells and upregulated the senescence markers p21 and p16, while it suppressed mineralization, ALP activity, and the expression of osteogenesis-associated markers (BMP2, OCN, OPN, Runx2, Osterix) in yDPSCs. Mechanistically, METTL3 was identified as a transcriptional target of E2F2. Overexpression of METTL3 reversed the inhibitory effects of E2F2 knockdown on odontogenic/osteogenic differentiation and the promoting effects on cell senescence in yDPSCs. E2F2 plays a critical role in suppressing DPSC senescence and promoting their osteogenic differentiation.

Physical inactivity among Indian elders represents a significant public health challenge, influenced by diverse barriers such as fear of falls, limited social support, and environmental constraints. This viewpoint explores the interplay of these barriers and facilitators, advocating for a paradigm shift from focusing solely on functional limitations ("eyesight") to addressing psychological, social, and environmental determinants of physical activity ("insight"). By integrating insights from geriatric health, urban planning, and behavioral sciences, this article underscores the importance of culturally tailored interventions. Recommendations include community-driven programs, inclusive urban designs, and caregiver engagement to foster sustained participation in physical activities. A holistic approach is crucial to empower Indian elders, improve their quality of life, and mitigate the burden of non-communicable diseases in aging populations.

This study examined the influence of frailty status and physical activity (PA) compliance on all-cause mortality and healthcare utilization among Korean adults aged 45 years and older. Data from 2104 participants in the Korean Longitudinal Study of Aging (KLoSA; 2006 - 2022) were analyzed. Frailty was assessed using a 38-item frailty index (FI), and PA was defined according to adherence to the World Health Organization guideline of at least 150 min per week. Participants were classified as robust, pre-frail, or frail. Cox proportional hazards models and generalized linear mixed models were used to evaluate associations with mortality and healthcare utilization. Compared with robust individuals, frail participants exhibited a markedly higher risk of all-cause mortality (hazard ratio [HR] = 3.37, 95% confidence interval [CI]: 2.42-4.69), while pre-frail individuals also showed an elevated mortality risk (HR = 1.72, 95% CI: 1.43-2.07). Frailty was consistently associated with greater healthcare utilization across outpatient visits, hospital admissions, length of hospital stay, and healthcare costs. Adherence to PA guidelines was not independently associated with reduced mortality among pre-frail and frail individuals after multivariable adjustment; however, a significant interaction indicated higher healthcare costs among frail individuals who met PA guidelines. In addition, higher BMI was associated with lower mortality risk, consistent with patterns described as the obesity paradox. These findings highlight frailty as a key, independent predictor of mortality and healthcare utilization beginning in midlife. Standardized PA recommendations alone may be insufficient for physiologically vulnerable populations, underscoring the importance of early frailty screening and individualized, function-sensitive intervention strategies to promote healthy aging.

The alpha-synuclein seed amplification assay in cerebrospinal fluid is the first validated molecular measurement of alpha-synuclein biology in a living person. The SAA test is transforming our understanding of aging and neurodegenerative diseases by detecting abnormal synuclein biology, and data suggests SAA positivity can occur across Parkinson's disease, Alzheimer's disease, and Dementia with Lewy Bodies. To accelerate development of this important research tool, the Michael J. Fox Foundation proactively funded a community of researchers to work both independently and collaboratively, leading to rapid and iterative progress and validation. The collective validation of the assay across industry and academic groups culminated in a Food and Drug Administration Letter of Support for the test in clinical trials for PD. This article describes the principles that accelerated the development of the assay including patient engagement, collaboration, a commitment to open science through data, sample, and knowledge sharing, and showcases how an international community of experts rallied together towards a common goal.

Aging and cancer are intricately linked through complex, bidirectional interactions, with immune remodeling representing a central point of convergence. Although studies of immune aging have largely centered on T cells, accumulating evidence indicates that B cells also undergo significant functional or phenotypic alterations during aging and tumorigenesis. Here, we introduce the concept of age-related B cell dysfunction to encompass a spectrum of changes that include impaired germinal center response, decline in B cell diversity, expansion of pro-inflammatory phenotypes, and increased autoreactivity. Aging and cancer share fundamental biological hallmarks, including genomic instability, epigenetic reprogramming, chronic inflammation, and dysbiosis, which profoundly reshape immune cell states. In this review, we synthesize emerging mechanistic evidence linking these processes to maladaptive B cell programs across tissues and tumor contexts, and discuss how such alterations influence tumor evolution, responses to therapy, and treatment-related toxicities. Finally, we highlight emerging strategies targeting age-related dysfunctional B cells in cancer, illustrating how insights from biology of aging and tumor immunology could inform future translational approaches.

Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is accompanied by overexpression of a shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC and megakaryocyte progenitor (MkP) signature genes via regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a Btaf1 variant that drives HSC aging phenotypes in mice.

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer's disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience.

Telomere maintenance has been portrayed primarily as a problem of DNA-protein architecture and chromatin control, yet a complementary layer has been revealed at the level of RNA chemistry. In this Review, RNA modifications and their writer-reader-eraser and RNA-editing systems are integrated into a framework for chromosome-end homeostasis. Epitranscriptomic regulation of the telomerase ribonucleoprotein is examined, and assembly, activity, and recruitment are shown to be reshaped by chemical marks on TERC, specialized RNA capping, and processing pathways. Telomeric transcripts, particularly TERRA, are discussed as modified substrates whose stability, trafficking, and propensity for telomeric RNA: DNA hybrid formation can be tuned by RNA marks and their readers. Downstream consequences for replication stress, DNA damage signaling, and recombination-driven alternative lengthening of telomeres are summarized, together with emerging examples in which modification of telomere-factor mRNAs has been linked to rewiring of maintenance networks. Across these themes, links to telomeropathies, aging-associated inflammation, environmental stressors, and cancer are collated to connect mechanism to phenotype. Experimental bottlenecks and opportunities-site-resolved mapping, locus-targeted editing, and pharmacologic modulation of RNA-modifying enzymes-are outlined as routes toward causal models and therapeutic utilization.

Background: Mitochondrial dysfunction is an emerging metabolic hallmark of age-related diseases, yet tools to directly profile mitochondrial pathways and test metabolic interventions in the living human eye remain limited. Multi-omics ocular liquid biopsy enables real-time proteomic and metabolomic profiling of the intraocular microenvironment, complementing systemic biomarkers and imaging surrogates. Here, we used this approach to define mitochondrial and tricarboxylic acid (TCA) cycle dysregulation in geographic atrophy (GA) and to assess whether oral -ketoglutarate (-KG) supplementation can modulate mitochondrial metabolites within the eye. Methods: Mitochondrial and TCA cycle-related proteins were profiled in aqueous humor (AH) samples from patients with GA using DNA-aptamer-based proteomics. In a phase 0 study, a second cohort undergoing sequential cataract surgery provided paired AH samples collected at first-eye surgery and at second-eye surgery after interim -KG supplementation. These samples underwent targeted metabolomic profiling using hydrophilic interaction liquid chromatography coupled with mass spectrometry. Results: In GA, 64 mitochondrial proteins were differentially expressed, including coordinated TCA-cycle deficiencies marked by reduced expression of enzymes regulating TCA entry and flux, including PDHB and DLST. In the phase 0 cohort, oral -KG supplementation significantly increased intraocular -KG levels and the -KG-to-succinate ratio (P < 0.05), with coordinated shifts across TCA intermediates consistent with enhanced TCA cycle flux. Conclusions: AH proteomics demonstrated mitochondrial pathway depletion in GA, consistent with reduced oxidative bioenergetic capacity. AH metabolomics provided first-in-human in vivo evidence that systemic -KG supplementation can modify intraocular metabolites and may enhance intraocular energy metabolism. These findings support ocular liquid biopsy as a precision-health framework for per-patient biomarker-guided metabolic trials in GA.

Abstract Background: The association between chronic lung disease (CLD) and osteoporosis (OP) is well-recognized, but the direction and magnitude of this relationship remain debated, particularly in aging populations. We aimed to quantify the bidirectional association between CLD (including COPD and asthma) and incident OP using a two-stage individual participant data (IPD) meta-analysis of three large longitudinal cohorts. Methods: We harmonized and analyzed individual-level data from the Health and Retirement Study (HRS, USA), the Survey of Health, Ageing and Retirement in Europe (SHARE, Europe), and the English Longitudinal Study of Ageing (ELSA, UK), all comprising adults aged greater than or equal to[≥]50 years. In the first stage, Cox proportional hazards models were fitted separately in each cohort to estimate hazard ratios (HRs) for the forward (CLD[->]OP) and reverse (OP[->]CLD) associations, adjusting for a comprehensive set of confounders (demographics, lifestyle, comorbidities, functional status). In the second stage, cohort-specific log HRs were pooled using fixed-effect meta-analysis. Heterogeneity was assessed with the I-squared statistic. Results: A total of 40,050 participants were included across the three cohorts. The pooled HR for incident OP among individuals with baseline CLD was 1.37 (95% confidence interval [CI] 1.24-1.51), with similar estimates for COPD (HR 1.47, 95% CI 1.27-1.69) and asthma (HR 1.35, 95% CI 1.22-1.50). For the reverse association, baseline OP was associated with increased risk of incident CLD (pooled HR 1.16, 95% CI 1.05-1.29), COPD (HR 1.28, 95% CI 1.11-1.47), and asthma (HR 1.17, 95% CI 1.05-1.30). Heterogeneity was low across all analyses (I2[≤]7.5%). Conclusion: This two-stage IPD meta-analysis provides robust evidence of a bidirectional relationship between CLD and OP in older adults. These findings underscore the need for integrated screening and management of both conditions in aging populations.

Aging is often associated with a maladaptive "stiffness" strategy of postural control, which limits adaptability and increases fall risk. Complex visuomotor training (e.g., juggling) may counteract this decline, but the relationship between biomechanical reorganization and cognitive cost reduction remains unclear. We hypothesized that juggling would induce a shift from stiffness to "active monitoring" and reduce the dual-task cost. This exploratory secondary analysis of a randomized crossover trial consists of twenty-five older adults (70 ± 4 years). Participants underwent 4 weeks of juggling training versus a passive control period. Postural sway was assessed using a force platform to analyze kinematic metrics reflecting sway activity (path density) and spatial precision (radial standard deviation). Cognitive cost was assessed via dual-task cost during a counting task. Linear mixed models were used for analysis. Juggling training significantly increased path density (p = 0.014) and improved central precision (reduced radial standard deviation, p = 0.040). This pattern indicates a transition to an "active monitoring" strategy, effectively "unfreezing" rigid postural control. However, this biomechanical reorganization was not accompanied by a statistically significant reduction in dual-task cost (p = 0.08). Visuomotor training effectively "unfreezes" rigid postural strategies in older adults, promoting active, exploratory control. However, these findings should be interpreted as hypothesis-generating. The lack of significant cognitive cost reduction suggests a temporal dissociation: biomechanical flexibility is restored before full automatization occurs, warranting verification in larger, longitudinal studies. The study was retrospectively registered (30.10.2023) at ClinicalTrials.gov (NCT06108713).

Major depression (or late-life depression [LLD]) is a prevalent and debilitating condition among older adults and is increasingly recognized as a contributor to accelerated biological aging. LLD has been associated with aging-related phenotypes, namely chronic inflammation and cellular senescence. However, stem and progenitor cell exhaustion, another pivotal hallmark of biological aging, remains understudied in this context. In this study, we investigated the absolute count and frequency of circulating progenitor cell populations in peripheral blood mononuclear cells (PBMC) of 38 older adults (LLD, n = 19; control, n = 19). CD34

All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same time or speed. For instance, although neurodegeneration is a key trait of aging, neurological symptoms normally manifest long after multiple indicators of aging in peripheral tissues. The genetic determinants of aging remain poorly understood. Mutations in leucine-rich repeat kinase 2 (LRRK2) are major genetic risk factors for Parkinson disease (PD). By analyzing PD patients and mice with an LRRK2 gain-of-function mutation (LRRK2GoF), we demonstrate that PD is an accelerated aging disease characterized by systemic low-grade STING-dependent inflammation (inflammaging) that first manifests in the periphery, then disrupts the blood-brain barrier and progresses to the brain, resulting in neurodegeneration. Mechanistically, we demonstrate that a primary consequence of aging or Lrrk2GoF is endolysosomal decline. This results in the cytosolic build-up of extraneous self-DNA and subsequent shedding of DNA-containing extracellular vesicles, thereby triggering the cGAS-STING pathway cell-intrinsically and intercellularly in distant host cells. This study unveils the cGAS-STING pathway and LRRK2GoF as key determinants and potential targets for preventive or therapeutic strategies against accelerated aging, inflammaging, and neurodegeneration.

Sleep-dependent memory consolidation relies on slow oscillations (SOs) that coordinate large-scale brain dynamics during non-rapid eye movement (NREM) sleep. Aging disrupts SO properties - reducing amplitude, density, and slope while altering the spatiotemporal patterns of slow-wave propagation - yet the circuit-level mechanisms linking structural brain changes to these disruptions remain poorly understood. Here we present a multi-scale, whole-brain thalamocortical network model incorporating biologically grounded human connectivity derived from diffusion MRI tractography, comprising over 10,000 cortical columns per hemisphere with spiking pyramidal and inhibitory neurons and an anatomically differentiated thalamic module. Simulating progressive synaptic loss, we find that selective degradation of recurrent excitatory connectivity, but not excitatory-inhibitory projections, reproduces empirically observed age-related SO changes. These results suggest that aging selectively disrupts the temporal structure of slow-wave sleep critical for interference-free memory consolidation, providing mechanistic insight into cognitive decline in the aging brain.

Epigenetic landscapes (ELs) are defined by the pattern of epigenetic marks (acetylation, methylation, etc.) layed over large chromatin regions. The information contained in the ELs is essential to sustain the patterns of gene expression that shape cell fate and identity. EL maintenance requires the precise regulation of chromatin-modifying enzymes (ChME) and their metabolic cofactors (McF). Competition for ChME or dysregulation of McF abundance can lead to degradation of ELs, triggering large-scale changes in the cell fate information contained in EL. Thus, predicting impending epigenetic tipping points (ETPs) by identifying early warning signals (EWS) may help to anticipate the onset of cell identity loss during aging and cancer. Since ELs are formed (and maintained) by a systems of writer/eraser enzymes that interact both in cis (local) and trans (long-range) modes, their mathematical description involves a high-dimensional dynamical system, where identifying ETPs and characterising the biological mechanisms that control them remains challenging. Here, we develop a general mathematical framework that incorporates different connectivity patterns generated by the 3D chromatin folding structure to analyze competition-induced ETP in large EL. This framework allows us to measure the sensitivity and robustness of ETP to the availability of metabolic cofactors and to identify potential EWS. Using a dimension reduction method, we derived coarse-grained (CG) equations for the collective observables associated with chromatin modifications. Analysis of the CG system allows the prediction of global transitions that shape the large-scale features of EL, accurately reproduce the corresponding microscopic benchmarks, and reveal the existence of tipping points under conditions of ChME competition. We applied the CG method to predict ETP under different connectivity patterns, including heterogeneous profiles such as those found in Hi-C data. Although a robustness measure for stable EL was derived from the CG dynamics in bistable regimes, sensitivity analysis revealed that metabolic cofactors have the greatest impact on EL robustness. In particular, we identified the metabolic cofactors SAM and acetyl-CoA as potential EWS for the catastrophic loss of hyperacetylated EL induced by ChME competition. The ability to predict global ETP can facilitate the discovery of predictive biomarkers and inform metabolic interventions aimed at limiting and reversing pathological cell fate decisions.

Rationale: Regular aerobic exercise protects against vascular aging and reshapes the circulating molecular milieu, but the relation between vascular function, circulating molecules, and exercise dose at extreme volumes remains poorly defined. The vascular and molecular consequences of chronic, multi-stage ultra-endurance running are particularly unclear. Objective: To define circulating molecular signatures associated with vascular dysfunction following the 64-stage, 4,486-km Trans Europe Foot Race (TEFR). Methods and Results: Integrated multiomics analysis (proteomics, lipidomics, metabolomics) of plasma from 27 finishers revealed a coordinated systemic shift driving an oxidative phenotype. Specifically, we identified altered arginine metabolism and a universal upregulation of lipotoxic ceramides consistent with incomplete fatty acid oxidation. In conjunction, we identified upregulation of innate immune system pathways including the acute phase response and the complement system. Central pulse wave velocity (cPWV) increased significantly after the race, consistent with arterial stiffening. To test whether the post-race circulating milieu could directly influence vascular mechanics, naive murine aortic rings were incubated with participant plasma. Post-race plasma acutely increased aortic elastic modulus, and this effect was attenuated by the superoxide dismutase mimetic TEMPOL, supporting a ROS-dependent component. In human aortic endothelial cells (HAECs), post-race plasma increased reactive oxygen species generation without detectable changes in eNOS phosphorylation, total eNOS abundance, or stimulated nitric oxide production. Endothelial ROS responses were associated with components of the terminal complement pathway. Conclusions: Extreme multi-stage ultra-endurance exercise induces a distinct systemic milieu associated with arterial stiffening through ROS-sensitive mechanisms. This response is characterized by remodeling of arginine-related metabolism, ceramide accumulation, innate immune activation, and oxidative stress, without evidence of reduced measured eNOS abundance or stimulated NO production. These findings identify candidate molecular pathways linking prolonged metabolic stress to vascular dysfunction.

Late-life cognitive impairment most commonly occurs in the setting of mixed neurodegenerative and cerebrovascular pathology, yet the molecular programs distinguishing vascular, neurodegenerative, and mixed pathology in the aging human brain remain incompletely defined. We performed neuropathology-stratified proteomic and transcriptomic profiling of postmortem brain tissue from participants in the Religious Orders Study and Rush Memory and Aging Project. Dorsolateral prefrontal cortex proteomics (n = 733) were analyzed alongside bulk RNA sequencing from dorsolateral prefrontal cortex (n = 938), posterior cingulate cortex (n = 569), and anterior caudate (n = 632). Participants were classified into vascular, neurodegenerative, and mixed pathology groups based on comprehensive autopsy assessment. Neurodegenerative and mixed pathology, relative to vascular pathology, showed coordinated upregulation of immune and inflammatory pathways and downregulation of mitochondrial and oxidative phosphorylation programs across molecular layers. Although few individual proteins differed between mixed and neurodegenerative groups, pathway-level analyses identified additional remodeling programs in mixed pathology, including extracellular matrix organization and vesicle-mediated transport. Proteomic co-expression network analysis identified immune-stress modules associated with amyloid burden, tau pathology, and cognitive decline, whereas a mitochondrial bioenergetic module showed relative preservation in vascular pathology. Cross-omics concordance was robust at the pathway level but limited at the level of individual genes and proteins. These findings define conserved molecular programs distinguishing vascular, neurodegenerative, and mixed pathology and demonstrate that pathway-level organization provides a stable framework for interpreting molecular heterogeneity in late-life dementia.

Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell-based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1-driven epithelial dysfunction as a potential therapeutic strategy.

Aging is a long-term and complex process characterized by cellular changes, including cell cycle arrest, increased production of the senescence-associated secretory phenotype (SASP), and nuclear membrane disintegration. To accelerate the aging process, various animal models are made using chemical inducers, such as D-galactose (D-Gal). D-Gal has been extensively applied to induce aging in experimental animals; however, its effects on the gastrointestinal system, particularly the colon, remain underexplored. Observation of molecular aging markers will provide a valuable approach to assess these cellular changes. This study aimed to observe the expression of genes related to cell cycle arrest (p53 and Cdkn1a), SASP production (Il-6 and Il-1β), nuclear membrane disintegration (Lmnb1), as well as histological inflammation process in the colon of D-Gal-induced aging rat models. Twelve-week-old male Sprague-Dawley rats (n = 12) were divided into the control and D-Gal (100 mg/kg/day for 6 weeks) groups. The expression levels of aging-related genes (p53, Cdkn1a, Il-6, Il-1β, and Lmnb1) were assessed by reverse-transcription quantitative polymerase chain reaction. The D-Gal group exhibited inflammatory cell infiltration. Il-1β immunohistochemical score along with Il-1β expression was significantly elevated in D-Gal group (p < 0.01), suggesting SASP activation and pro-inflammatory signaling. No statistically significant differences were observed in the expression levels of p53, Il-6, Cdkn1a, or Lmnb1 expression. Molecular and histological results demonstrated that D-Gal administration induces colonic inflammation, characterized by increased Il-1β expression, which subsequently promotes potential cellular senescence.

Aging-related degenerative diseases, particularly neurodegenerative, musculoskeletal, and cardiovascular disorders, represent a major global health challenge. Characterized by progressive and irreversible cellular and tissue deterioration, these conditions contribute substantially to disability, loss of function, and mortality in older populations. Despite advances in symptom management, early diagnosis and effective therapies remain limited, largely due to complex and multifactorial pathogenesis. DNA origami, an emerging nanotechnology, offers unique advantages such as nanoscale precision, structural programmability, biodegradability, and low toxicity, making it a promising platform for biomedical applications. Recent progress has highlighted its utility in biosensing, bioimaging, molecular detection, targeted drug delivery, immune modulation, and receptor recognition in models of aging-related degenerative diseases. Here, we summarize current advances in DNA origami-based biomedical applications for aging-related degenerative disorders and discuss key challenges including

Ovarian aging, marked by follicle depletion and oocyte quality decline, involves complex metabolic alterations. This review synthesizes evidence that dysregulated metabolic reprogramming, encompassing energy, lipid, and nutrient metabolism, drives ovarian functional decline. Central to this process is a self-reinforcing "metabolism-epigenetics-immunity" triangular network, where mitochondrial dysfunction and NAD

Biological aging is increasingly understood as a process of reversible epigenetic regulatory drift rather than irreversible structural deterioration. The Genesis Framework proposes a systems-control architecture for safe partial cellular rejuvenation, grounded in four interdependent regulatory principles: stoichiometric transcriptional control of OCT4, SOX2, and KLF4 at a 3:2:1 molar ratio to promote chromatin remodeling without pluripotency induction; transient self-amplifying RNA delivery via 72-hour pulse using non-integrating saRNA; a microRNA-based dual-gate safety architecture utilizing the Let-7 and miR-294 axis within the 3' UTR to ensure biological activity exclusively in mature somatic cells; and tissue-network coordination through GDF11 and TIMP2 paracrine signaling. Delivery is proposed via selective organ targeting SORT lipid nanoparticles incorporating DOTAP at 5 mol% with m1-Psi-modified saRNA for nuclease resistance. All framework parameters emerged from 21,000 dual-validation simulation cycles concurrently testing efficacy and safety using BioNetGen, Python, and AlphaFold 3 integrated with Human Cell Atlas stochastic noise parameters. Experimental validation is outlined using human dermal fibroblasts as a primary model with falsifiable predictions anchored to Horvath DNA methylation clock reversal and NANOG suppression as primary endpoints. This document is a theoretical framework and complete laboratory blueprint released under CC0 for unrestricted scientific replication by independent biological laboratories worldwide.

Brain dynamics provide the most direct substrate for neural function and representation. Extensive prior work has demonstrated that the human brain is organized into hierarchical structures across molecular, cellular, microstructural, and macroscale network levels. However, whether these hierarchies can be directly linked through shared patterns of neural dynamics remains unresolved, and clear evidence from data driven analyses is still lacking. A central open question is whether brain dynamics vary along a single continuous dimension, or whether they are instead composed of a limited number of reproducible coordination modes that could provide a unifying basis for cross scale integration. Here, using source resolved resting-state magnetoencephalography (MEG), we adopt a fully data driven approach that imposes no a priori assumptions about cortical hierarchy or gradient structure. By characterizing full spectrum power relationships across cortical regions, we identify a set of stable and reproducible spectral coordination modes. These modes capture how multiple frequency components jointly co vary across space, defining distinct dynamical configurations rather than conventional band limited oscillations or continuous gradients. The identified spectral coordination modes exhibit pronounced spatial differentiation across the cortex, distinguishing regions dominated by narrowband rhythmic activity from those characterized by broadband or multi-frequency coordination. Importantly, these modes do not correspond to predefined hierarchical axes, nor can they be reduced to existing MEG gradients or functional connectivity organizations. Instead, they emerge directly from the data, revealing a finite set of shared organizational patterns underlying cortical dynamics. Multimodal analyses further demonstrate that individual spectral coordination modes show selective associations with neurotransmitter system distributions, laminar microarchitecture, and cell type specific gene expression, suggesting that these dynamical patterns may serve as linking mechanisms between micro and macroscale brain organization. Computational modeling supports this interpretation, showing that differences in local circuit parameters are sufficient to generate distinct spectral coordination states without invoking a single global dynamical hierarchy. Across the adult lifespan, these coordination modes exhibit frequency- and region-specific reorganization, indicating multiple parallel trajectories of dynamical aging. In Parkinson's disease, alterations are observed in specific spectral coordination modes, particularly within higher order cortical regions, suggesting that the disorder preferentially disrupts distinct dynamical configurations rather than inducing a global breakdown of cortical dynamics. Together, these findings indicate that large scale brain dynamics are not organized along a single pre existing hierarchical axis, but instead are structured by a limited number of data-driven spectral coordination modes. This framework provides a new dynamical perspective for linking brain organization across modalities and scales, and offers a principled avenue for understanding systematic changes associated with aging and neurological disease.

Osteosarcopenia (OSP), a degenerative syndrome characterized by concurrent osteoporosis and sarcopenia, exhibits persistently high global prevalence due to aging and disuse, yet lacks targeted therapies. p38 MAPK plays a key regulatory role in musculoskeletal degeneration. Increased expression of DUSP4, a key inhibitor of the Mitogen-Activated Protein Kinase (MAPK) pathway, inhibits the phosphorylation of p38 MAPK. Thus, targeted delivery of microRNAs that inhibit DUSP4 expression can activate the p38 MAPK pathway and promote osteogenic and myogenic differentiation. However, the therapeutic efficacy of nucleic acid drugs critically depends on delivery systems with targeted specificity, stability, and biocompatibility. Therefore, we engineered a hybrid nanovesicle (miR@DT/iMNV) by fusing bone-muscle dual-targeting peptide-modified liposomes (miR@DT-Lipo) and iPSC-derived MSC-EVs (iMSC-EVs). The miR@DT/iMNV enables the dual-tissue targeted delivery of miR-206-5p (which is downregulated in OSP and can target and inhibit DUSP4) and exhibits excellent biocompatibility. Results demonstrated that miR@DT/iMNV enhances osteogenic/myogenic capacities of stem cells, modulates macrophage phenotypes, restores mitochondrial function, and increases bone/muscle mass in a disused OSP murine model. This dual-targeted, multi-mechanistic strategy presents an innovative therapeutic approach for OSP.

Period Life Expectancy (PLE) is a measure of longevity valued for its sensitivity to short and long-term changes. However, it refers to a hypothetical cohort, not to a real population, thereby undervaluing longevity under declining mortality conditions. Other measures such as the Average Cohort Life Expectancy (ACLE) only partially overcome this limitation, still underestimating population longevity. This article introduces a new indicator, the Population Life Expectancy (PoLE), defined as the mean age at death of active cohorts in the studied population. Using a log-linear Poisson model with age-period interaction to project mortality of non-extinct cohorts, we estimated PoLE in Switzerland and Norway over 1876-2024, and compared it to PLE, Cohort Life Expectancy (CLE), and ACLE. PoLE clearly exceeded PLE, increasing from 63.3 to 89.7 for Swiss men (PLE from 37.7 to 82.4), and from 65.4 to 91.3 for Swiss women (PLE from 41.4 to 85.9), revealing a gain of about +50% over 150 years, rather than +100% suggested by PLE. Comparable results were obtained in Norway. PoLE was also higher than CLE until the mid-20th century, when the relation reversed, indicating that life expectancy is now higher for newborns than for those already alive, a tangible sign of human progress. Keywords: period life expectancy, cohort life expectancy, population life expectancy, real population, mortality projections.

Intracellular proteins have a wide range of thermal stabilities; some are very sensitive to temperature and may be denatured even in normal physiological conditions. Here, we show that members of the nuclear transport factor Importin α family have a variety of thermosensitivities, and some subtypes can be denatured at physiological temperature. The thermal stabilities of Importin α subtypes changed remarkably depending on their binding partners. Proteomic analyses of Importin α-interacting proteins in the cytoplasm revealed that continuous nuclear transport cycles help maintain Importin α quality. Additionally, in senescent cells, the proportions of denatured thermosensitive Importin α subtypes increased, indicating that a low transport rate leads to further inhibition of transport efficiency. The denaturing temperatures of Importin α family members correlate with the body temperatures of the animals in which they are present, thus their thermosensitivity may be important for heat stress response and other cellular functions related to aging and growth.

Balanced metabolic homeostasis is critical for maintaining high-quality oocytes. Growing evidence suggests that metabolic dysregulation induced by postovulatory aging severely compromises oocyte quality. However, the metabolic signatures of postovulatory aged oocyte remain poorly characterized. In this study, we employed metabolomic sequencing to delineate the distinctive metabolic alterations in postovulatory aged (PostOA) oocytes. Notably, we identified that Harpagoside accumulation in PostOA oocytes leads to reduced nitric oxide (NO) levels, resulting in spindle/chromosome instability and DNA damage. Furthermore, we demonstrated that Taurine plays a crucial role in preserving the quality of PostOA oocytes. Exogenous Taurine supplementation significantly rescued meiotic defects in PostOA oocytes, primarily by restoring mitochondrial function and enhancing developmental competence. Collectively, our findings provide a valuable resource for understanding metabolic remodeling during postovulatory aging and highlight potential therapeutic strategies to mitigate aging-related oocyte deterioration.

Background: While immunologic aging impacts immune responses to vaccination, consistent biomarkers associated with aging of the immune system and suboptimal serologic response to influenza vaccination have not been well-studied. Identification of readily measurable biomarkers of immunosenescence may have predictive clinical utility and inform targeted influenza vaccination strategies and future research into aging of the immune system. Methods: We quantified multiple serum/plasma and cell-based parameters related to immune aging (CMV serostatus, plasma cytokines/chemokines, TREC, TERT, NK cell functionality, and DNA methylation clock) at baseline in an adult (age range 18-85) cohort of 2019-2020 influenza vaccine recipients (n=337) and evaluated their associations with vaccine-induced HAI response to influenza A/H1N1, A/H3N2 and B/Victoria strains. Results: CMV IgG titers were significantly positively correlated with vaccine-induced increases in HAI antibody titers to influenza A/H1N1 (p=0.02) and A/H3N2 (p=0.014). CMV IgG titers (p=0.00096) and CMV seropositivity (p=0.003) were also associated with Day 28 HAI seropositivity against influenza A/H3N2 in subjects seronegative at baseline. Conversely, plasma MCP-1 levels were negatively associated with HAI responses to the A/H3N2 (p=0.04) strain. These findings were significant independent of age, sex or vaccine type received (high vs standard-dose seasonal influenza vaccine) Conclusions: Our identification of significant relationships between easily quantifiable immune markers and HAI responses to influenza A vaccine strains across sex and age enhances our knowledge of specific links between immune aging and influenza vaccine-induced immunity. These markers could be leveraged for predicting response to influenza immunization.

The present study aimed to investigate the effect of obstructive sleep apnea (OSA) and its treatment with continuous positive airway pressure (CPAP), the gold standard treatment for OSA on changes of telomere length and its associated mechanisms. In this mechanistic pilot study of a selective patient population (middle-aged men, BMI < 35 kg/m

In the absence of telomerase, telomere shortening triggers replicative senescence, a tumor suppressor mechanism that is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics, and genomic instability, we develop a system in Saccharomyces cerevisiae to generate and track telomeres of precise length in the absence of telomerase. Using single-telomere and single-cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly in cis to the shortest telomere as Pol32-dependent non-reciprocal translocations that result in re-elongation of the shortest telomere and likely transient escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival.

Whether distinct visible aging traits, e.g., wrinkling, pigmentation, and inflammation, reflect shared or independent epigenetic programs remains unknown; existing clocks compress aging into a single chronological axis, leaving the phenotype-specific architecture of cutaneous aging uncharacterized. Here, we integrate AI-derived facial phenotypes with skin DNA methylation profiles from 706 individuals to develop EpiVision, a panel of 21 epigenetic predictors spanning structural, pigmentary, inflammatory, and textural aging traits. Predictors reveal shared and trait-specific pathways, including developmental patterning, epithelial remodeling, hormonal signaling, and UV damage responses, and capture environmentally induced acceleration in sun-exposed skin alongside lifestyle and topical treatment associated variation. These findings establish that visible skin aging comprises molecularly distinct axes with shared regulatory substrates and trait-specific drivers, providing a scalable epigenetic framework for intervention evaluation and aging biology research.

Glutathione (GSH) and cysteine (Cys) are crucial low-molecular-weight thiol antioxidants that protect ocular tissues from oxidative stress, a key driver of age-related eye diseases. The balance between their reduced (GSH/Cys) and oxidized (GSSG/CySS) forms reflect tissue oxidative status. Despite their importance, existing analytical methods typically quantify these analytes separately, requiring multiple assays. In this work, a robust liquid chromatography-tandem mass spectrometry method for the concurrent quantification of GSH, GSSG, Cys, and CySS in ocular tissues has been developed and validated. The workflow uses derivatization of reduced thiols with monobromobimane, followed by solid-phase extraction and separation using reversed-phase high-performance liquid chromatography with an 8-min gradient elution of acetonitrile and heptafluorobutyric acid. Analytes were detected by positive-ion mode multiple reaction monitoring on a triple quadrupole mass spectrometer and quantified using extracted ion chromatograms. The method demonstrated excellent linearity, precision, and accuracy, with all quality control samples meeting acceptance criteria. Method sensitivity and reproducibility were also validated. Application to human, rat, bovine, and rabbit lenses, as well as rat retina, cornea, aqueous humor, and vitreous humor revealed distinct tissue- and species-specific redox profiles. Rat ocular tissues were found to be in a predominantly reduced state, with reduced thiols at higher concentrations than their oxidized counterparts. Rabbit lenses exhibited the highest GSH concentrations, while human lenses showed lower levels, a finding potentially related to donor age. This method has broad applicability in studies investigating the role of oxidative stress in ocular health and the development of novel treatments to prevent ocular disease.

Motivation: Collagen fibrils are the primary load-bearing units of connective tissues. However, generating atomistic, simulation-ready models remains challenging due to collagen's hierarchical organization and the diversity of its crosslinking network across tissues, ages, and metabolic states. Notably, non-enzymatic advanced glycation end-product (AGE) crosslinks, central to aging and diabetic complications, are largely absent from current atomistic fibril modelling workflows. Results: Here, we present an extension of the ColBuilder framework to generate atomistic collagen fibril models that incorporate three representative AGE-derived crosslinks (glucosepane, pentosidine, and MOLD) alongside enzymatic crosslinks. Amber99-compatible parameters are provided and assessed against QM-optimized reference geometries using all-atom molecular dynamics (MD) simulations. As proof-of-concept, we examine the mechanical response of single D-period collagen microfibrils featuring enzymatic-only, AGE-only, and mixed crosslink patterns in Molecular Dynamics simulations under force, and observe that AGE crosslinks differently impact the fibril structure compared to enzymatic crosslinks. The extension to ColBuilder can aid future structure-based research on collagen aging. Availability and implementation: ColBuilder is available as an open-source Python command-line package at https://github.com/graeter-group/colbuilder.

Astroglia can counteract the harmful effects of -synuclein (-SYN) protofibrils and reverse premature cellular senescence by promoting tunneling nanotubes (TNTs). However, the mechanism behind this recovery is unknown. This study is the first to examine TNT-mediated mechanical stability in senescent astroglial recovery. We demonstrate that disruption of Lamin A/C in -SYN-protofibrils-treated senescent cells reduces actin-cytoskeleton stress, as measured by nucleus flatness index and isometric scale factor from quantitative microscopy. ROCK (Rho-associated kinase) inhibition, which is crucial for reducing actin-cytoskeleton tension, promotes TNTs. Small molecules like Cytochalasin-D, Nocodazole, and Jasplakinolide, which inhibit TNTs by altering actin tension other than ROCK pathway, cannot reverse senescence. RNA-sequence heatmaps reveal changes in senescence-, integrin-, and ROCK-pathway genes; STRING links these to the Hippo pathway. Experimental results show that cytosolic YAP translocation, a key regulator of Hippo pathway, is vital for TNT formation and actin-based stability in U87-MG astrocytoma and primary astrocytes. Interestingly, TNTs form between two cells with different actin tensions: one exhibits low actin tension with Hippo signaling on, while the other has higher actin tension with Hippo signaling off. The most notable observation is the high abundance of YAP inside the TNTs, along with actin. The study shows that TNTs maintain mechanical stability through Lamin A/C integrity and actin tension in -SYN-induced senescent astroglia, thereby protecting the cells, reversing senescence.

Synapses are the fundamental units of neural computation, yet quantifying their organization across circuit-level scales remains a critical bottleneck in neuroscience. While advances in fluorescent labeling and imaging can generate vast datasets, analysis is often the limiting factor. Several deep learning-based tools have been proposed to ameliorate these issues. However, existing applications primarily focus on dendritic spines and lack robust solutions for segmenting synaptic puncta in dense tissue preparations. To address this, we introduce SynAPSeg, which encompasses an open-source framework for deep learning-based analysis and, to the best of our knowledge, the first large-scale, publicly available instance segmentation dataset specifically curated for synaptic puncta. We use this dataset to train deep learning models that reach the performance of human experts across a unique benchmark dataset. SynAPSeg integrates these models into an interactive interface, with support for multi-dimensional data, enabling fully automated segmentation and quantification pipelines alongside an annotation module for refinement and validation. We demonstrate the framework's scalability by performing the first comprehensive mapping of nearly 4 million excitatory postsynaptic PSD95 puncta within inhibitory interneurons across the dorsal hippocampus, revealing regional differences in synapse properties. Finally, we show SynAPSeg's utility for 3D quantification by applying these models to study aging-associated synaptic changes in CA1 parvalbumin (PV)-positive inhibitory neurons. Through this approach, we uncover a reduction in PSD95 density along PV dendrites in the aged CA1, indicating reduced glutamatergic recruitment of PV neurons which could contribute to age-related cognitive decline. Collectively, these results demonstrate that SynAPSeg provides a scalable solution for comprehensively studying synaptic architecture in health and disease.

Environmental endocrine disruptors (EEDs) can accelerate the onset of age-associated liver dysfunction, yet the underlying molecular mechanisms remain poorly understood. Whether unexposed offspring experience differential aging of the liver due to ancestral environmental exposure is currently unknown. Here, we investigated the molecular underpinnings of aging in female medaka livers due to ancestral exposure to bisphenol A (BPA). Exposure occurred at the first (F0) generation, and the aging liver phenotype was examined at the third (F2) generation. Controls did not receive BPA while experimental fish were exposed to 10 μg/L BPA from 8 hours post-fertilization to 15 days post-fertilization, spanning their embryonic and perinatal development during which the liver forms and fully differentiates. The liver developed hepatic steatosis, characterized by increased expression of aging gene signatures commonly found in mice and humans. Transcriptome analysis revealed significant downregulation of 13 mitochondrial oxidative phosphorylation genes, indicating impaired mitochondrial transcriptional activity. A total of 189 aging-associated genes were identified as common between medaka and humans, which are known to regulate mitochondrial metabolism, chromatin remodeling, and inflammation. Functional enrichment linked these changes to oxidative stress, DNA damage, apoptosis, and impaired regenerative capacity. Integrated methylome-transcriptome analysis revealed hypermethylation of gene body CpG islands in core aging regulators, correlating with transcriptional repression and disruption of FoxO, PI3K-Akt, AMPK, and longevity pathways. These findings demonstrate that ancestral BPA exposure induces coordinated mitochondrial, transcriptomic, and epigenetic reprogramming of conserved aging networks, predisposing descendants to accelerated hepatic aging associated with increased severity of sex-biased NAFLD phenotype.

Aging is accompanied by chronic low-grade inflammation (inflammaging), driving age-related diseases. Urolithin A (UA), a gut microbial metabolite, possesses anti-inflammatory properties, yet its mechanism in hepatic aging remains unclear. This study investigated UA's effects on aging-associated inflammation and the involvement of Nur77 in D-galactose-induced macrophage senescence and mouse liver aging models using molecular docking, Western blotting, and immunoprecipitation. UA alleviated cellular senescence markers (p53, p21), suppressed pro-inflammatory factors (IL-6, IL-1β), and elevated anti-inflammatory IL-10. Mechanistically, UA enhanced Nur77 protein stability by inhibiting MDM2-mediated ubiquitination and degradation, thereby restoring inflammatory homeostasis. In vivo, UA ameliorated D-gal-induced liver injury and modulated the hepatic Nur77-MDM2 axis. Conclusion: UA stabilizes Nur77 by inhibiting its ubiquitination, alleviating hepatic aging-associated inflammation. This study identifies the MDM2-Nur77 axis as a potential therapeutic target for hepatic aging.

The oxysterol 27-hydroxycholesterol (27OHC), which is widely distributed in various tissues and circulation, plays a notable role in pathological processes, such as including breast cancer, atherosclerosis, and neurodegenerative diseases. Although these processes are closely linked to muscle pathophysiology, the effects of 27OHC on metabolic changes associated with muscular atrophy and sarcopenia remain poorly understood. In this study, we demonstrated that 27OHC decreased skeletal muscle viability by activating pro-apoptotic signaling pathways. RNA sequencing revealed that 767 and 989 genes were upregulated and downregulated, respectively, in 27OHC-treated myoblasts. Upregulated genes were associated with hypoxia-inducible factor 1-alpha response, whereas downregulated genes were commonly involved in the phosphoinositide 3-kinase pathway and muscle differentiation process. Myoblast cell death induced by 27OHC was mediated by generation of reactive oxygen species followed by mitochondrial morphological impairments and disruption of mitochondrial membrane potential (ΔΨm). Moreover, 27OHC reduced mitochondrial gene expression via glycogen synthase kinase-3 beta activation, ultimately leading to increased mitochondrial ROS. Concurrently, hypoxia-inducible factor 1-alpha induction upon 27OHC exposure activated cellular defense mechanisms to mitigate oxidative damage. In addition, a significant reduction was observed in the expression of genes involved in myotube differentiation and fusion index following 27OHC treatment, and hypoxia-inducible factor 1-alpha knockdown further aggravated the impairment of tube formation. Furthermore, mice treated with 27OHC exhibited reduced exercise endurance, decreased muscle cross-sectional area, and impaired muscle recovery following barium chloride-induced injury. As plasma levels of 27OHC are increased in elderly individuals, our findings suggest that pharmacological inhibition of 27OHC generation could be a therapeutic strategy to treat age-related muscle atrophy.

Low life-course socioeconomic position (SEP) has been associated with worse cognitive function in older age. However, its association with brain structure remains unclear. We assessed whether SEP at 3 periods of the life-course and socioeconomic mobility are associated with later-life MRI-derived brain volumes.

Risky decision-making under uncertainty reflects complex cognitive processes supported by distributed brain networks that are vulnerable to aging. However, it remains unclear whether risk-taking behavior can serve as a behavioral marker of brain aging. In the present study, we combined behavioral tasks, computational modeling, and structural magnetic resonance imaging to investigate the relationship between risky decision-making, chronological age, and brain age. A total of 55 young adults and 112 healthy older adults completed the Iowa Gambling Task (IGT) and the Balloon Analogue Risk Task (BART), along with neuropsychological assessments and neuroimaging scanning. Decision processes were quantified using computational models, including the Value-Plus-Perseveration model and Exponential-Weight Mean-Variance. Brain age was estimated from gray matter volume. The results showed significant age-related alterations in parameters reflecting feedback sensitivity, learning rate, and loss aversion in both tasks. Within older adults, several decision parameters were significantly associated with both chronological age and brain age. Regression analyses further showed that computational parameters significantly predicted chronological age and brain age, whereas traditional cognitive screening measures did not show significant predictive effect. Structural brain analyses indicated that IGT-related parameters were primarily associated with the basal ganglia, while BART-related parameters were linked to a broader network including prefrontal, cingulate, and temporal regions. These findings suggest that computational markers of risk-taking behavior capture subtle age-related changes in cognitive processes and brain deterioration. Therefore, risk-taking parameters may serve as reliable functional markers of brain aging, providing critical insights into the mechanisms underlying successful aging.

Effective goal-directed decision-making relies on memory and planning-processes that are known to decline with age. We tested the hypothesis that these declines stem from a common mechanism by focusing on mnemonic discrimination, a measure of memory precision that shows unique vulnerability to age-related decline.

The gut microbiome plays a critical role in metabolism, immunity, and aging. While endurance training has been shown to beneficially modulate the microbiome, the effects of resistance training remain less clear, with some studies reporting minimal changes. This project aims to investigate whether structured resistance training elicits significant changes in gut microbiome composition and diversity in sedentary, healthy adults. 150 participants (85 female, 63 male), between 24 and 61 years of age, completed an 8-week supervised resistance training program between May 2022 and July 2023 in the cities of Tübingen and Rottenburg, Germany. Session-level training data, including weights and repetitions, were recorded alongside metrics like load and compliance. Fecal samples were collected throughout the study period at designated timepoints for 16S rRNA gene amplicon sequencing to assess microbiome composition and for metabolomics analyses to evaluate microbial metabolic activity.

Some developmental processes initiated in embryos or larvae persist into adulthood, a prominent example being maintenance of stem cells. To what extent are the mechanisms regulating these cell populations similar during different stages of life history? We have been studying how adult C. elegans hermaphrodites regulate the population of germline progenitor cells in response to the male pheromone ascr#10. Here we show that upon encountering ascr#10 adult hermaphrodites increase this cell population using mechanisms that are similar to but distinct from those previously revealed to be involved in the expansion of the germline in larvae. The core of the signaling axis in adults, as in larvae, consists of a neuronally-expressed TGFβ ligand DAF-7 and Notch-like LAG-2 signaling from the germline stem cell niche. An adult-specific serotonin signal acts upstream of DAF-7 to increase the population of germline progenitors, but only in actively egg-laying worms. Our results also suggest that during normal aging, declining expression of lag-2 and daf-7 contribute to germline senescence. Expression of these genes in aging hermaphrodites could be restored to youthful levels by ascr#10 or by pharmacological increase of serotonin signaling. We posit that neuronal signals regulate an environmentally appropriate rate of germline production in adults and argue that one driver of reproductive aging is the reduced expression of neuronal factors that regulate the germline.