Longevity Papers

Negative social ties, or "difficult ties," are pervasive yet understudied components of social networks that may accelerate biological aging and morbidity. Using ego-centric network data and DNA methylation-based biological aging clocks from a state representative probability sample in Indiana, we examine how negative social ties are associated with accelerated biological aging and a broad range of adverse physical and mental health outcomes. First, we find that difficult social ties are surprisingly common: on average, one in four network members is described as difficult, and nearly 60% of individuals report having at least one difficult tie. Regression analyses show that having more negative ties is associated with accelerated biological aging, with the most pronounced associations observed among individuals whose networks comprise more than 50% difficult ties. Finally, having negative ties is also associated with multiple adverse health outcomes beyond epigenetic aging, including poorer self-rated health, higher levels of depression and anxiety, elevated inflammation, greater multimorbidity, and unfavorable anthropometric indicators such as increased waist-to-hip ratio and BMI. These findings together highlight the critical role of negative social ties in biological aging as chronic stressors and the need for interventions that reduce the impact of negative social stressors within close social networks to promote healthier aging trajectories.

The naked mole rat (NMR, Heterocephalus glaber) is a eusocial rodent that is native to northeastern Africa. NMRs exhibit extraordinary traits such as longevity, resistance to age-related decline, and remarkable hypoxia tolerance. Although the reference genome of this species has been determined because of its unique characteristics, the significance or role of intraspecific genomic variations remains unknown. In this study, we used PacBio long-read sequencing to generate a genome assembly of NMR reared in Japan. The assembled genome is 2.56 Gb. Benchmarking Universal Single-Copy Orthologs (BUSCO) revealed high completeness (95.2%). BRAKER3 estimated 26,714 protein-coding genes, and we successfully added functional annotations for 26,232 protein-coding genes using the functional annotation workflow. We identified 417 gene models that were previously undetectable in the reference genome of this species. We also identified structural and amino acid sequence variations between our assembly and the reference genome, suggesting the presence of intraspecific genomic variations. This new genomic resource could help uncover the molecular mechanisms underlying the behavioral and physiological traits of NMR.

Atherosclerosis is an age-related cardiovascular disease. The intersections and bends of blood vessels under the direct action of oscillatory shear stress (OSS) are susceptible to atherosclerotic plaque formation, and the expression of age-related factors is significantly increased in plaques. However, the molecular mechanism by which OSS promotes vascular senescence is still unclear. In this study, we found that the expression of age-related factors, such as P16 and P21, was increased in human aortic endothelial cells (HAECs) exposed to OSS. We also found that the expression of autophagy-related gene 5 (ATG5), microtubule-associated protein 1 light chain 3β (MAP1LC3B), and beclin 1 (BECN1) was increased in HAECs exposed to OSS. The expression of sequestosome-1 (SQSTM1/P62) was also increased. Immunofluorescence confirmed that OSS impaired autophagic flux in HAECs by inhibiting the binding of autophagosomes to lysosome, thereby promoting endothelial cell (EC) senescence. The OSS-sensitive gene integrin β3 (ITGB3), which is closely related to EC autophagy and senescence, was screened by proteomics analysis of HAECs in the control and OSS-treated groups. The protein and mRNA expression of ITGB3 was significantly increased in HAECs exposed to OSS. ITGB3 overexpression in HAECs significantly affected the autophagic flux of ECs and promoted EC senescence, resulting in an increase in cells in the G0/G1 phase and cell cycle arrest. ITGB3 knockdown significantly inhibited the block of OSS-induced autophagic flux and senescence in ECs. In addition, in vivo studies showed that treatment with the ITGB3 inhibitor Cyclo(arginine-glycine-aspartate-tyrosine-lysine) [Cyclo(RGDyK)] significantly inhibited high-fat diet-induced plaque formation in the aortae of apolipoprotein E (ApoE)-/- mice. In conclusion, OSS blocks HAECs autophagic flux and promotes senescence via ITGB3 activation, thereby affecting the development of atherosclerosis.

Acetylcholine (ACh) secreted by the non-neuronal cholinergic system (NNCS), an intrinsic system found in the mammalian heart, is not dependent on neuronal inputs for its synthesis. Accumulating evidence demonstrates that ACh exerts multifaceted cardioprotective effects through the NNCS. Under extreme stress or demand, ACh slows heart rate by modulating cardiac chronotropy. Simultaneously, it protects the myocardium from ischemic, hypoxic, and other stressors. Beyond its direct effects on the heart, ACh has also been found to play a vital role in controlling mitochondrial homeostasis via specific signaling pathways in hearts. Through these pathways, ACh induces mitochondrial biogenesis and the renewal of the mitochondrial network while suppressing the generation of reactive oxygen species (ROS) within the mitochondria. Aging weakens the cardiac NNCS, lowering the heart's local ACh availability. Reducing mitochondrial activity and ROS-related inflammatory stress are essential indicators of cardiac aging and related disorders. As individuals age, mitochondria become less efficient at generating sufficient ATP to sustain the heart's ability to pump oxygen-rich blood and reduce cardiac performance. Therefore, the exciting prospect of increasing ACh secretion or stabilizing ACh levels through therapeutic targeting of the NNCS may provide a beacon of hope in the fight against age-related cardiovascular disorders. Further elucidating the mechanisms by which the NNCS regulates cardiac function through mitochondria may develop a novel treatment that rejuvenates the properties of this evolutionarily conserved system of the heart.

The skin is a complex organ composed of multiple layers and diverse cell types, including keratinocytes, fibroblasts, adipocytes, and sensory neurons, which maintain its structural and functional integrity together. Conventional in vitro and ex vivo models help investigate drug permeation and selected biological effects. However, they are limited in replicating neural interactions critical for assessing the efficacy of neuropeptide-based therapies. To address this limitation, a sensory neuron-integrated skin spheroid (SS) model was established, incorporating key skin cell types and providing a rapid, adaptable, and physiologically relevant platform for screening the biological activity of topical delivery systems targeting neuronal pathways. The model's responsiveness was demonstrated using acetyl hexapeptide-3 (HEX-3), a neuropeptide that inhibits acetylcholine release. HEX-3 was internalized by spheroid cells, with preferential accumulation around sensory neurons, confirming targeted cellular uptake. In parallel, ex vivo human skin studies confirmed that HEX-3 can traverse the stratum corneum and accumulate in deeper layers. Treatment with this film enhanced skin hydration, reduced scaling, and improved the structural organization of the stratum corneum after 48 h. Functional assays using the SS model showed that HEX-3 treatment suppressed acetylcholine release, upregulated the antioxidant enzyme SOD2, and stimulated type I collagen synthesis. In aged skin samples, the application of HEX-3 significantly increased collagen levels. This effect was mirrored in the spheroid model, which reached collagen levels comparable to those of aged human skin upon treatment. These findings establish the SS model as a robust platform for evaluating the biological activity of neuropeptide-based topical therapies, offering valuable insights for developing advanced strategies for skin rejuvenation and repair.

Osteoporosis, characterized by decreased bone mineral density, is a common skeletal disorder in the aging population. Cellular senescence is a key factor in the pathophysiology of osteoporosis. This study aimed to identify senescence-related biomarkers and evaluate the functional role in osteoporosis by integrating microarray analysis, Mendelian randomization (MR), and experimental validation. Osteoporosis-related microarray dataset was downloaded from the Gene Expression Omnibus database for differential expression analysis. We integrated summary-level data from genome-wide association studies on osteoporosis with protein quantitative trait loci data to identify genes with causal relationships to osteoporosis. The senescence-related biomarker gene was identified using the SenMayo gene set and evaluated for the predictive performance through receiver operating characteristic (ROC) curve analysis. Functional enrichment analysis was conducted to explore the underlying mechanisms. Validation of gene expression was performed using quantitative real-time PCR in 50 clinical samples from patients with osteoporosis and controls. A total of 33 differentially expressed genes were identified between osteoporosis and control samples. MR analysis revealed 90 genes with causal effects on osteoporosis. Subsequently, CXCL1 was identified as the key senescence-related biomarker gene. ROC curve analysis demonstrated good predictive performance with an area under the curve value of 0.708. Functional enrichment analysis showed a significant association between CXCL1 and immune-related pathways in osteoporosis. The expression of the gene was successfully validated in clinical samples. This study identified and validated CXCL1 as a senescence-related biomarker with causal effects on osteoporosis through a combination of microarray analysis, MR, and experimental validation. These findings offer insights into the molecular mechanisms of osteoporosis and could inform the development of treatment strategies.

The senescence-associated secretory phenotype (SASP) is closely linked to aging by promoting inflammation and tissue degradation. Sensing SASP is crucial for early detection of and intervention in age-related diseases to enhance therapeutic outcomes. Herein, SASP-selective sensors (transforming growth factor [TGF]-β1 and interleukin [IL]-6 probes) were designed by utilizing TGF-β1/IL-6 aptamers-functionalized copper-immobilized polymer dots that promoted specific binding between TGF-β1/IL-6 aptamers on the probe surface with aging factors (TGF-β1 and IL-6).

Idiopathic pulmonary fibrosis (IPF) is a fatal aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA approved anti-fibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that the pre-treatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and non-vascular aspects of IPF.

This study examines the association between estimated glucose disposal rate (eGDR) and accelerated aging in middle-aged and older adults, with a focus on the mediating role of estimated pulse wave velocity (ePWV).

The Novara Cohort Study (NCS) is the first multidisciplinary cohort study on aging in Northern Italy. It is designed to explore aging trajectories and health outcomes in the general population. This study involves the collection of biological samples and extensive data, including socioeconomics, medical history, lifestyle habits, quality of life, and physical function. This paper outlines the rationale, objectives, and preliminary findings of the NCS pilot phase. It discusses baseline characteristics, initial biological characterization, and identifies key areas for improvement to ensure the successful implementation of the full-scale study. The NCS pilot phase enrolled participants aged 35 and older residing in Novara, Italy. The study involved the collection of biological samples, medical examinations, questionnaires, and functional tests. Data collected included demographic information, physical activity, sleep quality, diet, quality of life, mental health, medical history, and medication use. Key blood parameters were analyzed alongside clinical data.The pilot phase enrolled 123 participants, 68 (55.3%) females and 55 (44.7%) males with a median age of 65 years old. The NCS pilot participants had higher education levels, lower smoking rates, and higher physical activity levels than the general population. Blood biomarker profiling revealed significant variability across participants, offering exploratory and preliminary findings to guide the design and implementation of the larger cohort phase aimed at studying aging trajectories. The NCS pilot provided valuable initial insights into participant characteristics and identified areas for study protocol enhancement. These findings will guide refinements to optimize future study processes and outcomes, ultimately aimed at investigating the biological, social, and environmental determinants of aging in the Northern Italy area population.

Age-related macular degeneration (AMD) and Alzheimer's disease (AD), two prevalent neurodegenerative disorders, share overlapping pathophysiological features yet lack cross-disease therapeutic strategies. This study systematically investigates their parallel genes and shared molecular mechanisms to identify potential therapeutic targets for dry AMD, a condition with limited treatment options.

Sensory impairments are common with aging, but studies examining the relationships of these impairments with DNA methylation-based biomarkers of aging, strong predictors of morbidity and mortality, remain sparse. We investigated whether subjective measures of sensory impairment are associated with epigenetic age biomarkers. We conducted a cross-sectional analysis in a representative sample of 2344 U.S. adults from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES). We examined the relationships of self-rated auditory and vision function with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNA methylation telomere length, and DunedinPoAm. We adjusted for potential confounders including chronological age, other demographics, lifestyle factors, and general health. In adjusted survey-weighted models, self-reported deafness was associated with a significantly higher GrimAge2 (β = 4.19-years, 95% CI 2.29, 6.09, P = 0.004) and DunedinPoAm (β = 0.07, 95% CI 0.04, 0.09, P = 0.002) compared to good hearing. Deafness was also associated with significantly higher GrimAge2 estimates of TIMP1 (β = 459.51, 95% CI 287.00, 632.03 P = 0.002) and marginally higher estimated levels of ADM (β = 10.06, 95% CI 1.76, 18.36, P = 0.03), CRP (β = 0.34, 95% CI 0.11, 0.56, P = 0.01), and cigarette pack-years (β = 6.55, 95% CI 2.62, 10.47, P = 0.01). No associations were observed with self-rated vision. We describe associations of self-rated deafness with accelerated epigenetic aging, as measured by GrimAge2 and DunedinPoAm. These results provide a foundation for future research exploring epigenetic biomarkers as tools for predicting and understanding the biological processes underlying sensory impairments like deafness.

Epigenome is sensitive to metabolic inputs and crucial for aging. Lysosomes emerge as a signaling hub to sense metabolic cues and regulate longevity. We unveil that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. We discovered that the induction of lysosomal lipid signaling and lysosomal AMP-activated protein kinase (AMPK), or the reduction of lysosomal mechanistic-target-of-rapamycin (mTOR) signaling, increases the expression of histone H3.3 variant and elevates H3K79 methylation, leading to lifespan extension across multiple generations. This transgenerational pro-longevity effect requires intestine-to-germline transportation of H3.3 and a germline-specific H3K79 methyltransferase, and can be recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. This work uncovers a lysosome-epigenome signaling axis linking soma and germline to mediate the transgenerational inheritance of longevity.

Body composition (adiposity and muscle depots) is strongly associated with cardiometabolic risk. However, using body composition measures for future disease risk prediction is difficult as they may reflect total body size or typical aging rather than poor health. We used data from the UK Biobank (UKB) and the German National Cohort (NAKO) to calculate age-, sex-, and height-specific z-scores for body composition measures (subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle (SM), SM fat fraction (SMFF), and intramuscular adipose tissue (IMAT)) and describe changes across the lifespan. Multivariable Cox regression assessed the prognostic value of z-score categories (low: z<-1; middle: z=-1 to 1; high: z>1) for incident diabetes, major adverse cardiovascular events (MACE), and all-cause mortality beyond traditional cardiometabolic risk factors in the UKB. Among 66,608 individuals (mean age: 57.7{+/-}12.9 y; mean BMI: 26.2{+/-}4.5 kg/m2, 48.3% female), SAT, VAT, SMFF, and IMAT were positively, and SM negatively associated with age. In multivariable-adjusted Cox regression, z-score risk categories had hazard ratios of up to 2.69 for incident diabetes (high VAT category), 1.41 for incident MACE (high IMAT), and 1.49 for all-cause mortality (low SM) compared to middle categories. Body composition shows distinct age-related changes across the lifespan. Z-scores of age-, sex-, and height-adjusted body composition measures identify individuals at risk and predict cardiometabolic outcomes and mortality beyond traditional risk factors. Our open-source tool facilitates the clinical translation of age-specific body composition assessments and supports future research.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, age-associated, lung disease characterized by short telomeres in alveolar type 2 (AT2) cells, epithelial remodeling, and fibrosis. Objectives: This study investigated how telomere dysfunction in AT2 cells lacking Telomere Repeat Binding Factor 1 (TRF1) drives lung remodeling in SPC-creTRF1flox/flox mice and its relevance to IPF. Methods: Mouse model of telomere dysfunction was used to conditionally delete TRF1 in AT2 cells. SPC-creTRF1flox/flox mouse lung epithelial cells were used to perform single cell RNA sequencing. AT2 cells from IPF lungs were analyzed by single cell RNA sequencing in an organoid model. Measurements and Main Results: Single cell RNA-sequencing revealed distinct pathological AT2 cells enriched in DNA damage, senescence, oxidative stress, and pro-fibrotic genes, along with fewer normal AT2 cells and increased club cells in SPC-creTRF1flox/flox mice. Pathological AT2 cells showed different early and late-stage gene signatures, with a prominent p53 signature at both time-points. Genetic deletion of p53 in SPC-creTRF1flox/flox AT2 cells improved survival and prevented lung fibrosis. p53 deletion or inhibition improved organoid formation, surfactant protein C expression, and reduced pro-fibrotic gene expression in AT2 cells isolated from SPC-creTRF1flox/flox mice or IPF lungs. Conclusions: These data suggest that the DNA damage response to AT2 cell telomere dysfunction, driven by enhanced p53 activity, mediates early AT2 cell transdifferentiation and senescence, leading to epithelial cell remodeling and fibrosis and that reversing this reprogramming is a potential therapeutic approach for managing IPF.

Aging is a complex biological process that detrimentally affects the brain and cerebrovascular system, contributing to the pathogenesis of age-related diseases like vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). While cell-autonomous mechanisms that occur within cells, independent of external signals from neighboring cells or systemic factors, account for some aspects of aging, they cannot explain the entire aging process. Non-autonomous, paracrine and endocrine, pathways also play a crucial role in orchestrating brain and vascular aging. The systemic milieu modulates aging through pro-geronic and anti-geronic circulating factors that mediate age-related decline or confer rejuvenative effects. This review explores the impact of systemic factors on cerebrovascular and brain aging, with a particular focus on findings from heterochronic parabiosis, blood exchange, and plasma transfer experiments. We discuss how these factors influence fundamental cellular and molecular processes of aging and impact cerebrovascular endothelial function, neurovascular coupling mechanisms, blood-brain barrier integrity, neuroinflammation, capillary density, and amyloid pathologies, with significant consequences for cognitive function. Additionally, we address the translational potential and challenges of modifying the systemic milieu to promote brain health and prevent age-related cognitive impairment.

Small extracellular vesicles (sEV) derived from mesenchymal stem cells hold promise for anti-skin aging, yet their clinical application is hindered by poor transdermal permeability. Herein, we report an innovative light-controlled sEV-based spherical nucleic acid nanomotor (NM-ESNA). This nanosystem was composed of an sEV core and an MMP1-targeting siRNA shell, forming a 3D penetrative nanostructure. In addition, asymmetrically modified light-responsive gas-generating molecules were integrated into the nanomotor, enabling efficient dermal delivery. The light-controlled and enhanced transdermal delivery guaranteed synergistic anti-skin aging therapy through sEV-mediated paracrine effects and gene therapy targeting MMP1 in the dermis. On the basis of this deep transdermal delivery technology and the synergistic therapy strategy, NM-ESNA demonstrated outstanding anti-skin aging effects in a mouse model. This biocompatible nanosystem (NM-ESNA) enabled light-controlled and deep transdermal delivery, establishing a therapeutic platform with significant potential for sEV-based noninvasive anti-skin aging therapy.

Xeroderma pigmentosum (XP) is an inherited photoaging syndrome caused by mutations in genes involved in the nucleotide excision repair (NER) pathway. XP patients exhibit hypersensitivity to ultraviolet (UV) radiation, leading to accelerated skin aging and requiring lifelong sun avoidance. Here, we demonstrate that UV-induced DNA damage triggers cellular senescence and up-regulates senescence-associated secretory phenotype (SASP) genes in melanocytes derived from an XP patient. To explore the potential therapeutics for XP, we developed a cisplatin-based drug screening system and identified JAK inhibitors and curcuminoids as promising senomorphic agents. In addition, two classes of senolytic agents, BCL-2-like protein inhibitors and HSP90 inhibitors, effectively eliminate senescent melanocytes. Further analysis demonstrates that senomorphic treatment effectively counteracts senescence and reduces SASP gene expression in XP-derived melanocytes. Moreover, genes in senescence-related pathways, including the JAK/STAT, Type I interferon (IFN-I), and PI3K/AKT pathways, which are activated by both UV irradiation and cisplatin treatment, are down-regulated by senomorphic treatment. This study highlights a potential senotherapeutic strategy for XP, which may help alleviate photoaging symptoms in XP patients.

Paraneoplastic syndrome represents severe and complex systemic clinical symptoms manifesting in multiple organs of cancer patients, but its cause and cellular underpinnings remain little explored. In this study, establishing a Drosophila model of paraneoplastic syndrome triggered by tumor transplantation, we found that the innate immune response, initiated by translocated commensal bacteria from a compromised intestine, significantly contributes to reduced lifespan in tumor-bearing hosts. Our data identify the renal system as a central hub of this paraneoplastic syndrome model, wherein the pericardial nephrocytes undergo severe damage due to an elevated immune response triggered by gut dysbiosis and bacterial translocation. This innate immune response-induced nephrocyte damage is a major contributor to reduced longevity in tumor-bearing hosts, as blocking the NF-kB/Imd pathway in nephrocytes or removing gut bacteria via germ-free derivation or antibiotic treatment ameliorates nephrocyte deterioration and extends the lifespan of tumor-bearing flies. Consistently, treatment with a detoxifying drug also extended the lifespan of the tumor hosts. Our findings highlight a critical role of the gut-kidney axis in the paraneoplastic complications observed in cancer-bearing flies, suggesting potential therapeutic targets for mitigating similar complications in cancer patients.

Schizophrenia, a pervasive mental health condition, poses a global challenge to individual well-being. The intricate interplay of schizophrenia with the aging process is characterized by a shortened lifespan, underscoring the urgent need for an in-depth exploration of the underlying biological mechanisms that contribute to the unique aging trajectory within this specific patient population. Currently, this crucial aspect remains largely unexplored. To bridge this knowledge gap, in the present study, serum samples from of 29 subjects with schizophrenia were analysed via liquid chromatography-mass spectrometry (LC-MS) and compared with those of 30 nonpsychiatric controls. This exploratory analysis of circulating blood serum, albeit based on a limited sample size, provides valuable insights into the significantly altered molecular pathways linked to schizophrenia and clarifies the unique aspects of aging in the context of this particular disease. The data presented in this study constitute a compilation of molecular alterations associated with schizophrenia across the human lifespan. By distinguishing between schizophrenia patients and nonpsychiatric controls, we identified a panel of 342 differentially abundant metabolites and 544 differentially expressed proteins. Our pathway enrichment analysis was focused primarily on histone acetylation, the Wnt/β-catenin signaling pathway, the dopamine receptor signaling pathway, and fatty acid beta-oxidation, highlighting their pivotal roles in schizophrenia. Furthermore, we conducted a co-occurrence analysis of these metabolites and proteins, aiming to elucidate their connection with accelerated aging processes. This analysis revealed the involvement of metabolic pathways crucial for lipid metabolism, such as the peroxisome and peroxisome proliferator-activated receptor (PPAR) signaling pathways, as well as neurotransmitter-related metabolic pathways influencing tryptophan metabolism and the dopaminergic synapse pathway. The findings significantly increase our understanding of the intricate molecular mechanisms underlying schizophrenia and its co-occurring comorbidities across the spectrum of aging, providing insights into the dynamics of the progression of this complex disorder. However, this study has certain limitations, particularly the lack of its findings and the relatively small sample size, especially in the proteomic analysis.

The prevalence of type 2 diabetes mellitus (T2DM) increases with age, and cellular senescence of pancreatic β-cells plays a key role in T2DM pathogenesis. As canagliflozin and acarbose have been shown to increase lifespan in mice, we investigated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, α-glucosidase inhibitor or both on the cellular senescence of β-cells in a T2DM mouse model.

The rapid increase in the elderly population in China has led to the dual challenges of cognitive decline and physical functional decline. Grip strength, a key indicator of physical function, may have a bidirectional relationship with cognitive function. However, research on the association and bidirectional dynamics between the two, especially in the elderly population in China, remains limited.

Sarcopenia is a debilitating age-associated condition with no effective treatment options. Therefore, there is high interest in evaluating whether food components, such as polyphenols found in grapes, could mitigate sarcopenia. However, the exact influence of grapes on age-related muscle loss in humans remains unknown. Herein, we conducted a pilot double-blind parallel clinical dietary intervention trial with 15 healthy postmenopausal women who consumed, either freeze-dried grape powder or a control powder once daily for 6 weeks. We observed that women consuming grape powder had significantly increased hand grip scores, a measurement of muscle strength, from baseline to week six compared to the control group. Additionally, women consuming grape powder significantly improved their performance on the gait speed test over the six-week period. Furthermore, the age-adjusted model revealed that the grape group completed the gait speed test significantly faster, compared to the control group. Mechanistically, we assessed plasma irisin concentrations. Although, they did not reach statistically significance, when comparing the change from baseline to week six, the grape group presented a 14.4% (

Humans are distinguished from our closest living relatives, other great apes, by our extended postmenopausal longevity, later first births, and shorter birth intervals. Those features likely evolved as ancestral grandmothers\' foraging subsidised dependents in habitats lacking foods that youngsters could manage for themselves. If so, as female post-fertile years increased, older years increased in males too. Those still-fertile old males in the paternity competition pushed average male reproductive success below the female average. According to R. A. Fisher, Mendelian inheritance requires equal contributions from both sexes to descendant gene pools. Higher average reproductive success in one sex makes tendencies to overproduce it pass to more grandchildren, equalizing averages in descendant generations. Yet, men\'s lower average reproductive success persists, their fertility lasting decades longer than women\'s. Here, we present a simple mathematical model to investigate this phenomenon. We show that a male-biased adult sex ratio is consistent with a offspring sex ratio of 1:1. Assuming a stable age distribution, we show that if male fertile careers are twice as long as those of females, the corresponding reproductive value of males is larger than that of females, which acts to balance the effect of higher female reproductive success. We propose that extended male fertility balances the sex difference in average reproductive success, maintaining Fisher\'s equilibrium under human life history conditions.

Compelling evidence links age-related brain dysfunction and neurodegenerative processes to persistent disruptions in intracellular calcium (Ca2+) signaling, a central hypothesis in the Ca2+ theory of aging. Calbindin (CB), a classical Ca2+ buffer, has been implicated in region-specific susceptibility to aging-related effects. Specifically, CB-immunopositive (CB+) neurons have demonstrated an age-dependent decline in neuronal number across various cortical and subcortical regions. However, it remains unclear whether this decrease occur in the dorsal lateral geniculate nucleus (DLG), a crucial relay and modulatory center for visual processing. Additionally, the potential impact of aging on the cellular volume of CB+ neurons in the DLG has not been fully elucidated, albeit an age-dependent neuronal hypertrophy of this region has been reported. To address these questions, we investigated CB+ neurons in the DLG of six marmosets (Callithrix jacchus), aged between 29-143 months. Using design-based stereological techniques, we estimated the total number and somal volume of CB+ neurons in DLG layers. Our results revealed no signs of CB+ neuronal number loss and somal volumetric changes in aged DLG, particularly within the koniocellular layers, a stratum that primarily expresses CB and play a critical role in blue/yellow color vision. Altogether, our findings suggest a preserved neuronal number and cellular volume of the CB+ population during aging process in the marmoset DLG. Moreover, they provide a valuable basis for future investigations into the neuroprotective role of CB in visual processing during aging and open avenues for strategies designed to preserve vulnerable neuronal populations in age-related neurodegenerative conditions.

Growing evidence suggests that the gut microbiota plays a key role in shaping life history in a wide range of species, including well-studied model organisms like Drosophila melanogaster. Although recent studies have explored the relationship between gut microbiota and female life history, the link between gut microbiota and male life history remains understudied. In this study, we explored the role of gut microbiota in shaping male life history traits by correlating variation in life history traits across genetically homogeneous isolines with their naturally occurring gut microbiota. Using 22 isolines from the Drosophila melanogaster Genetic Reference Panel (DGRP), we measured lifespan, early/late-life reproduction, and early/late-life physiological performance. We characterized the gut microbiota composition in young (5 days old) and old (26 days old) flies using 16S rDNA sequencing. We observed significant variation in male life history traits across isolines, as well as age-related changes in gut microbiota composition. Using machine learning, we showed that gut microbiota composition could predict the age of the organisms with high accuracy. Associations between gut microbiota and life history traits were notable, particularly involving the Acetobacter genus. In early life, the abundance of Acetobacter ascendens was associated with functional aging, while Acetobacter indonesiensis was linked to reproductive senescence. In late life, higher abundances of A. ascendens and Acetobacter pasteurianus were negatively associated with lifespan. These findings highlight the potential role of gut microbiota, especially the Acetobacter genus, in male fitness and aging.

Aging processes underlie common chronic cardiometabolic diseases such as heart failure and diabetes. Cross-organ/tissue interactions can accelerate aging through cellular senescence, tissue wasting, accelerated atherosclerosis, increased vascular stiffness, and reduction in blood flow, leading to organ remodeling and premature failure. This interorgan/tissue crosstalk can accelerate aging-related dysfunction through inflammation, senescence-associated secretome, and metabolic and mitochondrial changes resulting in increased oxidative stress, microvascular dysfunction, cellular reprogramming, and tissue fibrosis. This may also underscore the rising incidence and co-occurrence of multiorgan dysfunction in cardiometabolic aging in the population. Examples include interactions between the heart and the lungs, kidneys, liver, muscles, and brain, among others. However, this phenomenon can also present new translational opportunities for identifying diagnostic biomarkers to define early risks of multiorgan dysfunction, gain mechanistic insights, and help to design precision-directed therapeutic interventions. Indeed, this opens new opportunities for therapeutic development in targeting multiple organs simultaneously to disrupt the crosstalk-driven process of mutual disease acceleration. New therapeutic targets could provide synergistic benefits across multiple organ systems in the same at-risk patient. Ultimately, these approaches may together slow the aging process itself throughout the body. In the future, with patient-centered multisystem coordinated approaches, we can initiate a new paradigm of multiorgan early risk prediction and tailored intervention. With emerging tools including artificial intelligence-assisted risk profiling and novel preventive strategies (eg, RNA-based therapeutics), we may be able to mitigate multiorgan cardiometabolic dysfunction much earlier and, perhaps, even slow the aging process itself.

Skeletal muscle undergoes many alterations with aging. However, the impact of aging on muscle's ability to secrete myokines and its subsequent effects on the body remain largely unexplored. Here, we identify myokines that have the potential to ameliorate age-related muscle and bone decline. Notably, circulating levels of cardiotrophin-like cytokine factor 1 (CLCF1) decrease with age, while exercise significantly upregulates CLCF1 levels in both humans and rodents. Restoring CLCF1 levels in aged male mice improves their physical performance, glucose tolerance, and mitochondrial activity. Furthermore, CLCF1 protects against age-induced bone loss by inhibiting osteoclastogenesis and promoting osteoblast differentiation in aged male mice. These improvements mirror some of the effects of exercise training. Conversely, blocking CLCF1 activity significantly abolishes these beneficial effects, confirming the crucial role of CLCF1 in mediating the positive effects of exercise on muscle and bone health in male mice. These findings collectively suggest that CLCF1 may contribute to the regulation of age-associated musculoskeletal deterioration, and warrant further investigation into its potential role as a modulator of musculoskeletal health during aging.

T-cell metabolism is a key regulator of immune function. Metabolic dysfunction in T cells from young mice results in an aged phenotype, accelerating immunosenescence. Physical activity (PA) maintains T-cell function and delays immunosenescence in older adults, but the underlying mechanisms are poorly understood. We investigated the effects of PA on the metabolic and functional profiles at a single-cell resolution of resting and stimulated T cells from young adults (N = 9, 23 ± 3 years) and physically active older adults clustered between higher PA (HPA, N = 9, 75.5 ± 4.7 years) or lower PA levels (LPA, N = 10, 76.4 ± 2.1 years). Compared to young donors, HPA older adults had higher mitochondrial dependence (MD) and lower glucose dependence (GD) in unstimulated naïve, central memory (CM) and effector memory (EM) CD4

Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.

This study employs Caenorhabditis elegans (C. elegans) as a model organism to explore the anti-aging effects of hydroxytyrosol (HT) and its underlying mechanisms.

Longevity is defined by the ability to maintain both physical and mental health throughout a long life and may results from adaptive mechanisms that mitigate aging's detrimental effects.

Continuous glucose monitoring (CGM) might be beneficial for investigating healthy aging since high glycemic variability may increase protein glycation, oxidative stress, and inflammation, resulting in vascular damage. Additionally, CGM data on the risks for hypoglycemia and hyperglycemia are scarce, have not been analyzed by individual day and night blocks, and have not been related to diet. Therefore, this study aimed to compare glucose parameters of healthy older and young adults and the relationship with diet. Participants were 34 young (age 20-35 years) and 27 older volunteers (age 60-75 years) with a normal glycated hemoglobin A

Growing evidence suggests that the epigenetic reader Brd4 (bromodomain-containing protein 4) is involved in aging and aging-related diseases. However, the specific mechanisms by which Brd4 influences vascular aging, especially senescence of vascular smooth muscle cells (SMCs), remain unexplored.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative trait methylation analysis to identify transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses reveal 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value < 0.05). Taken together, our study reports the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes.

Mitochondria play crucial roles in energy production, metabolism regulation, and cell death. Mitochondrial dysfunction is associated with many diseases, including cancers, aging, and neurodegenerative disorders. Consequently, developing methods for mitochondrial regulation and treating related diseases has garnered significant interest in biological and medical research. Here, a smart framework nucleic acid (FNA) strategy is presented for mitochondrial interference and targeted cell elimination. Our approach involves the design of tetrahedral DNA nanostructures (TDNs) modified with triphenylphosphine and single-stranded DNA sequences responding to specific nucleic acid biomarkers (e.g., microRNAs) presented in target cells. The interlinked DNA networks, formed in situ responding to specific biomarkers, enable targeting and enveloping of the mitochondria, leading to mitochondrial fragmentation and dysfunction. It is demonstrated that TDN-based FNAs targeted the cancer-associated microRNA (miR-21) may enhance the efficacy of cancer therapy by disrupting mitochondrial function, while also serving as carriers of anti-cancer drugs to reduce the side effects. Additionally, FNAs targeting the senescence-associated microRNA (miR-34a) specifically eliminate senescent cells in both cell and Caenorhabditis elegans models, thereby improving overall cell viability within mixed cell populations. This programmable and functionalized TDN-based platform opens new avenues for advancing anti-aging research and treating various diseases by achieving targeted cell elimination through mitochondrial interference.

Cognitive flexibility in the human brain engages dynamic interactions between the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN), a functional architecture that is metabolically demanding and thus potentially susceptible to age-related decline. How the aging brain reorganizes its functional architecture to sustain cognitive flexibility under metabolic constraints remains an open question. In this study, we modeled resting-state functional flexibility across the adult lifespan (ages 18-88) using structural balance theory. Our findings align with the predictions of the SENECA model (Synergistic, Economical, Nonlinear, Emergent, Cognitive Aging), revealing a midlife neurocognitive transition: (i) from a metabolically costly, flexible DMN-FPN architecture, toward (ii) a more redundant configuration dominated by low-cost, sensory-driven interactions. The medio-parietal DMN and the Cingulo-Opercular Network (CON) are crucial to this transition, contributing to maintain global brain activity near a critical dynamic regime in older adulthood that optimizes for cognitive flexibility in face of declining metabolic resources. These findings advance a theoretical and methodological framework for understanding neurocognitive flexibility in aging and underscore the importance of multimodal fMRI-PET studies in midlife. They also open promising avenues for translational applications in neuropathology.

There is growing evidence that many perceptual difficulties associated with age-related hearing loss are not solely due to cochlear damage and are exacerbated by changes within the central nervous system. We examined electrophysiological (EEG) responses to clicks and diffusion kurtosis imaging (DKI) in 49 older (29 female) and 26 younger (20 female) adults to determine the extent to which auditory nerve (AN) deficits in older adults contributed to functional and structural changes throughout the auditory system. Older adults exhibited smaller AN responses, similar brainstem responses, and larger auditory cortex (AC) responses, demonstrating progressive central gain. Audiometric thresholds were not predictive of EEG measures. Reduced AN function predicted deficits in cortical microstructure (lower AC fractional anisotropy, FA) in older adults, consistent with myelin degeneration. These lower FA values in the AC of older adults also predicted larger AC responses and more central gain. Older adults exhibited significantly lower AC FA and higher mean diffusivity (MD) than younger adults, and AC FA and MD were significant predictors of speech-in-noise (SIN) recognition in older adults. The results suggest that reduced afferent input in older adults not only results in functional changes throughout the auditory system consistent with progressive gain, but also contributes to deficits in AC structure beyond those explained by age alone, contributing to SIN deficits. Understanding the complex effects of age, reduced AN input, central gain, and AC structure on SIN recognition may provide potential therapeutic targets for intervention.

Physical activity and mobility are critical for healthy aging and predict diverse health outcomes. While wrist-worn accelerometers are widely used to monitor physical activity, estimating gait metrics from wrist data remains challenging. We extend ElderNet, a self-supervised deep-learning model previously validated for walking-bout detection, to estimate gait metrics from wrist accelerometry. Validation involved 819 older adults (Rush-Memory-and-Aging-Project) and 85 individuals with gait impairments (Mobilise-D), from six medical centers. In Mobilise-D, ElderNet achieved an absolute error of 8.82 cm/s and an intra-class correlation of 0.87 for gait speed, outperforming state-of-the-art methods (p < 0.001) and models using a lower-back sensor. ElderNet outperformed (percentage error; p < 0.01) competing approaches in estimating cadence and stride length, and better (p < 0.01) classified mobility disability (AUC = 0.80) than conventional gait or physical activity metrics. These results render ElderNet a scalable tool for gait assessment using wrist-worn devices in aging and clinical populations.

Female reproductive aging is marked by a decline in oocyte quality, yet the underlying molecular mechanisms remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice under controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries. Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, mitochondrial genes were disproportionately affected. We highlight Ndufs4, a Complex I subunit, as a case in which aging promotes a truncated isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I assembly, providing a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the existence of a splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence oocyte competence and ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.

Applicable methods of rejuvenating organisms and improving resistance to environmental stimuli are needed. During attempts to synchronize heart rates in unhealthy colonial chordates, we observed morphological rejuvenation. While the importance of endogenously generated bioelectric currents in development is well-established1,2, and exogenously applied current has shown promise in regenerative medicine3,4,5,6,7,8,9, a model that robustly increases longevity and fertility while providing detailed mechanistic insights has not been reported. Here, we report the establishment of such a model using pulsatile electrical current (PEC) in Botryllus schlosseri, an established colonial chordate model10,11,12,13,14,15. PEC treatment significantly improved survival, morphological integrity, stem cell mediated regeneration, and gonad production in Botryllus. Transcriptomic analysis revealed pathway changes associated with cellular metabolism, cell cycle, stem cell activity, DNA repair, and immune modulation. Notably, PEC-induced expression patterns resemble the exercise-induced macrophage-associated transcriptional response previously observed across several mammalian species16,17. This transcriptomic signature correlated with an increase in immune-cell-containing populations. These findings demonstrate that PEC can improve longevity, vitality, and reproduction in an established model renowned for defining broadly applicable biological principles. These studies offer insights into novel strategies for promoting healthy aging and organismal survival.

Background: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), yet their underlying biological mechanisms remain unclear. This study aims to identify the genetic architecture of limbic WM microstructure in older adults by leveraging harmonized data from multiple cohorts, including those enriched for cognitively impaired individuals. Methods: We analyzed diffusion MRI (dMRI) data from 2,614 non-Hispanic White older adults (mean age = 73.7 {+/-} 9.8 years; 57% female; 26% cognitively impaired) across 7 harmonized aging cohorts. WM microstructure was assessed in 7 limbic tracts, including the cingulum, fornix, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and transcallosal tracts of the inferior, middle, and superior temporal gyri (ITG, MTG, STG) using advanced diffusion MRI metrics corrected for free-water (FW): fractional anisotropy (FAFWcorr), axial diffusivity (AxDFWcorr), mean diffusivity (MDFWcorr), radial diffusivity (RDFWcorr). We performed heritability estimations, genome-wide association studies (GWAS) and post-GWAS analyses (genetic covariance, gene-level and pathway analysis, transcriptome-wide association [TWAS] studies). The AD relevance of the discovered variants was explored using bulk RNA-seq data from caudate, dorsolateral prefrontal, and posterior cingulate cortex human brain tissues. Results: Limbic WM microstructure demonstrated significant heritability (estimates between 0.26 and 0.60, pFDR < 0.05 for 15 of 35 tract-by-microstructure combinations). GWAS identified 6 genome-wide significant loci (p < 5.0x10-8) associated with WM microstructure. Notably, for MTG RDFWcorr, we identified a locus on chromosome 18 (lead SNP: rs12959877) comprising 38 SNPs that are eQTLs for CDH19, a gene involved in cell adhesion and highly expressed in oligodendrocytes. Other significant associations involved SNPs near KC6, SENP5, RORA, FAM107B, and MIR548A1. Bulk RNA-seq analyses revealed that brain tissue expression of RORA, FAM107B, and KC6 was significantly associated with cognitive decline and several AD pathologies (pFDR < 0.05). Post-GWAS analyses identified the genes SERPINA12 and DNAJB14, and highlighted the involvement of insulin signaling, immune response, and neurotrophic pathways. Genetic covariance analyses indicated shared genetic architecture between limbic WM and lipid profiles (e.g., HDL cholesterol), cardiovascular traits, and neurological conditions (e.g., multiple sclerosis) (pFDR < 0.05). Conclusion: This multi-cohort imaging genetics study identified several novel genes and biological pathways associated with limbic WM microstructure in an aging population enriched for cognitive impairment. The association of several identified genes with cognitive decline and AD pathology underscores their AD relevance. Our findings further suggest that the genetic underpinnings of limbic WM microstructure are linked to vascular health and inflammation, highlighting these pathways as promising avenues for future AD-related therapeutic development.

Moderate dietary restriction (DR) is known to extend lifespan, but its long-term safety remains unclear. In this study, silkworms of P50 were divided into libitum feeding (AL) and DR groups, with the DR group receiving 65% of the AL group's intake. Using the contemporary DR cohort as the parent generation, the identical dietary restriction methodology is perpetuated across successive generations to establish a multi-generational DR model. We recorded body weight, lifespan, spawning amount, and cocoon shell rate at each generation, and analyzed tissue sections of the G6 generation. Biochemical indices of hemolymph were assessed in the G0 and G3 generations, and the expression levels of genes associated with DR metabolism were analyzed using quantitative PCR. The result showed that DR initially caused weight loss, which then stabilized, and significantly extended lifespan. Biochemical indicators showed that silkworm's antioxidant capacity improved significantly in DR group, with notable differences between the current (G0) and successive (G3) generations. Gene expression related to oxidative stress was significantly altered depending on there function in G3 compared to G0. This suggests that long-term moderate DR can extend lifespan and reduce weight and fat, mainly due to enhanced antioxidant capacity. Additionally, animals demonstrated adaptability to prolonged moderate DR, indicating its feasibility across generations in insects. Our study confirms that boosting antioxidant capacity is a healthy, life-extending strategy under dietary restriction and highlights the adaptability of animals to such diets over generations, supporting the development of safe, long-term dietary plans for humans and large animals.

Iron-induced lipid peroxidation of phosphatidylethanolamine (PE) species is a key driver of ferroptosis in retinal pigment epithelial (RPE) cells, a process closely associated with age-related macular degeneration (AMD). The previous studies have demonstrated that induced retinal pigment epithelial (iRPE) cells generated by transcription factor-mediated reprogramming exhibit superior therapeutic efficacy in treating AMD. In this study, it is found that these iRPE cells are resistant to ferroptosis and further identified phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1) as a critical regulator underlying ferroptosis resistance. Mechanistically, PHOSPHO1 inhibits ferroptosis through two distinct mechanisms. First, it reduces PE levels in the endoplasmic reticulum, thereby limiting PE-derived lipid peroxidation. Second, it suppresses autophagy and ferritinophagy, leading to a reduction in intracellular free iron accumulation. Experiments using an in vivo rat model confirm that PHOSPHO1 effectively protects RPE cells from ferroptotic damage. These findings highlight PHOSPHO1 as a potential therapeutic target for AMD, providing insights into novel ferroptosis-based intervention strategies.

There is little understanding of how aging serves as the strongest risk factor for Alzheimer\'s disease (AD) and other neurological disorders. Specific neural cell types, such as microglia, undergo maladaptive changes with age, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in regulating plasticity and brain ECM dynamics, we examined the impact of TIMP2 on microglial function in the setting of aging. We show that TIMP2 deletion exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, increased microgliosis, and increased levels of stress and inflammatory proteins measured in the brain extracellular space by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increased microglial activation and altered myelin phagocytosis. Treating aged mice with TIMP2 reversed several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced synapse phagocytosis. Our results identify TIMP2 as a key modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

Lead (Pb), mercury (Hg), and cadmium (Cd), prevalent neurotoxic heavy metals in the environment, are commonly detected at low concentrations in the blood of the general population. Our previous studies demonstrated that Pb, Hg, and Cd mixture induced neurodevelopmental toxicity even at very low levels. However, the long-term effects of low-level Pb, Hg, Cd exposure on brain aging remain unclear. In this study, female rats were exposed to a mixture of 10 mg/L Pb(CH

We have previously extensively characterized the role of DJ-1 in oxidative stress regulation in the retina and RPE during aging. However, the DJ-1 protein also plays a role in regulating mitochondria\'s response to oxidative stress by translocating to the mitochondria where it helps clear generated reactive oxygen species (ROS). To study the effects of aging and oxidative stress in the retina, the DJ-1 KO mouse was analyzed. Freshly dissected ex vivo retinal punches were analyzed for real-time live cell metabolism. Total DNA and protein were isolated from RPE, and retina of 3- and 15-month-old DJ-1 WT and DJ-1 KO mice. The mitochondrial DNA (mtDNA) genome was divided into four discrete regions (RI-RIV), and lesions/10kb were quantified using long-extension PCR. mtDNA content was analyzed using RT-qPCR. Protein levels of OXPHOS complexes, POLG, OGG1, SOD2, and PGC1a; were measured by western blotting. Seahorse analysis detected significantly decreased basal and maximal OCR in 3- and 15-month-old DJ-1 KO compared to age-matched DJ-1 WT. In the RPE, a significant decrease in the protein levels of the NDUFB8 subunit of CI, the SDHB subunit of CII, and MTCO1 of CIV in 15-month-old DJ-1 KO mice compared to 15-month-old DJ-1 WT, while the ATP5A subunit of CV was significantly decreased in 3-month-old DJ-1 KO mice compared to 3-month-old DJ-1 WT. In the retina, significantly decreased levels of NDUFB8 subunit of CI and MTCO1 of CIV were detected in the in 3-month-old DJ-1 KO mice compared to 3-month-old DJ-1 WT. We observed a significant increase in mtDNA gene content in 15-month-old DJ-1 KO RPE and retina compared to age-matched DJ-1 WT. The PGC1a; levels significantly decreased in 3- and 15-month-old RPE lysates compared to their age group DJ-1 WT. However, in the retina, there was only a decrease in DJ-1 WT with aging. The POLG levels increased when 15-month-old DJ-1 KO lysates were compared to 15-month-old DJ-1 WT. The mtDNA lesions in the RPE detected a trend of increase in 15-month-old DJ-1 WT and DJ-1 KO RPE in all regions compared to 3-month-old mice. In the retina, a significant increase in mtDNA lesions/10kb accumulation in the 15-month-old DJ-1 WT RIV was detected compared to 3-month-old DJ-1 WT. The OGG1 levels significantly increased in 3-month-old retinal lysates compared to the 3-month-old DJ-1 WT. Our findings suggest that DJ-1 is critical for mitochondrial regulation and function in RPE and retina. The observed changes reflect mitochondrial dysfunction related to absence of DJ-1.

The loss of ovarian estrogen during the menopause transition has been identified as a risk factor for increased cardiometabolic and neurovascular dysfunction, age-related cognitive decline, and Alzheimer\'s disease. A wealth of studies using rodent models of menopause have highlighted the cardio- and neuroprotective effects of 17{beta}-estradiol (E2) treatment when administered within a critical period, though these have yet to be successfully translated to human populations in clinical trials of hormone therapy. A proposed explanation for this mismatch in results is the \"healthy cell bias,\" where estrogen is only beneficial when initiated in physiologically intact systems. Our study investigates whether pre-existing metabolic dysfunction attenuates the effects of E2 on neurovascular coupling (NVC) in a rodent model of menopause. Female mice were fed a high-fat diet (HFD) or control diet (CD) for 11 weeks to induce metabolic dysfunction, followed by ovariectomy (OVX) and subsequent E2 or vehicle (Veh) treatment. NVC was assessed in awake mice using two-photon laser scanning microscopy of penetrating arterioles (PAs) in the somatosensory cortex, barrel field. Mice developed glucose intolerance and increased adiposity yet displayed intact NVC following 11 weeks of HFD exposure. Following ovariectomy, E2 treatment enhanced NVC responses regardless of diet. Interestingly, in HFD-fed mice, E2 appeared to reduce basal PA diameter relative to Veh, suggesting health status-specific mechanisms of action. These results indicate that PAs retain functional sensitivity to estrogen treatment in the face of metabolic impairment, which has implications for the use of hormone therapy in women that arrive at the menopause transition with varied pre-existing cardiometabolic disorders.

Rapamycin has been shown to extend lifespan and acts on pathologies underlying Alzheimer's disease and related dementias in animal models. However, rapamycin's clinical application remains underexplored.

Female reproductive aging is a complex process with profound systemic health implications, yet the molecular and structural dynamics of aging across reproductive organs and tissues remain largely unexplored. Here, we integrate deep learning-based analysis of 1,112 histological images with RNA-seq data from 659 samples across seven reproductive organs in 304 female donors aged 20-70 years. We show that female reproductive organs and tissues have asynchronous aging dynamics: while the ovary and vagina age gradually, the uterus undergoes an abrupt transcriptional and cellular transition around the age of menopause. Tissue segmentation highlights that the myometrium in the uterine wall is the most age-affected tissue, marked by extracellular matrix remodeling and immune activation. Across reproductive organs, the epithelial tissue is also strongly affected by age, with the vaginal epithelium showing a unique sharp menopausal transition. Integration via multi-omics factor analysis links these tissue-specific histological transformations to specific molecular shifts, many with nonlinear expression trajectories and enriched in heritable reproductive traits such as pelvic organ prolapse and age at menarche. These findings position menopause as a key inflection point in female aging and provide insights with tissue-specific focus to support healthier menopausal transitions and reduce age-related disease risk.

Immunosenescence is the loss and change of immunological organs, as well as innate and adaptive immune dysfunction with ageing, which can lead to increased sensitivity to infections, age-related diseases, and cancer. Emerging evidence highlights the role of gut-vitamin D axis in the regulation of immune ageing, influencing chronic inflammation and systemic health. This review aims to explore the interplay between the gut microbiota and vitamin D in mitigating immunosenescence and preventing against chronic inflammation and age-related diseases.

Aging varies across individuals, highlighting the need for better markers of functional decline. This study investigates the hypothesis that T cell energy metabolism is correlated with functional health in older adults. We used flow cytometry-based profiling to examine energy metabolism, focusing on mitochondrial OXPHOS activity (MitoDep, expressed as percentage), in peripheral CD4 and CD8 T cell subsets from 187 participants aged 70-89 years (mean age 78.7 [SD 5.3], 57.7% [n = 108] women) within the Inspire-T cohort. Associations with Fried frailty phenotype were evaluated, using logistic regression. Relationships with intrinsic capacity (IC) score were assessed using partial least square regression (PLS) and piecewise linear regression models, adjusting for age, sex and comorbidities. MitoDep was significantly lower in prefrail/frail individuals (47% of the study population) across several T cells subsets. In CD4 regulatory T cell (CD4Treg) subsets, higher MitoDep was significantly associated with reduced odds of prefrailty/frailty. Piecewise regression identified a breakpoint in memory CD4Treg MitoDep at 58.5% (95% CI, 50.7-67.5). Below this threshold, reduced MitoDep was significantly associated with lower IC (β = 0.40, p = 0.0104). This study establishes a novel link between T cell mitochondrial OXPHOS activity and functional health in older adults, offering insights for improved patient stratification and personalized lifestyle or therapeutic interventions.

As global life expectancy increases, research reveals a critical challenge in aging: the progressive deterioration of immune function, termed immunosenescence. This age-related immune decline is characterized by a complex dysregulation of immune responses, which leaves older adults increasingly vulnerable to infections, chronic inflammatory states, and various degenerative diseases. Without intervention, immunosenescence significantly contributes to morbidity and mortality among the elderly, intensifying healthcare burdens and diminishing quality of life on both individual and societal levels. This review explores the essential role of zinc, a trace element critical for immune health, in mitigating the impact of immunosenescence and slowing the cascade of immunological dysfunctions associated with aging. By modulating the activity of key immune cells and pathways, zinc supplementation emerges as a promising approach to strengthen immunity, reduce oxidative stress, and counteract "inflammaging," a state of chronic, low-grade inflammation that accelerates tissue damage and drives disease progression. Zinc's involvement in cellular defense and repair mechanisms across the immune system highlights its ability to enhance immune cell functionality, resilience, and adaptability, strengthening the body's resistance to infection and its ability to manage stressors that contribute to diseases of aging. Indeed, zinc has demonstrated potential to improve immune responses, decrease inflammation, and mitigate the risk of age-related conditions including diabetes, depression, cardiovascular disease, and vision loss. Given the prevalent barriers to adequate zinc intake among older adults, including dietary limitations, decreased absorption, and interactions with medications, this review underscores the urgent need to address zinc deficiency in aging populations. Recent findings on zinc's cellular and molecular effects on immune health present zinc supplementation as a practical, accessible intervention for supporting healthier aging and improving quality of life. By integrating zinc into targeted strategies, public health efforts may not only sustain immunity in the elderly but also extend healthy longevity, reduce healthcare costs, and potentially mitigate the incidence and impact of chronic diseases that strain healthcare systems worldwide.

Chronic neurodegenerative diseases, such as tauopathies, cause major metabolic changes in the brain affecting gene expression at both the transcriptional and translational levels. Our understanding of how regulation of translation changes with disease has focused on mRNA and its translational regulatory factors, RNA binding proteins, and microRNAs, despite clear evidence for translational and post-translational dysfunction in ADRD and tauopathies. The neurobiology of tRNA has only recently begun to be studied, but the impact of chronic neurodegenerative diseases on tRNA biology and translational dysfunction is largely unknown. We have previously shown that the tRNA pool and tRNA modifications behave as a system to regulate the cellular stress response by undergoing stress-specific reprogramming and causing selective translation of mRNAs from codon-biased stress response genes. Here we tested this stress-induced tRNA reprogramming and codon-biased translation system in the response to mutant tau expression by performing mass spectrometric quantification of ~8500 proteins and 49 tRNA modifications, AQRNA-seq analysis of 222 cytosolic and mitochondrial tRNAs and other small RNAs, and informatic analysis of codon usage patterns in >23,000 protein-coding genes. Analysis of these datasets revealed that aging and tauopathy elicit major adaptation of the tRNA transcriptome and epitranscriptome as well as corresponding evidence of a program of translation of families of codon-biased genes for aging and disease responsive proteins. The mitochondrial tRNA transcriptome showed a strong response to aging and disease with 21 of the 22 mt-tRNAs showing age and disease-linked increases in expression, accompanied by mitochondria-specific modifications such as ms2i6A and f5C. Surprisingly, there were few significant changes in the 203 cytosolic tRNA isodecoders. However, a 10-fold increase tRNA isodecoder tRNA-Arg-TCT-5-1 was accompanied by increased translation of proteins encoded by genes highly enriched in its AGA cognate codon. These changes in tRNA biology are mirrored by strongly biased use of synonymous codons among the most highly upregulated and downregulated proteins in the P301S MAPT mice. Taken together these findings suggest the aging and disease brain produces an integrated response for translational control that is highly integrated with changes in tRNA biology.

L-glutamate (Glu) is accumulated abundantly in skeletal muscle cells and plays a central role in energy production, amino acid metabolism, and protein synthesis. If intracellular Glu leaks due to plasma membrane fragility or injury, it may adversely affect the surrounding myocytes. In the present study, we examined the effects of high extracellular Glu concentration on skeletal myogenesis. Five mM Glu stimulation decreased the expression of fast-twitch myosin heavy chain isoforms and myogenin, an indicator of C2C12 cell differentiation into myocytes, and inhibited the cell fusion. This stimulation reduced the expression of metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor 1 (NMDAR), which are glutamate receptors on the C2C12 plasma membrane. Furthermore, phosphorylation of p38 mitogen-activated protein kinase, myocyte enhancer factor 2A, and cAMP response element binding protein, which are downstream of these Glu receptors, was reduced, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) decreased. Moreover, reduced mGluR5 and NMDAR expression and muscle weight were observed in the tibialis anterior muscle of mice with increased aging markers. These findings provide insights into the molecular mechanisms contributing to age-related muscle fragility and highlight the potential detrimental effects of elevated Glu on muscle health.

As ageing is linked to the development of neurodegenerative diseases (NDs), such as Alzheimer's Disease and Parkinson's Disease, it is important to disentangle the independent effect of age-related changes from those due to disease processes. To do so, changes to central nervous system (CNS) cells as a function of advanced age need better characterisation. Microglia are of particular interest due to their proposed links with the development and progression of NDs through control of the CNS immune response. Therefore, understanding the extent to which microglial dysfunction is related to phyisological ageing, rather than a disease process, is critical. As microglia age, they are believed to take on a pro-inflammatory phenotype with a distinct dystrophic morphology. Nevertheless, while established hallmarks of ageing have been investigated across a range of other cell types, such as macrophages, a detailed consideration of functional changes that occur in aged microglia remains elusive. Here, we describe the dynamic phenotypes of microglia and evaluate the current state of understanding of microglial ageing, focusing on the recently updated twelve hallmarks of ageing. Understanding how these hallmarks present in microglia represents a step towards better characterisation of microglial ageing, which is essential in the development of more representative models of NDs.

Complex diseases often exhibit sex-dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex-dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer's disease, and the female-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed that sex-dimorphic aging rates are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.

Background: Changes to the epigenetic landscape play an important role in cardiovascular aging, where alterations in histone modifications influence gene expression by regulating DNA accessibility and chromatin structure. Our investigation into epigenetic changes during myocardial aging revealed that the repressive epigenetic mark H3K27me3 is significantly upregulated in aged mice and humans. This increase in H3K27me3 was shown to impair cardiomyocyte autophagy and drive metabolic reprogramming, key features of myocardial aging and causatively linked to dysfunction. Notably, by alleviating this repressive mark through a modified diet, we successfully mitigated the aged myocardial phenotype. Methods: Heart tissue from young and aged mice and humans was analyzed for H3K27me3 levels using immunoblotting and immunofluorescence staining. Genes regulated by H3K27me3 were identified through CUT&RUN-Seq and RNA-Seq, while metabolites were profiled using metabolomics. In neonatal rat ventricular myocytes (NRVMs), H3K27me3 levels were elevated by siRNA-mediated knockdown of UTX. Cellular metabolism was investigated using a Seahorse analyzer in cardiomyocytes with basal or elevated H3K27me3 levels. In further human studies, we assessed how circulating glutamine levels associate with the incidence of heart failure and the association of genetic variants within the SLC1A5 region with heart disease. In aged mice, H3K27me3 levels were reduced through a modified diet, and heart function was evaluated using echocardiography. Subsequently, hearts were processed for biochemical analysis, and autophagy was assessed using electron microscopy Results: H3K27me3 was significantly elevated in the aged mouse and human myocardium. This observed elevation in H3K27me3 was found to be attributed to impaired glutamine metabolism, resulting from reduced expression of the glutamine transporter SLC1A5 in the aged myocardium. Furthermore, elevation in H3K27me3 was found to contribute to impaired cardiomyocyte autophagy and metabolic dysfunction. In aged mice supplemented with a high glutamine diet this attenuated myocardial H3K27me3 and improved cardiac function. Furthermore, a high-glutamine diet reversed H3K27me3-mediated impairment in cardiac autophagy in aged mice. Conclusions: Reduction in SLC1A5 during aging is likely to lead to increased myocardial H3K27me3 that results in impaired autophagy and metabolic reprogramming that contribute to the aged cardiac phenotype. Our findings also suggest glutamine may improve cardiac health in the aged population by lowering H3K27me3.

Cognitive decline associated with healthy ageing is complex and multifactorial: brain based and lifestyle factors uniquely and jointly contribute to distinct neurocognitive trajectories of ageing. To evaluate existing models of neurocognitive ageing such as compensation, maintenance, or reserve, we explore how various known brain-based and cardiorespiratory fitness factors intersect to better understand cognitive decline. In a preregistered study (https://osf.io/6fqg7), we tested 73 neurologically healthy older adults aged 60 to 81 (M = 65.51, SD = 4.94, 49% female) and collected neuroimaging (functional, structural, and perfusion MRI), cardiorespiratory fitness, and behavioural performance data to investigate a well-documented, prominent cognitive challenge for older adults: word-finding failures. Blood-oxygen level-dependent (BOLD) fMRI signal was recorded while participants responded to a definition-based tip-of-the-tongue task, high-resolution T1-weighted imaging was employed to estimate grey matter volume, and perfusion (or cerebral blood flow) was indexed using a multi-delay pseudocontinuous arterial spin labelling approach. Commonality analyses were used to analyse the multi-domain data (neuroimaging, cardiorespiratory fitness, language skills, demographic characteristics). We aimed to uncover associations between predictors, which have previously been theoretically-implicated, in explaining age-related tip-of-the-tongue rates. Commonality analyses revealed that functional activation of language networks associated with tip-of-the-tongue states is in part linked with age and, interestingly, cardiorespiratory fitness levels. Age-associated atrophy and perfusion in regions other than those showing functional differences accounted for variance in tip-of-the-tongue states. Our findings can be interpreted in the context of the classic models of neurocognitive ageing suggesting compensation. Brain health indices in concordance with cardiorespiratory fitness measures have the potential to provide a more holistic explanation of individual differences in age-related cognitive decline.

Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a critical regulator of extracellular matrix turnover. Mutations in TIMP-3 cause Sorsby fundus dystrophy, an inherited macular dystrophy that is similar to age-related macular degeneration (AMD), but which generally presents earlier. SFD is characterised by the accumulation of mutant TIMP-3 protein in Bruch\'s membrane, a multilamellar extracellular matrix underlying the retinal pigment epithelium (RPE). Here, we show that RPE cells regulate wild-type TIMP-3 levels post-translationally, with ARPE-19 and hTERT RPE-1 cells endocytosing the protein via the low-density lipoprotein receptor-related protein (LRP) family of scavenger receptors. LRP-mediated endocytosis of the SFD TIMP-3 variants S204C and Y191C was significantly delayed, establishing a molecular mechanism for their extracellular accumulation in SFD. In contrast, endocytosis of the SFD variant H181R TIMP-3 was unaltered, suggesting it accumulates through a distinct molecular mechanism, potentially via increased retention on extracellular matrix heparan sulfate proteoglycans. These findings reveal heterogeneity in the molecular mechanism of SFD pathogenesis, which has direct implications for therapeutic development. Genotype-specific interventions may be required, such as strategies to enhance receptor-mediated clearance or disrupt extracellular TIMP-3 retention. Our study also has broader implications for AMD, where TIMP-3 and other LRP and heparan sulfate ligands accumulate in drusen within Bruch\'s membrane. Age- and inflammation-dependent alterations in LRP expression and heparan sulfate structure may contribute to drusen formation and AMD progression. Understanding TIMP-3 trafficking in both physiological and pathological contexts could inform targeted treatments for SFD, AMD, and other degenerative disorders involving extracellular matrix dysregulation.

Mesenchymal stem cell (MSC)-derived exosomes have been intensively studied for their therapeutic effects on tissue repair and regeneration. However, the specific contributions of exosomes derived from endogenous bone marrow MSCs to the maintenance of bone tissue homeostasis remain unclear. In this study, we impaired MSC-derived exosome secretion by specifically deleting vascular protein sorting 33B (VPS33B). Mice deficient in VPS33B (VPS33B-cKO mice) exhibited premature bone loss and imbalanced bone remodeling processes, which were associated with a reduction in MSC number and an increase in bone marrow inflammation. MSCs derived from VPS33B-cKO mice exhibited impaired self-renewal, proliferation, osteoblastic differentiation, and increased cellular senescence. Incubation with exosomes (Y-Exo) derived from MSCs of wildtype young mice greatly ameliorated senescent phenotypes observed in VPS33B-deficient MSCs. We further demonstrated exosome autocrine pathway through a fluorescent-labeled uptake assay and observed a significant association between autocrinal exosomes and the senescence of MSCs. Mechanistically, miR-136-3p and miR-146a-5p were highly enriched in Y-Exo but not in exosomes from senescent MSCs, which promoted cell proliferation while inhibiting inflammation by targeting the PI3K-Akt and NF-κB pathway, respectively. Furthermore, intramedullary transplantation of Y-Exo successfully mitigated age-related MSC exhaustion and bone loss. Our findings indicate that endogenous MSC-derived exosomes play a crucial regulatory role in the maintenance of bone homeostasis, and propose the potential therapeutic application of young MSC-derived exosomes for the treatment of senile osteoporosis.

Medial arterial calcification (MAC), an age related vascular histological alteration, accounts for cardiovascular mortality, where cellular senescence and disturbed redox haemostasis play a role. Liraglutide (LRGT), an approved anti-diabetic agent, recently showed vascular benefits. So, we examined the probable protective impact of LRGT against aging-induced MAC and in addition, the role of MiR-34a/SIRT6 pathway is delineated. Rats were classified into two groups; young (3-4 months old) and aged (24 months old n = 24). Eight rats from the aged group were sacrificed at the beginning of the experiment and the remaining rats completed the study with or without LRGT for 8 weeks. Administration of LRGT ameliorated medial calcification, as shown by Alizarin red staining and calcium content assay, and downregulated runt-related transcription factor 2 (RUNX2) and osteocalcin, while enhancing α-SMA immunoexpression and improving histological appearance in aged rats' aorta. Additionally, mitigation of aging-induced elevation of blood pressure (SBP and DBP), the senescent p53 and p16 proteins, and senescence-associated secretory phenotype including TNFα and IL-6 was also evident with LRGT. Moreover, LRGT treatment was associated with decline in MDA, 8-OHdG and Keap1 and increased GSH, NRF2, and its targeted antioxidants such as HO-1, NQO1, and GCLC. LRGT also enhanced eNOS immunoexpression in aged rats. At the molecular level, LRGT upregulated aortic SIRT6 mRNA epression and downregulated its upstream MiR-34a transcript level. We concluded that LRGT alleviated MAC during physiological aging mostly through MiR-34a/SIRT6-mediated repression of cellular senescence and repairing the Keap1/NRF2/antioxidants cascades.

Individual non-essential metals (NMs) have been linked with biological aging. However, the effects of NM mixture and their mechanisms remain unclear.

Otoliths play an important role in maintaining body balance, and age-related decline in theis function and morphological integrity can lead to falls. In recent years, the herbal medicine rikkunshito (RKT) and the antioxidant coenzyme Q10 (CoQ10) have been studied for their anti-aging properties; however, their effects on otoliths remain unknown. Therefore, we aimed to investigate whether RKT and CoQ10 can prevent age-related functional and morphological changes in otoliths. To this end, 30 male and 30 female 8-week-old C57BL6N mice were used in this study. The mice were divided into three groups: a control group, CoQ10 group (0.2 % CoQ10 special diet), and RKT group (3 % RKT special diet). At 80 weeks of age, micro-computed tomography (μCT) images were taken and analyzed for otolith volume and CT number. Furthermore, eye movements induced by the linear vestibulo-ocular reflex (LVOR) were analyzed to assess otolith function.

Ceramides are bioactive sphingolipids that are central to cellular metabolism, signaling, and stress responses. Synthesized de novo in the endoplasmic reticulum (ER) through a tightly regulated enzymatic pathway, ceramides can also be generated from hydrolysis complex sphingolipids, including hexosylceramides and sphingomyelins, and the salvage pathway. Their dynamic turnover across distinct cellular compartments results in spatial regulation of ceramide levels and its functional consequences. Mitochondrial ceramide accumulation, in particular, is a critical factor of apoptosis, where ceramides can disrupt membrane integrity. In addition to apoptosis, ceramides are implicated in replicative senescence. However, the mechanisms of ceramide regulation and function in senescence remain incompletely understood. In this study, we employed comparative lipid profiling, gene expression analysis and Raman spectroscopy to dissect sphingolipid regulatory networks that might be responsible for ceramide regulation and localization in senescence. We found that while both apoptotic and senescent cells exhibit elevated ceramide levels, only senescent cells display a marked depletion of sphingomyelins, especially very-long-chain species. Despite transcriptional upregulation of sphingomyelin synthase 1, enzymatic activity remained unchanged, suggesting impaired ceramide transport. Pharmacological inhibition of Ceramide Transfer Protein (CERT), the ER to Golgi ceramide transporter, phenocopied the senescent sphingolipid profile and enhanced senescence markers. Furthermore, Raman spectroscopy revealed ceramide accumulation at the ER but not the mitochondria in senescent cells, consistent with a non-apoptotic phenotype. Together, our results identify disrupted ceramide turnover to sphingomyelin as a key feature of senescence and highlight the importance of subcellular ceramide localization in determining cell fate.

Over the last century, there has been a growing increase in life expectancy, and longevity brings with it a decline in cognitive functioning, negatively affecting people's lives. Thus, there is significant interest in developing non-invasive interventions that can enhance life expectancy and delay functional decline, especially during the early stages. Transcranial photobiomodulation (tPBM) is a technique that involves exposing neural tissue to a low fluence of light capable of stimulating brain activity. Physical training is a crucial strategy to mitigate the decline in cognitive and brain health associated with aging. The synergy of tPBM and exercise may support the maintenance of cognitive functions and possibly delay the onset of age-related cognitive decline. Here we conduct a narrative review, and we found that despite promising findings regarding this synergy, several research gaps remain, with preclinical studies in animals being essential for advancing the understanding of the effects of PBM and exercise in older adults. These studies would allow for the investigation of optimal PBM parameters such as wavelength, intensity, and duration, providing insights that could influence future clinical trials, assess the safety and efficacy of combined PBM and exercise interventions, and identify risks or potential contraindications. PBM, when combined with exercise, holds substantial promise for improving motor and cognitive health in aging populations at risk of cognitive impairment. In conclusion, ongoing research in this area is essential for understanding and promoting brain health and reducing the effects of aging and neurodegeneration.