Longevity Papers

The steroid hormone 5-androstene-3{beta},17{beta}-diol (ADIOL) was discovered in humans nearly a century ago, yet its physiological roles remain poorly defined. Here, we show that fasting and caloric restriction, two forms of dietary restriction, induce transcriptional upregulation of genes encoding CYP11A1, CYP17A1, and 17{beta}-hydroxysteroid dehydrogenase family enzymes, promoting ADIOL biosynthesis. ADIOL, in turn, acts on the nervous system to reduce levels of kynurenic acid, a neuroactive metabolite linked to cognitive decline and neurodegeneration. This effect requires NHR-91, the C. elegans homolog of estrogen receptor {beta}, specifically in the RIM neuron, a key site of kynurenic acid production. Consistent with the known benefits of fasting and caloric restriction on healthspan, enhancing ADIOL signaling improves multiple healthspan indicators during aging. Conversely, animals deficient in ADIOL signaling exhibit reduced healthspan under normal conditions and in genetic models of caloric restriction, underscoring the functional significance of this pathway. Furthermore, ADIOL suppresses cellular stresses induced by the Alzheimer\'s-associated APOE4 variant, highlighting its potential as a neuroprotective agent. Notably, ADIOL does not significantly impact lifespan, indicating that its healthspan benefits are not simply a byproduct of lifespan extension. Together, these findings establish a physiological role for ADIOL in mediating the neuroprotective and pro-healthspan effects of fasting and caloric restriction and suggest that boosting ADIOL signaling may help narrow the gap between lifespan and healthspan. This positions ADIOL as a promising mimetic of dietary restriction effects on healthspan that could be used as a therapeutic strategy for age-related neurodegenerative conditions.

RNA engineering has yielded a new class of medicines but faces limitations depending on RNA size and function. Here we demonstrate the synthesis and enzymatic stabilization of telomerase RNA component (TERC), a therapeutically relevant long non-coding RNA (lncRNA) that extends telomere length and replicative lifespan in human stem cells. Compared with therapeutic mRNAs, engineered TERC RNA (eTERC) depends on avoiding nucleoside base modifications and incorporates a distinct trimethylguanosine 5' cap during in vitro transcription. We show that the non-canonical polymerase TENT4B can be repurposed to enzymatically stabilize synthetic RNAs of any size by catalysing self-limited 2'-O-methyladenosine tailing, which is critical for optimal eTERC function in cells. A single transient exposure to eTERC forestalls telomere-induced senescence in telomerase-deficient human cell lines and lengthens telomeres in induced pluripotent stem cells from nine patients carrying different mutations in telomere-maintenance genes, as well as primary CD34

Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.

HMGB1 Box A gene therapy is a promising therapeutic approach for age-associated diseases, based on evidence from

Introduction: Aging is associated with progressive loss of renal function and vascular structure, with and without chronic kidney disease. However, the mechanisms driving renal vascular aging and potential therapeutic interventions remain poorly understood. Methods: To model this state of affairs, we used African turquoise killifish (Nothobranchius furzeri), a naturally short lived vertebrate. We then inhibited the sodium glucose co transporter 2 inhibition (SGLT2i) to test a potential therapeutic intervention. Histological, immunofluorescent, and 3D vascular imaging were used to evaluate glomerular, tubular, and vascular changes. Single nuclei transcriptomic profiling was performed on whole kidneys to identify age and treatment associated molecular signatures. Results: Aged killifish kidneys exhibited hallmark features of human renal aging, including glomerulosclerosis, tubular fibrosis, and vascular rarefaction. Functional changes included increased proteinuria and altered tubular transporter expression. Transcriptomic profiling revealed a metabolic shift from oxidative phosphorylation to glycolysis and upregulation of proinflammatory pathways. Aged vasculature also displayed a marked reduction in tight junctions and cell cell contacts. Dapagliflozin attenuated age related vascular rarefaction, preserved functional peritubular capillary networks, and reduced albuminuria by restoring a youthful transcriptional profile and enhancing intercellular signaling. However, fish lifespan was not extended. Conclusion: This study establishes the killifish as a translational model for investigating renal vascular aging. We show that SGLT2i preserves renal microvascular structure and function, reduces proteinuria, and reprograms the aged transcriptome. These results support a vascular protective role of SGLT2i in mitigating age related renal deterioration.

In an aging society, mitigating cognitive decline is a critical challenge. However, reviews on exercise effects and optimal parameters for healthy older adults remain limited. This systematic review evaluated the effects of chronic exercise interventions on executive function in healthy older adults. Following PRISMA guidelines, we registered the review with PROSPERO (CRD42024618878) and searched Scopus, PubMed, EBSCOhost, and other sources for studies published before December 2024. We included randomized controlled trials involving adults aged ≥60, with pre- and post-intervention executive function measures, comparing chronic exercise with non-exercise controls. Studies involving physical or neurological conditions or acute interventions were excluded. Risk of bias was assessed via Cochrane RoB 2 tool. Data synthesis followed the PICOS framework, with narrative and quantitative summaries. A total of 76 studies (n = 7101; 69 % female) met inclusion criteria. Of these, 71 % (54/76) showed significant improvements in executive function. Aerobic, resistance, and coordination exercises had similar effects (64 %-71 %). Optimal parameters included short session duration (≤45 min), high frequency (5-7/week), long-term duration (25-48 weeks), and vigorous intensity. High adherence appeared to enhance outcomes. These findings support chronic exercise as an effective strategy to improve executive function in healthy older adults and highlight the importance of exercise type, dosage, and adherence in promoting healthy aging.

Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability for these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have analyzed the effects of partial chemical reprogramming on mitochondrial structure in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. We also discover that partial chemical reprogramming upregulates the formation of intracellular lipid droplets. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues, and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight and body condition scores. In the livers and kidneys of these animals, we observe significant increases in oil red o staining indicative of excessive lipid droplet accumulation in these organs. Thus, the upregulation of lipid droplet formation during partial chemical reprogramming may cause toxicity hindering the rejuvenation of cells and tissues in aged mammals.

Pancreatic β-cells are essential for maintaining glucose homeostasis throughout life. Although rodent models have been instrumental in elucidating β-cell biology, notable differences exist between rodents and humans across fetal, postnatal and adult stages. This review provides a comparative analysis of β-cell development, proliferation and regenerative capacity between these two species, highlighting critical divergences that must be considered when translating preclinical findings to human therapies. During fetal development, distinct temporal patterns of hormone expression and islet architecture are observed, with human β-cell maturation extending postnatally. Postnatal β-cell expansion in rodents is driven predominantly by replication, whereas in humans, proliferation peaks within the first two years of life and declines sharply thereafter. Adult human β-cells exhibit limited regenerative capacity compared to rodents, attributed to intrinsic constraints such as elevated expression of cell cycle inhibitors and chromatin remodeling associated with aging. Additionally, key signaling pathways that robustly stimulate β-cell proliferation in rodents are less effective in humans. Understanding these species-specific differences is vital for the development of therapeutic strategies aimed at β-cell preservation and regeneration in diabetes. Here, we emphasize the need for human-relevant models, including stem cell-derived β-cells and pancreatic organoids, to bridge the translational gap. Future research should prioritize uncovering mechanisms that can safely and effectively enhance β-cell mass in humans, acknowledging the distinct biological landscape that aging imposes on human pancreatic β-cells.

Salvianolic acid B (Sal B) exhibits great potential in treating skin photoaging. However, its therapeutic activity is severely hindered by poor skin permeability, making the preparation of a transdermal formulation an urgent need. To overcome this limitation, the microwave method was employed to prepare chitosan-coated gold nanoparticles (CS-Au NPs), and the preparation process was optimized for co-encapsulation of Sal B and CS-Au NPs with hyaluronic acid and Pluronic F-127 (CAS@HF). Subsequently, the microscopic morphology and transdermal drug release capabilities of CAS@HF were evaluated using transmission electron microscopy and Franz diffusion cells, respectively. It was found that CAS@HF exhibited a fluid state at 25 °C and underwent gelation at 36.3 °C, forming a porous structure and demonstrating excellent skin permeability and retention. Furthermore, a photoaging cell model was established, and its anti-photoaging activity in vitro was assessed through CCK-8 assays, scratch assays, β-galactosidase staining, and Western blot analysis. It revealed that CAS@HF promoted cell migration, alleviated cellular senescence, and reduced ROS levels, which were associated with the inhibition of the P53/P21 pathway and the promotion of NRF2 translocation. Finally, a photoaging mouse model was constructed to further validate the anti-photoaging potential of CAS@HF in vivo using H&E staining, Masson's trichrome staining, and ROS staining. The results showed that CAS@HF mitigated photoaging phenomena, increased collagen levels and reduced ROS levels. In conclusion, CAS@HF enhanced the transdermal delivery of Sal B and potentiated its therapeutic effect on skin photoaging. This discovery provided potential therapeutic strategies and theoretical support for clinical treatment of photoaging.

Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.

Chronic obstructive pulmonary disease (COPD) is the world's fourth highest reason for mortality, accounting for 3.5 million deaths in 2021, and about 5 % of total global deaths. Emphysema and chronic bronchitis are the two major pathologies of COPD. Tobacco smoke, dust, vapors, and fumes, outdoor air pollutants, genetic factors, ageing, infections, and asthma are the risk factors of COPD. On the other hand, senescence is permanent halt in cell cycle accompanied by phenotypic alterations due to ageing, oxidative stress like; irreparable DNA damage, telomere shortening, oncogene activation or inactivation of tumor suppressors. COPD is often considered an accelerated ageing process of the lungs, with senescent cells impairing tissue repair and regeneration, causing progressive lung function decline. Although, cellular senescence is seen as powerful defense against risk of carcinogenesis in COPD as it arrests cell proliferation irreversibly, excessive collection of senescent cells releases senescence-associated secretory phenotype (SASP) that increase oxidative stress to lungs and leads to long-term inflammation, tissue damage, and hindered lung recovery. This review will address the accelerated ageing process and cellular senescence in COPD, therapeutic approaches targeting senescence regulation in COPD; clinical research and trial studies demonstrating the use of therapies aimed at senescence in COPD along with current obstacles and potential solutions.

Cytomegalovirus (CMV), a common herpesvirus, establishes lifelong latency and increases in prevalence with age; yet its systemic impact on the aging immune system remains incompletely understood. We profiled circulating immune cells from healthy older adults (median age: 73) who were CMV(+) or CMV(-) using single-cell RNA-sequencing and validated key findings by flow cytometry. CMV(+) individuals exhibited significant expansion of adaptive immune cells: CD4 and CD8 TEMRA T, GZMK+ CD8 T, {gamma}{delta} T, and atypical B cells. Among innate immune cells, monocytes and dendritic cells remained largely unchanged while KLRC2+ (adaptive) NK cells increased and CD56dim NK cells decreased. To facilitate CMV assessment in datasets with unknown CM serostatus, we developed CMVerify, a machine learning classifier that accurately predicts CMV serostatus from single-cell data across platforms and age groups (97% accuracy). These findings reveal extensive CMV-associated immune remodeling in older adults and underscore the importance of incorporating CMV status in studies of immune aging.

Assessing and validating circulating biomarkers is essential for the development of pre-clinical biomarkers that predict biological aging and aging-phenotypes in mice. However, comprehensive proteomics of serum, especially in longitudinal mouse studies, is limited by low volumes of samples. In this study, we develop a workflow for comprehensive and quantitative proteomic analysis of low volume mouse serum and demonstrate its utility and performance in identifying and evaluating key associations with aging phenotypes. Notably, a nanoparticle (NP)-based serum processing workflow coupled to mass spectrometry (MS) increases proteomic coverage by 2 to 4-fold across a range of volumes and provides a quantitative and reproducible (CV < 10%) pipeline for NP-based studies. In a study of 30 mice (aged 12, 24, and 30 months), we uncovered 3992 protein groups across all samples (2235 on average) in 20uL of serum and highlight novel insights into aging-associated changes in serum and associations with glucose and body composition. With 1uL additional serum, a 48-cytokine assay quantified 39 additional proteins not identified by MS. This study establishes a powerful workflow that enables deep quantitative proteomics of biologically relevant proteins in volumes feasibly obtained from mice (20 uL of serum) and presents fundamental insights into the aging serum proteome.

The World Health Organization (WHO) defines healthy ageing as the process of developing and maintaining functional ability, comprising an individual's intrinsic capacity, the environment and the interaction of the two. The framework is based on a positive approach to ageing, giving value to the resources individuals can rely upon as they age and that they can build their physical, mental and social health, and overall well-being. To promote healthy ageing, it is important to understand better the biological mechanisms underlying this phenomenon from this positive perspective. Our knowledge about cellular processes that drive human ageing has increased dramatically, with current evidence identifying 12 hallmarks of ageing. Dysbiosis is one of these and is broadly defined as a 'deranged microbiological composition in and on the human body'. It is often measured by quantitatively and qualitatively evaluating the bacterial species in the gut. A major feature of dysbiosis and other markers of ageing is that these focus on age-related impairments, contributing to the onset of adverse outcomes over time rather than highlighting features that promote healthy ageing. Scientific literature addressing the hallmarks of healthy ageing, including those potentially positively affecting intrinsic capacity, is lacking. To this end, we propose the concept of gut eubiosis, the homeostatic state of commensal gut bacteria and their metabolites, as proof of concept, serving as a hallmark of healthy ageing. Importantly, this work adopts a life course approach to explore how a person's intrinsic capacities evolve with gut microbiota modifications at different life stages.

Given the dual effects of iron on health, we carried out this study to explore its relationship with phenotypic age (PhenoAge) and to evaluate the roles of inflammation and oxidative stress in this regard. Since these associations are still poorly understood, elucidating them is vital for understanding aging-related health outcomes. A cross-sectional study was conducted using NHANES 2017-2018 data, involving 8692 participants aged 20 years or older. The nonlinear relationships between iron intake and PhenoAge acceleration (PhenoAgeAccel) were assessed using weighted restricted cubic splines (RCS). Multivariable-adjusted analyses were performed using weighted generalized linear models (GLMs). K-means clustering was employed to identify patterns of iron co-exposure. Interaction effects were assessed using likelihood ratio tests, while mediation analyses were conducted to quantify the contributions of inflammation and oxidative stress markers. This study identified a U-shaped relationship between total iron intake and PhenoAgeAccel (breakpoint: 18.441 mg/day). Below this threshold, higher iron intake was protective against aging (β = -0.126); above it, aging accelerated (β = 0.021). Notably, dietary iron derived solely from food was not associated with any harmful effects on aging. In contrast, supplemental iron intake showed a positive association with PhenoAgeAccel (β = 0.017), highlighting the potential risks of excessive supplement use. Moreover, the aforementioned associations showed no gender differences. Cluster analysis split participants into two groups: dietary iron reference (DIR), mostly below the UL (45 mg/day) with minimal supplemental iron; and supplement-driven iron overload (SDIO), all exceeding the UL, with supplemental iron comprising 83.44 % of total intake on average. SDIO showed significantly faster phenotypic aging (β = 1.774) than DIR. However, anti-inflammatory or antioxidant diets were able to counteract this detrimental effect (P for interaction = 0.025). Inflammation-related markers partially mediated SDIO-associated aging acceleration (mediation proportion: 15.53 %-25.63 %). The results stayed robust even after adjusting for variables related to anemia and post-menstrual status. This study suggests that excessive use of supplements, resulting in iron overload, may accelerate individual aging through inflammation-related pathways. Nevertheless, a diet abundant in anti-inflammatory or antioxidant properties could counteract this heightened risk of aging.

The elderly and astronauts exhibit strikingly similar phenotypes. Although much research has addressed the comparison between these two groups at the level of the whole organism or organ level, like the musculoskeletal system, comparative studies at the cellular level remain limited. Therefore, this article aims to address this gap by conducting an extensive scoping review, comparing cell function and alterations with advanced age to those observed in altered gravity. The broad review spans different cell types and species, highlighting the generic nature of aging and its relationship to gravity. We identified 165 signs of aging at the cell level, deducted from leading aging papers, and grouped them into 11 themes: DNA and epigenetics, mitochondria, nucleus, immune system, protein and metabolism, lysosome and degradation, cell cycle, cytoskeleton, extracellular matrix (ECM), cell mechanics, and cell signaling. Following this classification, we conducted a comprehensive search using the databases Web of Science and PubMed to examine the behavior of these signs in altered gravity conditions. The results reveal that only 29% of the responses are similar in (simulated) microgravity compared to biological aging, while others show contrasting behavior, thereby highlighting the complexity of cellular responses in these conditions. However, the majority of the signs remain unexplored in altered gravity. Mechanotransduction emerges as a potential key player in the observed phenotypic resemblances between aging and microgravity. Since there still is quite a lack of knowledge of aging-related effects on a cellular level in gravity-related research, we recommend further gravity research on the many components making up the links that facilitate mechanotransduction, which can aid in understanding the origins of these shared phenotypes and could lead to new insights into age-related and space-induced health challenges.

Both age and genetic risk are associated with risk of thoracic aortic aneurysms (TAA). This study seeks to explore the association between phenotypic age acceleration (PhenoAgeAccel), a novel biomarker of aging, and risk of TAA, as well as to conduct risk stratification for TAA based on PhenoAgeAccel and genetic risk.

Urine-derived renal progenitor cells (UdRPCs) from healthy individuals have been identified as having the potential to repair kidney damage. However, it remains uncertain whether UdRPCs retain their functionality in chronic kidney disease (CKD) patients. In this study, UdRPCs were isolated from healthy individuals and CKD patients. Notably, senescent cells were observed in the UdRPCs of CKD patients, which increase with the severity of CKD, hindering the repair of renal tissue damage and exacerbating the progression of CKD. This senescence phenotype is characterized by decreased proliferation, increased expression of kidney injury marker 1 (KIM-1), and an enhanced senescence-associated secretory phenotype (SASP). Transcriptomics analysis revealed a significant correlation between long intergenic non-coding RNA 01806 (LINC01806) and UdRPCs damage and senescence. LINC01806 activation modulates the expression of KIM-1 and senescence-related factors (p53, p21 and p16), promotes SASP secretion by stimulating the MAPK pathway, thereby inducing damage and senescence in UdRPCs. Mechanistically, the IRF8-RUNX1 complex binds to the promoter of LINC01806, promoting its expression in the nucleus. Our findings clarify the pathogenesis of CKD from a new perspective, and more importantly, provide new targets for drug screening and potential therapeutic interventions.

Moderate consumption of red wine has been associated with healthy aging and longevity, defined as one drink per day for women and two drinks per day for men (approximately 142 ml or 5 oz per drink). Previous research has revealed the health benefits of red wine, particularly in relation to cardiovascular disease. However, the influence of genetic factors on these benefits remains to be elucidated. In this study, we explored genes linked to red wine and created a curated gene set that intersects with those related to centenarians, who are markers of exceptional longevity. Utilizing over 190 databases, we identified and validated a curated list of genes, and conducted gene set enrichment analysis as well as enrichment analysis of annotations and diseases. Our findings highlighted 43 genes connected to centenarians, suggesting that these genes play a crucial role in stress response and apoptosis, which are essential for cell survival and renewal. Additionally, we noted that these genes were enriched in pathways associated with smooth muscle cell proliferation, neuroinflammation, nucleotide excision repair, and lipoprotein metabolism (false discovery rate, FDR < 3 x 10-07). Gene set enrichment analysis indicated significant tissue expression in the gastrointestinal, cardiovascular, and respiratory systems. Furthermore, the disease-gene enrichment analysis pointed to associations with the diseases related to the tissues, including cardiovascular disease (heart disease and stroke), type 2 diabetes, gastrointestinal diseases and metabolic diseases, immune diseases, and cancer (FDR < 9.37 x 10-6); notably, cardiovascular diseases, diabetes, and cancer are leading causes of death, suggesting that the genes may be protective against those diseases. Although further research is necessary to uncover additional genes, this study provides the first genetic overview of the health benefits of red wine, emphasizing its potential in supporting healthy aging and longevity.

Age-related cognitive decline poses significant challenges to healthy aging, yet its underlying molecular mechanisms remain poorly understood. In this study, we employed Morris Water Maze and hippocampal transcriptome analysis to investigate age-related cognitive decline in a rat model. Aged rats (RA) exhibited significant spatial memory deficits compared to young rats (RY). Transcriptome analysis identified ‌121 differentially expressed genes (DEGs)‌ in the hippocampus ‌of‌ RA group compared with RY group, including ‌54 up-regulated and 67 down-regulated genes. The qRT-PCR validation revealed significant up-regulation of Cd74 and Cd4 expression, along with marked down-regulation of Col1a1, Col3a1, and Serpine1 expression in RA group compared to RY group. Bioinformatics analysis revealed these DEGs were enriched in the biological processes of chronic inflammation, loss of proteostasis, and extracellular matrix pathways. These findings suggest hippocampal transcriptomic alterations may contribute to cognitive aging, providing potential predictors for cognitive function and ‌a‌ foundation for exploring molecular mechanisms.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked to age at maturity in humans and male Atlantic salmon through GWAS, as an antagonistically pleiotropic gene in the turquoise killifish (Nothobranchius furzeri). Selective disruption of vgll3 isoforms accelerates male growth and maturation in an isoform- and dose-dependent manner. Transcriptomic analysis, supported by cellular and physiological phenotypes, indicated increased cell proliferation and elevated germline production. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit elevated age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.

α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H

Background: Chronic heart failure (CHF), the terminal phase of cardiovascular disease progression, has emerged as an increasingly severe global public health concern. Despite current therapeutic approaches aimed at symptom relief, their long-term effectiveness remains limited, urgently necessitating the exploration of novel treatment strategies. This study endeavored to explore the role of cellular senescence in CHF, identify the characteristic genes linked to cellular senescence, and predict potential therapeutic agents. Methods: We acquired CHF-related datasets from the Gene Expression Omnibus database and cell senescence-related genes from the CellAge database to identify differentially expressed cell senescence-related genes. We then conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to elucidate the functions of these differentially expressed genes, constructed a protein-protein interaction network, and screened hub genes. Using receiver operating curve (ROC) analysis, we developed a diagnostic model based on these hub genes. Furthermore, we constructed networks for the hub genes involving miRNAs, lncRNAs, transcription factors, and drugs. Subsequently, we explored the potential mechanism of action of metformin in the treatment of CHF through molecular docking studies. Lastly, we verified the expression of the hub genes in a doxorubicin-induced CHF model in rats. Results: We ultimately identified nine hub genes associated with cellular senescence: STAT1, MMP9, MAP2K1, SOCS1, SDC1, MET, EIF4EBP1, ATF3, and NAMPT. These genes exhibited significant differential expression between CHF and normal tissues. The constructed diagnostic model demonstrated robust diagnostic performance in ROC curve analysis, with an area under the curve exceeding 0.7, thereby providing biomarker support for early CHF diagnosis. Furthermore, we identified a regulatory network comprising 94 lncRNAs, 63 miRNAs, and 11 transcription factors and screened 42 potential therapeutic drugs. Subsequent molecular docking simulations revealed that metformin could effectively bind to the hub genes. Finally, we validated the expression of some hub genes in a rodent CHF model, in which gene expression regulation varied across diverse experimental settings. Conclusions: Our research identified nine genes cellular senescence-related genes with potential roles in CHF pathogenesis, offering fresh perspectives concerning the diagnosis and treatment of CHF.

Sirtuins are NAD+-dependent histone deacetylases that play a key role in metabolism. Sirtuin activity is compromised in aging and metabolic disorders, and pharmacological strategies that promote sirtuin function including NAD+ boosting approaches show potential as therapeutics. To study the impact of nicotinamide mononucleotide (NMN) supplementation in mice in high fat diet (HFD) induced obesity and the role of SIRT1, a sirtuin family member, in mediating the NMN response, we administered NMN to mice in drinking water to boost NAD+ in control and in inducible SIRT1 knock-out mouse models and performed a combination of metabolic phenotyping, lipid profiling and plasma proteomics in these mice. We discovered that supplementation with NMN mitigated diet induced weight gain by enhancing energy expenditure, corrected dyslipidemia, and reversed perturbations in fasting blood glucose, all in a SIRT1-dependent manner. On the other hand, NMN-induced reductions in fat mass, fluid mass, eWAT and mesenteric WAT were SIRT1 independent. Proteomic approaches in plasma samples using O-Link and mass-spectrometry provided novel insights into key obesity- and NMN-dependent changes in circulating molecules with potential relevance to inflammation, liver function, and dyslipidemia. We discovered SIRT1 dependent and independent alterations in key circulating plasma proteins and identified key metabolic and molecular pathways that were significantly affected by HFD, several of which were reverted by oral NMN administration. Glucose metabolism, cholesterol metabolism and immune-related pathways are among the most significantly affected changes. Causal analysis of proteomic data suggests that observed effects could be mediated by transcription regulators FBXW7, ADIPOR2 and PRDM16. Collectively, our data support the hypothesis that promoting SIRT1 function by boosting NAD+ levels in vivo may be a useful strategy to mitigate obesity and associated cardiovascular complications such as dyslipidemia.

Lens epithelial cell (LEC) senescence is one of the key pathological processes of age-related cataract (ARC) and is associated with oxidative stress, mitochondrial dysfunction, and protein aggregation. This study aimed to elucidate the pathogenesis of LEC senescence in ARC. The protein expression level of silencing regulatory protein 1 (SIRT1) and aptamer protein (p66Shc) was quantified. Reactive oxygen species (ROS) and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Senescence-associated protein expression (p21 and p53) and SA-β-galactosidase staining were employed to assess the aging status of LEC. Targeted metabolic analysis was conducted to explore energy changes during LEC senescence, and mitochondrial morphology and function were assessed in the cell models. The aging and damage conditions of the lens in ARC rats were evaluated through histological staining, transmission electron microscopy, expression of senescence-related proteins, and oxidative stress markers. We comprehensively investigated the downregulation of SIRT1 expression and the upregulation of p66Shc expression in human cataract samples, UVB-induced rat cataract models, and UVB-treated LEC. SIRT1 could alleviate UVB-induced oxidative stress, as well as mitochondrial dysfunction, inhibiting p66Shc expression in LEC. Nicotinamide mononucleotide (NMN) effectively alleviated the abnormal expression of aging-related proteins and inhibited mitochondrial morphological and functional disorders by activating SIRT1. In conclusion, NMN activated SIRT1, inhibiting mitochondrial dysfunction, oxidative stress, and senescence in LEC, delaying lens opacity. This mechanism could be associated with the onset and progression of ARC, providing a new strategy for its prevention and treatment.

Accelerated epigenetic aging has been associated with changes in cognition. However, due to the lack of neuroimaging epigenetics studies, it is still unclear whether accelerated epigenetic. Aging in young adulthood might underlie the relationship between altered brain dynamics and cognitive functioning. We conducted neuroimaging epigenetics follow-up of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort in young adulthood and tested the possible mediatory role of accelerated epigenetic aging in the relationship between dynamic functional connectivity (DFC) and worse cognition. A total of 240 young adults (51% men; 28-30 years, all of European ancestry) participated in the neuroimaging epigenetics follow-up. Buccal swabs were collected to assess DNA methylation and calculate epigenetic aging using Horvath's epigenetic clock. Full-scale IQ was assessed using the Wechsler adult intelligence scale (WAIS). Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired using a 3T Siemens Prisma MRI scanner, and DFC was assessed using mixture factor analysis, revealing information about the coverage of different DFC states. In women (but not men), lower coverage of DFC state 4 and thus lower frequency of epochs with high connectivity within the default mode network and between default mode, fronto-parietal, and visual networks was associated with lower full-scale IQ (AdjR

The reproductive conflict hypothesis suggests menopause is rare in nature because it is only evolutionarily favoured in specific dispersal and mating systems. In social groups with local mating, shared resource competition and female-biased dispersal, an increase in a breeding female's relatedness to her fellow community members with age is expected to favour late-life reproductive cessation as a response to intergenerational reproductive competition. Here, we use observational and genomic data from the Ngogo chimpanzee community to characterize kinship dynamics and investigate the potential role of reproductive conflict in explaining a recent report of menopause in this community. We first find that, as predicted by simple models, the combination of female dispersal and local breeding leads to age-specific increases in relatedness between female and male community members. Next, we use the observed kinship dynamics in inclusive fitness formulae to test whether reproductive cessation might have been selected for in chimpanzee females. We find that kinship dynamics measured within subgroups of the community, where competition is presumably most intense, favour the evolution of menopause beginning around age 40. This is consistent with patterns of age-related fertility declines observed in Ngogo, suggesting reproductive conflict may have contributed to the evolution of chimpanzee post-reproductive lifespans.

Psychological resilience, commonly conceptualized as the capacity to rebound or surmount various forms of adversity, reflects the dynamic adaptability to the aging process. This study examines the impact of change in psychological resilience on all-cause and cause-specific mortality in older adults.

To investigate the biological effects of low-dose ionizing radiation (LDIR) on living organisms, we analyzed the effects of LDIR of 0.05 Gy and its mechanism on the

MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as a biological aging indicator and their associations with health outcomes using population-level data.

The relationship between intrinsic capacity (IC) and falls has not been studied in Western European older adults. This study aimed to examine the relationship between IC, falls, and physical activity (PA) in a Western European country, and to examine whether PA mediates the relation between IC and falls.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.

Protein homeostasis controlled by the 26S proteasome plays a pivotal role in the adaption of plants to environmental stress, contributing to survival and longevity. During ageing in animals, proteasome activity declines resulting in senescence, however, in plants this is so far largely unexplored. Both in Arabidopsis and barley we found that genes encoding for proteasomal subunits are upregulated at the transcript level during the onset of leaf senescence. In contrast, at the protein level a decrease in proteasomal subunit abundance was observed. Moreover, in Arabidopsis 26S proteasome capacity deteriorates with leaf age, while 20S proteasome activity increases. In contrast, in barley a potential increase in proteasome activity was observed with age. As ribosome-associated RNAs levels of proteasomal subunits increase in Arabidopsis during senescence, it suggests a high-turnover. Furthermore, chemical inhibition of the proteasome results in accelerated leaf senescence in Arabidopsis and barley. In Arabidopsis, 26S proteasome activity could be restored by external cytokinin application, resulting in delayed senescence. Finally, we identified several senescence-associated transcription factors that acts as novel transcriptional regulator of proteasomal genes in Arabidopsis. Taken together, this work provides new insights into the dynamic regulation of proteasome activity which deepens our understanding on leaf senescence in plants.

While aging is a natural biological process, it is associated with a greater risk for multiple diseases, including cancer, neurodegeneration, and cardiovascular disease. Thus, it is important to study the biochemical mechanisms involved in aging to understand how to treat and prevent these health conditions. The discovery that calorie restriction (CR) promoted longevity in various organisms is a major breakthrough for aging research. Molecular studies of CR have revealed that it mediates its anti-aging effects by activating key signaling pathways, including the AMPK pathway. This pathway is important for regulating various processes, including energy homeostasis, metabolism, and proteostasis. Despite the advantages associated with CR, this practice can have detrimental effects, including decreased liver, body, and muscle mass. Additionally, CR is difficult to track and maintain, limiting its long-term potential. Interestingly, direct activation of the AMPK pathway offers a potential approach to increase longevity and quality of life without dietary restrictions. Remarkably, a recent discovery revealed that lithocholic acid (LCA), a metabolite from bile acid, could directly activate the AMPK pathway. Activation of the AMPK pathway by LCA leads to the beneficial effects of CR without the negative effects. These recent findings point to the possibility that supplementation of specific doses of LCA could offer a novel approach to induce anti-aging pathways that lead to increased longevity and improved quality of life.

Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identified via mathematical transformations of data to favor a linear transition from start to end, even if they erase any natural biological pattern. It is given that expected correlations, e.g., time lived (age) and time left to live (mortality), would persist in such mathematically optimized models, biologically meaningful or not. Here, we further clarify the workings of the clocks, explain the trade-off between mathematical optimization and biological interpretability, and discuss a hallmark of aging, inflammaging, that age clocks struggle to detect. We expand on the negative consequences of incoherence in linear models where some DNA methylation (DNAm) features increase with aging and disease, while others correspondingly decrease, yet positive weights are assigned to both. We quantify the misalignment between major DNAm clocks and actual changes in DNAm, providing an interactive visualization of these errors for each model. We demonstrate that major conventional age clocks are both incoherent and skewed toward leukocyte fractions and that rectifying incoherence makes the model balanced and not skewed toward neutrophils and better detects inflammaging. We briefly outline non-linear ML age clocks and the advantages of identifying a natural trajectory of aging directly from the primary data.

Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.

Antiaging vaccines have recently been found to elicit long-term benefits in slowing the aging process. Meanwhile, high CD38 expression in organs is an aging characteristic contributing to a decreased NAD

Telomere length is a known indicator of biological aging, typically decreasing with age. Biological age is a benchmark for assessing an individual's health and aging. Correlations between telomere length and lifestyle factors have primarily been investigated from the perspective of a single variable and predominantly examined in postmenopausal women in Korea. This study aimed to analyze the effects of multiple lifestyle factors on telomere length in a diverse Korean population comprising 368 healthy adults (174 men and 194 women). We measured anthropometric and blood-related parameters and collected data on lifestyle-related factors, such as exercise, smoking, alcohol consumption, sleep, and stress, using surveys. Telomere length was quantified using monochrome multiplex quantitative real-time polymerase chain reaction (qPCR), and the relationship between lifestyle factors and telomere length was analyzed using correlation and regression analyses (p-value <0.10). Our findings indicated that telomere age, derived from telomere length, significantly increased with each adverse lifestyle factor. For men, significant contributors included exercise, smoking, and stress, whereas for women, significant contributors were exercise, alcohol consumption, sleep, and stress. The results showed that lifestyle and biological age considerably affected telomere age and accelerated the aging process. These results emphasize the importance of lifestyle in the management of biological aging.

Scientific understanding of the relationship between environmental hazards and cognitive health at older ages in low- and middle-income countries (LMICs) is poor. Using data from the Longitudinal Aging Study of India and the World Health Organization's Survey on Global AGEing and adult health for 4 LMICs, we examine the association of direct and local exposure to polluting cooking fuels with cognitive health at older ages. We document the negative influence of both: Cognitive health is poorer among members of households that use polluting fuels and among residents of neighborhoods where the use of polluting fuels is more common. These associations cannot be explained by accounting for individual or local differences in socioeconomic status. Consistent with direct impacts of polluting fuels, we find that women in households where the use of polluting fuels is common have the lowest predicted cognitive scores. Our findings reveal the substantial direct influence and negative externalities of polluting fuel use in LMICs and help understand why overall cognitive health may be poor in these settings. Moving away from polluting fuels toward clean fuels may reduce individual risk and community-level exposure to air pollution, contributing to better cognitive health in older ages. This article is part of a Special Collection on Cross-National Gerontology.

Aging leads to alterations in the sensorimotor system and balance control but it is not well understood how changes in sensorimotor function affect how people respond to postural disturbances. Elucidating the relationships between balance control and sensorimotor function is crucial for developing effective rehabilitations. Here, we compared the kinematic responses to platform translations and rotations during standing in 10 young and 30 older adults and explored relationships between sensorimotor function and balance responses. We found that older adults were less able to withstand perturbations without stepping, not because their non-stepping strategies were less effective but because they chose to step at smaller deviations of the extrapolated center of mass. Older adults performed worse than young adults on measures of sensory and motor function but lower stepping thresholds were associated with susceptibility to unreliable visual information and not with reduced sensory acuity or reduced strength. Poor sensory reweighting may contribute to and combine with age-related cognitive rigidity, leading to a higher priority on safer strategies. Older adults may resort to stepping, even if a step is not necessary, rather than rely on potentially inaccurate sensory signals to inform a corrective response. Our results provide initial evidence that sensory reweighting could be a potential target for fall prevention methods.

Budding yeast undergoes replicative aging through asymmetric cell divisions. Yeast mother cells progressively age as they generate successive daughter cells, until they ultimately die. However, their daughters are born rejuvenated, that is, most of them recover a full lifespan potential, with little impact of their mothers' age at their birth. In this review, we will discuss recent findings regarding the mechanisms of replicative aging and rejuvenation. Based on these insights, we will also discuss which evolutionary forces may have presided over the emergence of aging in yeast. We suggest that aging and rejuvenation represent two adaptive strategies that each bring their own benefits.

Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabolic, cellular and functional changes that occur in white and thermogenic adipose tissue during distinct ageing stages, across different adipose tissue depots. We emphasize the influence of ageing on different cell types within adipose tissue, including adipocytes, adipocyte progenitors, immune cells and senescent cells, and their collective effect on adipose tissue function and systemic metabolism. We also decipher the correlation between adipose tissue ageing and prevalent age-related conditions such as metabolic dysfunction-associated fatty liver disease and cardiovascular diseases. Finally, the Review delves into the potential of current anti-ageing interventions to beneficially affect adipose tissue, encompassing caloric restriction, metformin, glucagon-like peptide 1 receptor agonists and senolytics. The discussion extends to the exploration of whether targeting adipose tissue through such interventions could emerge as a prominent therapeutic strategy for mitigating age-related diseases and enhancing the healthspan and lifespan of the ageing population.

The increasing global population aging has made the prevention and control of aging-related diseases a major public health challenge in the twenty-first century. Nicotinamide mononucleotide (NMN), as a precursor of nicotinamide adenine dinucleotide (NAD

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

This review investigates the emerging role of exosomal microRNAs (miRNAs) as pivotal mediators of bidirectional communication between the skeletal muscle and bone tissue, with significant implications for age-related musculoskeletal disorders. In aging populations, sarcopenia often coexists with osteoporosis, forming osteosarcopenia, which markedly increases fracture risk, disability, and mortality. While traditional paradigms emphasize mechanical loading and endocrine pathways, emerging evidence has revealed that exosomes carrying bioactive miRNAs represent a novel class of paracrine factors in the muscle-bone axis. We examined how muscle-derived exosomal miRNAs (miR-34a and miR-27a-3p) influence bone metabolism, while bone-derived exosomal miRNAs (miR-486-5p) modulate muscle physiology. For each miRNA, we identified the target messenger RNAs (mRNAs) and signaling mechanisms. Importantly, exercise has emerged as a potent modulator of this crosstalk, altering exosomal miRNA profiles to promote anabolic outcomes in both tissues. This bidirectional communication contributes to osteosarcopenia pathophysiology, leading us to propose a novel "Exosomal miRNA Regulatory Network" for diagnosis and pathogenesis. Exosomal miRNAs show promise as early biomarkers for subclinical deterioration and therapeutic targets. However, methodological challenges in exosome isolation, incomplete characterization of miRNA networks, and aging complexity must be addressed before clinical implementation.

Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.

Metformin is a widely used antidiabetic agent for obesity-related type 2 diabetes mellitus, providing significant health benefits such as reduced blood glucose levels and body weight. Emerging evidence suggests that metformin may play a beneficial role in delaying aging. However, the causal relationship between metformin use and frailty index (FI) remains uncertain and warrants further investigation. This study aimed to explore the genetically predicted causal relationship between metformin targets and FI.

Dietary restriction (DR) extends lifespan in animals and plants, but its evolutionary causes are elusive. Adaptive hypotheses posit that DR extends lifespan because organisms reallocate resources from reproduction to survival (\"disposable soma\") or recycle cellular waste to maximize either their immediate reproduction (\"nutrient recycling\") or survival (\"clean cupboards\"). We developed an experimental paradigm that tricks Caenorhabditis elegans nematodes into increasing their reproductive effort under DR via food odour, thus allowing us to test these hypotheses. We found that experimentally increased reproduction under DR does not affect immediate or long-term survival benefits compared to DR animals that did not reproduce, thus refuting all three adaptive hypotheses. Our data suggest that a large part of suppressed fertility under DR is a result of organisms refraining from producing offspring in a poor environment. We developed a model based on Hamiltonian forces of selection to show that lifespan extension under DR evolves because DR suppresses fertility, directly increasing selection against mortality in DR environment. Our analytical approach suggests that DR-driven lifespan extension can evolve under a broader range of conditions not previously anticipated, such as a relaxed need for physiological or genetic trade-offs. Instead, we show how reduced survival on plentiful food can evolve via mutation accumulation.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune dysregulation and joint destruction. Cellular senescence has been implicated in the progression of RA through the senescence-associated secretory phenotype (SASP), yet its molecular links to inflammation remain unclear. Rapamycin, an mTOR inhibitor with anti-inflammatory and anti-senescence properties, provides a valuable tool for exploring these mechanisms.

Cannabinoid receptor type-1 (Cnr1) signalling declines with age, which may contribute to the ageing process, as Cnr1 activity influences several hallmarks of ageing. Indeed, previous studies have shown that mice with a genetic deletion of Cnr1 (Cnr1

Emotion dysregulation disrupts normal biological function by increasing inflammation, thus putting people at risk for long-term health issues. These risks are amplified through aging, and accelerated biological aging poses a significant threat to longevity. This pilot study examined several emotion regulation skills, as well as emotion dysregulation broadly, and their relationship with inflammation among physically healthy adults.

Age-related decline in dual-task (DT) performance is closely associated with falls in older adults, posing a significant public health concern. Virtual reality (VR) training has emerged as a novel intervention to enhance motor-cognitive integration, yet its effects on dual-task performance require systematic evaluation.

Osteoporosis and Alzheimer's disease (AD) are age-related health conditions that significantly impact patients and society. Sclerostin, a glycoprotein secreted by osteocytes, regulates bone metabolism by inhibiting the Wnt/β-catenin signaling pathway, which controls bone formation. Elevated sclerostin levels in osteoporosis contribute to increased bone resorption and reduced osteoblast activity. Recent studies suggest that sclerostin also affects the central nervous system, where its expression in brain tissues may impair synaptic function and accelerate cognitive decline in AD. Both osteoporosis and AD share common risk factors, such as aging, neuroinflammation, and oxidative stress, which exacerbate disease progression. Targeting sclerostin with therapies like Romosozumab, a monoclonal antibody that inhibits sclerostin activity, has shown promise in treating osteoporosis by promoting bone formation. Given the potential connection between sclerostin and AD, there is growing interest in exploring sclerostin modulation as a therapeutic strategy for AD, though challenges such as crossing the blood-brain barrier remain. This review discusses the emerging relationship between osteoporosis and AD, emphasizing the shared molecular pathways and the potential for sclerostin-targeted therapies to benefit both conditions. Further research is needed to understand the causal links between sclerostin, osteoporosis, and AD, and to assess the effectiveness of sclerostin modulation in managing both diseases simultaneously.

Cellular senescence is a significant contributor to various age-related diseases. Tet methylcytosine dioxygenase 3 (TET3) is a pivotal regulator of epigenetic modifications, and this study aimed to elucidate its role in cellular senescence. The study utilized replication and paraquat (PQ)-induced senescent endothelial cells, as well as TET3 heterozygous, p53 heterozygous, and PQ-induced senescent mice as experimental models. Senescent endothelial cells were analyzed using hydromethylated DNA immunoprecipitation sequencing, β-galactosidase staining, real-time PCR, western blotting, immunofluorescence staining, dot blot, chromatin immunoprecipitation assay, and luciferase reporter assays. These analyses were conducted following TET3 knockdown and gene overexpression. TET3 is instrumental in the elevation of 5-hydroxymethylcytosine (5-hmC) levels in both replication and PQ-induced senescent endothelial cells, as well as in the cardiovascular systems of PQ-induced aging mice. TET3 significantly promoted cellular senescence in PQ-induced endothelial cells and mice. TET3 facilitates the upregulation of the Sp1 transcription factor (SP1) through 5-hmC modification, leading to a synergistic interaction between SP1 and ETS proto-oncogene 1 that further enhances p53 expression. Moreover, p53 not only promotes cellular senescence in vitro and in vivo but also reciprocally enhances TET3 and 5-hmC levels. These findings underscore the critical role of elevated TET3 and 5-hmC levels in cellular senescence.

Collagen is the most abundant structural protein in mammals. Collagen in tissues is exposed to cross-linking processes such as glycation which might cause progressive tissue stiffening. Tissue stiffening might be considered a landmark of aging. Yet a quantitative characterization of the elastic modulus of collagen nanofibers under different cross-linking processes and stages is not available. Bimodal AFM was applied to generate time-lapsed maps of Young's modulus of type I collagen nanoribbons under two cross-linking processes associated, respectively, with the presence of ribose and glutaraldehyde in the solution. Elastic modulus maps were acquired for different incubation times (0, 30 min, 12 h, 24 h and 1 week). The experiments were performed in liquid. The Young's modulus showed an initial sharp increase after an incubation time of 30 min, from a few MPa (native) to 100 MPa. From then onwards we measured a monotonic increase until a saturation value of about 2 GPa was reached after one week. We did not observe a dependence on the elastic modulus evolution using ribose

Sex differences in hippocampal aging have been increasingly recognized, with females showing greater vulnerability to neurodegeneration, particularly after menopause. However, the underlying neurobiological mechanisms remain unclear, especially at the level of hippocampal subfields. Leveraging high-resolution T1-, T2-weighted, and multi-delay arterial spin labeling MRI from 650 adults in the Human Connectome Project-Aging dataset, we examined sex-specific alterations in hippocampal subfield volume, arterial transit time (ATT), and cerebral blood flow (CBF) across the adult lifespan. All hippocampal subfields showed age-related atrophy and ATT prolongation. An age × sex interaction effect on ATT was observed in CA1 and CA2, indicating that age-related increases in ATT were more pronounced in females than in males in these subfields. Moreover, females exhibited more pronounced hippocampal subfields CBF reductions with aging and atrophy, while males showed relatively preserved CBF, with an increase in subiculum perfusion. Furthermore, CA1 showed the lowest perfusion and the strongest association with atrophy among hippocampal subfields. To investigate the potential impact of menopausal hormonal changes on sex-specific patterns, we explored the hypothalamic structure and hemodynamic alterations during aging and their effects on the hippocampus, given that hypothalamus regulates gonadal hormone secretion through the hypothalamic-pituitary-gonadal axis. We found significant hypothalamic atrophy during aging in both sexes, accompanied by ATT prolongation exclusively in females, which was associated with hippocampal atrophy and impaired hemodynamics. Our study highlights the intricate interplay between hippocampal structure and vascular function, revealing sex- and subfield-specific aging trajectories. These findings provide a normative quantitative imaging reference to age-related neurodegenerative diseases such as Alzheimer's Disease.

Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.

As individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by "inflammaging," a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.

Sarcopenia is the age-related degeneration of skeletal muscle. Healthy skeletal muscle secretes metabolites and macromolecules that are systemically important for the immune system (e.g. myokines) and the central nervous system (e.g. BDNF). Exercise interventions to stimulate skeletal muscle are therapeutic for sarcopenia and limit risk and/or provide neuroprotection in neurodegenerative disease models. Metabolic analysis of aged skeletal muscle has identified altered skeletal muscle metabolomes at an old age. Many of the molecules identified are amino acids that also act as neurotransmitters. In this review, we summarize how 13 amino acids act as neurotransmitters or as precursor to neurotransmitters, and how these are involved in the skeletal muscle secretome, sarcopenia, and (healthy) aging.

The integration of mindfulness activities into the daily lives of older adults has demonstrated profound benefits for their overall well-being and vitality. However, evidence on how mindfulness correlates with muscle strength in older adults remains limited. To fill this gap, we explored the association between mindfulness activities and handgrip strength (HGS) in older adults in India. We also examined whether this association varies by sex.

To identify signature proteins potentially linked to resistance to autoimmunity in the blood of centenarians.