Longevity Papers

C9ORF72 intronic repeat expansions are the most frequent mutation found in Amyotrophic Lateral Sclerosis (ALS), producing toxic arginine-rich dipeptides (DPR) that disrupt RNA metabolism and trigger the accumulation of orphan ribosomal proteins (RP). Through a large phenotypic chemical screen, we identified SALSa, a novel compound that mitigates DPR toxicity. Mechanistically, SALSa acts as a chemical inducer of ribophagy, a specialized form of autophagy that promotes RP clearance. Interestingly, this effect is unrelated to mTOR inhibition, the main regulator of autophagy. In contrast, this is due to an effect of the drug in ribosome biogenesis, which triggers a protective response to clear defective ribosomes. Accordingly, SALSa accumulates in nucleoli and perturbs the final steps of rRNA maturation. SALSa reduces DPR toxicity in differentiated neurons and significantly extends lifespan in a Drosophila melanogaster model of C9ORF72 ALS. These findings suggest that stimulating ribophagy could be beneficial for pathologies associated to dysfunctional ribosome biogenesis, including C9ORF72 ALS.

Lactate, once viewed merely as a glycolytic byproduct, is now recognized as a key signaling molecule and epigenetic regulator through the recently identified post-translational modification known as lactylation. In diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic peripheral neuropathy (DPN), persistent hyperglycemia promotes metabolic reprogramming toward glycolysis and leads to excessive lactate production. This sustained metabolic stress drives cellular changes, such as mitochondrial dysfunction, chronic inflammation, and epigenetic alterations, which closely mirror hallmarks of premature aging. This review synthesizes emerging evidence linking the lactate-lactylation axis to the development of microvascular injury in diabetes, framing these complications as manifestations of accelerated cellular and metabolic aging. We outline the molecular framework of lactylation, including its writers, erasers, and readers, and summarize how lactate-induced histone and non-histone lactylation reshapes gene transcription in retinal, renal, and peripheral nerve cells. In DR and DKD, accumulating studies indicate that lactylation contributes to cellular dysfunction across multiple microvascular cell types, while in DPN, although evidence remains limited, lactylation may influence Schwann cell biology and axonal integrity under metabolic stress. Notably, lactate-driven epigenetic remodeling reinforces features of metabolic memory and tissue-specific aging, such as mitochondrial dysfunction, chronic inflammation, and cellular senescence, by maintaining maladaptive transcriptional programs that persist despite glycemic control. We further discuss the therapeutic potential of modulating lactylation pathways and the possible utility of lactate as a biomarker. By integrating metabolic, epigenetic, and aging perspectives, this review highlights the lactate-lactylation axis as a converging pathway that mechanistically links hyperglycemia to the premature aging phenotype of diabetic microvasculature, and outlines future avenues for diagnostic and therapeutic innovation.

Oxidative damage is an important cause of aging. Saikosaponin A (SSA) is a major triterpenoid naturally occurring in Radix Bupleuri (RB), a well-recognized superior-grade Chinese herb. Additionally, a rare secondary glycoside, namely prosaikogenin F (PSF) can be obtained after removal of one glucose from SSA. This study aimed to efficiently prepare PSF from SSA, and further investigate and compare their anti-aging activities in Caenorhabditis elegans. Evaluation of antioxidant capacity, heat stress resistance, and aging-related physiological change were conducted, and potential mechanisms were revealed as well. The results showed that Aspergillus niger demonstrated the highest conversion efficiency, achieving a relative PSF yield of 83.9%. Average lifespan of nematodes was extended by 9.32% after treatment with 120 μM SSA, which was further increased to 11.41% while PSF being applied. Under thermal stress stimulation, 120 μM PSF prolonged survival time of nematodes by 35.76% compared to SSA by 33.59%. In addition, they increased the activity of antioxidant enzymes, reduced lipid peroxidation, enhanced the body's resistance to stress damage, and effectively prolonged the lifespan of nematodes. The expression of daf-16, hsp-16.2 and sir-2.1 in the nematodes treated with SSA or PSF were significantly up-regulated, whereas that of the daf-2 gene was significantly down-regulated (p < 0.05). In conclusion, the rare secondary triterpenoid saponin PSF was conveniently obtained from abundant SSA by microbial biotransformation. It showed stronger anti-aging activity than its primary form SSA and acted via regulation of insulin/insulin-like growth factor signaling (IIS) pathway, demonstrating its greater potential for applications in anti-aging and antioxidant.

Vascular cognitive impairment and dementia (VCID) is increasingly recognized as one of the leading causes of cognitive decline in aging populations. VCID is driven by the interplay of endothelial dysfunction, chronic inflammation, oxidative stress, and metabolic dysregulation. Aging exacerbates cerebrovascular damage by impairing endothelial function, compromising the blood-brain barrier (BBB), and promoting neuroinflammation, all of which contribute to the progression of small vessel disease (SVD) and white matter hyperintensities (WMHs), which are hallmarks of VCID. Epidemiological evidence suggests that aging is associated with modifications in circulating low-density lipoprotein (LDL) and high-density lipoproteins (HDL), particularly oxidation, which further accelerates neurovascular pathology. Oxidized LDL (oxLDL) disrupts endothelial homeostasis, enhances leukocyte adhesion, and triggers chronic inflammatory signaling through microglial and astrocytic activation. Additionally, oxLDL-mediated oxidative stress exacerbates mitochondrial dysfunction and epigenetic alterations in cerebrovascular cells, reinforcing a cycle of vascular injury and neurodegeneration. These mechanisms contribute to neurovascular uncoupling, cerebral hypoperfusion, and cognitive decline in aging individuals. This review examines the pathophysiological role of oxLDL in VCID, with a focus on its impact on endothelial integrity, BBB function, neuroinflammation, and lipid-mediated neurodegenerative processes. Furthermore, we discuss emerging therapeutic strategies targeting LDL oxidation, inflammation, and endothelial dysfunction as potential interventions to mitigate the burden of VCID in aging populations.

Aging is the strongest risk factor for chronic diseases such as cardiovascular disease, Alzheimer's, and cancer. DNA methylation (DNAm) clocks offer a promising measure of biological age, but most rely on linear models that miss non-linear dynamics and CpG interactions. To address this, we developed a deep neural network (DNN)-based DNAm clock trained on 29,167 samples profiled on Illumina EPIC v1.0 and v2.0 arrays. Using 12,234 CpGs selected through sex- and age-stratified correlations, our model achieved high accuracy (1.89 years) and outperformed published deep learning and elastic net based epigenetic clocks in a separate validation cohort. Using Shapley Additive Explanations (SHAP), we further uncovered phase-structured, wave-like dynamics in age-influential CpGs: an early-life module, a midlife transition, and late-life remodeling, with distinct timings by sex. These epigenetic waves cohere with non-linear, multi-omic "aging waves" reported in proteomics and longitudinal omics. SHAP further enabled interpretable CpG attribution, revealing structured, sex-specific aging phases: early-life male clocks involved developmental pathways, while female clocks emphasized cytoskeletal regulation; late-life divergence included immune activation in males and transcriptional remodeling in females. Our framework thus unites accuracy with mechanistic interpretability, revealing sex-specific windows when molecular aging reconfigures most rapidly.

Healthy lifestyles are well-established determinants of longevity, yet it remains unclear whether they continue to shape survival in extreme old age. This study examined the association between healthy lifestyles and survival beyond age 100, and quantified absolute survival gains.

Epigenetic clocks derived from DNA methylation patterns are among the most promising biomarkers of biological aging

Mitochondrial stress (MS) is a hallmark of a number of aging-associated neurodegenerative diseases, including Parkinson's disease (PD). Chronic MS in PD disrupts neuronal proteostasis, causing dopaminergic neurodegeneration through inactivation of an E3 ubiquitin ligase, parkin, although the mechanism of its inactivation is not understood. Here, we elucidate a mechanistic framework linking progressive changes in mitochondrial mass with MS-induced alterations in parkin activity. We showed that acute and chronic MS differentially modulate parkin activity and regulate mitochondrial biogenesis by transcriptional control of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), through parkin substrate PARIS (parkin-interacting substrate). Acute exposure to the PD neurotoxin, 1-methyl-4-phenylpyridinium (MPP

Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted.

Despite several age-related processes impacting motor performance, older adults often retain the ability to implicitly adapt to sensory prediction errors. Here, we leverage the fact that implicit adaptation is not attenuated by aging to study the impact of aging on responses to motor errors. In other domains, such as reinforcement learning, aging has been shown to influence how task outcomes or rewards are processed and used to guide subsequent actions, with some studies emphasizing that older adults react more strongly to a miss than to a hit. We aimed to extend these reinforcement learning findings to the motor domain with two preregistered experiments testing whether missing the target leads to larger implicit adaptation in young and older adults to the same extent. In addition, we compared these results to one reinforcement learning task in the motor domain (Boolean feedback after reaching in the absence of visual feedback) and one in the cognitive domain (reward-based decision making). While we found age-related effects in the cognitive domain, we did not observe a consistent effect of age on the modulation of reaching direction or motor adaptation by task outcomes. These results suggest a domain-specific nature of age-related changes in sensitivity to task outcomes.

The global aging trend highlights the need for effective strategies to prevent cognitive impairment and depression. This study aimed to examine the mediating role of DASH diet quality in the association between sustainable dietary behaviors, cognitive function, and depressive symptoms among older adults.

With advancing age, the immune system's capacity to effectively combat pathogens diminishes. This decline of the overall immune function impacts both the innate and adaptive compartments, contributing in many cases to a systemic state of chronic inflammation which further increases the risk of the most prevalent non-communicable diseases and severe infections. Given the increase in median life expectancy with a demographic development towards a larger number of elderly people, identifying interceptive strategies to mitigate the individual and societal impact of diseases related to immune aging is of paramount importance. We developed a molecularly defined strategy to guide interventions with the aim to reduce immune aging. We introduce an omics-based drug screening platform to identify and characterize the pharmacological profile of immune senomodulators applicable to cross-age human cohorts using human-derived peripheral immune cells. To this aim we developed a robust experimental approach to screen for effective anti-aging compounds directly on human cells. This methodology allows us to quickly screen for drug candidates at different scales: from cost-effective bulk transcriptomics for a broader high-throughput overview of cellular responses, down to single-cell resolution approaches for a more detailed look at gene expression and other molecular data. This in vitro screening method is designed to maximize the clinical relevance of our findings, providing a direct link between preclinical research and patient care. By analyzing how different compounds affect the immune cells of individual persons, we can identify treatments that are most likely to be effective against aging in a subject-specific manner, a key step toward personalized medicine. In short, our approach enables a faster translation of anti-aging immune treatments from the lab to the clinic, tailoring them to each individual's unique biological makeup.

Proteins are essential elements controlling cellular processes. Their synthesis and assembly are vital to the cell as their defect would have deleterious consequences. A finely tuned conserved biological machinery known as the protein quality control (PQC) is in place to correct the defect. The PQC includes the unfolded protein response (UPR), devoted to recognizing, unfolding and refolding abnormally arranged proteins, and the clearance apparatuses composed of the Ubiquitin Proteasome System (UPS) and the Endoplasmic Reticulum Associated Protein Degradation (ERAD). Abnormally folded proteins accumulate in idiopathic dilated cardiomyopathy (iDCM). In this study we investigated the transcriptional and translational landscapes of the UPR and UPS systems using polymerase chain reaction (PCR) and western blotting (WB) of myocardial tissues from iDCM patients and age, ethnicity and biological sex matched control cases. Our results show an increase of the three main UPR axis at the transcription and translational levels, suggesting an activation/inactivation of all axes, with altered PTM/cleavage/splicing eliciting abnormal downstream function. Notably, aging independently affects this machinery in diseased and control individuals. In addition, mutation in presenilin gene associated with Alzheimer's disease led to post-translational changes of the UPR components suggesting that genetic risk may exacerbate the natural age and disease-driven protein dyshomeostasis. In conclusion, our findings highlight that abnormalities of UPR are a still largely unexplored feature in heart failure to be view in its entirely. The combined alteration of several target proteins of these pathways configures defective proteostasis as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.

Aging is a crucial factor in the development of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. Marking the 10th anniversary of the original "Hallmarks of the aging lung" published in this Journal, we present an updated review highlighting key cellular and molecular features of aging that drive the onset and progression of these conditions. Aging stands as the most significant risk factor for chronic lung diseases, which are characterised by structural and functional changes such as reduced elasticity, persistent inflammation, and impaired repair capacity. Recent evidence confirms that nearly all recognised hallmarks of aging play a role in the pathogenesis of these diseases. Notably, extracellular matrix (ECM) dysregulation - first proposed as a lung aging hallmark in 2015 - has become an integral aspect of aging in lung disease. Environmental exposures, such as cigarette or wildfire smoke, accelerate age-related changes by increasing oxidative stress, promoting cellular senescence, and disrupting tissue homeostasis. In lung cancer, aging contributes to genomic alterations, epigenetic dysregulation, immune evasion, and therapeutic resistance. Additionally, the roles of extracellular vesicles and microbiome changes in shaping these aging phenotypes are emerging areas of research. Early clinical studies are now targeting specific aging hallmarks, such as cellular senescence, with the goal of reducing age-related pathology and improving outcomes. Overall, integrating aging biology into lung disease research paves the way for innovative diagnostic and therapeutic strategies that address common molecular mechanisms across multiple chronic lung conditions.

Oral health is key but often overlooked in healthy aging. Tooth loss and poor oral function can impair nutrition, communication, and well-being, yet evidence from low- and middle-income countries (LMICs) on their impact on longevity is limited. This study assessed whether tooth retention and dental prostheses are associated with total life expectancy (TLE) and disability-free life expectancy (DFLE) in older Brazilian adults. In a 15-year cohort of 1734 participants, oral health was defined by edentulous vs. non-edentulous status and prosthesis use. TLE and DFLE were estimated using multistate life table models adjusted for time-varying confounders via inverse probability of treatment weighting. Analyses were stratified by sex and education. At age 60, non-edentulous adults lived 0.9 years longer (95 % CI 0.2-1.8) and spent 1.6 additional disability-free years (95 % CI 0.8-2.3) than edentulous adults. Among those with remaining teeth, prosthesis use added 0.6 (95 % CI 0.1-1.2) disability-free years. Women lived longer overall but spent a higher proportion of their lives with disability; prosthesis use improved women's DFLE by 1.1 years (95 % CI 0.5-1.8), while in men, prostheses mainly increased TLE (0.8 years, 95 % CI 0.1-1.6). Higher education was associated with 1.9 more disability-free years (95 % CI 1.1-2.7); prostheses reduced disparities by nearly 30 %. Findings were robust to sensitivity analyses (E-value 2.3). Maintaining natural teeth and ensuring dental prostheses access are associated with meaningful gains in TLE and DFLE, supporting oral health preservation and rehabilitation as strategies to promote healthy, independent, and socially equitable aging in Brazil.

The ageing global population faces a rising prevalence of chronic kidney disease (CKD), now recognized as a state of accelerated ageing driven by chronic low-grade inflammation-inflammaging. This review synthesizes current evidence positioning the kidney not merely as a passive target but as an active participant in systemic inflammaging, a process fueled by immunosenescence, metabolic reprogramming, and cellular senescence. We explore how resident renal cells, including tubular epithelial cells, podocytes, and mesangial cells, adopt a senescence-associated secretory phenotype (SASP) that perpetuates inflammation, fibrosis, and functional decline. Key mechanisms (NLRP

The global aging population faces heightened vulnerability to infectious diseases due to immunosenescence, which diminishes the potency, durability, and breadth of vaccine-induced immunity. While the leading shingles vaccine, Shingrix, provides protection against herpes zoster virus for adults aged 50 and older, it is often associated with severe local and systemic reactogenicity, which limits vaccine compliance. Here, we report an injectable polymernanoparticle (PNP) hydrogel platform for the sustained delivery of a shingles subunit vaccine to enhance immune responses while mitigating reactogenicity in aged mice. Hydrogel-based vaccination elicited significantly more potent and durable humoral immune responses than Shingrix, while inflammatory cytokine levels remained below the limit of detection. Moreover, aged mice vaccinated with the hydrogel-based vaccine exhibited robust antigenspecific cellular immune responses. These findings demonstrate that controlling the temporal presentation of vaccine components can overcome age-associated declines in immune responsiveness without inducing excessive inflammatory signaling. By decoupling immunogenicity from reactogenicity, our hydrogel-based delivery strategy offers a promising approach to improve both the efficacy and tolerability of subunit vaccines for the elderly and may be broadly applicable to other vaccines targeting aging populations.

The traditional simultaneous distillation-extraction (SDE) method was innovatively employed to co-extract both volatile aroma compounds and water-soluble polysaccharides from steamed Polygonatum cyrtonema Hua (SPCH). Key aroma-active compounds were identified through molecular sensory science, revealing six components with OAV > 1, among which 2-acetyl-1-pyrroline and furfural were particularly crucial to the distinctive aroma profile. Through sequential ethanol precipitation, twelve polysaccharide fractions were obtained. Among them, a glycoprotein (95-C2) was selected for further investigation due to its relatively uniform molecular weight (Mw: 8.5 kDa; Mw/Mn = 1.5) and exceptional free radical scavenging activity (IC₅₀ = 0.1050 ± 0.0445 mg/mL for DPPH; 0.2323 ± 0.0264 mg/mL for ABTS). Consequently, 95-C2 was evaluated in a D-gal-induced senescence model using PC12 cells, where it significantly reduced SA-β-gal-positive staining, ameliorated cell cycle arrest and apoptosis, and suppressed intracellular ROS generation while restoring mitochondrial membrane potential. The senescence-associated secretory phenotype was mitigated through reduced secretion of TNF-α, IL-1β, and IL-6. Mechanistic studies at both gene and protein levels indicated that these anti-aging effects were potentially mediated through suppression of the p53-p21-p16 signaling pathway. This work represents the first attempt at simultaneous flavor-polysaccharide analysis using SDE, discusses their potential relationships, provides a referable framework for future research, and offers new insights into SPCH's potential in functional food applications.

The age-specific magnitude of the impact of hormones on aging and the role of hormone replacement therapy (HRT) remain unclear.

Dietary restriction (DR) extends lifespan in many animal species. In C. elegans, Eat mutants with pharyngeal defects that impair feeding exhibit reduced growth rate and fertility and are typically long-lived, suggesting a DR effect. We report that Eat mutant longevity is largely or wholly a consequence of suppression of feeding activity-dependent infection of the pharynx by their E. coli food source. eat-2 mutants, widely used as a DR model, were among only 2/8 Eat mutants tested whose longevity were to any degree independent of bacterial infection. Moreover, among Eat mutants, phenotypic indicators of reduced nutrition correlated with one another, yet not with longevity. Thus, eat-2 longevity is partially due to infection resistance rather than DR, and residual, infection-independent longevity could equally reflect DR or some other consequence of their cholinergic signaling defect. We therefore conclude that eat-2 mutants are not at present a trustworthy model for studies of DR.

Vascular dysfunction, including endothelial cell (EC) senescence and hypertension, is a hallmark of metabolic syndrome, yet its underlying mechanisms remain unclear. Here, we show that metabolic stress upregulates regulated in development and DNA damage response 1 (REDD1), driving vascular dysfunction. Overexpression of REDD1, but not the REDD1

Mapping behavior of individual vertebrate animals across lifespan could provide an unprecedented view into the lifelong process of aging. We created a platform for high-resolution continuous behavioral tracking of the African killifish across natural lifespan from adolescence to death. We found that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine-learning models accurately inferred age and even forecasted an individual's future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions, revealing precise structure for an architecture of aging.

The prevalence of age-related dry eye disease (DED) is rapidly increasing with global aging, and progressive lacrimal gland (LG) dysfunction represents a central pathogenic mechanism for which targeted therapies remain limited. Semaglutide (Sema), a glucagon-like peptide-1 receptor agonist widely used in metabolic diseases, has recently shown anti-aging effects in multiple tissues, yet its effects on LG aging and age-related DED have not been defined. Here, using a naturally aged mouse model, we show that long-term Sema treatment significantly alleviates DED-related phenotypes and preserves LG structural integrity. High-throughput single-cell transcriptomic analyses revealed that LG aging was characterized by extensive remodeling of cellular composition, loss of acinar cells, expansion of fibroblasts and immune populations, and enhanced intercellular communication, all of which were broadly attenuated by Sema treatment. SenMayo-based profiling demonstrated widespread accumulation of senescent cells across epithelial, stromal, and immune compartments, accompanied by activation of stress-, inflammatory-, and apoptotic transcriptional programs. Sema markedly reduced senescent cell burden and senescence-associated transcriptional activation, consistent with decreased SA-β-gal activity, p21 expression, and SASP-related factors in LGs, and reduced systemic inflammatory cytokines. Mechanistically, Sema exerted cell-type-specific effects by alleviating oxidative stress and enhancing stress adaptation in acinar cells, suppressing extracellular matrix remodeling and pro-fibrotic programs in fibroblasts, and dampening pro-inflammatory and chemotactic activation in macrophages. Together, these findings demonstrate that Sema mitigates age-related LG dysfunction and DED through coordinated attenuation of senescence-associated pathological programs, supporting cellular senescence as a pharmacologically tractable mechanism and highlighting Sema as a potential therapeutic strategy for age-related DED.

BACKGROUND Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODS We examined 5844 women from the Women's Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n=1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n=956, 16.4%); vs. 3) death before age 90 (n=2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. FINDINGS Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR=0.66; 95% CI 0.61-0.71), PCGrimAge (OR=0.64; 95% CI 0.59-0.69), PCPhenoAge (OR=0.73; 95% CI 0.68-0.78) and DunedinPACE (OR= 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. INTERPRETATION All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Farnesoid X receptor (FXR), a ligand-dependent nuclear receptor predominantly expressed in enterohepatic tissues, is also present in the ovary; however, its role in female reproduction remains unclear. In this study, we investigated the role of FXR in regulating the ovarian reserve using a novel FXR knockout (FXR-KO) mouse. FXR-KO mice exhibited an increased number of ovulated oocytes, associated with an enlarged pool of secondary follicles, suggesting enhanced recruitment from the primordial follicle pool. During the neonatal period, FXR-KO ovaries showed accelerated primordial follicle activation, evidenced by increased Forkhead box O3 (FOXO3) nuclear exclusion, while pharmacological activation of FXR suppressed this process in wild-type ovaries. Mechanistically, FXR directly bound to the FoxO3 promoter, increasing its expression without altering FOXO3 phosphorylation, indicating transcriptional regulation. In vitro, activation of FXR in granulosa cells by an agonist upregulated cell cycle inhibitors and suppressed proliferation, suggesting FXR maintains primordial follicle dormancy by restraining granulosa cell differentiation and potentially enhancing oocyte quiescence. These findings identify FXR as a novel regulator of ovarian reserve maintenance, highlighting its potential as a pharmacological target to modulate reproductive lifespan and fertility management in mammals.

Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population

Nutrient metabolism influences HIV-1 replication, antiviral immunity, and chronic inflammation, yet is difficult to leverage for therapeutic gain. We sought to modulate metabolism in the non-human primate model of HIV-1 by caloric restriction (CR), a modality canonically known for its anti-aging benefits. Four months of 30% CR was safe and resulted in broad and systemic metabolic reprogramming in healthy adult male and female rhesus macaques. Relative to that of ad libitum-fed animals, CR lowered the frequencies of target CCR5+ CD4 T cells in the gut mucosa. Upon infection with SIV, CR reduced acute-phase viremia, dampened type I interferon signaling, and overall permitted a more vigorous cycling of CD8+ T cells in lymphoid tissues. CR-induced protection from SIV was associated with a robust up-regulation of glycolysis, which supported an early reduction in viremia that ultimately waned over time. During virologic suppression with antiretroviral therapy (ART), CR significantly limited gastrointestinal (GI) immune activation, improved tricarboxylic acid cycle flux, and lowered concentrations of soluble CD14 and several TNF-related molecules in plasma. Blood SIV DNA levels, however, were unchanged by CR, suggesting that residual GI dysfunction and inflammation can be decoupled from viral persistence. Our findings highlight that a dietary modality can limit pathology in a primate lentiviral infection. They also reveal the robust but temporally constrained nature of glycolysis in supporting an acute antiviral response.

The accumulation of senescent cells during aging contributes to age-associated diseases. Current models posit that replicative senescence is driven by telomere dysfunction, including telomere shortening, telomere-associated DNA damage response (DDR), and telomere oxidation. Here, we first show that aging primary human fibroblasts gradually increase the time spent in a CDK2-low non-cycling state and increase senescence biomarker expression. We then evaluate telomere features as single-cell senescence biomarkers in a workflow linking high-throughput, long-term time-lapse imaging with confocal imaging to map cell-cycle dynamics to telomere features in the same cell. Our results show that telomere length and DDR do not reliably distinguish cycling from non-cycling cells at any age, and that telomere oxidation is not associated with cell-cycle withdrawal. Instead, lysosomal content, cell size, genomic architecture, and p21 more reliably mark senescence induction, depicting replicative senescence as a complex state transition with currently measurable telomere features being weakly correlated with senescence.

Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacetylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting its degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit increased global protein synthesis in the hearts, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression reduces global protein synthesis in the hearts of SIRT2 transgenic mice. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation could be a potential therapeutic strategy for treating diseases associated with increased protein synthesis.

Vascular stiffness, a hallmark of aging and cardiovascular disease, involves vascular smooth muscle cell (VSMC) senescence and extracellular matrix (ECM) dysregulation. This study investigates the role of fibulin-1 (Fbln1) in these processes. Plasma proteomic profiling identified dysregulated proteins in vascular stiffness pedigrees. Fbln1 knockout mice and dual vascular stiffness models (natural aging and chronic angiotensin II [Ang II] infusion) were established. Phenotypic assessments included pulse wave velocity (PWV), histology, and molecular markers. Mechanistic investigations integrating DNA pull-down assays, dual-luciferase reporter assays, and RNA sequencing (RNA-seq) were employed to dissect the transcriptional and signaling axis regulating Fbln1 expression and function. Elevated plasma Fbln1 correlated with hereditary vascular stiffness. Both aging and Ang II promote vascular stiffness, whereas Fbln1 knockdown ameliorates this phenotype by reducing PWV, reversing VSMC senescence, and attenuating collagen deposition. Zinc Finger Protein 384 (ZNF384) was identified as a transcriptional activator of Fbln1, which promoted VSMC senescence and collagen deposition via transforming growth factor-beta (TGF-β)/SMAD family member 3 (Smad3). Inhibiting TGF-β/Smad3 signaling abolished Fbln1-driven senescence and ECM remodeling. Fbln1 exacerbates vascular stiffness through ZNF384-mediated transcriptional activation and TGF-β/Smad3-dependent ECM/senescence pathways. Targeting Fbln1 or its regulators may offer therapeutic strategies for age-related vascular pathologies.

Awards intended to "build the train tracks" for approval of therapies to extend healthy life.

To investigate the associations of plasma aldosterone concentration (PAC), plasma renin activity (PRA), and aldosterone-to-renin ratio (ARR) with Gompertz law-based biological age difference (GOLD BioAgeDiff) in patients with primary aldosteronism versus essential hypertension (EHT), and to determine whether GOLD BioAgeDiff relates to cardiac mass.

Aging and metabolic syndrome, common risk factors for ischemic stroke, are associated with collateral rarefaction. We investigated the effects of aging and diet-induced obesity on cerebral collateral arteriogenesis and the restoration of cerebrovascular reserve following proximal arterial occlusion, using a right common carotid artery occlusion (RCCAO) model. Male and female C57BL/6J mice from three age groups (young: 4-6, aging: 16-20, aged: 24-28 months) and a high-fat diet group underwent either RCCAO or sham surgery. The diameters of the circle of Willis (COW) arteries and pial collaterals were measured 4 weeks after RCCAO. Resting cerebral blood flow (CBF) and CBF reserve during induced hypotension were assessed by laser speckle flowmetry at 3 hours and 4 weeks after RCCAO. In young mice, RCCAO induced a significant increase in the diameters of the COW and pial collaterals, leading to complete recovery of baseline CBF at 4 weeks. In contrast, aging progressively diminished arteriogenesis, resulting in partial (aging) and absent (aged) CBF recovery. Cerebrovascular reserve was diminished with advancing age. Diet-induced obesity had milder effects on arteriogenesis. Our study revealed that cerebral collateral arteriogenesis is a strong determinant of impaired cerebrovascular reserve following proximal arterial occlusion and progressively diminishes with aging.

Sarcopenia, the age-related decline in muscle mass and strength, poses a significant threat to functional independence in older adults. Despite strong evidence supporting resistance training as a preventive and therapeutic strategy, adherence to muscle-strengthening guidelines remains low. Mobile health (mHealth) technologies offer a promising avenue to bridge this gap; however, few apps are tailored to older adults or designed with their input.

Background: Geroprotective interventions, including the mTOR inhibitor rapamycin, slow aging in preclinical models. Translation to humans remains challenging because clinical trials require endpoints detectable within feasible timeframes. Multi-modal in vivo imaging could address this limitation by enabling simultaneous assessment of age-related pathology across multiple organ systems, but its feasibility in clinical trials is uncertain. Objective: To evaluate the feasibility of deploying a multi-modal, multi-organ imaging battery in a geroprotective intervention trial of rapamycin and to collect exploratory efficacy data across multiple domains of age-related pathology. Methods: In a single-center, open-label, single-arm pilot trial, 14 participants with early-stage Alzheimer's disease (MCI or mild dementia; Montreal Cognitive Assessment [≥]18; amyloid-positive) received oral rapamycin 7 mg once weekly for 26 weeks. Participants underwent baseline and end-of-treatment imaging including retinal optical coherence tomography (OCT); [18F]FDG positron emission tomography/computed tomography (PET/CT) of the head, thorax, and lower spine; dentomaxillofacial MRI; and cardiac MRI with stress perfusion and arterial pulse wave velocity. Feasibility outcomes included completion rates and technical or logistical barriers. Exploratory pre-post changes were assessed using paired t-tests. Results: Of the 14 enrolled participants, 13 completed follow-up imaging. Among these, completion was 100% for OCT, [18F]FDG PET/CT, and dentomaxillofacial MRI. Cardiac MRI and pulse wave velocity were completed in 69% (9/13), primarily limited by scanner access during a healthcare worker strike. No imaging-related adverse events occurred. Exploratory analyses showed nominally significant pre-post increases in cardiac output (p=0.017), late diastolic (A-wave) kinetic energy (average: p=0.044; peak: p=0.024), left retinal ganglion cell layer thickness (p=0.044), and optic nerve head [18F]FDG uptake (p=0.040). Bone mineral density showed no significant pre-post changes, while muscle cross-sectional area decreased numerically but not significantly (p=0.058). In exposure-response analyses, higher rapamycin blood concentration was significantly correlated with greater skeletal muscle density (r=0.64, p=0.035) and, albeit not significantly, smaller loss of cross-sectional area (r=-0.53, p=0.097). Conclusions: A multi-modal imaging battery spanning several organ systems was successfully integrated into a clinical trial, with high completion rates for most modalities. Logistical constraints were the primary barriers affecting cardiac measures. These findings inform the design of future randomized trials of geroprotective interventions, where such imaging batteries may help detect changes in age-related pathology over relatively short timeframes.

Aging is a complex multifactorial process that affects cellular function and tissue homeostasis over time. Despite substantial research, the molecular mechanisms driving cellular aging remain poorly understood. Many studies focused on changes in DNA methylation as an indicator of aging. In particular, methylation at polycomb CpG islands was shown to be predictive of phenotypic changes associated with aging. Since many age-related pathological processes are thought to originate from single cells, we asked whether polycomb CpG island methylation occurs preferentially in a subset of cells within a population. Using single-cell whole-genome methylation data across ages and tissues, we identify polycomb CpG methylation as a hallmark of cellular aging. This revealed that aging occurs at varying rates, with faster proliferating cells showing accelerated gain of methylation. Differential gene expression analysis identified changes in immune response, translation, tumorigenesis and neurodegeneration. These results challenge traditional models of homogeneous cellular aging and suggest that aging is a highly individualized process at the single-cell level, that may be driven by programmed changes in polycomb CpG island DNA methylation.

The EAT-Lancet diet (ELD) and plant-based diets (PBDs) are recommended for their potential health and environmental benefits, but comparative analyses of these dietary patterns in relation to mortality risk remain limited. This study aimed to evaluate the associations of ELD and PBDs with mortality and life expectancy in two nationwide cohorts. Participants from the UK Biobank and the US National Health and Nutrition Examination Survey (NHANES) (2003-2018) were included. Dietary intake was assessed using 24-h dietary recalls. The ELD index (ELD-I), overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI) were calculated and categorized into tertiles. Primary outcomes were all-cause mortality, cause-specific mortality, and life expectancy. After full adjustment, the hazard ratio (HR) for all-cause mortality when comparing the highest versus lowest tertiles was 0.87 (95% CI 0.82-0.92) for ELD-I, 0.88 (0.83-0.93) for PDI, 0.90 (0.85-0.95) for hPDI, and 1.14 (1.02-1.21) for uPDI in the UK Biobank; equivalent HRs in the US NHANES were 0.71 (0.65-0.78), 0.71 (0.64-0.78), 0.83 (0.73-0.94), and 1.44 (1.32-1.57), respectively. In both cohorts, PDI was associated with a lower risk of cardiovascular disease mortality, while ELD-I showed inverse associations with cancer mortality and respiratory disease mortality. At age 45 years, participants with higher adherence to the ELD-I and PDI had an average increase in life expectancy of 2.07 to 4.31 years and 1.33 to 3.90 years, respectively. These findings demonstrated that greater adherence to ELD and overall PBD was associated with a lower risk of all-cause mortality and longer life expectancy across diverse populations, highlighting the significant benefits of these environmentally friendly diets for human longevity.

Evolutionary theory predicts that variation in longevity persists due to trade-offs between early-life fitness traits (e.g., growth or fecundity) and long-term somatic maintenance. However, such trade-offs can be difficult to detect and may often become apparent only under certain conditions. For instance, developing in novel or atypical environments may alter the genetic architecture of traits, revealing trade-offs that are otherwise hidden under normal conditions. To test this, we compared full-sibling families of the Mexican spadefoot (Spea multiplicata) reared across two larval diets: a typical detritus diet and an atypical live shrimp diet, which they are competitively excluded from in nature. The shrimp diet significantly increased broad-sense genetic variance and heritability for larval growth rate, whereas heritability for post-metamorphic telomere length - a known longevity correlate - remained similar across diets. Moreover, only on the shrimp diet did families with faster growth exhibit shorter telomeres, consistent with a diet-dependent trade-off between growth and somatic maintenance. Overall, our study shows that developing under atypical dietary conditions exposes previously cryptic genetic variation in growth, thereby revealing a trade-off with somatic maintenance. These findings have implications for understanding how environmental change, such as rapid dietary shifts, can shape aging processes and vulnerability to age-related disease.

Parkinson's disease (PD) is a progressive neurological disorder that primarily affects motor movement but also causes a range of non-motor symptoms. Characteristic hallmarks include progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the buildup of intracellular protein aggregates known as Lewy bodies containing the protein alpha-synuclein. While the etiology of PD is multifactorial, aging is widely recognized as the most significant risk factor for the disorder. Cellular senescence, a hallmark of aging, has in recent years emerged as a potential driver of neurodegeneration associated with PD. Senescent cells accumulate in the aging brain, exhibit a proinflammatory secretory phenotype, and are believed to contribute to the pathogenesis of PD through multiple mechanisms. This mini-review examines the evidence linking cellular senescence to PD, discusses potential underlying molecular and cellular mechanisms involved in this process, and evaluates the therapeutic potential of targeting senescent cells for treatment of the disorder.

A growing body of evidence supports the role of nutrient sensing and metabolism pathways in regulating ageing rate and healthspan, but the diversity of human lifestyles challenges our ability to identify the mechanisms of this age acceleration. Here, we examine how the transition of wild King penguins to zoo husbandry can closely mimic the shift to a Western lifestyle in humans, and shed light on conserved epigenetic changes in responses to sedentary conditions. We show that, just like modern humans, zoo-housed male King penguins experience an extended lifespan, but this comes at the cost of accelerated epigenetic ageing throughout life. This accelerated ageing is associated with differential methylation in key growth and maintenance pathways, including the mTOR and PI3K/Akt networks. Our results demonstrate the conserved link between lifestyle and age acceleration. Such evolutionary evidence may help us to improve risk detection and, ultimately, therapeutics for lifestyle-induced age acceleration in humans.

Cellular metabolism and gene transcription are closely linked. The conserved transcriptional regulator SIN3 acts as a scaffold for histone deacetylase (HDAC)-containing complexes and is crucial for development, stress resistance, and overall organismal health. SIN3 regulates metabolic gene expression in Drosophila cultured cells, however, an understanding of the extent of its role in coordinating responses to metabolic stress in whole organisms is incomplete. In this study, we explored how SIN3 controls glycolytic gene expression across developmental stages and under genetic and dietary disruption of glycolysis in Drosophila melanogaster. Focusing on four key glycolytic enzymes: phosphofructokinase(Pfk), enolase(Eno), pyruvate kinase(Pyk), and pyruvate dehydrogenase beta(Pdhb), we found that reducing Sin3A levels increases their expression in both larvae and adults, indicating that SIN3 plays a consistent role in balancing metabolic gene transcription. Genetic interaction experiments indicate that Sin3A interacts with Pyk and Eno, regulating transcription in a gene-specific manner. Disrupting glycolysis via genetic or dietary means alters glycolytic gene expression, and SIN3 modulates this response. These findings indicate that SIN3 functions as a metabolic sensor, regulating transcription in response to cellular metabolic stress. Additionally, we demonstrate that reducing Sin3A levels shortens Drosophila lifespan on both low- and high-sucrose diets, emphasizing the importance of SIN3 in longevity. Overall, these results show that SIN3 is a context-dependent regulator of glycolytic gene expression and lifespan in Drosophila, integrating metabolic signals with chromatin-based transcriptional regulation.

Background: Obesity and metabolic disease drive premature aging and reduced lifespan. While metabolic interventions like calorie restriction, protein restriction, and time restricted feeding have been shown to improved lifespan, they are either not effective or sustainable for most humans. Bariatric surgery is the most efficacious metabolic intervention available and is associated with increased lifespan. However, whether its longevity benefits derive solely from weight reduction or reflect surgery-specific metabolic reprogramming remains unknown. Methods: We employed a lean mouse model of sleeve gastrectomy (SG) in which young, lean male C57BL/6J mice underwent SG or sham operation while maintained on low-fat chow, then were challenged with high-fat diet (HFD) in midlife. We assessed glucose metabolism, body composition, energy expenditure, hepatic histology, adipose tissue inflammation, and cecal microbiome composition. Results: Despite identical weight and food intake on low-fat chow, SG mice demonstrated improved glucose tolerance and insulin sensitivity prior to HFD challenge. Upon HFD exposure, SG animals exhibited enhanced metabolic flexibility with greater capacity for fat oxidation, increased energy expenditure, attenuated weight gain, and reduced adiposity compared to sham controls. SG further reduced hepatic lipid accumulation and attenuated visceral adipose tissue inflammation, marked by decreased pro-inflammatory cytokine expression and reduced macrophage infiltration. These metabolic benefits occurred independently of caloric intake. Cecal microbiome profiling revealed surgery-specific remodeling characterized by Lactobacillus enrichment and reductions in Verrucomicrobia and Clostridia; a pattern distinct from caloric restriction and consistent with prior SG studies. Conclusions: Early-life SG confers durable, weight-loss-independent protection against midlife metabolic deterioration. Gut microbiome remodeling, particularly enrichment of Lactobacillus species, represents a candidate mediating mechanism and a potential therapeutic target for aging and metabolic disease.

This study used a group-based multi-trajectory model (GBMTM) to identify distinct muscle health trajectories and examine their associations with physical activity (PA) in middle-aged and older adults.

The postmenopausal decrease in estrogen production contributes to a significant increase in the risk of age-related diseases. There is an identified gap in the field regarding the effectiveness of targeted interventions for specific groups of women at increased risk, and whether these interventions can support successful aging and reduce mortality. Data regarding 2239 Caucasian female participants of the PolSenior study aged 65 and over were analyzed. Based on strict criteria, participants were divided into successfully aging (SA) and not successfully aging (UA), and the differences in reproduction system-related factors on aging trajectory and survival were investigated. The mean age of menarche and menopause and the mean length of the reproductive period were similar in SA and UA women. However, the mean number of pregnancies and the percentage of women who gave birth to at least four children were higher in UA than in SA women (P < 0.001). SA women were more commonly involved in the reproductive health-promoting behaviors (all P < 0.001). In a multifactorial fully adjusted analysis, the number of pregnancies was negatively associated with SA. Kaplan-Meier survival curves showed that being nulliparous and having four or more children was associated with a shorter survival of UA (P < 0.0001) but not SA women, while regular gynecological examination, cytology, mammography, and breast self-examination were associated with a better survival in both SA and UA women. In Cox regression models adjusted for all confounding factors significant in univariate analysis, these health-promoting behaviors remained independent predictors of better survival in UA women while in SA women, only breast self-examination remained an independent predictor. Successful aging and survival of women are associated with the reproduction history and reproduction system-related health-promoting behaviors. Reproduction system-related health-promoting behaviors endure the effect of the reproduction history.

Aging is accompanied by profound changes in both the gut microbiome and the immune system, which engage in continuous, bidirectional communication. Alterations in microbial diversity and metabolism, particularly reductions in short-chain fatty acid (SCFA) producers as well as shifts in bile acid and tryptophan-metabolizing species, can incite and worsen inflammation, damage barrier integrity, and accelerate immunosenescence. Concomitantly, immune aging and reduced mucosal IgA promote microbial dysbiosis, forming a self-reinforcing cycle that fuels chronic inflammation ("inflammaging"). Microbial metabolites such as SCFAs, secondary bile acids, and indole derivatives play central roles in this gut-immune dialog, influencing regulatory T-cell balance, epithelial repair, and neurological health through the gut-brain axis. Emerging evidence suggests that diet, probiotics, postbiotics, and microbiome transplantations can restore beneficial microbial and, consequently, immune functions, offering opportunities to promote healthy aging and potentially reverse adverse symptoms. Understanding and targeting the gut microbiome-immune feedback loops may reveal new strategies to modulate inflammaging and extend health span.

Ageing biomarkers can predict mortality risk beyond chronological age. Recently, plasma proteins were used to estimate the biological ages of eleven human organs, including the brain, heart, liver, kidneys, and pancreas. Accelerated organ ageing is linked to higher all-cause mortality; however, systematic benchmarking against established ageing biomarkers is lacking. Here, we pursued two complementary aims. First, we benchmarked proteomic organ ages against multimodal ageing biomarkers for all-cause mortality (444 deaths; [≤]17-year follow-up) using Cox regression in 861 Lothian Birth Cohort 1936 (LBC1936) participants. Ageing biomarkers included epigenetic age (GrimAge2), telomere length, neuroimaging, general cognitive function (g), and physical function (grip strength, walk time, and respiratory function). Among proteomic organ ageing biomarkers, accelerated liver (HRperSD [95% CI] = 1.43 [1.30-1.58]), immune (1.42 [1.29-1.57]), and heart (1.38 [1.25-1.53]) ageing were most strongly associated with higher mortality risk. However, GrimAge2 acceleration, total brain volume (TBV), grey matter volume, respiratory function, and g exhibited higher hazard estimates (HRperSD = 1.44-1.62) than organ ageing biomarkers. In a Cox model including all biomarkers, only TBV, white matter hyperintensity volume, g, and walk time associated with mortality. Second, survival analyses of SomaScan 11K plasma proteins identified 202 proteins associated with mortality and enriched for the liver and immune-related biological processes, with the strongest effects observed for GDF15 (HRperSD [95% CI] = 1.53 [1.37-1.72]), CST3 (1.48 [1.29-1.69]), and COL18A1 (1.47 [1.30-1.68]). These findings provide a systematic, cross-modal benchmarking of proteomic organ ages against established ageing biomarkers and highlight plasma proteomic signatures of mortality.

Aging impairs cartilage repair, with young animals exhibiting superior regenerative capacity due to enhanced tissue repairing and reduced inflammation compared to aged counterparts. This study employed single-cell omics to dissect age-dependent immune cell heterogeneity in cartilage injury, revealing a critical deficiency in anti-inflammation macrophage subsets in aged animals. We identified Arg-1 as a central regulator of macrophage polarization, demonstrating that its overexpression rescues impaired repair in aged animals. These findings establish Arg-1 as a novel therapeutic target to counteract age-related declines in cartilage regeneration, offering new insights into macrophage-driven tissue repair mechanisms. The integration of single-cell analysis with functional validation provides a framework for developing precision interventions for age-impaired tissue regeneration.

Mitophagy enhancers show great potential as therapeutic agents for preventing age-related muscle disorders. Asperuloside (ASP), a naturally occurring iridoid, has been shown to activate mitophagy and maintain mitochondrial homeostasis. However, the exact mechanisms underlying its action and its overall efficacy in relation to muscle aging have yet to be fully elucidated. In senescent myoblasts, techniques such as cell staining, western blotting, fluorescence imaging, and Seahorse analysis were employed to study the effects of ASP on senescence phenotypes, mitochondrial health, mitophagy, and related upstream regulators. Using small interfering RNA, the study explored whether mitophagy and its regulators mediated the effects of ASP. The efficacy of ASP on muscular health was characterized in 17-18-month-old high-fat diet-induced aging mice. Our study demonstrated that 2.5 μM ASP significantly alleviated senescence-associated phenotypes and enhanced mitochondrial health in senescent C2C12 myoblasts. Mechanistic investigations revealed that ASP induced BNIP3-dependent mitophagy by modulating the FOXO3 transcription factor, thus contributing to the maintenance of mitochondrial homeostasis. Moreover, the ASP intervention at a dose of 50 mg/kg BW/day reduced fat accumulation and other pathological changes in the gastrocnemius muscle of aging mice. Similarly, ASP supplementation also improved mouse muscle function and the morphology of muscular mitochondria. This study further identified ASP as a potential natural active component for the prevention of muscle aging. It emphasized the importance of mitochondrial homeostasis and the activation of appropriate mitophagy pathways in maintaining muscle health during the aging process.

Pet dogs share human-like environments while aging on a compressed timescale, making them a powerful translational model for aging research. Using genomic and phenotypic data from 7,627 dogs in the Dog Aging Project, including 976 profiled for 159 blood metabolites and clinical analytes, we generated the first GWAS catalog in dogs. Blood traits map to orthologous loci in dogs and humans, indicating deeply conserved pathways. Breed ancestry explains substantial variance in blood traits, and selection on visible characteristics such as fur type has pleiotropic metabolic effects. Leveraging mosaic ancestry in mixed-breed dogs and longitudinal mortality data, we identify blood traits elevated in short-lived breeds that predict individual mortality risk - including globulin and potassium - and protective traits enriched in long-lived breeds, such as ethanolamine. Although some aging-associated traits relate to growth hormone pathways, many do not, indicating that aging in dogs is multifactorial. These findings establish dogs as a translational system for identifying genetic determinants and biomarkers of aging relevant to extending healthy lifespans.

Rising life expectancy and an aging population highlight the importance of cancer control. DNA methylation (DNAm)-based biological age (BA) may provide insights into aging, carcinogenesis, and cancer prevention and care. We estimated five BA metrics among 1916 participants aged 50-75 years at baseline in the German ESTHER cohort, with repeat BA measurements available for 894 participants after 8 years. Multivariable linear regression was used to assess associations between prior cancer and baseline BA, while Cox proportional hazards models and restricted cubic splines evaluated associations of BA levels and trajectories with subsequent cancer risk. A history of malignant tumors was associated with higher baseline PCHannum and PCGrimAge in fully adjusted models. Older BA levels were significantly associated with increased long-term cancer risk, with hazard ratios up to 1.67 (95% CI 1.25-2.24) per standard deviation (SD) increase in PCGrimAge. Except for PCGrimAge, BA trajectories showed monotonic, linear associations with cancer risk, corresponding to a 33% to 37% higher risk per SD increase in slopes of four BA matrices. Accelerated biological aging was consistently associated with increased overall cancer risk, highlighting the potential value of longitudinal BA measures for cancer risk assessment, prevention, and monitoring.

Whether and how genetic regulation of DNA methylation (DNAm) change across the lifespan remains unclear. Here, we map age dependent methylation quantitative trait loci (longitudinal mQTLs) using linear mixed models applied to repeated blood DNAm measures from birth, childhood, adolescence and adulthood in the Avon Longitudinal Study of Parents and Children. We identify 2,210 longitudinal mQTLs (2,393 SNP-CpG pairs; 7.3% trans) and observe consistent genotype by age effects in two independent cohorts of diverse ancestries (Pearson's r = 0.85 in the Generation R Study; r = 0.56 in the Drakenstein Child Health Study). Longitudinal mQTLs show increasing effects with age at half of loci and associations with multiple phenotypes. CpGs with longitudinal mQTLs are more heritable and enriched in regulatory elements and pathways related to multicellular organism development and cell adhesion. These results chart dynamic genetic influences on the human methylome and provide a novel perspective on epigenetic regulation.

Neurodegenerative diseases are a set of devastating medical conditions in which neuronal loss associated with the aggregation of toxic proteins leads to progressive cognitive impairment. These diseases are usually modeled in animals by mimicking late disease stages through genetic modifications that aggressively accumulate proteins that damage the brain. However, these diseases typically unfold over decades, and disease-associated genes are known to have important, but understudied, biological functions in early life stages. To address this research gap, we suggest that the larval zebrafish, which has conserved orthologs of most neurodegeneration-linked genes, is an excellent model to examine early mechanisms that set the stage for disease progression, such as altered neuronal function, synaptic re-wiring, and proteostasis. We propose a systematic genetic modeling and phenotyping pipeline in zebrafish that integrates CRISPR editing, high-throughput behavioral assays, brain-wide activity mapping, and pharmacological screens to capture neurodegenerative disease-related changes that occur well before clinical disease emerges. Studying diseases of aging in larval zebrafish may sound paradoxical; however, by uncovering cellular dysfunction at the earliest stages of disease in a living vertebrate brain, this approach could identify critical therapeutic targets at timepoints before degeneration becomes irreversible.

Infraslow (<0.1 Hz) global brain activity, quantified by the global mean blood-oxygenation-level-dependent (gBOLD) signal in resting-state functional magnetic resonance imaging (fMRI), is elevated during sleep and coupled to cerebrospinal fluid (CSF) dynamics, a key pathway for the brain waste clearance implicated in neurodegenerative disorders such as Alzheimer's disease. However, the effect of sleep deprivation on gBOLD activity and its interaction with aging remain poorly understood. Using a rigorously controlled in-laboratory total sleep deprivation (TSD) protocol, we demonstrate that TSD significantly increases both the gBOLD signal amplitude and its coupling with CSF flow, suggesting a compensatory mechanism that may enhance glymphatic clearance following acute sleep loss. Notably, these TSD-induced enhancements exhibit robust age dependency, with markedly attenuated responses in midlife adults (40 to 50 y). The absence of this compensatory mechanism in midlife may exacerbate age-related impairments in neurotoxic clearance and increase dementia susceptibility, thereby offering mechanistic insights into the nexus between sleep disruption, aging, and neurodegeneration.

Proteins orchestrate essential cellular processes, including metabolism, communication, survival, and regeneration, making proteomic profiling a powerful strategy to elucidate complex biological responses. Snail slime (SnS) has emerged as a bioactive material with documented pro-healing, antioxidant, and anti-inflammatory properties; however, its effects at the proteome level in normal human dermal fibroblasts (NHDFs) remain unexplored. In this study, an LC-MS-based proteomic approach (Data are available via ProteomeXchange with identifier PXD075292) combined with network and Gene Ontology enrichment analyses was employed to investigate SnS-induced molecular reprogramming in NHDFs, followed by functional assays. Results show that SnS is well tolerated for up to 72 h, confirming its cytocompatibility, followed by proteomic analysis revealing enrichment of biological processes related to apoptosis regulation, oxidative stress response, wound healing, cell migration, and anti-aging. Network analysis identified AKT, PI3K, SRC, and KRAS family members as key hub proteins, indicating convergence on central signaling pathways controlling survival, redox balance, and migratory activity. Functional assays demonstrated a time-dependent, controlled modulation of apoptosis consistent with cellular turnover, alongside a hormetic redox response characterized by transient ROS signaling followed by enhanced antioxidant capacity. Importantly, SnS significantly accelerated fibroblast migration, achieving complete wound closure within 24 h. Collectively, these findings demonstrate that SnS induces coordinated proteomic and functional reprogramming that integrates redox modulation, controlled apoptosis, and enhanced migration, providing a mechanistic basis for its pro-healing and anti-aging effects and supporting its potential as a regenerative biomaterial. Keywords: Snail slime; Proteomics; LC-MS analysis; Wound healing; Apoptosis; Biomaterials

Aging is a major contributor to β-cell dysfunction in type 2 diabetes, with cellular senescence increasingly recognized as an important underlying mechanism. Here, we established a doxorubicin (DOX)-induced senescence model using MIN6 mouse insulinoma β-cell line to elucidate the mechanisms by which senescence remodels organelle homeostasis and insulin secretion. Senescence was validated by senescence-associated β-galactosidase positivity, p16

Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.

Pharmacological modulation of ageing is viewed as a viable route to extending lifespan and healthspan, yet the efficacy of putative geroprotectors may depend strongly on physiological and environmental context. Lithium chloride (LiCl) has been reported to extend lifespan in several model organisms, but evidence remains inconsistent and the role of reproductive investment-an energetically costly and often lifespan-correlated process-has rarely been examined. We tested the effects of dietary LiCl on survival and reproductive performance in male Drosophila melanogaster, comparing unmated (UM) and frequently-mated (FM) males. Contrary to previous work, both a concentration previously reported as beneficial (25 mM), and a lower concentration (10 mM) reduced survival, with effects driven exclusively by UM males. FM males were comparatively protected, revealing a strong mating-dependent interaction. LiCl had no detectable effect on male late-life mating latency, sterility, or paternity share, but reduced some post-copulatory performance in FM males by increasing female remating, indicating that somatic and reproductive responses to LiCl can be decoupled. These results demonstrate that lithium's effects on survival are strongly dependent on reproductive environment, highlighting the importance of reproductive context when evaluating its impact on lifespan.

Critical segmental bone defects in elderly patients pose a formidable clinical challenge due to limited autograft availability, senescent bone dysfunction, and compromised healing from fibrous tissue invasion. Here, we present a development-based in vivo bioreactor strategy wherein BMP-2-loaded biomaterials trigger the body's intrinsic developmental programs, using the organism as a bioreactor to engineer bone. Distinct from classical developmental engineering, this in vivo bioreactor-derived bone (vBR-Bone) recapitulates native osseous architecture, including vasculature, cortical bone, trabeculae, and bone marrow niche. In aged murine models, the vBR-Bone exhibits a rejuvenated restoration of bone bioactivity lost in aging, with reduced senescence, elevated remodeling, and improved stem cell functionality. Capitalizing on its restored remodeling capacity of high bone turnover, the vBR-Bone fragments enclosed in an asymmetric biomimetic periosteum achieved 6-week repair of critical-sized 1/3 femoral shaft segmental defects. Through a "compartmentalized" approach that partitions the defect into manageable fragments, vBR-Bone progressively remodeled and integrated into functional trabecular bone, ultimately restoring bone mineral density, volume, and microstructure in defects of aged mice. The biomimetic periosteum inhibits fibrous invasion while permitting vascular ingrowth, thereby creating a space for regeneration. Mechanistically, the multifactors within vBR-Bone reconstitute a bone-remodeling microenvironment, wherein matrix-released TGF-β1 activates the PI3K/AKT/mTOR signaling axis via TRAF6-dependent ubiquitylation to promote robust osteogenesis. This strategy overcomes autograft shortage and senescence-associated dysfunction, offering a clinically translatable solution for critical age-related segmental bone defects.

The human testis, a crucial organ in male reproduction, is mainly responsible for spermatogenesis and androgen production. As men age, testicular function declines, yet the underlying molecular mechanisms are still not well understood. To elucidate the mechanisms of human testicular aging, we performed an integrated analysis of single-nucleus transcriptomes and chromatin accessibility (snRNA-seq and snATAC-seq) on pathologically confirmed non-tumor testicular tissues from young and aged individuals. Our integrated multi-omic analysis reveals significant age-induced alterations in the testis transcriptome, particularly affecting genes linked to spermatogenesis. Significant age-related changes were also observed in Sertoli and Leydig cells, with Sertoli cells exhibiting increased sensitivity to environmental influences as age. Furthermore, the expression of Wntless (WLS), a Wnt transporter, was substantially upregulated in Sertoli cells of aged testes, which was correlated with cellular senescence and the disruption of tight junctions. Overexpression of WLS in Sertoli cells significantly accelerated senescence in vitro, implying a potential role for WLS in testicular aging. Our study provides a detailed multi-omic map of the transcriptomic and chromatin accessibility changes in the human testis during aging, offering insights into the cellular and molecular mechanisms behind these changes, and identifying potential therapeutic targets for interventions against age-related declines in male reproductive health.

Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) in vivo. These nanoparticles directly fuse with cytoplasmic cell membranes and thus evade endocytosis. We found that once in the circulation FL spontaneously acquire a protein corona, which is highly enriched in ApoE, a key ligand for brain endothelial low-density lipoprotein receptors (LDLR). Based on this observation, we engineered an ApoE-functionalized protein corona around FL (ApoE-FL) to systematically evaluate whether this mechanism could be exploited for targeted brain delivery. Following optimization and physicochemical characterization, the RSV-loaded liposomes were evaluated in vitro using human cerebral microvascular endothelial cells and in vivo C57BL/6 aged mice to assess their therapeutic potential. Both FL and engineered ApoE-FL liposomal delivery systems exhibited a strong affinity for endothelial cell membranes in vitro. The knockdown of the ApoE receptor, low-density lipoprotein receptor-related protein 1 (LRP1), significantly reduced liposomal docking. Microscopy analysis revealed that both ApoE-FL and non-functionalized FL directly fused with endothelial plasma membranes, thus bypassing intracellular organelles and minimizing lysosomal degradation. This suggests that the naturally formed ApoE corona in vivo may contribute to efficient cerebrovascular targeting, a property successfully replicated by the engineered ApoE corona strategy. In vivo biodistribution and kinetic studies demonstrated that especially ApoE-FL achieved enhanced brain-targeting efficiency, prolonged cerebrovascular retention, and extended targeting distance along the arteriovenous axis. This emphasizes that fusogenic liposomes effectively engage almost the entire microvascular network, including capillaries and post-capillary venules. Functionally, fusogenic liposome-delivered RSV improved blood-brain barrier (BBB) integrity, enhanced neurovascular coupling (NVC) responses, and promoted brain vascularization in aged mice. Single-cell RNA sequencing (scRNA-seq) revealed enhanced endothelial angiogenesis and barrier protective transcriptional profiles in cerebrovascular cells treated with ApoE-FL/RSV, suggesting a molecular basis for the observed vascular benefits. Liposomal RSV delivery achieved near-complete cerebrovascular and cognitive rejuvenation in aged mice applying a 2000-fold lower RSV dose than oral administration used as control sample. Thus, ApoE-FL liposomes exhibited exceptionally high delivery efficiency in deeper brain regions, further expanding their therapeutic potential. These findings underscore the importance of targeted drug delivery in optimizing therapeutic outcomes and establish ApoE-functionalized fusogenic liposomes as a promising strategy for mitigating brain vascular aging and cognitive decline.

Ischemic cerebrovascular events are among the leading causes of death and disability worldwide, disproportionately affecting the elderly due to vascular aging, oxidative stress, and chronic inflammation. During cerebral ischemia, oxygen and glucose deprivation trigger a cascade of pathological events, including excitotoxicity, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. Emerging evidence identifies Klotho as a multifunctional protein with anti-aging, antioxidant, and anti-inflammatory properties that may confer neuroprotection against ischemic injury. Aging is associated with a progressive decline in Klotho expression, correlating with increased stroke susceptibility and poorer recovery outcomes. Experimental studies demonstrate that Klotho attenuates glutamatergic excitotoxicity by regulating the GluN2B subunit and excitatory amino acid transporters. It reduces oxidative stress through inhibition of NADPH oxidase and activation of SOD2 and FOXO3 pathways, while preserving blood-brain barrier integrity by downregulating aquaporin-4 and matrix metalloproteinase-9. Moreover, Klotho suppresses pro-inflammatory signaling by inhibiting NF-κB, RelA, and NLRP3 inflammasome activation, and enhances anti-inflammatory responses via PPAR-γ modulation. Beyond limiting neuronal death, Klotho promotes neurogenesis and synaptic plasticity by regulating neurotrophic factors and Wnt signaling, thereby supporting neural stem cell survival and functional recovery after ischemia. Collectively, these findings position Klotho as a central regulator of neuronal homeostasis and post-ischemic repair. This review provides the first comprehensive mechanistic integration of Klotho's neuroprotective role in ischemic cerebrovascular injury, proposing it as a unifying molecular axis linking brain aging to ischemic vulnerability and regenerative capacity.

Exosomes are nanoscale extracellular vesicles that facilitate intercellular communication by transporting regulatory molecules, such as microRNAs, proteins, and lipids. Acting as "software updates" for cells, exosomes influence gene expression and cellular behavior without altering the genetic code. Their emerging roles in tissue repair, immune modulation, and age-related rejuvenation have positioned them as promising tools in regenerative and aesthetic medicine. The authors of this systematic review aim to explore the therapeutic potential of natural and bioengineered exosomes, focusing on their mechanisms of action and applications in regenerative therapies and aesthetic interventions. A structured literature search was conducted across PubMed, Scopus, and Web of Science, including English-language studies available online as of April 2025. Eligible studies consisted of original in vitro, in vivo, and clinical research examining exosome-based applications in tissue regeneration, wound healing, and anti-aging therapies. Studies were thematically grouped by exosome origin, engineering strategy, and therapeutic context. A narrative synthesis approach was employed because of methodological heterogeneity. Exosomes represent a novel class of therapeutic agents capable of modulating biological processes critical to repair and regeneration. In addition to mammalian-derived vesicles, plant-based and hybrid systems offer scalable, biocompatible platforms for targeted molecular delivery. The integration of exosome-based therapies with advances in cellular reprogramming and bioelectric signaling may further expand their clinical utility. However, broader clinical adoption will require continued research addressing safety, manufacturing scalability, regulatory challenges, and ethical considerations. Level of Evidence: 3 (Therapeutic).

Emerging evidence implicates organelle dysfunction, particularly within peroxisomes, as a critical driver of hair follicle degeneration and alopecia. While mitochondrial defects are well characterized in the context of hair loss, the contribution of peroxisomal failure to follicular homeostasis remains largely unexplored. Here, we identify peroxisomal dysfunction as a central molecular and metabolic defect underlying hair follicle aging and loss. Comprehensive transcriptomic analysis of human dermal papilla cells from alopecia patients revealed marked downregulation of peroxisome-associated pathways, including fatty acid β-oxidation, lipid degradation, and detoxification of reactive oxygen species. These alterations were recapitulated in

Clinical evidence links bone loss to skin thinning during aging, yet the causal role of bone in skin regulation remains unclear. Here, we show that the partial ablation of osteolineage cells induces skin aging, manifested by dermal thinning, reduced epidermal proliferation, delayed wound healing, and impaired hair regeneration. Single-cell RNA sequencing revealed that osteolineage cells ablation profoundly alters bone marrow macrophages, characterized by pro-inflammatory activation, metabolic dysregulation, and enhanced SASP signaling, accompanied by myeloid skewing. These dysfunctional macrophages infiltrated the skin and were associated with aging-like changes in skin parenchymal cells, including impaired epithelial differentiation, hair follicle stem cell dysfunction, and increased inflammation. Integration with published aging skin datasets confirmed that osteolineage cells ablation recapitulates key molecular features of natural skin aging. Together, our findings identify a skeletal-immune-skin axis linking bone marrow homeostasis to peripheral tissue aging.

The activation of hepatic stellate cells (HSCs) plays a vital role in liver wound healing, including liver regeneration and repair. However, as senescent cells increase with the continued activation, the secretion of extracellular matrix, collagen, transforming growth factor-β, and other cytokines increases, leading to liver fibrosis, cirrhosis, and liver cancer. This study investigated the effects of lipid peroxidation-derived aldehydes (LPDAs) such as 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE), which accumulate with aging, on HSC senescence. Additionally, it investigated the inhibitory effects of nicotinamide mononucleotide (NMN), a precursor of NAD

Healthy aging brings widespread shifts in aperiodic (non-oscillatory) electroencephalographic (EEG) components, which may underlie physiological changes in cognitive performance. Education, a known protective factor against age-related decline in cognitive performance, has been largely overlooked in studies linking aperiodic EEG components to cognition. This study addresses this gap, hypothesizing that education moderates the interplay between age, aperiodic components, and cognitive performance, as measured by Mini-Mental State Examination (MMSE) scores. We reanalyzed an open-source EEG dataset of 714 healthy individuals aged 18-91 years using Generalized Additive Mixed Models. Aperiodic components (exponent and offset) declined with age, but higher education levels mitigated these declines. Notably, the aperiodic components interacted with age and education in predicting MMSE performance in a widespread way across the cortex. Among older adults, the relationship between the aperiodic components and cognitive performance diverged by education: those with lower education showed worse cognitive outcomes with lower exponents and offsets, whereas higher-educated individuals after 60 years showed a reverse pattern, with lower exponents and offsets predicting better MMSE performance. Our findings suggest that the link between aperiodic components and cognitive aging is not straightforward but depends on moderating factors such as education. These results underscore the importance of accounting for individual differences, like educational background, when exploring age-related changes in EEG aperiodic components and cognition.

Animals face declining fitness contributions near the end of life, termed reproductive senescence. Though reproductive senescence frequently stems from physiological inefficiencies, animals making their final attempts at reproduction have the greatest incentive to succeed, raising the question of whether this deterioration is inevitable or if they can compensate to enhance fitness. Here, we examined whether foraging effort serves as behavioural compensation for reproductive senescence in female mule deer (Odocoileus hemionus). We expected that, as animals approach the end of their lifespans, they would increase foraging effort as a means of compensating for declining reproductive output. To assess compensatory foraging, we disentangled two components of lifetime fitness: energy acquisition and allocation. We used animal-borne activity sensors to quantify foraging effort (time devoted to energy acquisition) and followed animals across the annual cycle to measure reproductive output and seasonal fluctuations in stored energy (body fat). Then, we evaluated whether foraging effort mediated the effect of age on allocation to current reproduction and future fitness contributions. For senescing animals, foraging effort positively influenced newborn size, providing evidence of compensation for declining fitness contributions. Moreover, we detected a possible diversion of resources away from future survival and to current reproduction. Senescing animals with high foraging effort accumulated little fat over summer, likely diverting incoming energy to finance current reproduction (lactation) over future fitness. Our work demonstrates that, facing their final opportunities to reproduce, animals may use behaviour to compensate for the physiological declines associated with aging to improve their chances of reproductive success. By evaluating the role of behaviour in fitness components, we reveal processes underlying senescence, and its alleviation, in wild populations.

Pregnancy functions as a "stress test" with implications for women's long-term health. We hypothesize that maternal biological aging, measured by epigenetic age acceleration (EAA), can be influenced by one-carbon nutritional status (folate, vitamin B₁₂, homocysteine), adherence to the Mediterranean diet, and prenatal multivitamin use. We analyzed data from 742 mothers enrolled in the Boston Birth Cohort (1998-2013). EAA was defined as the difference between the Levine epigenetic clock-DNA methylation-based measure and chronological age at delivery. Mediterranean-diet adherence and prenatal multivitamin use were assessed using a validated food frequency questionnaire administered within 24-72 h postpartum. Blood DNA and plasma samples used to measure folate, B

Age-related hearing loss (ARHL), the most prevalent sensory impairment in older adults, is closely associated with NOD-like receptor thermal protein domain-containing protein 3 (NLRP3) inflammasome activation and mitochondrial dysfunction. Quercetin, a natural flavonoid, shows anti-inflammatory and antioxidant properties, but its role in ARHL remains unclear. In this study, we investigated the protective effects and underlying mechanisms of quercetin on ARHL in a mouse model, focusing on both NLRP3 inflammasome and mitophagy.

Skin photoaging, primarily induced by chronic UVB exposure, lacks effective therapeutic options. Schisandrin A (Sch A), a bioactive compound from Schisandra chinensis, has been traditionally used in East Asian medicine for its anti-inflammatory and antioxidant properties. However, the precise mechanisms by which Sch A exerts photoprotective effects against UVB-induced damage remain unclear, warranting further mechanistic exploration. This study aimed to explore the protective effects of Sch A against UVB-induced damage in HaCaT keratinocytes and ICR mice. Sch A improved cell viability, reduced senescence and apoptosis, and enhanced antioxidant defenses by increasing SOD activity and GSH levels while reducing MDA accumulation in mice. Histological analysis showed that Sch A decreased epidermal thickness and preserved dermal collagen. Molecular assays revealed that Sch A activated AMPK and Nrf2 signaling, promoted autophagy, reduced oxidative stress, and inhibited MMP expression. These findings suggest that Sch A alleviates photoaging by modulating oxidative stress, apoptosis, and autophagy via the AMPK/Nrf2 pathways, offering a promising strategy for skin protection.

Mesenchymal stromal cells (MSCs) possess potent immunomodulatory, pro-angiogenic, and regenerative capacities, offering broad clinical promise in regenerative medicine. However, clinical application is constrained by low in vivo survival, poor targeting, variable efficacy, replicative senescence and insufficiently characterized in vivo cell fate. The accelerating global aging trend further complicates MSC therapy for age-associated diseases. Biomaterials have emerged as powerful tools to enhance MSC function and direct cell fate. This review adopts a materiobiology perspective to detail how biomaterial design-across physical (stiffness, topography), chemical (surface chemistry, ion release), and biological (growth factor release, gene delivery) parameters, can proactively steer MSC fate and function to amplify therapeutic efficacy. Subsequently, focusing on the characteristics of aging-related diseases from three perspectives-reactive oxygen species scavenging, epigenetic regulation, and telomere protection-this review summarizes the anti-aging functional design of biomaterials. To bridge biomaterial-driven MSC regulation with in vivo therapeutic outcomes, we systematically review post-transplant fate-tracking technologies, including imaging-based approaches (MRI, CT, fluorescent probes) and transcriptomic monitoring, which enable quantitative evaluation and causal understanding of MSC survival, biodistribution, functional states, and aging trajectories in vivo. Building on these methodological foundations, we summarize engineering solutions for MSC-biomaterial combination therapies in representative aging-related diseases, such as fibrosis, osteoarthritis, heart failure, and wound healing. Importantly, in vivo outcomes can in turn guide subsequent biomaterial design. Finally, we discuss policy and technical hurdles, current limitations, and future directions-including mitochondrial homeostasis control, microfluidics-based dynamic culture, and machine learning for structure-function prediction-to inform next-generation, intelligent MSC-biomaterial combination therapies.