Longevity Papers

The ovary is one of the first organs to lose functionality with age. We found that aging of the Drosophila ovary is characterized by an accumulation of phenotypes in the somatic compartment, including failure of the follicle cells to encapsulate germ-cell cysts, an extended S phase, and increased DNA damage. In aged ovaries, follicle encapsulation defects are associated with the lack of a germ-cell cyst checkpoint in early oogenesis. Single-cell RNA sequencing revealed that, across all cell types in the ovary, cells in the follicle lineage have the highest number of differentially expressed genes. Overexpression of Atg8a, a key autophagy machinery gene homologous to mammalian LC3, specifically in follicle cells prevents age-associated decline in the follicle epithelium and loss of reproductive capacity. Collectively, these findings demonstrate that genetic manipulation of a small population of ovarian somatic cells is sufficient to improve both cell-autonomous and non-autonomous features of reproductive aging.

The nematode Caenorhabditis elegans is a favorable model for studying cell-surface protein interactomes, given its well-defined and stereotyped intercellular contacts. Here, we report an extracellular interactome dataset for C. elegans. Most of these interactions were unknown, despite recent datasets for flies and humans, as our collection contains a larger selection of protein families. We uncover interactions for all four major axon guidance pathways, including ectodomain interactions between three of them. We demonstrate that a protein family, previously known for maintaining axon positioning, functions as secreted binders for insulins and that their overexpression in vivo extends lifespan, consistent with inhibition of insulin signaling. We reveal interactions of cystine-knot proteins with putative signaling receptors, which may extend the study of neurotrophins and growth factors to nematodes. Finally, our dataset constitutes a resource for uncovering the logic of neuronal connectivity, intercellular communication and adhesion, and signaling pathways involved in aging and disease.

Maintenance of skeletal muscle function is essential for functional independence, quality of life and healthspan. Muscle RING-finger protein-1 (MuRF1) negatively regulates muscle function and mass through ubiquitination and degradation of muscle proteins. Accordingly, genetic and pharmacological inhibition of MuRF1 attenuates muscle wasting and weakness under catabolic stress. To explore the potential of MuRF1 inhibitors (e.g., MyoMed-205) to improve muscle health, we investigated here the long-term effects of MyoMed-205 on functional capacity and muscle physiology in rats under basal conditions. Wistar rats were randomized to control or MyoMed-205 groups and were followed for 4 or 8 weeks. Body weight, food and water intake, and exercise capacity were monitored weekly. At each endpoint, the soleus muscle was collected for histological analyses. MyoMed-205-treated rats showed normal basic survival-related behaviors and body growth. After 8 weeks, MyoMed-205-treated animals exhibited enhanced exercise capacity (speed (m/min): +45%, p = 0.01; endurance (min): +47%, p = 0.03; and distance covered (m): +87%, p = 0.04) compared with baseline performance. Conversely, no differences were found in soleus fiber type distribution, cross-sectional area, or lipid and collagen content. Our findings indicate that MyoMed-205 enhances functional exercise capacity independently of changes in soleus muscle structure in rats under basal conditions.

There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize senotypes and senescent cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed SenCat. We found that, while senescent cells from all primary tissue types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Machine learning analysis of the SenCat transcriptomic and proteomic datasets successfully identified independent sets of senescent human cells, and senescent-like cells in mouse lung and kidney. In sum, SenCat represents a much-needed resource to identify senescent cells across tissues in the body.

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age. This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of MO may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

MicroRNAs play a crucial role in regulating gene expression in most biological processes, including cardiac disease, regeneration and aging. They are therefore an attractive and novel therapeutic option, and extensive research in small animal models has demonstrated this potential in the heart. While the therapeutic outcomes obtained in large animal models are also promising, far fewer studies have been conducted in this species. Even fewer microRNA therapeutics have reached clinical trials, only CDR132L and MRG-110. This highlights a bottleneck in their development primarily associated with challenges in their in vivo delivery, specifically due to their limited stability and ability to penetrate the heart tissue. This review aims to describe the current state of development of cardiac microRNA therapies in relation to these challenges and to provide a comparative overview of the progress made in overcoming them. A special focus is set on the application of pharmaceutical nanotechnology and the development of targeted delivery strategies to the heart. These approaches have been tested primarily in small animal models and have shown to improve the cardiac penetration, accumulation and/or stability and of microRNAs and, therefore, their therapeutic efficacy compared to naked delivery. Notably, the latter is typically the method of choice in late preclinical research and early clinical trials. Consequently, targeted microRNA nanotherapies could be pivotal in overcoming the current bottleneck and realizing the therapeutic potential of microRNAs in the heart. In conclusion, this review offers an outlook of the future applicability of microRNA therapies leveraging the latest advances in non-viral targeted delivery with nanocarriers.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have transformed the management of type 2 diabetes by effectively lowering glucose levels through the promotion of glucosuria and natriuresis. Beyond these primary actions, a growing body of experimental and clinical evidence suggests that this drug class exerts a wide range of pleiotropic effects independent of glycemic control. Laboratory studies have shown that SGLT2 inhibitors influence fundamental aspects of cellular metabolism and survival, including the promotion of ketogenesis as an efficient energy source, upregulation of sirtuin 1 that modulates stress resistance and longevity, and attenuation of inflammation and oxidative stress through adenosine monophosphate-activated protein kinase - mechanistic target of rapamycin complex 1 (AMPK - mTORC1) signaling. Collectively, these pathways suggest cytoprotective properties that may underlie the emerging benefits of SGLT2 inhibitors in cardiovascular, renal, and other systemic diseases. This review provides an updated and comprehensive overview of the molecular and cellular mechanisms underlying the extraglycemic actions of SGLT2 inhibitors, links these mechanistic insights to ongoing clinical trials, and underscores their expanding potential for therapeutic repurposing beyond diabetes management.

Tremella fuciformis is an edible fungus with a cultivation and consumption history of over a thousand years in China. In traditional Chinese medicine, it has the effects of moistening the lungs, soothing the intestines, nourishing the skin, and prolonging life, and is often used as a tonic food or added to soups. Its core bioactive component is Tremella fuciformis polysaccharides, which are widely concerned for their potential in health maintenance and disease adjuvant treatment.

Dermal fibroblasts are pivotal in maintaining skin integrity through extracellular matrix (ECM) production, a process compromised during aging due to oxidative stress from excessive reactive oxygen species (ROS). Salvia miltiorrhiza Bunge (Danshen, DS), a medicinal plant rich in bioactive compound-rich dried roots, has demonstrated broad therapeutic potential. This study investigates the anti-aging properties of Danshen callus (DSC)-an undifferentiated cell mass derived from leaf tissue culture, as a sustainable and controlled source of bioactive compounds. Using hydrogen peroxide (H

Biopsychosocial frailty, a new construct combining modifiable physical, psychological, and social domains, was associated with increased risk of dementia, mild cognitive impairment, and their subtypes. The aim of the present study was to estimate the role of biopsychosocial frailty on the incident risk of cardio- and cerebrovascular disease, i.e., myocardial infarction, peripheral artery disease (PAD), and definite stroke. From the eight municipalities of the population-based Italian Longitudinal Study on Aging, we examined 2410 older individuals in a longitudinal analysis with an 8-year follow-up. Biopsychosocial frailty operationalization was based on the results of a previous comprehensive geriatric assessment and the presence of physical frailty. Generalized estimating equation models assessed the independent contribution at three different follow-ups of baseline individuals with biopsychosocial frailty on occurring new events of myocardial infarction, PAD, and stroke. The prevalence of biopsychosocial frailty in older individuals with myocardial infarction was 10.9%, in older subjects with PAD was 8.9%, and in older individuals with definite stroke was 23.7%. After 8 years of follow-up, participants with biopsychosocial frailty showed an increased odds ratio (OR) of definite stroke [OR 2.67; 95% confidence interval 1.11-6.40]. No statistically significant associations between biopsychosocial frailty and myocardial infarction or PAD were observed. Over an 8-year follow-up, in a large, older cohort, a biopsychosocial frailty phenotype was associated with incident cerebrovascular disease, in particular with definite stroke. This complex phenotype of frailty has several modifiable components and could be an optimal target for potential interventions and prevention strategies.

With an aging population, muscle health, encompassing locomotion and metabolic function, has become a public health priority. Handgrip strength is a validated surrogate measure of general muscle strength, but measurement may not be feasible in low-resource settings. The SARC-F questionnaire (Strength, Assistance in walking, Rise from a chair, Climb stairs, and Falls) provides a simple, low-cost, and practical tool for sarcopenia screening, though its optimal cut-off remains debated.

Lycium barbarum L. (goji berry), a traditional medicinal and edible herb, has long been employed for its anti-aging, vision-enhancing, and anti-inflammatory properties. Lycium barbarum glycopeptide (LbGP), a major bioactive glycoconjugate isolated from this plant, possesses documented antioxidant and immunomodulatory activities. However, its specific therapeutic efficacy in counteracting reproductive aging and the precise mechanisms underlying its protective effects on oocyte quality remain to be fully elucidated.

Sirtuin 6 (SIRT6) is an important regulator of DNA repair, metabolism, chromatin maintenance and longevity. SIRT6 Serine 10 phosphorylation controls SIRT6 recruitment to the sites of DNA damage. To explore the effect of SIRT6 Serine 10 phosphorylation on lifespan, we generated two SIRT6 mutant mouse strains: phospho-null S10A and phosphomimetic S10E. The S10E mutant mice demonstrated enhanced DNA repair capacity, elevated LINE1 expression and reduced lifespan in male mice compared to the wild-type and S10A mice. This result suggests that SIRT6 S10E mutation enhances DNA repair capacity at the expense of reduced LINE1 silencing leading to shorter lifespan. While both SIRT6 functions in DNA repair and chromatin maintenance are important for longevity, our results suggest that when the balance between these functions is shifted, diminished of LINE1 control has a stronger impact on lifespan than enhanced DNA repair.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, characterized by tubular epithelial cell (TECs) senescence, inflammation, and fibrosis. This study investigates the role of estrogen-related receptor alpha (ERRα) in regulating TECs senescence in DKD through nitric oxide synthase 2 (NOS2)-mediated citrulline metabolism. We demonstrate that ERRα expression is significantly downregulated in renal tubular cells of both diabetic mice and DKD patients, correlating with increased senescence markers and the senescence-associated secretory phenotype (SASP). Mechanistically, transcriptome and chromatin immunoprecipitation sequencing confirmed that ERRα regulates NOS2 transcription. TECs-specific knockout of ERRα led to reduced NOS2 expression and decreased citrulline levels, exacerbating TECs injury and senescence. In contrast, TECs-specific knock-in of ERRα alleviated TECs injury and senescence and restored citrulline metabolism. These findings indicate that ERRα plays a critical role in regulating NOS2-mediated citrulline metabolism, which is essential for maintaining kidney function and mitigating tubular senescence in DKD. Furthermore, overexpression of NOS2 and supplementation with citrulline ameliorated renal dysfunction and cellular senescence in diabetic mice, underscoring the importance of this metabolic axis. Modulating ERRα and NOS2 activity may present a potential therapeutic strategy to reduce kidney injury and slow the progression of DKD.

Background: Aging is accompanied by widespread transcriptional remodeling across tissues, yet how aging impacts different categories of tissue-resident macrophages is not well understood. Macrophages are highly specialized innate immune cells shaped by their local microenvironments, suggesting that aging may elicit both shared and niche-specific transcriptional responses. Here, we performed a meta-analysis of publicly available bulk and single cell RNA-sequencing datasets to characterize age-associated transcriptional changes in murine macrophages across tissues and sexes. We curated and uniformly processed 33 macrophage transcriptomic datasets, derived from 10 distinct tissue niches, in male and female C57BL/6 mice using age as the covariate of interest. Results: The similarity of differentially expressed aging genes was compared across niches and pathway-level analyses uncovered conserved age-associated functional annotation signatures across macrophage populations, including increased antigen presentation, extracellular matrix remodeling, antioxidant responses, and negative regulation of ferroptosis, alongside decreased Wnt, GTPase, and cell-cycle-related signaling. Transcription factor activity inference analysis identified consistent age-associated activation of stress- and inflammation-related regulators such as AP-1 (Jun), Sp1, and Egr1 across niches. Meta-analysis further defined a core set of 35 genes consistently altered with age across mouse macrophage populations, highlighting coordinated dysregulation of small GTPase signaling as a shared feature of murine macrophage aging. Conclusions: These findings demonstrate that macrophage aging is shaped by both tissue niche and sex and provides a framework for understanding the transcriptomic signatures of macrophage aging across tissues.

Trichloroethylene (TCE), a pervasive groundwater contaminant, has been epidemiologically linked to cardiovascular diseases, yet its potential to initial cardiac aging remains uncharacterized. Using H9c2 cardiomyocytes and zebrafish larvae, we dissected the molecular mechanisms underlying TCE-induced cardiac senescence. Exposure to an environmentally relevant dose of TCE (60 μg/L) triggered a robust premature aging program, characterized by flattened morphology, elevated senescence-associated SA-β-gal activity, up-regulation of p16/p21 expression, and reduced Lamin B1 levels, without compromising acute cell viability. Mechanistically, TCE engaged the aryl hydrocarbon receptor (AhR) pathway, leading to ROS overproduction and ATM-dependent DNA damage. Pharmacologic inhibition of AhR, ROS scavenging, or ATM blockade each abrogated senescence onset. Transcriptomic profiling identified IL-1 as the dominant senescence-associated secretory phenotype cytokine downstream of ROS. Critically, IL-1 receptor antagonism attenuated DNA damage and reversed senescence markers, establishing a feed-forward inflammatory loop that perpetuates cardiac senescence. Concurrently, AhR suppressed canonical Wnt/β-catenin signaling by upregulating components of the β-catenin destruction complex, thereby amplifying IL-1-driven inflammation. Restoration of Wnt activity with a GSK-3β inhibitor curbed IL-1 expression and attenuated senescence phenotype. Importantly, in vivo TCE exposure in zebrafish validated the in vitro findings: AhR signaling, oxidative DNA damage, Wnt suppression, IL-1β induction, and p53/p21-mediated senescence in cardiac tissue, confirming the translational relevance of our mechanistic axis. These results identify TCE as an exogenous trigger of premature cardiac senescence and uncover the AhR- IL-1 axis as a druggable pathway for mitigating environmentally accelerated cardiac senescence.

With the accelerating global aging process, health issues among older adults have become increasingly severe. To address the challenges brought about by the aging population, a shift from a disease-centered to a function-centered healthcare model is urgently needed. The World Health Organization (WHO) introduced the concept of intrinsic capacity and published the Integrated Care for Older People (ICOPE): Guidance for Person-Centred Assessment and Pathways in Primary Care

Older adults are susceptible to infections in part due to waning of immune memory. To uncover mechanisms of a long-lasting immune memory, we contrasted varicella zoster virus antigen-specific memory T cell responses in adults vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine conferring durable protection only when given at young age or with an adjuvanted component vaccine eliciting long-lasting immunity in older adults. Unlike VZV-specific CD4

Amygdala-related functional connectivity plays a crucial role in human emotion, cognition, and mental well-being. The amygdala is a highly heterogeneous structure, with subregions that have both distinct and overlapping functions. However, the connectivity patterns of different amygdala subregions, and how these associations vary with age, remain poorly understood. Functional MRI data were analyzed from 68 younger adults and 66 older adults during movie watching in a 7T MRI scanner. Partial least squares (PLS) analysis was used to identify latent variables capturing variance associated with age-related differences in the functional connectivity patterns of three amygdala subregions: the basolateral (BLA), centromedial (CMA), and superficial (SFA) nuclei. In addition, covariance between behavioral measures, such as emotional resilience and cognitive function, and functional connectivity of these subregions was examined. We further explored the associated cognitive processes, correspondence with large-scale brain networks, and the underlying chemoarchitecture of the identified connectivity patterns of the BLA, CMA, and SFA. Multivariate analyses revealed age-related and subregion-specific functional connectivity patterns. Functional connectivity patterns of amygdala subregions were further associated with emotional resilience, which largely overlapped across widespread brain regions; however, their associations differed by age. Stronger coupling of amygdala subregions predicted higher resilience in older adults but lower resilience in younger adults. The identified connectivity patterns were linked to the salience, control, and default mode networks and showed spatial correspondence with mGluR5 and 5-HT6 receptor distributions. These findings highlight age-dependent reorganization of amygdala-related networks that support emotional resilience and provide novel insights into how functional and neurochemical changes of the amygdala subregions contribute to adaptive emotional and cognitive functions in aging.

Aging is the gradual accumulation of structural and functional changes in an organism over time, including immune remodeling and a progressive increase in basal inflammation, or inflammaging. The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention. Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17-producing {gamma}{delta} T cells, particularly in the peritoneal cavity. After a peripheral inflammatory LPS challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related {gamma}{delta} T cell expansion and neuroinflammation associated with systemic inflammation.

Although neuromuscular decline is well documented with aging, emerging evidence indicates that it may begin as early as midlife, around age 50. As this stage represents a critical window for early intervention, the present study investigated age- and sex-related differences in muscle activation using high-density surface electromyography (HD-sEMG) of the biceps brachii (BB). Physically active individuals were categorized into three age groups: young (20-30 years), middle-aged (45-55 years), and older adults (65-75 years). HD-sEMG signals were recorded during isometric contractions at 20%, 40%, and 60% of maximal voluntary contraction (MVC). Muscle activation amplitude, spatial distribution, and signal complexity were analyzed. Although strength remained similar across groups, RMS amplitude was primarily influenced by contraction level, with age-related differences emerging in an intensity-dependent manner. In men, older participants exhibited lower RMS amplitudes compared to younger men at higher contraction levels (60% MVC, p<0.05). In women, middle-aged participants consistently exhibited lower RMS amplitudes across contraction levels, accompanied by altered spatial organization of muscle activation, reflected by higher RMS CoV and lower modified entropy at moderate-to-high contraction intensities (p<0.05). Signal complexity, assessed using sample entropy, did not show robust age-related differences, although descriptive trends toward lower values were observed in older adults at low contraction level. Taken together, these findings suggest that midlife, in women, may be characterized by subtle, task-dependent neuromuscular reorganization rather than a generalized decline. Early identification of such changes using HD-sEMG metrics may support timely interventions aimed at preserving neuromuscular function across the lifespan.

The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology.

Aged hematopoietic stem cells (HSCs) show diminished capacity of self-renewal, skewed lineage output and compromised proteostasis. Ubiquitin proteasomal systems are critical for maintaining protein homeostasis. We show that the levels of Ube2g1, a E2 ubiquitinconjugating enzyme likely involved in clonal selection of HSCs, was elevated in aged murine and human HSCs. We hypothesized that elevated levels of Ube2g1 causally contribute to hematopoietic system aging. Elevated levels of Ube2g1 in young murine HSCs resulted in increased myeloid-to-lymphoid ratio and reduced naïve T-cells, both known hematopoietic aging hallmarks. Interestingly, the ubiquitination function of Ube2g1 didn't primarily account for the observed phenotypes. Elevated levels of Ube2g1 affected global tyrosine phosphorylation, mediated through a Ube2g1-Shp2 axis, which correlated with impaired Tcell development and reduced HSC function. Our work identifies a novel connection between proteins involved in the regulation of ubiquitination and phosphorylation in HSCs that affect phenotypes linked to aging of HSCs.

Skeletal muscle aging is characterized by progressive functional decline and molecular remodeling, yet how different muscle types respond to aging remains incompletely understood. Here, we performed integrated transcriptomic and metabolomic profiling of three functionally distinct muscles-gastrocnemius (GA), soleus (SOL), and tibialis anterior (TA)-from young (3-month) and aged (24-month) C57BL/6J male mice. Our multi-omics approach revealed both shared and muscle-specific molecular signatures of aging. While all three muscles exhibited a core set of 83 commonly altered genes enriched in circadian rhythm, xenobiotic metabolism, and immune signaling pathways, each muscle displayed unique aging trajectories. GA showed 881 differentially expressed genes with prominent alterations in PI3K-Akt and p53 signaling; SOL exhibited 1232 changes emphasizing oxidative phosphorylation and inflammatory responses; TA demonstrated the most extensive remodeling with 1492 altered genes, particularly in extracellular matrix organization and fatty acid metabolism. Metabolomic analysis revealed muscle-specific metabolic reprogramming: GA showed disrupted pentose phosphate and arginine pathways; SOL exhibited altered branched-chain amino acid metabolism; TA displayed TCA cycle perturbations. Notably, the coordination between transcriptomic and metabolomic changes varied by muscle type-GA showed decoupled responses, while SOL and TA demonstrated compensatory inverse relationships. Lipid metabolism emerged as a critical aging-associated process with distinct muscle-specific adaptations: SOL upregulated antioxidant defenses, TA activated compensatory PPAR and PI3K-Akt signaling, while GA showed intermediate responses. Furthermore, receptor-ligand correlation analysis revealed age-dependent reorganization of intermuscular communication networks, with enhanced chemokine signaling and altered growth factor crosstalk. These findings establish that skeletal muscle aging involves both systemic responses and highly muscle-specific molecular adaptations, providing insights for targeted therapeutic strategies against sarcopenia.

To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.

Although most research on testicular aging has traditionally centered on germ cells, recent transcriptomic evidence shows that Sertoli cells are actually the most sensitive cell type to aging, displaying the highest number of aging-related differentially expressed genes and the greatest increase in transcriptional noise. As age advances, Sertoli cells undergo progressive quantitative loss, aberrant morphology, and disorganization of cytoskeletal and junctional structures, changes that collectively impair their ability to maintain the seminiferous epithelium and support germ cell development. This review therefore focuses on the key molecular processes underlying Sertoli cell aging, particularly the accumulation of cellular damage-including oxidative, mitochondrial, metabolic, and DNA lesions-and epigenetic alterations, such as dysregulated histone methylation and chromatin remodeling. Through addressing whether Sertoli cells predominantly undergo apoptosis, necrotic-like degeneration, or persist in a dysfunctional, senescence-associated state, this review highlights how their altered fate contributes to age-related male reproductive decline.

Psychological stress (or simply "stress") is a major contributor to chronic disease worldwide, affecting 35% of the global population, including younger generations. Furthermore, it plays a significant role in human premature aging; hence, its detrimental effects on people's health compel us to comprehend and control the ways in which psychological stress impacts our bodies, including our skin. For example, flavonoids, a class of polyphenolic phytochemicals, are an important group of plant secondary metabolites and appear as a promising solution. These compounds exhibit a number of general biological activities, such as anti-inflammatory and antioxidant properties, as well as certain skin-specific ones, like wound healing, photoprotection, and the treatment of inflammatory and cancerous disorders associated with the skin. For this reason alone, flavonoids could be regarded as a promising solution. Further, these substances have demonstrated beneficial effects on the different hallmarks of aging, demonstrating their potential as anti-aging agents. They also have the ability to influence hormones linked to stress, which, considering their effects on skin health and aging mechanisms, seems to suggest that flavonoids may be effective ways to mitigate the negative effects of stress on premature skin aging. Therefore, this review seeks to demonstrate the potential of flavonoids as potential anti-aging agents for the skin, either by improving the so-called hallmarks of aging or by directly protecting the skin from external aggressors like UV radiation while reducing the negative effects of psychological stress and its known mediators.

Purpose of the ResearchUsing longitudinal data from the Survey of Health, Ageing and Retirement in Europe (SHARE), we examined whether childhood book environment is associated with higher cognitive functioning and better cognitive maintenance later in life, especially among individuals with lower education.Major FindingsAmong 86,619 adults aged 60+ (226,515 person-wave observations from Waves 4-8, with retrospective childhood circumstances from Waves 3 and 7), even modest childhood access to 11-25 books is associated with higher overall cognition levels, independent of education and other covariates, with greater benefits observed in less-educated adults. Book-rich environments are also associated with a more favorable cognitive trajectory over time, particularly for more educated adults, given the potential for steeper late-life decline.ConclusionsFindings support a critical period model of higher cognitive functioning and a cumulative advantage model of longitudinal change, which also align with reserve-depletion patterns.

Aging doesn't just dull our memories; it destabilizes our emotions while further impairing sleep quantity and NREM sleep quality. Emotional dysregulation and anxiety symptoms in older adults accelerate their risk of cognitive decline and dementia, yet the underlying mechanisms remain largely unclear. In young adults, reductions in deep sleep, specifically the loss of slow wave activity (SWA) during non-REM sleep, impair the brain's ability to regulate anxiety overnight. This raises a testable hypothesis: Does age-related decline in SWA contribute to increased anxiety symptoms in older adults? We test this hypothesis in 61 cognitively healthy older adults (>65 y) experiencing varying levels of anxiety. Each participant underwent polysomnography-recorded sleep in the lab, followed by a structural MRI the next morning to assess atrophy in anxiety-sensitive brain regions. A subset of 24 participants was tracked longitudinally over 4 ± 2.02 years. The findings were consistent. Greater impairment in nighttime SWA predicted higher next-day anxiety in older adults, both at baseline and at follow-up. Brain imaging revealed the mechanism: atrophy in key emotion-processing regions was associated with reduced capacity to generate robust slow waves needed for overnight anxiety regulation. Critically, mediation analysis showed that impaired SWA fully accounted for the relationship between regional atrophy and disrupted overnight anxiety regulation. These findings suggest that even in the presence of age-related brain atrophy, intact SWA may preserve emotional stability by rescuing the brain's nightly emotional recalibration process, protecting mental health in aging populations.

The increasing elderly population has brought healthy aging into focus. Aging is a multifactorial process characterized by the progressive decline of cellular and tissue functions, largely due to cumulative oxidative stress. Antioxidant-based strategies have therefore gained prominence as potential interventions. This study investigated the protective and therapeutic effects of Squalene (SQ) and Saponin (SP), individually and in combination, on aging-related biomarkers in brain tissue using a D-Galactose (D-Gal)-induced rat model. Forty-eight male Sprague-Dawley rats (200-250 g) were randomly divided into eight groups (n = 6). Aging was induced in four groups via intraperitoneal administration of D-Gal (300 mg/kg/day) for six weeks. One group received no antioxidants, while others were treated orally with SQ (2.66 mL/kg/day), SP (100 mg/kg/day), or their combination. Non-aging groups received the same antioxidant treatments without D-Gal. At the end of the intervention, brain tissues were collected for biochemical analysis. Spectrophotometric assessments included Malondialdehyde (MDA), Glutathione (GSH), Nitric oxide derivatives (NOx), Ascorbic acid (AA), and Protein carbonyls (PC). Forkhead Box O3A (FOXO3A), Nuclear factor erythroid 2-related factor 2 (NRF2), Sirtuin 1 (SIRT1), Paraoxonase 1 (PON1), and Klotho were quantified by ELISA. Combined SQ and SP treatment significantly decreased oxidative stress markers (MDA, NOx, PC) and increased antioxidant defenses (GSH, AA) as well as aging-related molecules (FOXO3A, NRF2, SIRT1, PON1, Klotho) (p < 0.05). Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) levels were also reduced. These findings demonstrate, for the first time, that combined SQ and SP administration can mitigate aging-related oxidative stress and molecular alterations in brain tissue.

Cereal grains contain bioactive compounds that may influence longevity. We investigated the effects of 20 cereal varieties on longevity and healthspan in Drosophila melanogaster, including triticale, bread wheat, durum wheats, ancient wheats, and regional varieties. Cereal-based diets exhibited sex-specific differences relative to cereal-free controls: females showed 3-13% longer lifespans while males exhibited reduced lifespans by up to 19%. In females, clear patterns were observed: pronounced lifespan differences (3-11% longer than controls) were concurrent with higher thermotolerance, while moderate lifespan differences (2-6% longer than controls) were associated with greater oxidative stress resistance and locomotor activity, but lower starvation resistance than controls. Males demonstrated higher stress resistance than controls despite shortened lifespan. Gene expression analysis revealed that female-specific lifespan differences were concurrent with elevated expression of immune-related genes (AttA, CecA1, DptA). These results suggest cereal-mediated longevity differences operate through sex-specific physiological pathways involving trade-offs between stress resistance and metabolic regulation.

Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation.

The cerebellum contributes to motor, cognitive, and affective functions that progressively decline with aging. The search for effective therapies to delay age-related degeneration has become a focus of the scientific community. Resveratrol, a natural polyphenol, exhibits neuroprotective properties through antioxidant and anti-inflammatory actions in different models of brain injury and aging. Here, we evaluated the effects of resveratrol on fine motor performance, oxidative stress, glial reactivity, and Purkinje cell survival in the cerebellum of male Wistar rats treated for 6, 12, 18, or 24 months. Three-month-old rats were randomly assigned to receive either vehicle (drinking water) or resveratrol (10 mg/kg, orally, daily by gavage between 8:00 and 10:00 a.m.). Fine motor skills were assessed using the balance beam test. Rats treated with resveratrol for 18 or 24 months showed improved motor coordination and fewer slips compared with controls. Histological analysis revealed less cellular disorganization and greater preservation of Purkinje cells after 12, 18, and 24 months of treatment. Nissl staining confirmed that resveratrol attenuated neuronal disintegration and preserved cerebellar architecture. Moreover, resveratrol significantly reduced GFAP immunoreactivity at 12, 18, and 24 months, indicating decreased astrocytic activation and inflammation. In conclusion, chronic resveratrol treatment exerted neuroprotective effects in the cerebellum, improving fine motor performance and reducing glial reactivity. These findings support resveratrol as a potential strategy to mitigate motor decline, inflammation, and cerebellar neurodegeneration associated with aging.

Mitochondrial dysfunction affects skeletal muscle (SkM) function and is critical in the etiology of age-related sarcopenia. The sirtuin 1-PGC1α pathway is a key regulator of mitochondrial mass, structure, and function. However, pathway activity decreases with aging. Cacao flavanols show promise in their ability to activate mitochondrial pathways. We evaluated the capacity of the flavanol (+)-epicatechin (+Epi) to stimulate such a pathway and favorably impact mitochondrial and oxidative stress (OS)-associated endpoints in aged SkM. Using 23-month-old male Sprague-Dawley rats, an 8-week oral administration of +Epi (1 mg/kg/day) was implemented, and results were compared versus vehicle-treated controls. Assessments included the nicotinamide adenine dinucleotide (NAD)/sirtuin 1/PGC1α pathway, acetylated proteins levels, mitochondrial function and biogenesis, as well as OS-related endpoints in SkM. +Epi increased the NAD/NADH ratio, activation of sirtuin 1, the deacetylation of nuclear protein content, including that of PGC1α. Also, +Epi induced increases of TFAM and NRF1 mRNA levels, deacetylation of mitochondrial complex I and V, increases in complex I activity, sirtuin 3, complexes I and V, mitofilin, and TFAM protein levels. SkM citrate synthase activity and ATP content increased with +Epi. OS markers in proteins and lipids were reduced, while buffering systems (superoxide dismutase 2 and catalase protein and activities) increased. In white blood cells, we documented serial reductions in mitochondrial DNA content and citrate synthase activity with aging, which were either fully or partially reversed with +Epi. Results demonstrate that +Epi treatment yields positive effects on mitochondrial biogenesis and function, leading to decreased OS and improved SkM bioenergetics in aged rats.

Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in polar metabolites, how the lipidome changes across tissues and between sexes during aging remains incompletely understood. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We quantified 809 lipid species across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences at throughout life. Spleens from male mice had higher levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to females. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.

While significant progress has been made in understanding the genetic architecture of ageing in model organisms, our understanding of human ageing remains limited. We performed a multi-tissue Transcriptome-wide association study (TWAS) on human lifespan, integrating GWAS data from >1 million parental lifespans with gene expression prediction models derived from reference transcriptomic datasets; followed by replication using healthspan and longevity phenotypes as additional readouts of ageing. The TWAS uncovered 563 significant gene associations, of which 139 replicated. TOMM40, encoding a component of the mitochondrial outer membrane translocase that is fundamental for mitochondrial function, had the strongest association with parental lifespan and longevity and was fine-mapped as a putatively causal lifespan gene at the APOE-TOMM40 region. Uniquely in our study, we identified fly orthologues of replicating genes and examined if modulating their expression impacts Drosophila longevity. The nine novel associations with all three ageing outcomes included COASY, encoding Coenzyme A synthase. Knocking down its fly orthologue, Ppat-dpck, resulted in significant lifespan extension in flies. Hence, in addition to discovering new genes associated with human ageing, by combining human TWAS with experimental Drosophila work, we provide evidence for the role of COASY (Ppat-dpck) in ageing across species.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, attention deficit/hyperactivity disorder, intellectual disability, and Down syndrome, are increasingly examined through the lens of aging. Emerging evidence indicates that individuals with NDDs may exhibit accelerated or atypical brain aging, characterized by cognitive decline and increased vulnerability to neurodegenerative conditions such as Alzheimer's and Parkinson's disease. This narrative review synthesizes current findings on biological mechanisms implicated in altered aging trajectories, with emphasis on oxidative stress, chronic neuroinflammation, mitochondrial dysfunction, and cellular senescence. These processes, detectable from early development, mirror pathways involved in neurodegeneration, suggesting shared molecular cascades that increase susceptibility to early aging. Biomarker studies report telomere shortening, elevated plasma glial fibrillary acidic protein and neurofilament light chain levels, and deviations in neuroimaging-derived brain age, supporting the hypothesis of altered biological aging in NDDs. However, the limited number of longitudinal lifespan studies, along with marked heterogeneity in etiology, clinical profiles, and comorbidities, constrains causal inference. Psychosocial and environmental factors, including chronic stress, social exclusion, medical comorbidities, and lifestyle influences, further shape aging outcomes. Integrating biological, behavioral, and environmental markers is essential to advance monitoring and inform early interventions aimed at promoting healthier cognitive and functional aging in neurodivergent populations.

Intrinsic biological rhythms regulate key physiological and behavioural processes, yet the influence of sex and age on these rhythms is not fully understood. We comprehensively examined 24 h (circadian) and >24 h (infradian; 5 and 10 day) rhythms in wheel-running and ingestive behaviours in single-housed young and middle-aged male and female mice. Circadian analysis revealed that middle-aged mice, particularly females, exhibited more precise daily rhythms and shifted a greater proportion of activity and feeding to the lights-on phase than young female mice. Middle-aged animals also ran for longer durations per day, suggesting age-related changes in activity regulation. Analysis of infradian rhythms further highlighted sex- and age-specific differences. Young female mice displayed robust 5 day rhythms in wheel-running activity, which were absent in middle-aged females. In contrast, few males (young or middle-aged) showed significant 5 day rhythms. Ten-day rhythms were most prominent in male mice, while females rarely expressed this periodicity. Physiologically, middle-aged mice lost more body weight in response to single housing, with middle-aged females being most affected. Interactions among behavioural rhythms in females also showed greater complexity, which increased with age. These findings reveal distinct sex- and age-dependent patterns in circadian and infradian rhythms as well as in physiological responses to isolation. Our work highlights the need to account for sex and age in chronobiological research, with broader implications for understanding vulnerability to age-related metabolic and behavioural disorders. KEY POINTS: Physiological findings: -Middle-aged mice lost more body weight after single housing, with females most affected. Circadian findings: -Older mice show more daytime activity. -Precision in daily rhythm differs by sex and age. -Middle-aged females showed prolonged daily wheel running. Infradian findings: -Young females had robust 5 day rhythms, absent in middle-aged females. -Some males showed 5 day rhythms, but 10 day rhythms were most prominent in males. Complexity of rhythms: -Complexity of interactions among behavioural rhythms increases with age, particularly in females.

Although mechanistic studies support a beneficial effect of several dietary flavonoids on telomere length (TL), to our knowledge no studies have examined associations between habitual flavonoid intakes and TL in population-based studies. We examined the associations between habitual intake of major flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols and their polymers, and anthocyanins) and TL in a cross-sectional analysis of 4,944 disease-free females from the Nurses' Health Study (NHS). Flavonoid intakes were collected using food frequency questionnaire data, and TL was measured in peripheral blood leukocytes using quantitative real-time polymerase chain reaction. Multivariable-adjusted least squares mean leukocyte TL (z scores and corresponding standard error [SE]) for total and all flavonoid subclasses were calculated using generalized linear models. Although no individual flavonoid subclass was significantly associated with TL in the overall population, when we restricted analyses to younger and middle-aged participants (aged < 55 y), a higher anthocyanin intake associated with longer TL (least squares means ± SE: 0.06 ± 0.06 for the highest versus 0.24 ± 0.07 for the lowest quintile; P-trend = 0.042), corresponding to 6.6 (95% CI, 1.7-14.5) years of aging. In food-based analyses, participants aged < 55 y who consumed more berries had longer TL (Mean TL: 0.10 ± 0.04 for never/rarely; 0.21 ± 0.04 for ≤ 1 serving/week; 0.44 ± 0.26 for ≥ 2 servings/week; P = 0.033 for trend). Similarly, a higher anthocyanin intake was associated with longer TL among pre-menopausal females (0.46 ± 0.11 for the highest versus 0.02 ± 0.08 for the lowest quintile; P-trend = 0.001). Overall, habitual flavonoid intake was not associated with TL attrition in this cross-sectional analysis. However, in females aged < 55 y a higher anthocyanin intake was associated with longer TL, which raises the possibility that anthocyanin-rich foods may promote healthy aging and warrants further investigation with respect to age.

Cellular aging is characterized by progressive changes in gene expression that contribute to tissue dysfunction; however, identifying genes that regulate the aging process, rather than merely serve as biomarkers, remains a significant challenge. Here we present PRISM (Pseudotime Reversion via In Silico Modeling), a computational pipeline that integrates pseudotime trajectory analysis with Boolean network analysis to identify cellular rejuvenation targets from single-cell RNA sequencing data. We applied PRISM to a published dataset of human skin comprising 47,060 cells from nine donors aged 18 to 76 years. Analysis of keratinocytes revealed two distinct aging trajectories with fundamentally different regulatory architectures. One trajectory (labeled Y_272) exhibited "aging as convergence," where cells were driven toward a single dominant aged attractor (aging score +2.181). A second trajectory (labeled Y_308) exhibited "aging as departure," where cells escaped from a dominant youthful attractor basin (aging score -0.536). Systematic perturbation analysis revealed a critical distinction between genes exhibiting age-related expression changes (phenotypic markers) and genes controlling attractor landscape architecture (regulatory controllers). Switch genes marking the aging trajectories proved largely ineffective as intervention targets, while master regulators operating at higher levels of the regulatory hierarchy produced substantial rejuvenation effects. BACH2 knockdown was identified as the dominant intervention for Y_272, shifting the aging score by {Delta}=-3.746 (98.9% improvement). ASCL2 knockdown was identified as the top target for Y_308, with synergistic enhancement observed through combinatorial perturbation with ATF6. These findings demonstrate that attractor-based analysis identifies different and potentially superior therapeutic targets compared to expression-based approaches and provide specific hypotheses for experimental validation of cellular rejuvenation strategies in human skin.

Age-associated dysbiosis, marked by shifts in the composition of gut microbiota and gut microbiota-derived metabolites (GMDMs), is increasingly implicated in driving systemic low-grade inflammation during aging. The disrupted GMDM pools, including altered levels of short-chain fatty acids (SCFAs), secondary bile acids (BAs) and tryptophan (Trp) metabolites, lead to mucosal barrier dysfunction, immunometabolic dysregulation, and modulation of innate and adaptive immune cells. In turn, this cascade of events drives tissue degeneration, chronic inflammation, and the onset of age-related diseases (ARDs). Here, we summarize the immunomodulatory role of major GMDMs and how aging may increase susceptibility to ARDs through changing GMDMs. We then explore the latest findings linking altered GMDM profiles to immune dysfunction across major gut-organ axes, including the liver, adipose tissue, muscle, and brain. Last, we highlight recent advances in harnessing GMDMs as geromedicine to improve aging parameters and discuss the potential of artificial intelligence (AI) in accelerating the bench-to-bedside translation of GMDM research. Together, this review positions GMDMs as actionable targets in a dysbiosis-driven network of immune aging, offering new possibilities for the development of healthspan-extending precision geromedicine.

The nuclear envelope (NE) is essential for cellular homeostasis, yet its integrity declines with age, accelerating functional deterioration. Here we report a mitochondria-to-NE signalling pathway that safeguards NE integrity through redox-dependent lipid metabolism. In Caenorhabditis elegans, reducing mitochondrial ETC activity preserves NE morphology during ageing. This effect requires developmental mitochondrial superoxide, which downregulates SBP-1 (SREBP orthologue) and suppresses unsaturated fatty acid biosynthesis. The resulting reduction in unsaturated fatty acid levels limits lipid peroxidation, thereby preserving NE structure. Interventions targeting lipid peroxidation preserve NE integrity, extend lifespan in worms and ameliorate senescence-associated phenotypes in human fibroblasts and monkey cells mimicking Hutchinson-Gilford progeria syndrome disease. Our findings reveal a previously unrecognized role for mitochondrial superoxide as a protective developmental signal that programs long-term NE integrity. This work establishes lipid peroxidation control as a conserved strategy to delay nuclear ageing and highlights redox-lipid cross-talk as a therapeutic axis for healthy ageing.

Age-related fat infiltration of skeletal muscle contributes to sarcopenia, declines in physical performance, and metabolic disorders such as insulin resistance in the elderly. However, the underlying mechanisms remain incompletely defined. Here, we investigated the effects of small extracellular vesicles (sEVs) derived from aged small-intestinal on intermuscular adipose tissue (IMAT) infiltration. In mouse models, systemic tail-vein administration of these sEVs in vivo, together with direct exposure of cultured cells to sEVs in vitro, promoted adipogenic differentiation of fibro-adipogenic progenitors (FAPs), thereby increasing IMAT infiltration and decreasing muscle strength in young recipient mice. High-throughput sequencing and functional analyses identified sEVs-derived miR-214-3p as a critical mediator of this phenotype; this microRNA suppresses the Wnt/β-catenin pathway by directly targeting the gene encoding β-catenin. Collectively, these findings reveal a mechanistic connection between intestinal signaling and muscle composition during aging, highlighting the gut-muscle axis as a promising therapeutic target for prevention or treatment of sarcopenia.

While human lifespan has increased dramatically over the past century, the extension of healthspan, the period free of chronic age-related disease, has lagged behind. Blood flow and angiogenesis are significantly reduced in aging humans, playing a crucial role in mediating cardiovascular disease and heart failure - major causes of reduced lifespan. However, these mechanisms have not been studied as extensively as cellular and molecular mechanisms in animal models. Healthful aging, due to angiogenesis and improved blood flow, is the focus of this review. Here we considered 25 rodent models of healthful longevity. Seven of these had direct evidence of improved blood flow and angiogenesis contributing to enhanced exercise, preserved organ function and resistance to ischemic injury and heart failure. Four others exhibited mixed results, but did not show clearly improved blood flow and angiogenesis Fourteen models did not examine these mechanisms. The mechanisms mediating the improved angiogenesis and, as a result enhanced blood flow, include not only vascular growth hormones and mitochondrial protection, but also a role for a less well studied factor, namely brown adipose tissue (BAT). For example, a recently studied rodent model, the Regulator of G Protein Signaling 14 knockout mouse, exhibited a marked increase in angiogenesis and improved blood flow through a BAT mechanism, i.e., when BAT was removed, blood flow and angiogenesis were no longer improved, but when it was transplanted into wild type mice, blood flow and angiogenesis were enhanced. Given the potential importance of angiogenesis and improved blood flow, these factors need to be considered for future healthful longevity therapeutic translation.

Muscle strength decline is a hallmark of aging and contributes to frailty and bone deterioration, yet the genomic and epigenomic mechanisms predicting functional strength remain unclear. We applied a multi-omics approach to identify genetic and epigenetic signatures of muscle strength variability in postmenopausal women. A total of 141 women aged 50-70 years underwent functional tests, biochemical analysis, anthropometry, blood pressure assessment, and dual-energy X-ray absorptiometry. Participants were classified into higher and lower strength groups based on validated upper and lower limb tests. Genome-wide genotyping was performed with the Illumina Global Screening Array, and DNA methylation was measured using the Illumina EPIC 850K array. A polygenic risk score (PRS) was generated in a training cohort (n = 100) and validated in an independent group (n = 41). EpiScores were calculated using MethylDetectR, and four fitness-related epigenetic clocks (DNAmGrip, DNAmGait, DNAmVO2max, DNAmFitAge) were derived with the methylclock package. Twelve SNPs were associated with strength phenotypes, and the PRS predicted group classification with 51.2% accuracy. Epigenetic analysis revealed 12 differentially methylated regions, including higher BMP1 EpiScore levels in women with greater strength. Functional enrichment indicated pathways related to bone remodeling and vascular regulation. In the lower strength group, BMP1 EpiScore correlated inversely with femoral neck T-score (r = -0.66, p = 0.037). A meta-analysis of public muscle transcriptomes showed that resistance training increases BMP1 expression. These findings highlight molecular mechanisms linking genetic and epigenetic variation to musculoskeletal aging and functional decline in postmenopausal women.

Understanding oocyte and ovarian aging has become critically important, as trends in family planning evolve, with many women choosing to have children later in life. The ovary, a crucial organ in female reproduction, is particularly susceptible to age-related changes and is one of the organs that exhibit functional deterioration most distinctly with age. The aging of female reproductive systems also affects longevity and various health outcomes. A better understanding of both oocyte and ovarian aging will lay the cornerstone to elucidate the phenomenon of longevity in women. Here, clinical data from 400 women of various ages undergoing intracytoplasmic sperm injection (ICSI) have been analyzed, including Anti-Müllerian Hormone (AMH) and Follicle-Stimulating Hormone (FSH) levels, the number of recovered oocytes, blastocyst rates, pregnancy rates, and live birth rates. Our analyses revealed significant differences in the aforementioned rates between patients of young and advanced age. For the biomarker analysis, we further utilised a novel predictive performance of age-associated gene expression signatures for oocyte aging, demonstrating its potential to provide molecular-level insights into oocyte quality over time. By analyzing RNA sequencing data generated from human oocytes of different ages, a genome-wide landscape of age-associated gene expression has been described. Additionally, metabolome profiling has been performed on young and reproductively aged mice, serving as a model for human ovaries. Changes in metabolites of the murine ovaries during aging have been recorded. In conjunction with traditional biomarkers, multiomics data represent a transformative approach in reproductive health, and they may offer personalised risk assessments and interventions to mitigate age-related fertility decline in women. Our metabolome profiling provides a valuable resource for elucidating the metabolomic basis of ovarian aging. Our findings offer novel insights into systemic shifts associated with oocyte and ovarian aging. This integrated approach may unlock new avenues for fertility preservation, ovarian rejuvenation, and assisted reproduction.

Aging commonly causes decline of testosterone or estrogen, leading to overaccumulation of fatness in males or females, respectively. Although such phenomenon can be readily explained by estrogen's direct action on adipocytes in females, accumulative evidence does not support the direct action of testosterone in adipocyte lipid metabolism, suggesting that there is a missing intermediary link. Herein, we propose that glycoprotein hormone β5 (GPHB5) is the intermediary linkage between testosterone and the regulation of adiposity. In clinical samples, blood levels of GPHB5 were correlated negatively with men's ages, and positively with circulating testosterone. Testosterone directly stimulated the expression of GPHB5 in cultured cells, pharmacological blockade of androgen receptor (AR) functions abrogated such effect. Knockout of AR led to not only development of obesity but also reduction of GPHB5 expression. Genetic ablation of GPHB5 in the males, but not in the females, lowered the browning of white adipose tissue, diminished energy expenditure and caused severe obesity. Importantly, elevated blood testosterone didn't exert its catabolic actions in GPHB5 null mice, and yet, recombinant GPHB5 protein was able to stimulate energy expenditure and reduce adiposity. Taken together, these results provided the strong proof that GPHB5 is the "missing" intermediary hormone linking testosterone (and aging) and its well-known catabolic effect on adipose tissue.

The analysis of spatial transcriptomics is hindered by high noise levels and missing gene measurements, challenges that are further compounded by the higher cost of spatial data compared to traditional single-cell data. To overcome this challenge, we introduce spRefine, a deep learning framework that leverages genomic language models to jointly denoise and impute spatial transcriptomic data. Our results demonstrate that spRefine yields more robust cell- and spot-level representations after denoising and imputation, substantially improving data integration. In addition, spRefine serves as a strong framework for model pretraining and the discovery of novel biological signals, as highlighted by multiple downstream applications across datasets of varying scales. Notably, spRefine enhances the accuracy of spatial ageing clock estimations and uncovers new aging-related relationships associated with key biological processes, such as neuronal function loss, which offers new insights for analyzing ageing effect with spatial transcriptomics.

Aging impairs the regenerative capacity of bone and is associated with poor healing outcomes. The mechanical environment is of fundamental importance to the regenerative response in bone - yet the effect of aging on the mechano-responsive capacity of bone regeneration remains largely unresolved. To investigate age-dependent mechanobiological responses in bone regeneration, we established an experimental framework consisting of: (i) an established femur defect mouse model, (ii) the use of PolgAD257A/D257A (PolgA) mice - a mouse model of premature aging, and (iii) our recently established spatial transcriptomics-based ''mechanomics'' platform which permits gene expression to be analyzed as a function of the local in vivo mechanical environment. Aging impaired the regenerative response in PolgA mice, resulting in an increased occurrence of delayed and non-unions, delayed bone formation / resorption responses, impaired osteogenesis and delayed mineralization of new bone. Cyclic mechanical loading significantly enhanced the regenerative response in young PolgA mice inducing sustained bone formation, suppressing bone resorption, and enhancing mineralization, with the strongest effects observed in peripheral regions of the fracture site. In aged PolgA mice, the mechanosensitivity of the regenerative response was retained with an anabolic response localized to the defect center. Cyclic mechanical loading applied during the reparative and remodelling phases of fracture healing thus represents a potential translational strategy to harness the mechanosensitivity of aged bone.

Cognitive performance is central to health and quality of life. Studying the factors that sustain performance may offer insights into maintaining cognitive function into advanced ages and may inform strategies to promote healthy cognitive aging. To identify single nucleotide polymorphisms (SNPs) underlying cognitive function, we performed genome-wide association studies (GWAS) of nine neuropsychological test scores capturing performance in three cognitive domains in 2,455 participants of the Long Life Family Study (LLFS). We identified 12 variants in seven tests and three domains that reached genome-wide significance (p < 5e-8). Three rare (minor allele frequency, European population MAF < 0.01) protective, intronic variants, rs190287985 (CCSER1), rs75730801 (FHOD3), and rs552842447 (LINC00508), were uniquely associated with semantic fluency, phonemic fluency and number span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, were associated with performance on the Hopkins Verbal Learning Test-Revised (HVLT-R) learning trials and lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT-R delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained Ethylmalonic acid (EMA) pathways. We compared the results with GWASs of a general cognitive factor (GCF) and reaction time (RT) in the UK Biobank and meta-analysis results of the UK Biobank, CHARGE and COGENT by Davies et al. We found that rs535509651 associates with HVLT-R delayed recall in the LLFS and nominally associates (p < 0.05) with GCF, and that rs10424537 associates with Immediate Logical Memory in the LLFS and nominally associates with RT. Furthermore, we identified 5 genome-wide significant loci in Davies et al. that reached loci adjusted significance in the LLFS (GCF p < 0.05/128 and RT p < 0.05/39). Each locus was associated with a single cognitive domain in the LLFS. We annotated the genome-wide significant results with quantitative trait loci (QTL) analyses of whole blood transcriptomic, serum metabolomic data, and gene set enrichment analyses (GSEA) using all nominally significant transcripts (p < 0.05/12). QTL analyses discovered 1 SNP-transcript (ECHDC1, p < 3e-6), no SNP-lipid (p < 2e-4), and no SNP-polar metabolite (p < 2 x 10-4) associations. Gene set enrichment analyses identified three pathways at FDR < 0.05. Our findings provide insight into the domain-specific genetic architecture of cognitive function.

Evidence regarding neighborhood socioeconomic status (nSES) as an upstream determinant of cognitive outcomes has largely lacked a life-course perspective. We examined racial differences in the associations between midlife and late-life nSES and cognitive function in a cohort of 330 Black and White older Americans aged 70 + .

BackgroundCognitive decline represents a major challenge in aging populations. Probiotics have been proposed to influence cognitive function through gut-brain interactions, but clinical findings remain inconsistent.ObjectiveThis study evaluated the effects of probiotic supplementation on cognitive function as the primary outcome, and on BDNF levels, inflammatory markers, and oxidative stress biomarkers as secondary outcomes in adults aged 50 years and older.MethodsA systematic search of PubMed, EBSCO, ProQuest, and Google Scholar was conducted through 1 May 2024 using predefined search terms related to probiotics, cognitive function, BDNF, inflammation, and antioxidant activity. Study quality was assessed using the RoB 2 tool. Meta-analyses were performed using random-effects models, and publication bias was explored using Egger's test where study counts permitted.ResultsSixteen studies demonstrated significant improvement in cognitive function among participants receiving probiotics compared to placebo. Cognitive function, measured using the Mini-Mental State Examination (MMSE), yielded a standardized mean difference (SMD) of 0.747 (95% CI 0.307-1.186) which corresponds to moderate-to-large effects. In comparison, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) showed significant results with an SMD of 0.340 (95% CI 0.032-1.366) which corresponds to small-to-moderate effects. Probiotics also led to significant changes in several biochemical parameters, including BDNF, TNF-α, 8-OHdG, IL-6, IL-10, MDA, TAC, and GSH. Multi-strain probiotics showed better results compared to single-strain.ConclusionsProbiotic supplementation may offer modest cognitive benefits in aging populations, particularly in studies enrolling cognitively impaired individuals, but substantial heterogeneity and limited biomarker evidence restrict the certainty of these findings. Larger, longer-duration, and standardized trials are needed to clarify the clinical relevance and potential biological pathways underlying probiotic effects on cognition.

Osteoarthritis (OA), a leading cause of chronic disability worldwide, is increasingly recognized to be driven by the accumulation of senescent chondrocytes (sCDs) and their deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Existing therapies, including senolytics and senomorphics, lack cell-specific targeting and fail to neutralize the heterogeneous components of SASP. Here, we develop a dual-engineered macrophage membrane camouflaged, self-assembled nanoplatform (BS@MD) that combines senolytic and senomorphic functions synergistically. Within the OA microenvironment, BS@MD acts as a "nanosponge" to broadly neutralize SASP through overexpressed cytokine receptors derived from LPS-primed macrophage membranes. This process alleviates chondrocyte senescence and facilitates the phenotypic shift of pro-inflammatory M1 macrophages toward an anti-inflammatory M2 state. Additionally, surface conjugation with an anti-DPP4 antibody enables BS@MD to selectively target sCDs and disassemble in the acidic lysosomal environment, releasing bortezomib (BTZ) and sabutoclax (Sab). These agents act synergistically to inhibit the NF-κB and BCL-2 pathways, thereby inducing sCDs apoptosis and suppressing SASP production, effectively disrupting the senescence-inflammation feedback loop. In the anterior cruciate ligament transection (ACLT)-induced OA mouse model and naturally aged OA mouse model, BS@MD enhances joint retention, reduces cartilage degradation and inflammation, and promotes cartilage homeostasis. Overall, this work pioneers a dual-pronged senotherapeutic strategy for non-surgical OA management.

Aging leads to cognitive decline due to reduced neuronal plasticity and increased brain inflammation. Disruption of perineuronal nets (PNNs) is a recognized strategy to enhance neuroplasticity. Hyaluronan forms the backbone of PNNs, and 4 methylumbelliferone (4MU), an inhibitor of hyaluronan synthesis, has been proposed to disrupt PNNs and enhance neuroplasticity in young rodents. In addition, 4MU is also known as an immune response regulator, although its effects within the central nervous system (CNS) have been less characterized. In this study, we investigated the impact of long-term oral 4MU administration in aged mice (20 to 22 months old), focusing on PNNs intensity, memory, and neuroinflammation. PNN intensity increased with age, and 4MU treatment reduced it in 22 month old mice to levels observed in 10 month old animals; in the novel object recognition test, treated 22 month old mice performed comparably to or better than 10-month-old controls. Moreover, markers of aging associated neuroinflammation including astrocytic and microglial activation as well as peripheral immune cell infiltration were normalized to 10 month old levels or further diminished following 4MU treatment. Importantly, chronic 4MU administration was well tolerated in aged mice, with no serious adverse effects observed. Together, these results suggest that 4MU mitigates PNNs accumulation and neuroinflammaging while enhancing recognition memory, supporting its potential as a safe therapeutic approach for age related cognitive decline.

Advanced Glycation End Products (AGEs), formed through the non-enzymatic Maillard reaction, are pivotal molecular culprits linking metabolic dysfunction, chronic disease, and the acceleration of biological aging. While AGEs are synthesized endogenously, modern Western diets, defined by thermal food processing, introduce a substantial and increasing pool of exogenous dietary AGEs (dAGEs). This viewpoint critically assesses the evidence supporting the outdated theory that AGEs are not inert biomarkers but active, etiological factors driving pathology. The impact of AGEs is characterized by a dual mechanism: the direct impairment of structural integrity via irreversible protein cross-linking, and the systemic induction of oxidative stress and chronic inflammation ("inflammaging") through binding and activation of the Receptor for AGEs (RAGE). This persistent systemic load-heavily contributed by high-fat, high-protein foods cooked at dry, high heat-is implicated in accelerating insulin resistance, cardiovascular complications, and neurodegeneration. Nutritional strategies have focused on mitigating this exogenous burden through simple culinary modifications, such as utilizing moist heat and acidic ingredients, which significantly curb dAGE formation in the kitchen. However, a critical gap remains: while short-term mechanistic studies are compelling, definitive, long-term human intervention trials are lacking. We argue that future research must rigorously quantify the independent contribution of dAGE restriction to health span and longevity to fully legitimize its role as a primary, evidence-based nutritional intervention for preventative health.

Mitochondrial dysfunction is a common pathological hallmark of neurodegenerative diseases. In Parkinson's disease (PD), the most popular age-related movement disorder, the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is closely associated with mitochondrial energetic deficits, reflecting their exceptionally high metabolic demand. The electron transport chain (ETC), essential for ATP production, comprises multiple protein complexes that require coordinated assembly and redox-sensitive regulation. In this study, we identified LRRK2-the most common genetic contributor to both familial and sporadic PD-as a regulator of cytochrome c oxidase (COX), the terminal enzyme of the ETC, through its control of the redox status of mitochondrial copper chaperones. Expression of pathogenic LRRK2 G2019S mutant increased the proportion of reduced (Cu-deficient) forms of COX11 and SCO1, two chaperones essential for COX metalation, thereby impairing COX assembly and promoting ETC dysfunction. Within this regulatory hierarchy, COX19 functions as a downstream effector of LRRK2 and an upstream modulator of COX11 and SCO1 redox status. Moreover, LRRK2 and COX19 reciprocally regulate each other's expression and cooperatively disrupted COX biogenesis. In vivo, exogenous expression of COX19 via AAV gene delivery induced dopaminergic neurodegeneration and motor deficits, which were effectively rescued by pharmacological inhibition of LRRK2 kinase activity. Together, these findings define a positive feedback LRRK2-COX19 signaling axis that governs mitochondrial redox homeostasis and COX assembly, highlighting a promising therapeutic target for PD and related mitochondrial disorders.

The DJ-1 protein was initially identified as an oncogene, but subsequent studies revealed its crucial protective role in neurodegenerative diseases. Increasing evidence indicates that DJ-1 possesses critical physiological functions in skeletal muscle, but the underlying mechanisms remain to be systematically elucidated. Existing research has conclusively demonstrated that DJ-1 is widely expressed in skeletal muscle and functions as a central hub integrating multiple pathways to establish a multi-level cellular protection network: it safeguards energy metabolism by maintaining mitochondrial structure and function; enhances antioxidant capacity by directly scavenging ROS and regulating Nrf2/ARE signaling; and delays muscle aging by inhibiting protein aggregation and preserving protein homeostasis. Under pathological conditions, DJ-1 dysfunction is closely associated with muscular dystrophy, inflammatory myopathy, metabolic myopathy, and muscle atrophy. Its abnormalities lead to mitochondrial damage, exacerbated oxidative stress, and disrupted protein homeostasis, ultimately triggering muscle structural deterioration. Based on these insights, researchers have developed various DJ-1 regulatory strategies, including small-molecule activators, transcriptional modulators, and functional peptide compounds, which show promising therapeutic potential. This review represents the first systematic, cross-disease integration of DJ-1's role in aging-related sarcopenia, diabetic myopathy, inflammatory myopathies, and neuromuscular degenerative diseases. It elucidates DJ-1's core function as a central integrator coordinating antioxidant defense, mitochondrial homeostasis, metabolic regulation, and protein homeostasis. A deeper understanding of DJ-1's mechanisms will provide critical theoretical foundations for elucidating the common pathological basis of skeletal muscle diseases and developing novel therapeutic strategies.

Aging is the primary risk factor for numerous chronic diseases, making the identification of safe and effective anti-aging strategies a critical focus in biomedical research. Heterochronic parabiosis by blood exchange shows that the exchange interaction between young and old plasma can exert anti-aging effects through exchange of bloodborne factors. However, the limited plasma source greatly affects clinical translation. Here, we demonstrate that periodic therapeutic phlebotomy in D-galactose-induced aging models exerts significant and comprehensive anti-aging effects, which is reflected by a notable improvement in aging-associated behavioral deficits and neurogenesis, a significant decrease in the level of circulating senescence-associated secretory phenotypes, and an obvious mitigation of aging-associated structural degradation and molecular alterations within the muscle, bone, liver, kidney, and nervous systems. Mechanistically, periodic therapeutic phlebotomy induces bone marrow microenvironment restoration through functional rescue of mesenchymal stem cells and endothelial cells, thereby reestablishing balanced hematopoietic homeostasis. This hematopoietic revitalization subsequently drives systemic improvements in peripheral blood composition and function. In conclusion, our work provides preliminary evidence suggesting that periodic therapeutic phlebotomy exerts anti-aging effects by restoring bone marrow function and mitigating aging phenotypes, subsequently driving peripheral blood functional restoration. Given its technical simplicity and safety profile, this periodic therapeutic phlebotomy strategy will hold potential to pave the way for clinical translation.

Excessive glucocorticoid (GC) administration is a major contributor to bone marrow senescence, which subsequently contributes to the development of osteonecrosis. Conventional therapeutic approaches have shown limited efficacy, largely because current interventions are typically initiated only after a definitive diagnosis of bone deterioration-by which time the disease has often progressed to an intermediate or advanced stage, thereby missing the optimal therapeutic window for effective intervention. Here, we report that a semi-synthetic sulfated chitosan (SCS) can effectively prevent the onset of GC-induced osteonecrosis by suppressing complete senescence of the bone marrow and maintaining coupling between arterial vascularization and osteogenesis. SCS attenuates the spread of GC-induced primary adipocyte senescence into secondary senescence, effectively limiting the progressive amplification of the senescence cascade. Rather than directly intervening in the prostaglandin/PPARγ/INK positive feedback loop within the senescent adipocyte lineage, SCS functions as an extracellular matrix component that activates the IGF-1/PI3K/Akt/mTOR signaling cascade. This activation reprograms the GC-induced lineage commitment bias of bone marrow leptin receptor

The World Health Organization (WHO) public health framework for healthy aging advocates for action on the trajectories of intrinsic capacity (IC) across a person's life course to optimize functional ability. While the WHO integrated care for older people (ICOPE) framework provides guidance on a systematic care pathway on IC screening, clinical assessment to clarify IC deficits and person-centered management, its real-world implementation and evaluation remain nascent. The Intrinsic Capacity Promotion in Primary Care for the Frail (IMPACTFrail) program for mildly frail older adults in Singapore's primary care seeks to operationalize WHO ICOPE and national strategies.

Vascular smooth muscle cells (VSMCs) are crucial components of the arterial wall, playing a vital role in maintaining vascular integrity and function. Previous studies have identified HRD1 as a potential target for alleviating senescence in VSMCs. Ginsenoside Rb1 has been shown to counteract endothelial cell senescence triggered by H

Histone lysine methylation regulates the expressions of mitochondrial function-related genes, which presents a "nucleus-to-mitochondria" signal communication, playing a key role in aging control. However, the underlying mechanisms remain elusive due to the complexity of histone lysine methylation in transcription modulation. In this study, using

The functional network architecture of the aging brain undergoes significant systematic and idiosyncratic changes. Emergent individualized network mapping approaches may yield better or more sensitive explanatory insight about age-related neural and behavioral variability, although most applications have focused on young adults. In the current study, we tested the validity and impact of mapping individual-specific topography in two fMRI datasets comprising 112 young (18-35 years) and 176 older adults (60-92 years). Older adults had more idiosyncratic network topography than young adults. Individualized maps from resting-state fMRI improved network homogeneity and fidelity to task fMRI activations, while also exhibiting intra-individual reliability and inter-individual discriminability over a 2-year interval. Last, traditional group-averaged (vs. individualized) network mapping had a moderate-to-large impact on individual-level estimates of network segregation, a widely-studied measure of functional brain aging. Therefore, individualized network mapping captures important heterogeneity in older adulthood and may yield more precise characterization of neurocognitive aging.

To investigate the impact of Life's Essential 8 (LE8) on mortality risk and life expectancy in patients with and without cardiometabolic multimorbidity (CMM).

Mitophagy dysfunction is a critical contributor to retinal pigment epithelial (RPE) cell damage during the progression of retinal degenerative diseases, including age-related macular degeneration (AMD). In this study, we investigated the effects of paeoniflorin (PF) on mitophagy in RPE cells, with a particular focus on the CUL3/LKB1/AMPK/ULK1 signaling pathway. ARPE-19 cells were treated with different concentrations of PF to evaluate cytotoxicity, and its protective effects were further examined in H₂O₂-induced oxidative stress models in vitro and in sodium iodate (NaIO₃)-induced RPE injury models in vivo. Protein levels of CUL3, apoptosis-related factors, mitophagy markers, and components of the LKB1/AMPK/ULK1 pathway were assessed by western blotting, and mitophagy was visualized using MitoTracker labeling. Cycloheximide (CHX) and coimmunoprecipitation (Co-IP) assays were performed to analyze the interaction between CUL3 and LKB1. PF treatment enhanced mitophagy in H₂O₂-stimulated ARPE-19 cells, whereas Parkin knockdown markedly attenuated this effect. In oxidatively damaged cells, PF promoted AMPK and ULK1 phosphorylation, increased mitophagy-associated protein expression, and alleviated mitochondrial dysfunction; these protective effects were abolished by pharmacological inhibition of AMPK or ULK1. In addition, CUL3 overexpression significantly attenuated PF-induced mitophagy activation and reduced PF-associated phosphorylation of LKB1, AMPK, and ULK1. Mechanistically, PF downregulated CUL3 expression, while CUL3 promoted the ubiquitination and degradation of LKB1. Silencing CUL3 induced mitophagy in H₂O₂-treated cells, whereas concurrent knockdown of CUL3 and LKB1 abolished this effect. In vivo, PF mitigated RPE cell loss, enhanced mitophagy, and activated the CUL3/LKB1/AMPK/ULK1 signaling pathway in the retinal tissues of NaIO₃-induced mice. Collectively, these findings indicate that PF protects against RPE injury in an NaIO₃-induced AMD-like model by downregulating CUL3 expression and activating LKB1/AMPK/ULK1-mediated mitophagy.

As populations age at an unprecedented pace globally, frailty has emerged as a critical challenge in perioperative care. While clinicians broadly acknowledge the value of frailty assessment, embedding it systematically in care pathways remains difficult to implement systematically. We compared perioperative frailty guidelines from the United Kingdom, United States, Europe, and the Asia-Pacific, finding significant inconsistencies in tool selection, risk stratification criteria, and pathway design. Strikingly, approximately 99.6% of frailty research remains confined to risk characterization, whereas only 0.4% is directed toward improving care, highlighting a substantial gap between evidence and practice. Digital technologies promise a wider uptake of frailty screening, and yet algorithmic bias threatens to under-detect frailty in underserved groups if left unchecked. We outline five policy priorities: first, an internationally coordinated consensus on core assessment standards needs to be reached; second, end-to-end pathways that span screening, graded assessment, targeted intervention, and outcome tracking need to be devised; third, digital technology needs to be accelerated along with the devising of explicit safeguards for equity; fourth, high-quality evidence needs to be generated through function-centered outcomes and cost-effectiveness analyses to demonstrate the real-world value of frailty-focused care pathways; and fifth, frailty management needs to be integrated into national chronic-disease frameworks. Closing the gap between detection and action will require global collaboration and a reframing of frailty, not as a passive label but as a call to intervene.

Biochemical aging involves progressive declines in energy metabolism and redox maintenance. The peroxiredoxin enzyme family is critical for maintenance of cellular redox states. In mice, enucleate mature red blood cells (RBCs) persist for roughly 50 days, providing an ideal system for tracking cellular aging