Longevity Papers

Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging.

The colon is one of the gastrointestinal organs most profoundly affected by aging. Recent advances in our understanding of both colonic physiology and the general mechanisms of aging have significantly expanded our knowledge of the types and underlying processes of colonic aging. In this review, we summarize current insights into the cellular and molecular mechanisms that drive physiological aging of the human colon. We examine the unique structural and functional features of key components of the colon, including the epithelium, local immune system, microbiome, enteric neurons, and smooth muscle cells, and explore how aging affects each of these cell populations, ultimately impacting overall colonic function. In the epithelium, increased mutational burden does not appear to be the primary driver of age-related dysfunction. Instead, dysregulation of signaling pathways such as EGF and Wnt is likely responsible for key phenotypic changes. Aged colonic neurons display protein misfolding and axonal dysfunction reminiscent of aging processes observed in the central nervous system. Similarly, smooth muscle cells exhibit impaired contractility, which is associated with disruptions in calcium homeostasis and deficits in cholinergic signaling. At the same time, age-related activation of the local immune system mirrors broader immunosenescence and may be further influenced by shifts in the gut microbiome, although a consistent aging-associated microbiome signature has yet to be identified. These multifaceted changes, combined with the colon's inherent regional and cellular complexity and the challenges of modeling human colonic aging, continue to fascinate but also pose substantial obstacles for research. Emerging experimental models and clinical strategies offer promising avenues for improving the prevention and treatment of age-associated colonic dysfunction.

Age-related hearing loss (ARHL) and cognitive dysfunction are established comorbidities, yet their molecular links remain unclear. This study employed a D-galactose-induced ARHL guinea pig model, along with multimodal analysis, to elucidate the bridging role of autophagy. ARHL animals exhibited significantly elevated hearing thresholds (>65 dB SPL) and spatial memory deficits (Morris Water Maze escape latency increased 0.77-fold). PET/CT revealed a 28.57 % reduced hippocampal glucose metabolism (SUV), negatively correlating with cognitive impairment. Molecular analysis revealed that the autophagic marker LC3B was initially upregulated (0-8 weeks) and then declined (12-16 weeks), while P62 paradoxically mirrored the dynamics of LC3B, indicating an imbalance in autophagy homeostasis. Transmission electron microscopy identified mitochondrial cristae dissolution, postsynaptic density thinning, and widened synaptic clefts, linking ultrastructural damage to metabolic compromise via autophagy dysregulation. We establish an evidence chain: "ARHL-autophagy imbalance-hippocampal hypometabolism-cognitive decline". Autophagy initially exerts neuroprotection by clearing damage but transitions to neurotoxicity under chronic dysregulation, causing neuronal energy insufficiency. These findings reveal novel mechanisms connecting ARHL and cognitive impairment, providing a foundation for autophagy-targeted therapies.

Aging in Caenorhabditis elegans is regulated by evolutionarily conserved pathways that coordinate cellular maintenance and systemic homeostasis. Here, we review recent advances on four major longevity regimens, including reduced insulin/insulin-like growth factor 1 signaling (IIS), dietary restriction (DR), mild inhibition of mitochondrial respiration, and germline deficiency. Each longevity-promoting regimen enhances protein and RNA quality control, metabolic remodeling, and stress resistance to delay functional declines with age. Reduced IIS strengthens proteostasis and RNA surveillance. DR remodels metabolism and activates autophagy. Mild mitochondrial inhibition elicits adaptive redox signaling and quality control responses. Germline deficiency links reproductive cues to somatic maintenance. We highlight that longevity arises from the integrated regulation of transcriptional, metabolic, and inter-tissue signaling networks. Our review will provide valuable insights obtained from C. elegans into the conserved mechanisms of aging, facilitating the development of interventions that promote healthy longevity in humans.

The budding yeast Saccharomyces cerevisiae is a well-established model for studying the genetic basis of complex traits, and it is a powerful system for investigating mechanisms of aging. Here, we examine the genomic and transcriptomic factors contributing to increased replicative age in recombinant yeast populations harboring standing genetic variation. Using Fluorescence-Activated Cell Sorting (FACS), we isolated young and aged cohort pairs across twelve biological replicates and sequenced their progeny to assess patterns of differentiation. Most differentiated alleles were located in coding regions, including significant variants within 132 unique genes. Transcriptomic analysis revealed 60 differentially expressed genes in aged populations, including 18 genes with increased expression in aged cohorts, and 42 genes with decreased expression. Although only two genes (RFA3 and WSC4) were implicated in both genomic and transcriptomic analyses, functional overlap associated with protein homeostasis, DNA repair, and cell cycle regulation was evident across datasets. Notably, we found no strong evidence that differentially expressed genes were more likely to occur in close proximity to significant gene variants. This suggests that late-life survival is not predominantly governed by local cis-regulatory interactions (e.g. variants within promoter regions). These findings underscore the power of integrating genomic and transcriptomic data to elucidate the genetics of complex traits such as aging, demonstrating how multi-omics approaches can reveal functional relationships that may be overlooked by single-layer analyses.

Aging is a complex biological process characterized by the gradual deterioration of cellular functions, leading to an increased susceptibility to chronic diseases. In the search for interventions to promote healthy aging and extend lifespan, Pyrroloquinoline Quinone (PQQ) and Nicotinamide Mononucleotide/Nicotinamide Riboside (NMN/NR) have emerged as promising anti-aging agents. PQQ exerts its anti-aging effect primarily through enhancing mitochondrial biogenesis, exerting antioxidant activity, and modulating inflammatory pathways. On the other hand, NMN/NR act as key precursors in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in energy metabolism, cellular homeostasis, and DNA repair, thereby promoting longevity. This review systematically compares the mechanisms of action and efficacy of those compounds in mitigating age-related complications. Furthermore, this emphasizes the potent synergistic effect when PQQ and NMN/NR are used in combined formulations, highlighting their complementary pathways to support healthy aging. Despite supporting preliminary data and patented formulations, strong scientific evidence encouraging the synergistic anti-aging potential of PQQ and NMN/NR remains limited, highlighting the need for robust studies. Collectively, PQQ and NMN/NR offer distinct complementary strategies to promote healthy aging and prevent age-related diseases; their combination could offer a more effective approach to enhance healthy aging and longevity.

Cognitive decline is one of the key challenges with aging, with significant implications for independence, quality of life, and healthcare burden. As pharmacological treatments remain limited in efficacy and often carry adverse effects, there is growing interest in safe, accessible, non-pharmacological strategies to preserve cognitive function. This Short Review explores the potential of combining two approaches that, individually, have shown beneficial effects on cognitive function: ergothioneine, a naturally occurring amino acid with antioxidant and anti-inflammatory properties, and physical exercise. Ergothioneine accumulates in the brain and other high-stress organs, where it modulates the redox balance, dampens chronic inflammation and supports mitochondrial function. Meanwhile, physical exercise has well-documented benefits for neuroplasticity, cerebral perfusion, and cognitive performance. Preclinical studies suggest ergothioneine supports exercise performance and muscle recovery without attenuating adaptive responses. Despite their distinct and complementary mechanisms, currently there are no available studies exploring the combined effects of ergothioneine and exercise on cognition. We propose a future research agenda that includes mechanistic animal studies, dose-response trials, and clinical interventions in at-risk populations. Together, the combination of ergothioneine and exercise may offer a low-risk, multifaceted approach to enhancing cognitive resilience in aging.

Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test the hypothesis that non-neuroinvasive influenza A virus (IAV) pneumonia results in transcriptional responses in brain microglia that drive premature expansion of DAM. Using bulk and single-cell RNA-sequencing, metabolomics, and spatial transcriptomics, we profiled neuroimmune populations in young, middle-aged, and old male mice during IAV infection and recovery. We observed an increased abundance of DAM, interferon-responsive microglia (IRM), CD4+ T cells, and CD8+ T cells in white matter regions beginning in middle age and persisting in old animals, irrespective of IAV infection. DAM exhibited a metabolic shift toward aerobic glycolysis with disrupted TCA cycling, citrulline depletion, and an elevated itaconate/-ketoglutarate ratio. Spatial transcriptomic profiling of the human middle frontal gyrus (MFG) in normal agers, SuperAgers, and patients with dementia revealed an analogous accumulation of DAM and CD8+ T cells in white matter. IAV pneumonia induced a transient immunosenescent-like response in microglia, marked by glucocorticoid-responsive gene expression and Ccnd3 upregulation. In response to IAV pneumonia, DAM expanded in middle-aged mice, whereas old mice were elevated at baseline and were largely unaffected by IAV infection. The age-related expansion of DAM was unaffected by pharmacological depletion and repopulation of microglia with a CSF1R antagonist or genetic gain or loss of function of the phagocytic receptor MERTK, suggesting the DAM phenotype is driven by the CNS microenvironment, rather than cell-intrinsic mechanisms. Our findings suggest that IAV pneumonia induces an acute immunosenescence response in microglia and accelerates the age-dependent expansion of DAM in white matter.

This study aims to analyze the global research landscape and identify emerging trends in research hotspots, key technologies, and clinical applications in proteomics research in aging from 1998 to June 20, 2025. Publications related to aging and proteomics from 1998 to June 20, 2025 were retrieved from the Web of Science Core Collection. A bibliometric analysis was conducted using VOSviewer, CiteSpace, and R 4.3.3 to evaluate publication trends, research collaborations, and emerging topics. A total of 3,638 studies were included in the analysis. The USA, China, and Germany led in publication volume with 983, 829, and 227 articles respectively. Harvard University was the most prolific institution with 306 publications, followed by University of California System and Chinese Academy of Sciences. Key research was published in high-impact journals such as Journal of Proteome Research, Aging Cell, and Proteomics. Luigi Ferrucci, and D. Allan Butterfield were the most influential authors. Cluster analysis identified five research hotspots: protein expression and cellular senescence mechanisms, age-related diseases and neurodegeneration, cellular processes and molecular mechanisms, stress response and longevity mechanisms, and advanced proteomics technologies and biomarker discovery. Burst keyword analysis revealed recent research hotspots including health, dementia, extracellular vesicles and receptor. This study demonstrates that aging proteomics research has matured into distinct yet interconnected domains spanning basic molecular mechanisms, clinical disease applications, and technological innovations, reflecting the field's evolution toward translational and precision medicine approaches for age-related conditions. Future research directions may focus on clinical translation of aging biomarkers and development of precision medicine approaches for age-related diseases.

Skin is both the most visible and most environmentally exposed organ, with apparent aging phenotypes. DNA methylation clocks faithfully capture the progression of aging, but so far have been limited to training on abundant in vitro material or invasively collected samples to generate narrow methylomes using microarray platforms. Here, we demonstrate that skin biological age can be measured directly from a person's face with superior accuracy, using non-invasive tape-stripping. We developed two clocks, MitraSolo, based on single CpGs, and MitraCluster, on regions, trained on the largest enzymatic methyl-sequencing dataset of human epidermis (n = 462). Our models were validated on independent, longitudinal, and external datasets and were compared against established clocks. They predict age accurately, with an error of approximately 4 years, outperforming others on epidermal samples. They maintain high accuracy at low sequencing depths, enabling cost-effective scalability and show intra-individual prediction variation <2 years, highlighting their reproducibility. Their predictive capacity generalised across anatomical sites, conversion and sampling methodologies and on in vitro material. They also successfully captured the rejuvenating effects of Yamanaka factor treatment. MitraSolo and MitraCluster represent a new class of epigenetic clocks optimised for human skin with characteristics that support their use in clinical research, intervention monitoring, and skincare innovation.

Diabetic kidney disease (DKD) remains a serious microvascular consequence of diabetes mellitus globally. DKD pathophysiology is complex and multifactorial; while current therapies are limited, they offer partial renoprotection. However, disease progression continues, underscoring the need for novel therapeutic avenues. Recent advances highlight the "gut-kidney axis" as a pivotal contributor to DKD. Hyperglycemia-induced gut dysbiosis exacerbates renal injury through increased systemic inflammation, RAAS activation, and buildup of uremic toxins. These toxins epigenetically suppress renal expression of α-Klotho, an anti-aging protein with critical antioxidative, anti-inflammatory, and antifibrotic functions, thereby accelerating DKD progression. Despite its emerging importance, α-Klotho remains underexplored as a therapeutic target in DKD, particularly in gut microbiota regulation. α-Klotho could be a potential therapeutic target against DKD via gut-kidney axis modulation. This review elucidates the mechanistic link between gut dysbiosis and the progression of DKD. Additionally, it highlights the impact of uremic toxins on renal α-Klotho expression and subsequent progression to DKD. Therefore, we proposed α-Klotho as a potential therapeutic avenue against DKD through modulation of the gut-kidney axis. This review also highlighted that the combination therapy approach may offer synergistic benefits by targeting multiple pathogenic pathways.

Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep disorder characterized by chronic intermittent hypoxia (CIH), which has been increasingly recognized for its systemic effects on pediatric skeletal development. However, the mechanism by which CIH influences bone growth and homeostasis remains largely unexplored. In this study, it is demonstrated that CIH exposure in young murine models induces cellular senescence within the metaphysis of long bones, resulting in compromised bone formation and growth retardation. Through single cell sequencing and in situ immunostaining, it is identified that the senescent cells predominantly consist of osteoprogenitors. Mechanistically, CIH enhances the activity of hypoxia-inducible factor 1-alpha (HIF-1α) in osteoprogenitors and subsequently downregulates trimethylation of histone H3 at lysine 27 (H3k27me3) through the suppression of polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2), thereby facilitating the expression of senescence-associated genes. Employing both genetic and pharmacological strategies, it is demonstrated that the restoration of H3K27me3 levels via UTX inhibition (achieved through in vivo knockout or GSK-J4 treatment) effectively prevents CIH-induced senescence, promotes osteogenesis, and alleviates bone loss and growth retardation. These findings elucidate a novel epigenetic mechanism that underlies the skeletal impairments associated with CIH and underscore the therapeutic potential of targeting histone methylation to mitigate hypoxia-induced bone defects.

Cellular systems governing protein folding depend on functional redundancy and diversification to maintain proteostasis. Here, using Caenorhabditis elegans, we show two homologous ER-resident HSP70 chaperones, HSP-3 and HSP-4, have overlapping and distinct roles in ER proteostasis and organismal physiology. Their expression and function vary by tissue, age, and stress, impacting ER stress resistance, reproduction, body size, and lifespan. We also find HSP-3 and HSP-4 uniquely regulate dietary restriction and reduced insulin signaling-mediated longevity in C. elegans. Notably, knockdown of hsp-4, but not hsp-3, induces autophagy and enhances tolerance to protein aggregation stress; this process requires the ortholog of ER-Phagy receptor Sec-62 (C18E9.2) and IRE-1. Finally, human cell data suggests that the dissociation of chaperone Binding Immunoglobulin Protein (BiP) from IRE-1 during times of ER stress promotes autophagy by enhancing the interaction of IRE-1 and Sec-62. These findings reveal how ER chaperone diversification maximizes stress resilience and suggest a BiP-dependent regulation of autophagy.

Sarcopenic obesity (SO), a dual condition characterized by the coexistence of sarcopenia and obesity, elevates the risk of metabolic disorders, disability, and mortality to magnitudes exceeding the combined risks of both conditions individually, demonstrating a "super-additive impairment" effect on health. Therefore, this study aims to investigate the mechanisms underlying the pathogenesis and progression of SO. We utilized natural aging mice fed high-fat diets (HFD) to simulate the progression of muscle mass decline observed in geriatric populations and high-calorie diets prevalent in modern societies, creating an SO animal model with exceptional clinical relevance. Our study demonstrates that HFD exacerbates age-related reductions in muscle mass, accompanied by decreased physical performance and increased lipid accumulation. Importantly, HFD-induced lipid infiltration emerges as a significant contributor to the further decline in skeletal muscle mass in SO mice, and the Nrf2/Prdx6 pathway is a mechanism regulating this factor. Aerobic exercise, a safe and reliable means for older adults, is particularly effective for fat loss and muscle maintenance. In our study, aerobic exercise effectively alleviated the detrimental effects of HFD on muscle health in aging mice. Mechanistic studies revealed that Nrf2 and Prdx6 protein expression was significantly suppressed in vivo by HFD and in vitro following palmitic acid (PA) exposure. Conversely, overexpression of Nrf2 and Prdx6 in vitro was able to mimic the protective effects of aerobic exercise. Our results indicate that the Nrf2/Prdx6 pathway plays a crucial role in counteracting muscle mass loss induced by HFD and may underlie beneficial effects of aerobic exercise on skeletal muscle.

Lipofuscin, a marker of aging, is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons. Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation. However, recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes, and several questions remain unanswered. For instance, why do lipofuscin granules accumulate preferentially in aged neurons and microglia? What happens to these pigments upon neuronal demise? Particularly in neurodegenerative diseases like Alzheimer's disease (AD), why does amyloid β (Aβ) deposition usually begin in late adulthood or during aging? Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter? In this review, we argue that lipofuscin should be revisited not as a simple biomarker of aging, but as a potential modulator of neurodegenerative diseases. We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction, oxidative stress, lipid peroxidation and disease onset-mechanisms critically implicated in neurodegeneration. We also explore the potential interactions of lipofuscin with Aβ and their spatial location, and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation. Finally, we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES), to train mortality prediction-based phenotypic ages (PhenoAge [systemic] and organ-specific ages [cardiovascular, kidney, liver, and musculoskeletal]) from NHANES-III, and applied it in the continuous NHANES. Weighted linear regression analyses revealed significant associations between five diet scores-Healthy Eating Index 2020, Alternate Healthy Eating Index, Dietary Approaches to Stop Hypertension, Alternate Mediterranean Diet Score, and Dietary Inflammatory Index-derived from 24-hour diet recalls and accelerations in biological ages, encompassing both phenotypic and epigenetic measures (GrimAge2 and DunedinPoAm). Reduced rank regression was used to derive five aging-related diet scores that considered food groups within each previously established score as predictors and phenotypic age accelerations as response. The strongest food predictors of favorable aging-related diet scores included dietary patterns high in vegetables, fruits and high-quality protein (dairy, fish and legumes), and low in added sugar, sugar-sweetened beverages and red/processed meat. Weighted Cox regression models revealed that aging-related diet scores were more strongly associated with mortality risk than their respective diet scores alone.

Age-related auditory dysfunction affects half of all individuals 60 years and older, yet its causes are poorly understood. While commonly associated with cochlear dysfunction, a growing body of literature suggests that dysfunction originating in the auditory cortex itself is also a major contributor. Here, we review recent literature that describes the effects of aging on the primary auditory cortex in humans, non-human primates, rodents, and a variety of other species. During aging, individuals with auditory cortical dysfunction experience deficits in spectral and temporal processing of sounds, resulting not only from a loss of inhibition but also from an extensive restructuring of cortical circuits. Importantly, aging in the auditory cortex is sex-dependent, yet few studies account for this variable. A lack of comprehensive knowledge on aging in the auditory cortex hinders the path toward restoring cortical function through auditory training or broader cortical rehabilitation paradigms. Thus, we propose a cohesive mechanism of aging in the primary auditory cortex that involves a complex interaction between excitatory and inhibitory neurons, which several factors can modify. These factors include input from higher-order cortical areas, such as the orbitofrontal cortex, as well as the wide-ranging effects of neuromodulators and the external sensory environment, which must be accounted for in a sex-dependent manner.

Cellular hallmarks of aging have been discovered and characterized in a number of model species for studying aging biology - such as humans, mice, fruit flies, and nematodes. Whether these canonical age-related changes to cellular physiology are present across diverse species that have variable rates of demographic aging remains less studied. Here, we tested whether several ubiquitous cellular hallmarks of aging - mitochondrial function, reactive oxygen species generation, and inducible DNA damage - change with age and in a sex-dependent manner in a species with indeterminate growth and reproduction (painted turtles, Chrysemys picta). A further feature of their biology that recommends them for an ecological model of vertebrate aging is their female-biased longevity, despite an absence of genotypic sex determination. Thus lifespan and aging may be reliable features of sex-specific life-histories. We measured aspects of mitochondrial health (cellular basal, maximal, and spare oxygen consumption rates), cellular levels of reactive oxygen species, and aspects of DNA damage and repair from exposure to UVB. We used these measures across several physiological axes as proxies for age-related physiological dysfunction. We further assessed our measures across several populations of painted turtles. We found that sex explained the largest proportion of variation, with males differing from females in mitochondrial function, reactive oxygen species production, and inducible DNA damage. In several cases, age significantly interacted with sex, but the effect size was small relative to sex alone. Thus, we found that sex, rather than age or size, was a consistent predictor of cellular aging physiological in this species with where females live longer and age slower.

Mobility and cognitive functions are closely linked in old age. Although a relationship between mobility and cognitive function has also been demonstrated in midlife, it has not been tested under conditions that might reflect real-life locomotion. In this study, the association between attention and processing speed, as measured by choice reaction time (CRT), and mobility in midlife was examined using spatiotemporal gait indices during outdoor walking and a self-perceived mobility questionnaire. Fifty middle-aged adults (53.98 ± 5.32 years) completed a 2-minute walk in an urban environment with and without a dual task of texting on a smartphone. Gait speed, gait variability (stride time variability), and gait similarity (dynamic time warping) in the anteroposterior and medio-lateral axes were measured, and self-perceived mobility was assessed using the Mobility in Middle Age Questionnaire (MMQ). Attention and processing speed were measured with the Deary-Liewald CRT. Slower CRT was associated with reduced medio-lateral similarity during dual-task walking (r = 0.316, p = 0.032) and with lower self-perceived mobility (MMQ, r = -0.422, p = 0.007). Hierarchical regression analysis showed that medio-lateral gait similarity explained 10.0% of the variance in CRT, while self-perceived mobility explained 14.4%. The relationship between mobility and cognition in ecologically valid contexts may indicate a common age-related mechanism that emerges in midlife and can be exploited by interventions and monitoring programs aimed at promoting healthy aging.

Age-friendly environments are a key determinant of healthy aging, while subjective age is assumed to be a psychological factor affecting one's behavior and well-being. This study explores how age-friendly environments play a role in promoting healthy aging through (1) putting macro-social and micro-family environments in the same context and (2) examining the moderating role of subjective age. In a random sample of 2,788 older adults, we found that (1) higher levels of age-friendly family and social environments were consistently associated with better health outcomes; (2) subjective age significantly moderated the social environment-frailty relationship (β = -0.26,

Aberrant innate immune responses contribute significantly to cellular senescence, yet the precise interplay between innate immunity and senescence remains poorly characterized. Here, we elucidate the pivotal role of nuclear respiratory factor 1 (NRF1) in orchestrating innate immune responses that drive senescence and the senescence-associated secretory phenotype (SASP). NRF1 deficiency delayed cellular senescence and ameliorated age-related deterioration in multiple organs. Mechanistically, NRF1 enhanced SASP by transcriptionally regulating TBK1 and IRF3, critical nodes in innate immunity essential for senescence induction. Conversely, NRF1 deficiency suppressed innate immune activation, thereby attenuating inflammation associated with senescence and aging. Additionally, DNA damage activated ATM kinase, which phosphorylated NRF1 at Ser393, augmenting the NRF1-TBK1/IRF3-type I interferon axis and exacerbating cellular senescence. Furthermore, NRF1 knockdown treatment effectively mitigated aging phenotypes and extended lifespan in aged mice. Collectively, our findings underscore the essential role of the ATM-NRF1-TBK1/IRF3-type I interferon axis in DNA damage-induced senescence, suggesting that targeted NRF1 modulation holds therapeutic promise for improving inflammaging.

Background: Epigenome-wide association studies (EWAS) have identified associations between DNA methylation and blood pressure, yet most rely on single-time-point data and cannot capture how methylation and blood pressure relationships change with age. Methods: We conducted a longitudinal EWAS of 1,945 blood samples from 976 participants in the Multi-Ethnic Study of Atherosclerosis using a spline-based varying-coefficient model to detect age-dependent associations between DNA methylation in blood and blood pressure traits. Findings were evaluated for replication in 1,187 samples from the Framingham Heart Study. Models were adjusted for sex, ancestry, and leukocyte composition to account for cellular heterogeneity. Results: Six CpG sites showed significant age-dependent associations with systolic or pulse pressure after correction for multiple testing. These included loci within STIP1, CSRP1, and KDM6A that replicated in the Framingham cohort. Several CpG sites demonstrated a reversal of effect direction with advancing age, where higher methylation was associated with higher systolic pressure in younger adults but lower pressure later in life. Pathway enrichment analyses identified focal adhesion, actin cytoskeleton remodeling, and Wnt/{beta}-catenin signaling, which are processes relevant to vascular aging. Drug target mapping identified 23 FDA-approved agents interacting with genes at these loci. Conclusions: Blood-derived DNA methylation shows dynamic age-related associations with blood pressure that likely reflect systemic or vascular aging processes rather than direct cellular mediation. Longitudinal analytical frameworks can reveal temporal patterns in epigenetic variation that are not detectable in single time point studies and may inform the discovery of biomarkers for age related cardiovascular risk.

In recent years, global life expectancy has risen significantly, leading to a marked increase in the elderly population. Aging disproportionately affects the brain, resulting in cognitive decline and increased susceptibility to neurodegenerative diseases. This vulnerability is largely due to the high metabolic activity of neural tissue and its sensitivity to reactive oxygen species (ROS). Consequently, oxidative and inflammatory processes are key contributors to cellular damage and age-related cognitive deficits. These oxidative processes may act as primary drivers of neuronal damage during aging. Recent evidence suggests that phenolic compounds may play a crucial role in neuroprotective strategies. Among these, gallic acid (GA) has garnered attention due to its potent antioxidant and anti-inflammatory properties, which enhance neuronal resilience in animal models. However, the effects of GA on hippocampal neurodegeneration during aging remain unclear. In this study, we evaluated the impact of GA on learning, memory, redox balance, neuroinflammation, apoptosis, and synaptic plasticity in the hippocampus (Hp) of aged rats. Male rats aged 18 months received a daily dose of GA (20 mg/kg) for 60 days. GA treatment significantly improved short- and long-term recognition memory. In the Hp, ROS, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and lipid peroxidation were reduced, while superoxide dismutase (SOD) and catalase (CAT) activities increased. GA administration also decreased caspase-3 expression. Collectively, these findings indicate that GA enhances antioxidant and anti-inflammatory defenses, thereby mitigating hippocampal damage and supporting its potential as a promising therapeutic strategy to prevent or reduce neurodegenerative disorders associated with aging.

Nicotinamide mononucleotide (NMN), a potent nicotinamide adenine dinucleotide (NAD

Insulin/insulin-like growth factor signaling inhibits FOXO transcription factors to control development, homeostasis, and aging. Here, we use proximity labeling to identify proteins interacting with the C. elegans FOXO DAF-16. We show that in well-fed, unstressed animals harboring active insulin signaling, DAF-16 forms a complex with the PAR-1/MARK serine/threonine kinase, a key regulator of cell polarity. PAR-1 inhibits DAF-16 accumulation and promotes DAF-16 phosphorylation at S249, at a conserved motif that PAR-1/human MARK2 phosphorylates in vitro. DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1. DAF-2 also promotes PAR-1 expression by inhibiting DAF-16. PAR-1 knockdown, or DAF-16 S249A, prolong lifespan, whereas phosphomimetic DAF-16 S249D suppresses the longevity of daf-2 mutants. At low insulin signaling, DAF-16 proximity labeling highlights transcription factors, chromatin regulators, and DNA repair proteins. One interactor, the zinc finger/homeobox protein ZFH-2/ZFHX3, forms a complex with DAF-16 and prolongs lifespan. Our work provides entry points for hypothesis-driven studies of FOXO function and longevity.

Western-style diets, high in saturated fats and refined carbohydrates and low in dietary fiber, are strongly linked to cognitive decline, particularly in aging. However, the specific macronutrient contributions and mechanisms underlying these effects remain unclear. Here, we investigated how short-term exposure to refined-ingredient diets (RDs) varying in fat and sugar content impacts memory, mitochondrial function, and metabolic signaling in young adult and aged male rats. A key finding was that amygdala-dependent memory was broadly impaired in aged rats across all RDs, regardless of fat or sugar content, suggesting a unique vulnerability of the aging amygdala to refined dietary ingredients. In contrast, hippocampal-dependent memory impairments were observed only in aged rats fed a high-fat, low-sugar RD. Functional mitochondrial assays revealed significant RD-induced reductions in oxygen consumption in amygdalar and hippocampal mitochondria isolated from aged rats. Cell-type-specific analyses identified aged microglia as particularly susceptible, showing widespread suppression of mitochondrial respiration with limited metabolic flexibility. Astrocytes and synaptic mitochondria exhibited more region- and age-specific effects. All RDs lacked dietary fiber, and consistent with prior findings, butyrate, a microbial-derived short-chain fatty acid, was rapidly and robustly depleted in both gut and circulation, especially in aged animals. Proteomic and phosphoproteomic analyses identified diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, including complex I subunits and glutamate receptor signaling. Together, these findings reveal that the aged amygdala is especially sensitive to refined diet exposure and highlight microbial, metabolic, and inflammatory pathways that may underlie diet-induced cognitive decline.

A greater metabolic cost of walking (CoW) is well-documented in older compared with young adults and is likely a catalyst for age-related mobility loss. Proximal redistribution of joint work during gait has been suggested as a contributor to greater CoW in aging. However, evidence to support this link is limited. We collected overground gait kinematics and kinetics as well as metabolic data during a 7-minute treadmill walk (7MTW) in 15 young (30-40 years, 8F) and 40 older (70-80 years) adults. We then separated the older adults into two groups based on whether they did (O

Growing evidence shows that epigenetic modification and mitochondrial dysfunction are hallmarks of aging and are associated with the development of a wide range of age-related diseases. Mitochondrial biogenesis, which is marked by mitochondrial DNA copy number (mtDNAcn), is one of the major regulations of mitochondrial function by a set of transacting elements, including mitochondrial DNA polymerase gamma (POLG), working on the mtDNA control region. In this study, we investigated the mtDNAcn and the methylation status at both mtDNA control and POLGA promoter regions in human blood cells from individuals with a wide range of ages. A total of 119 blood samples were collected, including 24 umbilical cord blood samples from newborns and 95 peripheral blood samples from individuals aged 18 to 96 years. We observed an increase in mtDNAcn, as well as a rise in the methylation levels of the mtDNA control region during aging, particularly in subjects aged ≥ 45. In addition, a positive correlation was also found between the methylation levels of the 4th CpG site in the POLGA promoter region and mtDNAcn during aging. These results suggest epigenetic regulation at mitochondrial and nuclear genes for mitochondrial biogenesis during aging in human blood cells.

Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.

The decline of intrinsic capacity is a key determinant of healthy aging. While social isolation is recognized as a risk factor for functional deterioration in older adults, the pathways through which it influences intrinsic capacity, particularly via sleep duration and pain, remain underexplored.

Biological aging clocks capture heterogeneous rates of aging in individuals and transform current medical practice toward translational preventive medicine. Here, we developed a clinical aging clock based on routine blood biochemistry markers from 59,741 healthy samples in a Southeast Asian cohort. We established a novel correction method to address the systematic skew in predictions from first-generation clocks. This correction improved the accuracy of age-acceleration predictions for disease risks and enhanced interpretability for disease-driven and organ-specific aging processes without relying on mortality data. Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Epigenetic age acceleration (EAA) reflects biological aging processes beyond chronological age and is associated with morbidity and mortality. However, the causal gene regulatory mechanisms underlying epigenetic age remain unclear. Here, we integrated single-cell expression quantitative trait loci (sc-eQTL) data across 14 immune cell types with Mendelian randomization (MR) and Bayesian colocalization to identify eGenes whose cell-type-specific expression causally influences four major epigenetic clocks: IEAA, HannumAge, GrimAge, and PhenoAge. We identified 58 unique eGenes with strong evidence of causality, including ATM, ENO1, DDX5, and PSMB9, with effects often confined to specific immune lineages such as CD8 T and NK cells. Functional enrichment analysis revealed that these eGenes are involved in immune regulation, NF-κB signaling, and mitochondrial metabolism. Phenome-wide association studies (PheWAS) further linked top eGenes, particularly ATM and DDX5, to a spectrum of aging-related traits, including metabolic and immune disorders. Our findings highlight the importance of immune-cell-specific gene regulation in shaping biological aging and provide candidate targets for future aging interventions.

Caloric restriction (CR) without malnutrition delays aging in diverse species, including primates, with metabolic changes implicated in this process. To facilitate exploration of CR metabolism with aging, we developed a 15-minute LC-MS/MS metabolomics and lipidomics method, leveraging monophasic extractions and wide elution-strength solvents. We analyzed 494 plasma samples collected over 25 years from male and female rhesus monkeys (Macaca mulatta) on a Control or CR (30% restricted) diet. Quantitation of 359 biomolecules revealed that aging, followed by sex and diet, had the largest impact on metabolite abundances. In both sexes, aging was associated with significantly lower plasma levels of sphingomyelins (SMs) and higher levels of diglycerides (DGs) and triglycerides (TGs), each of which was opposed by CR. Sex dimorphism was evident by the increased abundance of phosphocholine (PC)-containing lipids in females. These results highlight the utility of a rapid metabolomics and lipidomics approach to elucidate complex biology in large-scale studies.

As organisms age, physiological and pathological changes occur, with altered lncRNA expression playing a key role. However, their regulatory mechanisms in aging remain unclear. This study investigates the differential expression of lncRNAs between aged and young mice, and explores the lncRNA-miRNA-mRNA interplay to gain insights into the molecular basis of aging.

This study aimed to evaluate the independent and joint effects of adherence to healthy dietary patterns and slower biological aging on the incidence of diabetic microvascular complications in individuals with type 2 diabetes mellitus (T2DM), and to assess the mediating role of biological aging. In a prospective cohort of 13,294 T2DM participants without baseline DMCs, dietary quality was assessed using a validated 10-point score, while biological aging was calculated from nine biomarkers and chronological age. Cox regression models were used to assess associations, and mediation analysis was performed to estimate the mediating effects of biological aging. Over a mean follow-up of 11.9 years, 3197 participants developed DMCs, including 1392 cases of diabetic retinopathy (DR), 1908 of diabetic nephropathy (DN), and 598 of diabetic neuropathy (DPN). Higher dietary scores (6-10) were associated with reduced risks of composite DMCs (HR 0.845; 95% CI 0.742-0.962), DR (0.804; 0.659-0.981), and DN (0.766; 0.643-0.911), but not DPN. Phenotypic age acceleration (PhenoAgeAccel) ≤ 0 was also linked to a reduced risk of DMCs. In addition, biologically younger with higher dietary score (6-10 points) had 39.4%, 30.8%, 53.6%, and 41.9% lower risk of composite DMCs, DR, DN, and DPN, respectively. Mediation analysis revealed that PhenoAgeAccel accounted for 43.0%, 29.8%, and 33.5% of the diet association with composite DMCs, DR, and DN, respectively. The results suggest that healthier dietary patterns and slower biological aging can reduce the risk of DMCs in T2DM patients, with a substantial portion of the dietary benefits mediated through slower aging. Integrating dietary and aging-targeted interventions may offer a promising method to reduce DMC risk in T2DM.

Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events with implications for aging and Alzheimer disease (AD). LOY is linked to increased AD risk, whereas CHIP may be protective, and their co-occurrence remains unclear. We conducted whole-exome sequencing of CD4

Current metabolomic aging clocks inadequately capture individual heterogeneity in biological aging trajectories, constraining their clinical utility. Here, we developed a metabolomic age clock in the UK Biobank (n = 196,790) using a comprehensive panel of 249 plasma metabolites. This framework was trained to predict phenotypic age (PhenoAge), a validated composite biomarker that integrates clinical chemistry across multiple systems, and was evaluated for its utility to predict incident cardiovascular diseases (CVDs) and dementia. We found that this new measure accurately predicted actual PhenoAge (Pearson's r = 0.90) and was significantly associated with the incidence of seven CVDs, including major adverse cardiovascular events, atherosclerotic cardiovascular disease, myocardial infarction, stroke, aortic stenosis, heart failure, and abdominal aortic aneurysm, but not dementia. Furthermore, metabolomic aging was associated with biological, physical, and cognitive age-related phenotypes, comprising telomere length, frailty index, and reaction time. Incorporating the metabolomic age clock with PREVENT (Predicting Risk of CVD Events) risk score modestly improved the performance, as measured by C-statistic and net reclassification index. Genetic analyses revealed 91 genomic loci and 168 genes (e.g., SERPINA1, FADS cluster), with tissue-enrichment analysis highlighting the liver's significant role in metabolic aging. By bridging metabolomic profiles with multisystem aging information, this framework provides a measure of biological aging that is associated with age-related functional status and cardiovascular risk.

Senescent cells are characterized by the expression of the cell cycle inhibitor and biomarker of aging, p16INK4A, and the capacity to modify the microenvironment through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in physiological and pathological conditions, including aging. In spite of this, fibroblasts ectopically expressing p16INK4A do not release a SASP nor communicate with the microenvironment. Here, we find that human primary fibroblasts expressing p16INK4A release more small extracellular vesicles (sEV) as part of the SASP than proliferating cells. In addition, we show that sEV isolated from p16INK4A cells are able to mediate paracrine senescence by inducing a growth arrest and DNA damage response in proliferating cells albeit not stimulating the expression of IL-8. Furthermore, we show the transmission of paracrine senescence via sEV is conserved in two cellular models of ageing: expression of progerin, mimicking an accelerated form of ageing, and inducing telomere shortening using a dominant negative mutant. Importantly, sEV isolated from fibroblasts derived from old donors also induce paracrine senescence in fibroblasts derived from young donors. In conclusion, our data indicate that sEV released by senescent and aging cells are an important mechanism of intercellular communication and could potentially explain tissue dysfunction in aging.

The human utricle is a vestibular organ essential for balance, a function that declines with age. With the aging population projected to double to 2 billion by 2050 and no pharmaceutical or biological treatments available, balance disorders represent a significant unmet medical need. The utricle is composed of sensory and non-sensory cells, which are closely related. Non-sensory cells have limited capacity to regenerate sensory cells and, therefore, are a relevant therapeutic target. In this work, we profile the cellular and transcriptional landscape of the adult human utricle and its early response to ototoxic damage using bulk and single-cell RNA-sequencing of patient-derived samples. We identify six transcriptionally distinct non-sensory cell types, including a previously uncharacterized supporting cell-like population, demonstrating utricular heterogeneity. Following aminoglycoside-induced damage, we detect early transcriptional changes consistent with a capacity to respond to ototoxic damage within 24 hours and potentially initiate a regenerative response via an early-responding cell population, providing a foundation for regenerative strategies for balance recovery.

Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using SUCNR1

Organ shortage remains a major barrier in treating end-stage organ failure, with many patients dying while waiting or becoming medically unfit by the time an organ is offered. A substantial number of organs, particularly from older donors, remain unused due to concerns over age-related decline in quality. This review highlights emerging strategies to rejuvenate and optimize such organs by mitigating ischemia-reperfusion injury and reducing age-related immunogenicity. Advances in organ preservation, perfusion technologies, and novel therapies - including senotherapeutics, anti-inflammatory agents, and stem cell treatments - show promise in improving graft viability and bridging the gap between organ supply and demand.

The adaptation of taste perception to extreme and extraordinary environments remains poorly understood, yet it may offer valuable insights into the physiological processes of ageing and adaptation. This study explores how hypoxia - whether environmental, as experienced at high altitude, or constitutive, as observed in older adults - affects taste function, with implications for nutrition under both extreme and age-related conditions. The research was structured in two parts: i. an investigation of taste perception during a high-altitude. Himalayan expedition, and ii. a cross-sectional comparison of taste sensitivity across age groups. In the first part, 17 healthy adults underwent taste tests at low altitude (Kathmandu, 1450 m), high altitude (Pyramid Lab, 5050 m), and again at low altitude after descent. In the second part, 103 participants were grouped by age (18-40, 41-64, and over 64 years) to assess age-related differences in taste function. Preliminary findings suggest that high-altitude exposure may moderately reduce taste sensitivity, particularly for sweet stimuli, requiring higher concentrations for correct identification. Similarly, ageing appears to impair taste perception, though the effect is not uniform across all taste qualities-salty taste, for instance, remains relatively preserved. These results point to a possible shared mechanism: the role of hypoxia in modulating sensory function. While the hypoxia encountered at high altitude is acute and environmental, older adults may experience a form of chronic, low-grade hypoxia due to physiological ageing. This parallel invite a broader reflection on how the body adapts to oxygen-limited conditions, and how such adaptations might inform nutritional strategies in both extreme environments and geriatric care.

This study aimed to evaluate the anti-aging effects of L-theanine in a D-galactose-induced aging model in rats and to elucidate its underlying molecular mechanisms. Aging was induced via subcutaneous administration of D-galactose, while L-theanine was delivered orally for eight weeks. Skin aging was induced in rats by daily subcutaneous injection of D-galactose. L-theanine was administered orally for eight weeks. Skin condition was assessed through by macroscopic observation and histological examination. Enzyme-linked immunosorbent assays were conducted to measure oxidative stress parameters, inflammatory cytokines, and AGEs/RAGE expression levels. L-theanine administration significantly improved skin integrity, maintained epidermal thickness and collagen architecture, administration significantly preserved skin integrity, maintaining epidermal thickness and collagen architecture. It reduced AGEs and receptor for advanced glycation end products (RAGE) expression, enhanced antioxidant enzyme activities (SOD, CAT, GSH-Px, T-AOC), and downregulated reduced the accumulation of AGEs and the expression of RAGE, increased activities of antioxidant enzymes (SOD, CAT, GSH-Px, T-AOC), and decreased levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in a dose-dependent manner. L-theanine effectively delays delayed skin aging in rats by inhibiting the AGEs-RAGE signaling cascade signaling pathway, thereby modulating attenuating oxidative stress and inflammatory responses.

Introduction: Age-related declines in bone and muscle health contribute substantially to frailty, falls, and functional loss in older adults. Despite the established musculoskeletal effects of hormone therapy (HT) in younger transgender and gender diverse women (TGDW), data on ageing TGDW do not exist. TGDW >50 years receiving feminising HT exhibit an 80% higher fracture incidence than cisgender adults. This pilot study explored the practicality of community-based recruitment of TGDW receiving HT and provided the first characterisation of musculoskeletal health in this population. Methods: Cross-sectional pilot study recruited forty-eight TGDW aged >50 years undergoing feminising HT through two UK community festivals. Body composition (bioelectrical impedance analysis), bone quality (quantitative ultrasound of the radius and tibia), muscle strength and power (handgrip dynamometry, countermovement jump, and 5x sit-to-stand test), and physical activity (IPAQ-SF)were analysed using descriptive statistics, one-sample t-tests against clinical thresholds, and regression models exploring associations between HT duration and musculoskeletal outcomes, adjusting for age, BMI, and physical activity level. Results: Sarcopenia incidence varied from 9% (handgrip strength) to 38% (countermovement jump power), and 38% of participants recorded counter-movement jump power below sarcopenia thresholds, whilst 21% could not complete the sit-to-stand test. Osteoporosis prevalence (8-13%) was higher than in the UK population (5%). Seventy-three per cent of participants were classified as overweight, and 33% classified as obese, higher than UK population norms (26%). Twenty-three per cent of TGDW were classed as physically active compared to their age-matched population (63%). Regression analyses showed no significant association between hormone therapy duration and musculoskeletal outcomes, whereas BMI (countermovement jump power {beta}; = 192.1, padj=0.01; handgrip {beta}; = 0.60, padj=0.02) was a stronger predictor of function. Conclusion: High sarcopenia and osteoporosis prevalence, elevated obesity, and low physical activity highlight areas of concern. Larger longitudinal studies to characterise musculoskeletal ageing using clinical measures are needed.

The proteasome is the central macromolecular complex that is responsible for regulated protein degradation in eukaryotic cells. Its best characterized substrates are ubiquitinated proteins that are targeted to the 26S proteasome complex, consisting of a 19S regulatory particle (RP) capping the barrel-shaped 20S core peptidase (CP). The CP can interact with other caps that modulate its function, including Blm10/PA200, a large monomeric protein whose biological function is not well understood. Blm10 is highly upregulated during gametogenesis in budding yeast, suggestive of a natural stage-specific modulation of proteasome composition. Here, we investigate the function Blm10 during yeast gametogenesis, identifying it as a weak activator of the proteasome that can displace the 19S RP from the CP. Due to this competition for the CP, overexpression of Blm10 can lead to attenuation of ubiquitin-dependent degradation and consequent proteostatic defects. Cells lacking Blm10 also display markers of proteostatic stress, including Hsp104 foci and heat sensitivity, suggesting that Blm10 safeguards normal proteostatic balance. We find that Blm10 is important for maintaining gamete fitness and ensuring normal rejuvenation of aged cells following gametogenesis. Overall, our data suggest a role for Blm10-proteasomes in maintaining gamete proteostasis through fine-tuning of proteasome activity and prevention of protein aggregation.

Age-related cognitive decline poses a growing clinical burden, with mitochondrial oxidative stress recognized as a key mediator. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is a potential regulator of redox balance, but its role in hippocampal function and cognitive aging, particularly its translational potential, remains unclear.

This study applied the WHO ICOPE framework to identify patterns of intrinsic capacity (IC) decline among community-dwelling older adults in rural Taiwan. We conducted a cross-sectional survey of 1,367 adults aged 65 and above using the ICOPE Step 1 screening tool, assessing six IC domains. Cluster analysis (

Spectral flow cytometry is an advanced immunological tool that can enable comprehensive analysis of the immune system by simultaneously comparing innate and adaptive immune cells. Here, using a 40-color antibody panel, we advance our knowledge of innate-like cells by investigating chemokine receptors and maturation markers not usually assessed on these populations, examining age-related effects on these immune cell subsets. We characterize phenotypic changes of peripheral blood mononuclear cells (PBMCs) in three age groups: newborns (cord blood), adults aged 20-30 years, and adults aged > 70 years. We compare the age-related changes of innate cells, including ILCs, NK cells, monocytes, dendritic cells, and innate-like T cells, comparing them with memory T cells. We also examine subsets of CD4

DNA methylation-based aging clocks capture biological aging processes and may improve cardiovascular risk prognostication. However, evidence about epigenetic aging clocks, incident outcomes, and interactions with clinical biomarkers such as coronary artery calcium (CAC) in diverse cohorts are limited.

Background: Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a key contributor to aging-associated skeletal muscle degeneration and dysfunction. However, the interactive effects of aging, sex, and exercise modality on ferroptosis regulatory markers at the histological, protein, and gene expression levels remain poorly understood. Methods: Male (n = 23) and female (n = 23) mice aged 7 (young) and 17 (aged) months were assigned to sedentary control, voluntary wheel running, or forced treadmill exercise. Ferroptosis in the quadriceps muscle was assessed using histological markers (e.g., fibrosis, Fe3+; accumulation, 4-HNE, MDA), protein-level markers (e.g., GPX4, SLC7A11, p-AMPK, MDA, GSH/GSSG), and gene expression markers (e.g., SLC7A11, GSS, ACSL4, POR). Results: Aging significantly elevated histological indicators of ferroptosis, fibrosis, lipid peroxidation, and iron overload, regardless of sex. At the protein and gene levels, sex-dependent differences were evident: aged females exhibited lower MDA and GSSG levels and upregulation of antioxidant-related genes, compared with aged males. Both exercise interventions modulated ferroptosis markers, with forced exercise exerting more pronounced effects than voluntary exercise. Notably, aged females demonstrated the most substantial reductions in ferroptosis-related markers in response to forced exercise, indicating a significant sex-by-exercise interaction. Conclusion: Aging markedly increases ferroptosis-related changes in skeletal muscle, with partial sex-specific differences at the molecular level. Forced exercise provides more robust regulatory effect against ferroptosis than voluntary exercise, especially in aged females. These findings underscore the therapeutic potential of sex-specific, targeted exercise interventions for mitigating ferroptosis-mediated muscle deterioration during aging.

Three categories of explanations exist for why we age: mechanistic theories, which omit reference to evolutionary forces; weakening force of selection theories, which posit that barriers exist that prevent evolutionary forces from optimising fitness in ageing; and optimisation theories, which posit that evolutionary forces actually select for ageing under the constraints that exist due to limited energy and other resources. We now have a broad data set of observed features of ageing against which these categories of theories can be tested, including results of interventions like caloric restriction, features of long-lived organisms, the existence of mortality rate plateaus, longevity of eusocial insect queens, and the malleability of lifespan. Optimisation theories are the only ones that fit all the observed data. Moreover, this category of theory makes a very ordinary claim, consistent with significant other data: evolution by natural selection is operating in ageing. It is actually quite extraordinary, either implicitly or explicitly, to claim that natural selection fails to operate, as the other categories of theories do. A key prediction of optimisation theories that differs from other theories is that mutations that extend lifespan should generally reduce fitness under natural conditions. Contrary to some suggestions in the literature, to date the available evidence supports this prediction. Optimisation theories have several implications, including that lifespan should be relatively easy to manipulate by tapping into existing biological mechanisms, and that the geroscience hypothesis, which states that intervention on the rate of ageing should also modulate the incidence of age-related diseases, is likely to be correct.

PurposePulse wave velocity (PWV) is a measure of arterial stiffness that reflects vascular aging and predicts risk for cardiovascular disease. We developed a PWV measurement method that uses dual-impedance cardiography (d-ICG) to address limitations of other common methods (e.g., ultrasound, tonometry, etc.), as well as to enable PWV assessments across a broader range of populations. This pre-registered, cross-sectional study tested for the first time the extent to which d-ICG PWV associates with cardiometabolic risk factors (i.e., blood pressure and other metabolic syndrome components) and vascular markers of preclinical atherosclerosis (i.e., carotid-artery intima-media thickness [C-IMT] and plaque).MethodsParticipants were 366 otherwise healthy adults (aged 28-57; 63.4% female). In a subsample (N = 179), estimates of d-ICG PWV were compared for the first time against carotid-femoral PWV (cfPWV) measured by a Complior device.Resultsd-ICG PWV and cfPWV measures were comparably associated with age and blood pressure (r's ≥ .28, p's ≤ .001), and they exhibited moderate consistency (ICCs = 0.51 to 0.55, p's < .001). Across all cardiometabolic risk factors and markers of preclinical atherosclerosis, there were no clinically meaningful differences in the average composite (Fisher's Z-score) correlations with arterial stiffness measured by d-ICG and cfPWV based on Cohen's q values (q's = 0.042 to 0.097).Conclusiond-ICG PWV may be a low-cost, reliable, and alternative method for obtaining estimates of arterial stiffness that track with cardiometabolic risk factors and preclinical atherosclerosis.

Age-dependent oxidative stress is considered to be involved in degenerative processes in age-related neurodegenerative disorders. The L1 cell adhesion molecule (L1CAM or L1) plays an essential role in the regeneration process following neural lesions in the adult nervous system. Protein kinase D1 (PKD1) is increasingly implicated in neuroprotection. Hence, the present study aimed to investigate the possible functional association between L1 and phosphorylated PKD1 (pPKD1) in oxidative stress-induced senescence. The study revealed that recombinant L1 (rL1) upregulated PKD1 phosphorylation, the pErk1/2 level and the Bcl2/Bax ratio in SK-N-SH cells in a concentration-dependent manner, with a peak level observed at 5 nM. L1 also increased the pPKD1 level in human pluripotent stem cells. In the 20 µM H2O2-induced senescence SK-N-SH cell model, L1 also increased the pPKD1 level and decreased the number of SA-b-gal-positive cells. On the whole, the results of the present study suggest that L1 is capable of modulating PKD1 phosphorylation to inhibit oxidative stress-induced senescence.

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE

Previous studies have developed proteomic aging clocks to estimate biological age and predict mortality and age-related diseases. However, these earlier clocks were based on cross-sectional data, capturing only the cumulative aging burden at a single time point but were unable to reflect the dynamic trajectory of biological aging over time. We constructed a longitudinal proteomic aging index (LPAI) using data from 4684 plasma proteins measured by the SomaScan 5K Array across three visits in the Atherosclerosis Risk in Communities (ARIC) study (ages 67-90 at last visit). Our two-step approach applied functional principal component analysis (FPCA) to capture protein-level change patterns over time, followed by elastic net penalized Cox regression for protein selection. LPAI was constructed in a randomly selected training set of ARIC participants (N = 2954), tested among the remaining ARIC participants (N = 1267), and validated externally in Multi-Ethnic Study of Atherosclerosis (MESA) participants (N = 3726, ages 53-94 at last exam). Using Cox proportional hazards model, higher LPAI was associated with increased all-cause mortality (HR = 2.50, 95% CI: [2.15, 2.92] per SD), CVD mortality (HR = 1.79, 95% CI: [1.34, 2.39] per SD), and cancer mortality (HR = 1.96, 95% CI: [1.45, 2.64] per SD) risk in ARIC, with statistically significant and directionally consistent associations also observed in MESA. Additionally, higher LPAI was associated with increased multimorbidity and frailty. This study demonstrates the feasibility of developing biological aging measures from longitudinal proteomics data and supports LPAI as a biomarker for aging-related health risks.

Sinus node dysfunction, a prevalent arrhythmia in aging populations, is characterized by fibrosis and loss of pacemaker activity, necessitating pacemaker implantation. Current therapies fail to reverse the underlying pathology. Small extracellular vesicles derived from human induced pluripotent stem cells possess regenerative potential but lack targeted delivery. Here, we engineer platelet membrane-fused vesicles that synergistically combine collagen targeting for ischemic injury homing with immune evasion. In a rat model of sinus node dysfunction, these modified vesicles exhibit 3.1-fold higher accumulation in the sinoatrial node compared to unmodified vesicles, resulting in a 63% reduction in fibrosis and significant restoration of heart rate and intrinsic pacemaker function. The vesicles mitigate fibroblast activation and protect cardiomyocytes from oxidative stress. This study establishes a targeted, cell-free nanotherapeutic platform for resolving fibrosis and electrophysiological dysfunction in sinus node disease.

Aging is commonly attributed to accumulated damage, or evolved antagonistic genetic trade-offs, which lead to an accumulation of damage causing misexpression of genes necessary for longevity. We propose an atavistic dysregulation of gene expression at cellular and tissue levels during aging, framing aging as a gradual regression toward ancestral cellular states. Similarly to the atavistic model of cancer, in which cells revert to unicellular-like behavior, aging may result from the breakdown of coordinated morphogenetic control, leading organs and tissues toward less integrated, ancient unicellular states. We suggest that aging may involve a progressive reversal of the well-known ontogenetic tracing of prior phylogenetic embryonic characteristics. Moreover, aging could involve a loss of large-scale coordination, with tissues reverting to ancient gene expression to different degrees. We tested this hypothesis using a meta-phylostratigraphic analysis, finding: (1) An atavistic over-representation of differential expression in the most ancient genes and under-representation in the evolutionary youngest genes for two multi-tissue aging databases, and tissues covering skin, ovarian, immune, senescent and mesenchymal-senescent cells; (2) No significant atavistic over-representation of the differential gene expression during aging of brain cells and mesenchymal stem cells; (3) overall age-dependent increase of heterogeneity in the direction of the phylogenetic position of tissues' transcriptional profiles; (4) and an overall negative evolutionary age mean shift toward the most ancient genes. Our analyses suggest that aging involves uncoordinated and tissue-specific phylogenetic changes in gene expression. Understanding aging as a structured, heterogeneous atavistic process opens new avenues for rejuvenation, focusing on restoring multicellular coherence in evolutionarily youthful gene expression.

The hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, synchronizing peripheral clocks through oscillations in core clock genes and proteins. Circadian disruption contributes to immunosenescence, aging, and neurodegenerative disorders such as Parkinson's disease (PD). Previous work from our group demonstrated age-related changes in circadian rhythms of clock genes, protein levels, and serotonin metabolism in the SCN and substantia nigra (SN) of male Wistar rats. This study examined the age of onset for circadian misalignment in clock (rBmal1, rCry1, rCry2, rPer1, rPer2), immune (rCox2, rIl1β, rIl4, rTgfβ1), and PD-associated (rLrrk2, rPark2, rPark7, rSnca) genes in SCN and SN. Male Wistar rats aged 3 (adult), 12 (middle-aged), and 24 (aged) months were studied. In SCN, rPark2 decreased and rSnca increased in 12 months and 24 months, while rCry1 and rPer2 were elevated in 12 months. Rhythmicity of rTgfβ1 declined in 24 months. In SN, rBmal1 rhythmicity was abolished in 24 months, while rPark2 lost rhythmicity in 12 months and 24 months. rSnca and rIl1β were elevated in 24 months. Misalignments in rCry1, rPer2, rIl4, rIl1β, rTgfβ1, and rLrrk2 in SCN, and rCry2, rIl4, rLrrk2, rPark2, and rSnca in SN appeared by middle age. A ketogenic diet intervention (KDI) resulted in modulation of rhythmic expression of rPer2, rSnca, rCry1, rTgfβ1, and rPark2 in SCN and improved rPark2, rSnca, and rIl1β in SN. These findings indicate that translationally, circadian misalignment in PD-related genes emerges early, suggesting its potential as a biomarker for preclinical PD. Moreover, dietary strategies such as KDI highlight promising non-pharmacological approaches to preserve circadian integrity, delay neurodegeneration, and guide personalized interventions in at-risk individuals.

Sleep is a universal behavior that is critical for brain function and physiological homeostasis. While growing epidemiological and experimental evidence suggests reduced sleep quality is associated with negative health outcomes, the causal relationship between sleep loss and reduced longevity remains poorly understood. Here, we examine sleep across the lifespan and its relationship to longevity in Drosophila melanogaster. We examined the associations between numerous components of sleep at different life stages to longevity. Early life sleep, but not middle and late-life sleep, was positively associated with longevity. Age-dependent changes in sleep were consistent but accelerated, when flies are housed under stressful conditions including nutrient and temperature stress. Further, pharmacological restoration of sleep in the first 10 days of life, but not at later time points, increases longevity. Together, this work provides a systematic investigation of how different components of sleep impact longevity and suggests early life sleep may be particularly important in promoting sleep across the lifespan.

Many biological processes, including cellular senescence, manifest as diverse phenotypes that vary across cell types and conditions. In the absence of single, definitive markers, researchers often rely on the expression of sets of genes to identify these complex states. However, there are multiple ways to summarise gene set expression into quantitative metrics (i.e., signatures), each with its own strengths and limitations, and we know of no consensual framework to systematically evaluate their performance across datasets. We therefore developed markeR (https://bioconductor.org/packages/markeR), an open-source, modular R package that evaluates gene sets as phenotypic markers using various scoring and enrichment-based approaches. markeR generates interpretable metrics and intuitive visualisations that enable benchmarking of gene signatures and exploration of their associations with chosen study variables. As a case study, we applied markeR to 9 published senescence-related gene sets across 25 RNA-seq datasets, covering 6 human cell types and 12 senescence-inducing conditions. There was wide variability in gene set performance, as some signatures (e.g., SenMayo) were robust senescence markers across contexts, while others (e.g., those from MSigDB), performed poorly as such. We also used markeR to analyse gene expression in 49 GTEx tissues, revealing tissue- and age-related differences in senescence-associated signals. Together, these findings emphasise the difficulty of characterising molecular phenotypes and demonstrate the potential of markeR in facilitating the systematic evaluation of gene sets in various biological contexts.

Aging-related bone loss is closely linked to mesenchymal stem cell (MSC) senescence, but the underlying epigenetic mechanisms remain unclear. Here, the role of histone H3 lysine 27 acetylation (H3K27ac) and its downstream target IGF2BP2 in MSC aging are investigated. Integrated ChIP-seq and RNA-seq analyses revealed diminished H3K27ac levels in aged murine bone marrow-MSCs (BM-MSCs), accompanied by reduced IGF2BP2 expression. Functional studies demonstrated that both knockdown and overexpression of IGF2BP2 mitigated senescence phenotypes in hydrogen peroxide- and etoposide-induced models. The mutation frequency of H65Q, a key point mutation in IGF2BP2, exhibited variations according to age and sex, and enhanced its binding to

Sugarcane, rich in bioactive phenolics, offers significant health benefits. This study isolated a phenolic extract from sugarcane (ESM) and characterized its composition via HPLC and NMR spectroscopy. ESM and five major constituent phenolics (gallic acid, epigallocatechin, quercitrin, catechol, and rutin) exhibited potent in vitro radical scavenging activities. In Caenorhabditis elegans, ESM extended oxidative stress lifespan by up to 29.24 %, reduced reactive oxygen species (ROS) accumulation by 39.94 %, and elevated antioxidant enzymes activities. Transcriptomics revealed ESM modulated longevity-related genes (e.g., hsp-70, gst-20, akt-1) and enriched pathways including longevity regulation, cytochrome P450 metabolism, lysosomal function, and glutathione metabolism. Additionally, ESM regulated the mRNA levels of daf-2 and daf-16 and their downstream genes without significant positive effect on the survival rates in daf-16 (mu86) null mutant worms. These findings demonstrated the potential of ESM as a functional food ingredient for mitigating oxidative stress and aging.

Few studies have examined the associations of sarcopenia, frailty, and sleep quality (SQ) trajectories among middle-aged and older Chinese adults. Our aim was to investigate these relationships using a nationally representative longitudinal study.

Major depressive disorder (MDD) is more prevalent in women and associated with shorter telomere length, a marker of biological ageing, and an increased risk of age-related disease. However, the precise influence of depression-related genetic and environmental risk factors on telomere dynamics remains a topic of debate.

Inflammaging is a chronic, low-grade inflammation that accompanies aging and contributes to the development of age-related diseases. Recent research has increasingly focused on its impact in women, recognizing that aging and inflammatory processes differ between sexes. Estrogens, known for their anti-inflammatory effects, offer protection during reproductive years. However, their decline during menopause and the climacteric period is linked to increased inflammation and a higher risk of chronic diseases such as osteoporosis, cardiovascular disease, and arthritis. X-linked immune-related genes play a critical role in immune system regulation. Epigenetic changes associated with aging can affect the expression of inflammation-related genes, with hormonal and genetic differences contributing to sex-specific responses. Women generally exhibit stronger immune responses than men, which can enhance infection resistance but also increase susceptibility to autoimmune diseases and inflammaging. Lifestyle factors, including diet and physical activity, significantly influence inflammation. Due to metabolic differences, women may respond differently to these interventions. Postmenopausal women, for example, often exhibit higher levels of inflammatory markers like C-reactive protein (CRP) and interleukin-6 (IL-6), which are associated with elevated risks of cardiovascular and other age-related conditions. These findings suggest that strategies to reduce inflammation-such as anti-inflammatory diets or medications-should be tailored to the unique hormonal and physiological context of women. Understanding the distinct manifestations of inflammaging in women is essential for developing gender-specific approaches to promote healthier aging and reduce the burden of chronic disease in later life.

Frailty and cardiometabolic disorders are highly prevalent in the aging population and frequently coexist, amplifying each other's adverse effects. Frailty, defined by decreased physiological reserves and heightened vulnerability to stressors, often occurs alongside cardiometabolic conditions such as diabetes, hypertension, and cardiovascular disease. The intersection of these conditions poses substantial clinical challenges, impacting morbidity, mortality, and quality of life. Understanding the shared pathophysiological mechanisms underlying frailty and cardiometabolic disorders is critical for guiding effective prevention and management strategies. This systematic review, registered in PROSPERO (CRD420251164236), documents current knowledge on the definitions, epidemiology, and pathophysiology of frailty in the context of cardiometabolic disorders and highlights the main clinical implications of their coexistence. Additionally, we discuss evidence-based strategies for assessment, prevention, and management, emphasizing the importance of an integrated approach to improve outcomes in older adults. These insights aim to inform both clinicians and researchers about targeted interventions that can mitigate risk, enhance resilience, and optimize patient care.

Age-associated cognitive decline is a significant societal challenge, with several neurodegenerative diseases like Alzheimer\'s disease becoming prevalent. Normal ageing is associated with several molecular, cellular, and metabolic hallmarks, including epigenetic mechanisms. In particular, dysregulation of post-translational modifications on histone tails is emerging as a mechanism associated with functional decline. The hippocampus is a region of the brain that is essential for the formation of episodic and spatial memories, which are particularly susceptible to age-related decline. In this perspective manuscript, we have used mass spectrometry as an unbiased method to profile histone tail post-translational modifications both at baseline and after contextual fear conditioning (CFC) from young and aged mouse hippocampi to identify age- and activity-dependent changes. Using this approach, we identify epigenetic marks not widely studied in ageing and in activity-induced learning. We propose a framework on how to integrate these epigenetic marks into current knowledge and discuss how to use this new analysis to formulate novel hypotheses that will broaden this field of ageing research. We believe that this work will be of interest to scientists, clinicians and the wider public by making a significant contribution to our understanding of the molecular mechanisms responsible for age-associated cognitive decline and by reporting the identification of new mechanisms to focus on.

Countries with low mortality show uneven success in improving longevity. Smoking-still a dominant health risk-is a major determinant of these divergent trajectories. Our study aims to determine: a) the continuing influence of smoking on national mortality trends, and b) the extent to which other factors are preventing countries from realizing their health potential. Using mortality data from 20 low-mortality countries (1950-2019), we quantify life expectancy and age-specific mortality differences as calendar years behind the current longevity frontier, defined as record smoking-eliminated life expectancy. We find that current life expectancy largely reflects smoking-eliminated records from two decades ago, with a notable gender paradox across most countries: men are moving closer to the optimal health benchmarks, while women are drifting further away, although men still bear a greater burden of past smoking. While longevity leaders differ from laggards mainly in mortality at advanced ages, laggards show also extensive developmental delays throughout most of the working ages and the second half of life. Our results highlight the diminishing effect of smoking and the role of additional adverse factors in delayed mortality improvement. However, the positive effects from smoking declines have not yet been fully realized, as evidenced by the still comparatively high reduction in development delays after eliminating smoking. Nevertheless, the realization of further health potential largely depends on countries' ability to manage health in old age, including the increasing burden of chronic disease.

The aging paradox describes improvements in emotional wellbeing as a function of aging, despite declines in cognition. Conversely, late life depression has been associated with increased cognitive decline in aging. We sought to understand these seemingly contradictory patterns of cognitive and mental health in older age. Building on cognitive reserve, affective reserve, and brain reserve models of aging, we developed three alternative algorithmic approaches to group N=22,686 participants from the UK Biobank into different profiles of aging. Our results revealed that aging profiles identified using our data-driven brain reserve model, which incorporated measures of cognition, neuroticism, and brain volume, achieved the highest validation results. Importantly, only two of the four aging profiles were characterized by the aging paradox (i.e., improved emotionality and decreased cognition with age). We identified one profile characterized by particularly low levels of neuroticism and relative resilience to cognitive decline. Another profile benefited from relatively preserved brain volumes, potentially driven by younger ages and/or higher socioeconomic status. Conversely, we identified two profiles with poorer health characteristics, including one profile with elevated cardiovascular risk. Taken together, these findings enrich our understanding of the emotion paradox and highlight the value of taking a nuanced and stratified approach when studying aging. In the future, aging profiles could be used to target preventative strategies to address modifiable risk factors and improve lifespan and healthspan.

Objectives The rising incidence of sarcopenia and osteoporosis, conditions closely linked to natural aging and frequently occurring together, may have varying impacts on prognosis. The purpose of this research is to use the NHANES database to explore how sarcopenia and osteoporosis may impact all-cause mortality and to assess whether there is an additive effect of these two conditions. Methods Individuals in this research were categorized into four groups depending on whether they had sarcopenia or osteoporosis. This study employed survival curves, Cox regression analyses, and restricted cubic splines, encompassing subgroup and sensitivity analyses, to explore the relationship between sarcopenia, osteoporosis, and all-cause mortality. Results Findings from the study revealed that participants suffering from both sarcopenia and osteoporosis exhibited the lowest survival rates. After adjusting for all potential factors, individuals diagnosed with sarcopenia alone had a 45% higher chance of experiencing all-cause mortality, while those with osteoporosis alone faced a 32% increased risk of all-cause mortality. Furthermore, individuals with both sarcopenia and osteoporosis had a 282% higher risk of all-cause mortality compared to those without either condition. The relative excess risk due to interaction (RERI) between sarcopenia and osteoporosis was 4.48 [95% CI: 1.98-8.08], the attributable proportion due to interaction (AP) was 0.66 [95% CI: 0.38-0.79], and the synergy index (S) was 4.4 [95% CI: 1.9-10.2]. Conclusions This indicates that the combination of sarcopenia and osteoporosis may have an additive effect on all-cause mortality, leading to an increased likelihood of death in individuals with both ailments. This study was to emphasize the importance of prevention over treatment for osteoporosis and sarcopenia to reduce the risk of death in this population.

Sirtuin 6 (SIRT6) is an enzyme belonging to the class of nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylases. It has been of interest due to its multivariate biological role and association with aging-related diseases and metabolic dysfunctions. SIRT6 activation protects against metabolic diseases and aging, and its inhibition is considered a therapy against cancer and inflammation. Here, we explore the modulation of SIRT6 by bioactive molecules, providing a detailed view of the molecular interactions that lead to the activation or inhibition of this protein. Therefore, we investigated the interactions between the ligands quercetin (QUE), isoquercetin (ISO), catechin gallate (CG), and trichostatin A (TSA) with SIRT6, using computational methods from the perspective of molecular modeling through the Molecular Fractionation with Caps Conjugates (MFCC) technique and according to the calculation parameters of Density Functional Theory (DFT). The results revealed the energetic values of each amino acid residue constituting the interaction pocket with the analyzed ligands within a radius of up to 10.0 Å. The analysis of the interaction energies showed an order of priority among the ligands, highlighting CG as the most promising. The observation of the interactions between amino acid residues and ligands identified significant contributions from residues VAL70, PHE64, PHE82, and PHE86. In addition, residues such as PRO62, MET136, MET157, and VAL115 stand out as key components of the protein active site. These findings offer strategic insights into the molecular mechanisms underlying the binding of the studied ligands to SIRT6, providing a deep understanding of their affinity and pharmacological potential.

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-b; signaling (Serpine1, Dab2, Igfbp7), whereas skin senescence is dominated by keratinization and barrier homeostasis modules (Krt10, Lor, Sbsn). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm-1) that robustly marks p21+ senescent cells. To unify these layers, we develop a machine learning derived multimodal barcode that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ. In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10, Lor, Sbsn, Sfn, and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.

The Werner syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. In this study, we introduced a tumorigenic mutation p53N236S (referred as p53S later), which is found in immortalized WS mouse embryo fibroblasts, back into WS mice to investigate its impact on the telomere dysfunction-induced aging process. Intriguingly, the introduction of p53S rescued the aging phenotypes of WS mice, showing the extension of the lifespan and the delay in organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated the DREAM/MMB pathway and downstream DNA helicases and telomere maintenance proteins, facilitated the recruitment of these proteins to G-quadruplex (G4) DNA structures proximal to DNA replication forks, and promoted the unwinding of G4. By comparing the cellular responses to pyridostatin and hydroxyurea, respectively, we confirmed that p53S specifically regulates G4-related DNA replication stress. Thus, p53S compensates the loss of Wrn and telomerase function, solves the DNA replication, telomere lengthening, and cell proliferation problems in WS cells, and ultimately, rescues the aging phenotypes of WS. Together, our data indicate that certain tumorigenic features can be applied to balance with premature aging, rescuing the aging phenotype without tumor risk. This study suggests a new mechanism in aging regulation and provides the possibility of developing a tumor-free longevity strategy and targeting G4 and DNA replication in aging-related tumor therapy.

Cellular senescence, a state of irreversible growth arrest, is characterized by various phenotypic changes, including altered mitochondrial function. While the role of mitochondria in senescence is well-established, the mechanisms underlying their involvement remain unclear. Here, we investigate the early stages of therapy-induced senescence (TIS) and identify a novel anti-apoptotic mechanism mediated by Bcl-xL and VDAC1, two key regulators of mitochondrial calcium (Ca2+) homeostasis. We find that Bcl-xL expression increases in early TIS cells and localizes to the mitochondria, where it interacts with the voltage-dependent anion channel 1 (VDAC1). This interaction dampens mitochondrial Ca2+ uptake, thereby preventing Ca2+ overload and apoptosis. Disrupting this interaction using the BH3 mimetic ABT-263 or Bcl-xL targeting siRNA increases mitochondrial Ca2+ uptake, leading to apoptosis and blocking the formation of senescent cells. These findings uncover a previously unrecognized role of the Bcl-xL VDAC1 axis in regulating mitochondrial Ca2+ dynamics during the onset of senescence. Our work provides mechanistic insight into how senescent cells evade apoptosis, highlighting potential therapeutic targets for selectively eliminating them in cancer and age-related diseases.

Chaperone-mediated autophagy (CMA), once considered a secondary or auxiliary degradation pathway, is now recognized as a central regulator of synaptic proteostasis. A recent study by Khawaja et al. (2025) in

Testosterone treatment increases muscle mass, maximal voluntary muscle-strength, aerobic capacity, and some measures of physical function. Activational and epigenetic mechanisms by which androgens improve muscle mass and physical performance and how to apply these anabolic effects to treat functional limitations associated with aging and disease remain incompletely understood. Testosterone treatment induces hypertrophy of type 1 and 2 muscle fibers, and increases muscle progenitor cell numbers by promoting differentiation of mesenchymal progenitor cells into myogenic lineage by an androgen receptor (AR)-mediated pathway. Liganded AR binds to β-catenin, translocates into nucleus where it binds TCF4 and upregulates follistatin that blocks signaling through TGFβ-pathway to promote myogenesis and inhibit adipogenesis. Testosterone increases myoblast proliferation by stimulating polyamine biosynthesis. Stimulation of GH and IGF-1 secretion, intramuscular IGF1-receptor, and muscle protein synthesis, and inhibition of muscle atrophy genes further contribute to testosterone's anabolic effects. Testosterone improves muscle bioenergetics by increasing erythrocytes, oxygen availability, tissue blood flow, and mitochondrial mass and quality. Testosterone increases blood flow by nongenomic mechanisms involving NO production, and calcium and potassium channels in vascular smooth muscle. The conversion of testosterone to 5α-dihydrotestosterone is not required for mediating its anabolic effects. Mechanisms of testosterone's sexually-dimorphic epigenetic and tissue-specific activational effects; and roles of α-keto reductase and steroid 5α-reductase, one-carbon and polyamine metabolism in testosterone's actions remain poorly understood. Strategies to translate testosterone-induced muscle mass and strength gains into patient-important improvements in functional performance and health outcomes are needed to enable its clinical applications to treat functional limitations associated with aging and disease.

During a lifetime, normal cells accumulate thousands of changes in their genome sequence. These changes, termed somatic mutations, have mostly been studied in the context of cancer, but their presence in normal tissues is ubiquitous and widespread. Somatic mutation accompanies the aging process and is influenced by genetic and environmental factors. Differently from gene expression or imaging data, which fluctuate over time, somatic variants are non-reversible marks in the genome and accumulate over time. This property can be exploited to track the history of a cell, from conception to old age, providing information that cannot be acquired via classical histological tissue inspection nor other types of omics data. Mutations can track embryonic development, measure how clones compete in a tissue over time, or report the mutational processes active in cells and tissues throughout life. We discuss selected examples and emphasize how somatic mutation analysis can enable expanding applications at the service of physiology and cell biology, as well as a deeper understanding of the aging process.

Senile osteoporosis (SOP) is a typical ageing-related bone disease that is primarily prevalent in elderly people. The present study aimed to examine the therapeutic efficacy of artesunate (ART) administration in SOP and aged bone marrow stromal cells (BMSCs) and investigate its underlying mechanisms.

Myostatin and follistatin are the regulators of muscle growth and pivotal proteins that regulate muscle tissue function. An integrated approach is HIIT and resistance training provides a holistic strategy for promoting healthy aging and maintaining functional abilities, potentially through the modulation of myostatin and follistatin levels. This study aims to assess the effect of high-intensity interval training and resistance training on myostatin and follistatin protein concentrations in aged rats' serum and muscle tissue. In this study, 20-month-old female Sprague-Dawley rats were used in three groups: (1) Control (Con), (2) Resistance training (RT), and (3) High-intensity interval training (HIIT). The HIIT and resistance training protocols were carried out for 8 weeks and three sessions per week. The results showed serum levels and muscle tissue content of myostatin increased in the RT compared to the control group (p = 0.0001 and p = 0.04). The muscle tissue content of follistatin increased in the HIIT compared to the control group (p = 0.03). There is a significant difference in serum levels and muscle tissue content of follistatin between HIIT and RT groups (p = 0.0001 and p = 0.001). According to the roles of myostatin and follistatin in regulating muscle hypertrophy, present research shows HIIT has more effects on follistatin levels and resistance training has more effects on myostatin levels. This can indicate that according to the number of training sessions, HIIT can be a better and newer treatment method for older people.

The macrofungus Ganoderma is renown as a medicinal and edible mushroom in Asian countries for its potential to enhance vitality and promote longevity. Five previously undescribed lanostane triterpenoids, ganoderenic acids J-N (1-5), together with 42 known ones (6-47), were isolated from the fruiting bodies of Ganoderma lingzhi. The structures of the new compounds were elucidated through comprehensive spectroscopic analyses, NMR chemical shifts and electronic circular dichroism (ECD) calculations. Among them, compound 7 acted as a noncompetitive inhibitor against protein tyrosine phosphatase 1B (PTP1B) with IC

As an effective minimally invasive therapy for skin aging, 5-aminolevulinic acid photodynamic therapy (ALA-PDT) demonstrates superior efficacy. While Light-emitting diode (LED)-PDT offers advantages of broad-spectrum capabilities and low-cost over conventional laser-PDT, the absence of standardized parameter optimization impedes its clinical application. This study systematically investigated the combined effects of varying ALA concentrations and LED wavelengths to establish an optimized anti-aging protocol. Sixty mice (40 UVB-induced photoaging, 20 natural aging) were randomized into 12 groups receiving PDT with different ALA concentrations (2%/5%/10%), LED wavelengths (405/532/630 nm), and light dose (4.5/18 J/cm²). The cosmetic efficacy was evaluated through skin aging scores, skin laxity, skin elasticity testing and histopathology analysis. Compared to 532 nm, PDT-630 nm significantly ameliorated UVB-induced skin roughness and epidermal thickness while enhanced collagen fiber content and improved fiber arrangement, without causing 405 nm-associated scarring. Optimal results were achieved with 2% ALA at 630 nm, whereas 10% ALA induced collagen degradation. PDT using 630 nm LED light combined with 2%ALA at an energy density of 4.5 J/cm² provided an innovative and effective approach for skin anti-aging. This protocol promoted collagen remodeling to restore youthful skin structure while minimizing epidermal damage, suggesting its potential as an optimal intervention for photoaging.

Aging has emerged as a prominent area of academic inquiry. Brain aging is a complex physiological process characterized by features such as enhanced apoptosis, oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy. Currently, effective preventative or therapeutic approaches for age-related neurodegenerative disorders remain elusive. Ectoine, a naturally occurring compatible solute, possesses diverse applications in biological engineering, cosmetics, medicine, and the food industry. Ectoine is reported to exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties, making it a potential anti-aging agent. Consequently, the present study investigated the potential neuroprotective effects of Ectoine against D-galactose (D-gal)-induced brain aging. Accelerated aging was induced by subcutaneous injection of D-gal. Rats were subsequently divided into a control group, an aged group, and Ectoine-supplemented groups, receiving daily doses of 10, 20, and 40 mg/kg, respectively. Our findings revealed that Ectoine effectively and dose-dependently protected against D-gal-induced brain aging by inhibiting oxidative stress, enhancing the antioxidant system, decreasing neuroinflammation, restoring autophagy and mitochondrial homeostasis, and inhibiting apoptosis. Furthermore, Ectoine significantly restored the expression of miR-124 and its target genes; however, this effect is correlative and warrants further mechanistic validation. Additionally, while Ectoine's neuroprotective effects were observed at the tissue level, its cell-type specificity remains to be determined. These findings suggest that Ectoine may exert multi-pathway neuroprotective effects in brain aging. However, the current data are exploratory and warrant further validation to define causality and translational applicability.