Longevity Papers

As the global population ages, multimorbidity has become a critical public health issue. We analyzed 332,012 adults from the UK Biobank (2006-2022) to investigate the association between biological age-measured by the Klemera-Doubal method (KDM-BA) and phenotypic age (PhenoAge)-and a new comorbidity model encompassing physical, psychological, and cognitive disorders, with overall mortality outcomes over a median follow-up of 13.6 years. Logistic regression models examined the association between baseline health status and accelerated aging, while Cox proportional hazards models assessed mortality risk and disorder development. Cross-sectional analysis showed that accelerated aging was linked to higher comorbidity prevalence. Longitudinal follow-up revealed that individuals in the highest quartile (Q4) of aging speed (residual difference between estimated biological age and chronological age) had a 16%-17% higher risk of developing a single disorder, a 41%-44% higher risk of multimorbidity, and a 54% higher overall mortality risk compared with the lowest quartile (Q1). Among those with baseline single disorder, dual comorbidity, and triple morbidity, Q4 mortality risk increased by 89%-116%, 118%-166%, and 119%-156%, respectively. Multistate Markov models confirmed that accelerated aging (residual > 0) increased the risk of transitioning to disorder, comorbidity, and death by 12%-37%. Individuals aged 45 with triple comorbidity lost an average of 5.3 years in life expectancy (LE), further reduced by 5.8 to 7.0 years due to accelerated aging. This study highlights that KDM-BA and PhenoAge robustly predict multimorbidity trajectories, mortality, and shortened LE, supporting their integration into risk stratification frameworks to optimize interventions for high-risk populations.

Life-history traits such as body size, reproduction, survival, and stress resistance are fundamental to an organism's fitness and are highly influenced by nutritional environments across life stages. In this study, we employed a full factorial experimental design to investigate the effects of isocaloric diets (diets with equal caloric content but differing macronutrient composition) on key life-history traits in an outbred Drosophila melanogaster population. Our results demonstrated significant diet-induced plasticity, with male wing length (a proxy for body size) being influenced by the developmental diet; males reared on carbohydrate-rich developmental diets had larger wings as adults. Fertility increased with protein-rich diets at both developmental and adult stages, reaffirming the critical role of dietary protein in enhancing reproductive success. Lifespan exhibited sexually dimorphic responses to diet: carbohydrate-rich developmental diets extended male lifespan, while carbohydrate-rich adult diets reduced lifespan in both sexes. Stress resistance traits, including starvation and desiccation resistance, were unaffected by developmental diets but were influenced by adult diets, with carbohydrate-rich adult diets enhancing survival under both stress conditions in males and females. Importantly, while most traits exhibited additive effects of nutrition across life stages, a marginal interaction for male starvation resistance suggests that developmental and adult diets can interact in a trait- and sex-specific manner. Moreover, associations between dietary effects on life-history traits were context-dependent, driven primarily by adult diets and varying by sex. These findings emphasize the profound role of stage-specific nutritional environments in modulating life-history traits and their correlations, offering valuable insights into how organisms may adapt to changing ecological conditions and highlighting the importance of considering both developmental and adult dietary contexts in evolutionary studies.

Aging is a major risk factor for the development of many cancers, yet the mechanisms underlying this increased susceptibility remain incompletely understood. Traditionally, the accumulation of genetic mutations over time has been considered a primary driver of age-related tumorigenesis. However, emerging evidence highlights the critical role of the aging tissue microenvironment -- including changes in immune, stromal, and epithelial compartments -- in shaping cancer initiation and progression. In this study, we employed integrated single-cell and spatial transcriptomics to systematically characterize age-associated alterations in human skin and skin cancers. Our analysis uncovered widespread, cell type-specific transcriptional reprogramming with age, revealing key pathways and cellular populations that may contribute to a pro-tumorigenic environment. Notably, we identified a previously unrecognized fibroblast subtype marked by SFRP2 expression, which expands with age and is associated with poor prognosis in basal cell carcinoma. These fibroblasts appear to enhance Wnt signaling within the tumor niche, suggesting a potential mechanism by which the aging stroma supports malignancy. Collectively, our findings shed light on how age-related changes in tissue ecosystems may predispose to cancer and point to novel therapeutic opportunities for targeting the aged tumor microenvironment.

To examine the structural, metabolic, and functional trajectories of neuromuscular decline in aging and identify key mechanisms and early biomarkers to guide interventions preserving function and independence.

Leveraging clinical phenotypes, neuroimaging, proteomics, metabolomics, and epigenetics, biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2923 plasma proteins, 327 metabolites, and 6477810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs. Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based, 11 proteome-based, and 5 metabolome-based aging clocks, as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimers disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research.

Aging is the largest risk factor for the development of osteoarthritis (OA), a major contributor to increased years lived with disability. This review reflects on how age-related changes relevant to OA have been measured at various length scales. Key discoveries include increased chondrocyte DNA damage with age and the disruption of matrix homeostasis by cellular senescence. Epigenetic clocks have yet to show predictive value for OA, while transcriptomic changes and miRNA profiles are linked to aging and senescence. Protein biomarkers have gained traction in the context of post-traumatic OA and may also be useful in understanding risk profiles for age-related OA. Post-translational modifications provide insights into protein aging and the rate of matrix turnover at different joint sites. Non-enzymatic crosslinks also increase with age and may be responsible for changes to the mechanical properties of joint tissues. Finally, the walking speed declines with age and predicts incident OA. Despite these advances, more research is needed on age-related changes in tissues beyond cartilage. Efforts should be directed toward identifying biomarkers of aging that can integrate large studies on genetic risk factors with the deep phenotyping done in longitudinal cohort OA studies. Early intervention is crucial for treating OA and other age-related diseases, highlighting the importance of validating sensitive and predictive biomarkers that could support new treatment paradigms. Finally, reversing at least some aspects of age-related decline may be critical for improving joint function. Promising approaches include effective delivery of targeted senolytics and the use of partial reprogramming to rejuvenate chondrocytes.

There is robust evidence that senescence can be propagated in vitro through mechanisms including the senescence-associated secretory phenotype, resulting in the non-cell-autonomous induction of secondary senescence. However, the induction, regulation and physiological role of secondary senescence in vivo remain largely unclear. Here we generated senescence-inducible mouse models expressing either the constitutively active form of MEK1 or MKK6 and mCherry, to map primary and secondary senescent cells. Our models recapitulate characteristic features of senescence and demonstrate that primary and secondary phenotypes are highly tissue- and inducer-dependent. Spatially resolved RNA expression analyses at the single-cell level reveal that each senescence induction results in a unique transcriptional profile-even within cells of the same cell type-explaining the heterogeneity of senescent cells in vivo. Furthermore, we show that interleukin-1β, primarily derived from macrophages, induces secondary phenotypes. Our findings provide insight into secondary senescence in vivo and useful tools for understanding and manipulating senescence during aging.

Aging is a major risk factor for a plethora of diseases. The information theory of aging posits that epigenetic information loss is a principal driver of the aging process. Despite this, the connection between epigenetic information loss and disease has not been thoroughly investigated. Here, we analyzed tissue-unique methylation patterns in healthy and diseased human organs, revealing that for several diseases these patterns degrade, regressing to a mean form. We interpret this as epigenetic information loss, where tissue-unique patterns erode. Information loss is not limited to diseases. Age-related erosion of unique methylation patterns was observed in some tissues and cells, while other tissues and cells diverged away from the mean. Our findings demonstrate that analyzing methylation patterns in tissue-unique sites can effectively distinguish between patients and healthy controls at least in some diseases, and underscore the role of epigenetic information loss as a common feature in various pathological conditions.

Gut microbiota delays aging by regulating the immune, metabolic, and neurological functions of the host. However, current research on novel probiotics with antiaging properties significantly lags, impacting their application in clinical treatments. In this study, metagenomics, culturomics, and probiotic property screening were used to identify Bifidobacterium pseudocatenulatum NCU-08 as a potential probiotic with anti-aging properties. In addition, B. pseudocatenulatum NCU-08 effectively improved the behavioral characteristics, significantly reduced the levels of the age-related protein β-galactosidase (β-gal) (BP: M = 0.81 vs. 1.13, p < 0.05), attenuated neuronal damage in the hippocampus, and improved the composition of the gut microbiota of senescence-accelerated mouse tendency-8 (SAMP8) mice. The targeted metabolomics suggested that L-tryptophan (L-Trp) may be a key substance for B. pseudocatenulatum NCU-08 to exert anti-aging effects (BP: M = 14878.6 ng/mL vs. 5464.99 ng/mL, p < 0.01). Mechanistically, using the aging model of SAMP8 mice and HT22 mouse hippocampal neuronal cells, it was found that B. pseudocatenulatum NCU-08 might enter the intestine to regulate L-Trp, and then transport it to the brain. In the brain, L-Trp was metabolized to NAD

Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.

African turquoise killifish (Nothobranchius furzeri) is the shortest-lived vertebrate that can be bred in captivity, making it an ideal model organism for aging studies. However, whether the animal can be used for studying cardiac aging and whether cellular senescence contribute to this ageing process remain unclear. Here, we conducted a longitudinal study on the GRZ strain, aiming to identify phenotypic and functional markers for cardiac aging. We found that cardiac ageing in GRZ fish can be measured by comparing fish at 16 weeks to 8 weeks of age, using systemic markers such as body/fin coloration, body weight, BMI, cardiac ageing markers such as EF, E/A ratio, and swimming capacity, and cellular senescence markers such as SA-β-gal staining, p15/p16, γ-H2A.X, and SASP markers. Senolytic treatment with D (Dasatinib) and Q (Quercetin) from 12 to 16 weeks mitigated senescence and decelerated cardiac ageing. Together, our findings established GRZ as a useful vertebrate model for studying cardiac ageing and related cardiac senescence.

Frailty, a geriatric syndrome, is characterized by the age-related deterioration of physical capabilities and multiple organ systems. However, its age-associated and age-independent mechanisms remain vague, impeding prevention and clinical intervention. Here, the physical frailty status of young and old mice estimated using the frailty phenotype and frailty index values was used to divide mice into non-frail young/old (NF-Y/NF-O) and frail old (F-O) groups. Age-associated and age-independent transcriptional changes in frailty were investigated using single-cell RNA sequencing to profile transcriptomes in various cell types in limb muscles. We investigated the ratio of cell types, transcriptional regulation networks, and cell-cell communications in 15 major cell types in mice during relatively healthy aging (RHA), age-associated frailty (AAF), and age-independent frailty (AIF). Each group of RHA, AAF or AIF genes exhibited one major expression pattern and transcriptional regulation network. Besides its unique pattern, genes in the AAF group faintly exhibited the two major patterns seen in the AIF and RHA groups. B cells and satellite cells in both the AIF and AAF groups showed the most down-regulated and up-regulated differentially expressed genes, respectively. The transcriptional pattern of B cells, which showed stronger transcriptional changes than satellite cells in the AIF process, was validated by sorting B cells and performing SMART-sequencing. Thus, by analyzing these molecular events at the single-cell level, our study revealed the specific expression patterns and transcriptional heterogeneities of candidate cell types involved in relatively healthy aging and physical frailty, laying a foundation to characterize the detailed mechanisms and presenting possible therapeutic strategies for physical frailty.

Aging is the greatest risk factor for most diseases. We propose that aging manifests as disease as a function of tumor-suppressive capabilities. Adequate tumor suppression results in cell death or an accumulation of damaged cells leading to inflammation and tissue dysfunction that underlies diseases such as cardiovascular disease, neurodegenerative diseases, or type 2 diabetes. Conversely, inadequate tumor suppression leads to cancer. Telomeres are central to this process because they oppose hyperproliferation that is required for cancer initiation by enforcing two potent tumor suppressor mechanisms: senescence and crisis. Although senescent cells promote age-related diseases via inflammatory signaling, crisis cells have lost the p53 and RB pathways, have more unstable genomes, and harbor shorter telomeres, all of which could increase inflammation to a greater degree than is seen in senescence. This model emphasizes the intimate relationship between aging, telomeres, tumor suppression, and inflammation and suggests that crisis cells may represent an unexplored driver of inflammation in advanced age.

Aging is marked by a gradual decline in multiple physiological functions, increasing the risk of age-related disorders. Multiple factors have been identified as contributors to aging, many of which are regulated by the hypothalamus. Growth hormone-releasing hormone (GHRH) produced in the hypothalamus is a key regulator of growth hormone (GH) secretion. With aging, both GHRH and GH levels decline, leading to muscle loss, increased fat accumulation, metabolic dysregulation, and cognitive impairments. GH replacement therapy has been explored as a potential intervention to counteract these effects; however, its long-term use is associated with significant risks, including metabolic disturbances, cardiovascular complications, and potential cancer promotion. In contrast, studies suggest that GHRH-based therapies can improve body composition, muscle strength, cognitive function, and cardiovascular health while avoiding the risks linked to direct GH administration. Additionally, preclinical findings indicate that GHRH agonists may offer cardioprotective and immunomodulatory benefits. In this review, we summarize current knowledge on the roles of GHRH and GH in aging, highlight the limitations of GH-based therapies, and discuss the potential of GHRH-based approaches in mitigating age-related decline and improving health span.

Ultraviolet (UV) radiation from the sun causes adverse skin changes such as premature aging. UVA radiation is the primary factor for photoaging due to its deep penetration into the dermis, and UV-induced mitochondrial DNA (mtDNA) alterations, including deletions, contribute to photoaging and cellular dysfunction. The most frequent mtDNA rearrangement is the common deletion (CD), characterized by the loss of nearly one-third of the genome, 4,977 base pairs. UV radiation exposure leads to the formation of the CD, however, a distinct characterization of UV-induced CD and the underlying molecular mechanisms driving its initiation remains unexplored. In this study, we showed that increasing doses of UV radiation led to an increase in the CD in human skin fibroblasts. We found that UVA induce the formation of the CD by increasing the cellular reactive oxygen species (ROS) and oxidized bases content in the mtDNA. Preconditioning cells with antioxidants prevented the accumulation of the UVA-induced CD, suggesting that this mutational mechanism is ROS-dependent. In stark contrast, UVB did not alter cellular ROS levels but increased the formation of cyclobutane pyrimidine dimers (CPD), leading to CD generation though a ROS-independent mechanism. We corroborated our findings by using a 3D human full-thickness skin equivalent model, where we detected UVA-dependent CD formation in both the epidermal and dermal layers of the skin. By analyzing bulk RNA from UVA-exposed human skin fibroblasts by RNA-Seq, we found that UVA led to the upregulation of genes encoding mitochondrial DNA replication proteins and to the downregulation of genes involved genes encoding mtDNA repair factors. Taken together, our findings provide insight into how UVA and UVB differ in their detrimental effects on mtDNA, with UVA impacting mtDNA maintenance and transcription via a ROS-dependent mechanism. Our findings also established the mtDNA CD as a novel potential biomarker for monitoring UVA-induced oxidative stress and photoaging in skin cells in vitro and in vivo.

Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.

N6-methyladenosine (m6A), as the most common RNA modification at the post-transcriptional level, plays a role in various pathophysiological processes. However, its underlying mechanism in skin aging remains enigmatic. Here, we identified that fat mass and obesity-associated protein (FTO) serves as a protective factor against skin aging. FTO expression is downregulated in aging skin tissues and senescent fibroblasts. Furthermore, the depletion or inhibition of FTO exacerbates dermal fibroblasts senescence and accelerates skin aging. Additionally, RNA-seq combined with MeRIP-seq revealed that lysine acetyltransferase 8 (KAT8) is the downstream target of FTO. FTO deficiency leads to an increase in m6A levels and a decrease in mRNA stability of KAT8 in a m6A-YTHDF2-dependent manner. Notably, our integrated analysis of m6A sequencing and acetylation proteomics links changes in heterochromatin structure with aging. Mechanistically, KAT8 depletion leads to heterochromatin loss and the subsequent aging by acetylating remodeling and spacing factor 1 (RSF1) at K1050. Overall, our finding reveals a pivotal role of FTO-mediated m6A modification in the skin aging by regulating KAT8/RSF1-involved heterochromatin formation. It provides new insights into the mechanisms and strategies for delaying aging and improving healthspan.

Background: Leukocyte telomere length (LTL) has been implicated in aging and age-related diseases, including chronic respiratory diseases (CRDs). However, the extent and mechanisms of shared genetic architecture between LTL and respiratory health indicators (such as CRDs and lung function parameters) remain incompletely understood. Methods: We first systematically characterized the genetic correlations and genetic overlaps between LTL and multiple respiratory health indicators. We then performed horizontal pleiotropy analysis by integrating SNP-level functional annotation, gene mapping, and pathway analysis to identify candidate pleiotropic loci, genes, and shared biological pathways. Finally, we assessed the causal relationships among these trait pairs using the latent causal variable (LCV) and MRlap. Results: There was extensive genetic overlap between LTL and respiratory health indicators, regardless of whether these trait pairs had significant genetic associations. We identified 27,885 candidate pleiotropic loci and 82 pleiotropic genes. Notably, five key genes, such as STN1, MPHOSPH9, MTRFR, MAX, and UCKL1, showed significant pleiotropic effects in multiple phenotype pairs and mediated different patterns of genetic associations. Pathway enrichment analysis of these pleiotropic genes highlighted the close association of specific trait pairs with RNA metabolism and telomere maintenance. Finally, vertical pleiotropy analysis revealed negative causal associations of LTL-idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease-LTL. Conclusions: Our findings reinforce the roles of telomere biology and RNA processing in the pathogenesis of chronic lung diseases and support a shared genetic basis for common molecular pathways.

Cellular senescence is a process in which the cell cycle becomes permanently arrested, thereby inhibiting cell division, proliferation and growth. Various cellular stresses, such as DNA damage, telomere shortening and oxidative stress, can trigger cellular senescence. Physiologically, cellular senescence contributes to tissue development, repair and critical biological processes such as embryogenesis, whereas, pathologically, it plays a key role in diverse disease subsets. To this end, elucidating the underlying mechanisms and molecular regulation of senescence is crucial. Here, in this Review, we explore recent key findings on cellular senescence in experimental and human disease models, focusing on its molecular mechanisms, regulation and future research directions to advance the field and facilitate therapeutic translation.

Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Adaptive behavior depends on the brains capacity to vary its activity across multiple spatial and temporal scales. Yet, how distinct facets of this variability evolve from childhood to older adulthood remains poorly understood, limiting mechanistic models of neurocognitive aging. Here, we characterize lifespan neural variability using an integrated empirical-computational approach. We analyzed high-density EEG cohort data spanning 111 healthy individuals aged 9-75 years, recorded at rest and during passive and attended auditory oddball stimulation task. We extracted scale-dependent measures of EEG fluctuations amplitude and entropy, together with millisecond-resolved phase-synchrony networks in the 2-20 Hz range. Multi-condition partial least squares decomposition analysis revealed two independent lifespan trajectories. First, slow-frequency power, variance and complexity at longer timescales declined monotonically with age, indicating a progressive dampening of low-frequency fluctuations and large-scale coherence. Second, the temporal organization of phase-synchrony reconfigurations followed an inverted U-trend: young adults exhibited the slowest yet most diverse switching--characterized by low mean but high variance and low kurtosis of jump lengths at 2-6 Hz and the opposite pattern at 8-20 Hz--whereas children and older adults showed faster, more stereotyped dynamics. To mechanistically account for these patterns, we fitted a ten-node phase-oscillator model constrained by the human structural connectome. Only an intermediate, metastable coupling regime reproduced the empirical combination of reduced low-frequency variability and maximally heterogeneous synchrony dynamics observed in young adults, while deviations toward weaker or stronger coupling mimicked the childrens and older adults profiles. Our results demonstrate that development and aging entail changes in the switching dynamics of EEG phase synchronization, by differentially sculpting stationary and transient aspects of neural variability. This establishes time-resolved phase-synchrony metrics as sensitive, mechanistically grounded markers of neurocognitive status across the lifespan.

Shifts in the skin microbiome have shown a close link to chronological age. However, the contribution of skin microbiome in skin aging phenotypes remains unclear. To explore this, we performed phenotypic, metabolomic, metagenomic, and functional analyses on a cohort with divergent skin aging phenotypes. Genome-scale metabolic models (GEMs) integrated with metabolomic analysis revealed that Stenotrophomonas maltophilia, enriched in the younger group (categorized by AI-predicted age and skin elasticity), utilizes the glutathione cycle to maintain redox homeostasis. Cellular experiments showed its metabolites enhanced GSH synthesis and alleviated oxidative stress-induced skin aging by upregulating key genes in fibroblasts, including GCLM, PGD, SOD2, and NQO1. Additionally, GEMs highlighted its potential anti-aging roles in regulating host metabolic pathways involving betaine, lysolecithin, and porphyrin. In parallel, Acinetobacter guillouiae was found to influence host melanin metabolism by degrading dopamine (DA) and 3-methoxytyramine (3-MT), offering potential therapeutic strategies for mitigating pigmentation. Our findings highlight the dynamic interplay between skin microbiota and the host in aging, offering new insights for designing targeted anti-aging interventions.

Aging is a degenerative process, and while Rosa roxburghii Tratt has demonstrated notable anti-aging and antioxidant properties, the precise anti-aging effects of its seeds are not yet fully understood. The aim of this study was to employ a blend of in "dry" and "wet" approaches to investigate the anti-aging activity and underlying mechanisms of the polyphenol-rich extract from these seeds, Rosa roxburghii Tratt seed polyphenol extract (RRTSPE). UPLC-Q-Exactive Orbitrap/MS was employed to identify the chemical constituents of RRTSPE, resulting in the identification of 33 chemical components. Subsequent in vitro antioxidant assays demonstrated RRTSPE's moderate antioxidant capacity, and in vivo evaluations using Caenorhabditis elegans (C. elegans) confirmed its ability to extend lifespan, reduce lipofuscin accumulation, and enhance resistance to oxidative and heat stress. Network pharmacology analysis suggests that RRTSPE's anti-aging effects may involve key proteins linked to metabolic and inflammatory diseases. The predictions regarding the anti-aging effects of RRTSPE were further substantiated using mutant C. elegans strains (DR26, VC475, TJ1052, and CB1370), which confirmed the engagement of the insulin/IGF-1 signaling (IIS) pathway in RRTSPE's anti-aging effects. RRTSPE demonstrates its anti-aging effects in C. elegans through a multifaceted approach, which includes scavenging free radicals, diminishing reactive oxygen species (ROS), enhancing DAF-16 nuclear translocation, and modulating IIS pathway-related proteins like SOD-3 and HSP-16.2. It is the synergistic effect of these actions that underpins the broad-spectrum anti-aging potential of RRTSPE. Taken together, this study not only provides a scientific foundation for the utilization of Rosa roxburghii Tratt seeds as a natural anti-aging agent but also paves the way for further research and development in leveraging their potential health benefits.

Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.