Longevity Papers

Transcription factor-based direct conversion of somatic cells represents an interesting avenue for generating induced neural stem cells (iNSCs) from peripheral blood without transit through a pluripotent stage. While this paradigm has been shown to be associated with epigenetic de-aging, the dynamics of this process have remained unclear. Here, we used overexpression of the two reprogramming factors SOX2 and cMYC to generate iNSC from erythroid progenitors of donors ranging from neonatal to 101 years of age. Using an epigenetic clock algorithm, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging, preserving around 13 % and 5 % of the original donor age at low and high passages, respectively. Studying the dynamic of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted, continuing for several weeks and even beyond forced neuronal differentiation of iNSCs. Transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too. Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Interestingly, time course analysis of DNA methylation and RNA sequencing data revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge. The unexpected slow dynamics of these processes makes iNSC conversion an attractive model for dissecting the mechanisms underlying somatic transdifferentiation and de-aging.

Accumulating evidence links skeletal and vascular aging, yet the pathological cross-talk between osteoporotic bone and vascular calcification remains insufficiently understood. In this retrospective exploratory study, we show that osteoporotic individuals exhibit a distinct systemic milieu characterized by elevated eosinophil, neutrophil, and platelet counts, as well as altered levels of sCD40L, PDGF-BB, osteopontin, and SDF-1. These changes correlate with both bone metabolism and arterial stiffness, indicating a multifactorial bone-vascular interplay. Moreover, osteoporotic sera accelerated calcification of human vascular smooth muscle cells in vitro, with PDGF-BB emerging as a central mediator. Inhibition of PDGF-BB downstream signaling blocked this effect, suggesting a mechanistic role of PDGF-BB in linking the osteoporotic milieu to vascular calcification. Conceptualizing this cross-talk as a complex adaptive system advances our understanding of the disease dynamics between localized bone loss and vascular pathologies. Furthermore, it may guide therapeutic strategies, with PDGF-BB as a potential target, to support healthier aging.

As populations age worldwide, understanding the biology of aging and its contribution to disease becomes increasingly important. Cellular senescence, a hallmark of aging, plays a pivotal role in shaping inter-organ communication and systemic health. Once viewed primarily as a local mechanism to prevent the proliferation of damaged cells, senescence is now recognized as a dynamic, multifaceted process that influences physiology across the lifespan. Through senescence-associated secretory phenotype (SASP) proteins and other signaling modalities, including metabolites, extracellular vesicles, immune cells, and neural circuits, senescent cells contribute to both homeostatic regulation and the propagation of chronic inflammation, fibrosis, and age-related disease. These effects are often context-dependent, and senescence in one organ can influence distant tissues, driving asynchronous aging and disease vulnerability. This review examines the mechanisms by which senescent cells facilitate inter-organ communication, including emerging roles for blood-borne factors, immune cell dynamics, and neuroendocrine signals. We highlight illustrative examples of organ crosstalk and emphasize the potential translational relevance of these pathways. We also examine therapeutic strategies aimed at modulating senescence, including senolytics, senomorphics, and interventions targeting specific SASP components, as well as the potential of lifestyle modifications to mitigate biological aging. Understanding senescence and the associated inter-organ communication offers new insights into aging biology and opens promising avenues for addressing age-related diseases in an integrated, organ-spanning framework.

Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

Natural aging leads to various age-related changes that impair visual function and cause ocular diseases. Endothelial cells, key components of blood vessels, play a crucial role in vascular aging and retinal degeneration. However, the exact mechanisms by which endothelial cell aging promotes retinopathy are not fully understood. Mitochondrial homeostasis is vital for endothelial cell function, with mitophagy being essential for removing damaged mitochondria. FUNDC1, a receptor involved in mitophagy, regulates cellular senescence and inflammation. This study investigates whether retinal function decline is linked to mitochondrial imbalance in retinal vessels endothelial cells due to reduced FUNDC1 expression. In aged mice, FUNDC1 expression and mitophagy were significantly lower in retinal blood vessels. Aging leads to retinal vascular dysfunction characterized by increased vascular permeability assessed by fluorescein fundus angiography. Moreover, electron microscopy images showed mitochondrial swelling in endothelial cells of aging retina, accompanied with tight junction disruption and reduced expression of junctional proteins (VE-cadherin, occludin, and ZO-1). Strikingly, endothelial knockout of FUNDC1 exacerbated the age-related decline in retinal blood vessel function and retinal function. Cell senescence induced by D-galactose exhibited significantly decreased FUNDC1, impaired mitophagy, increased reactive oxygen species (ROS), and markedly increased endothelial permeability assessed by transendothelial electrical resistance assay. Conversely, overexpression of FUNDC1 can reverse the reduction of mitochondrial autophagy, the decrease in intercellular junction protein expression and the increase in endothelial permeability caused by aging. Collectively, these data suggest that FUNDC1 serves as a potential therapeutic target for the prevention and treatment of age-related degeneration of retinal function.

The increasing burden of age-related degenerative diseases highlights the need for novel preventive strategies. Plant-derived active peptides have garnered attention due to their high bioactivity, low molecular weight, ease of absorption, minimal toxicity, and low immunogenicity. The high protein content of quinoa makes it an extremely valuable raw material for generating protein-derived bioactive peptides. In this study, based on the active peptides (QBPP) found from quinoa bran in previous research, peptide extracts with a molecular weight less than 3kD (QBPP-L) were further isolated and purified, which exhibited significant anti-aging activity both in vivo and in vitro. QBPP-L significantly downregulated the expression of aging-related markers (SA-β-Gal, p53, p21, and p16) in NIH-3T3 cells through inhibition of the p53 signaling pathway. Furthermore, it ameliorated oxidative stress (SOD, MDA, CAT) and enhanced neuroprotective effects in aged mouse models. In summary, the study highlights the anti-aging activity of QBPP-L in vitro and in vivo, suggesting that QBPP-L from quinoa bran is a promising natural bioactive ingredient with anti-aging properties, supporting its potential development for functional foods aimed at healthy aging.

The rising prevalence of cardiometabolic multimorbidity (CMM), characterized by the coexistence of two or more cardiometabolic disorders, poses a significant public health challenge in aging populations. While ambient air pollution is a recognized environmental risk factor, its long-term impact on CMM remains underexplored, particularly in China. Utilizing data from the China Health and Retirement Longitudinal Study (CHARLS, 2015 wave), we analyzed 9,830 participants aged ≥ 45 years. CMM was defined as the concurrent presence of two or more conditions: diabetes/hyperglycemia, cardiovascular diseases (myocardial infarction, angina pectoris, coronary artery disease, or heart failure, or stroke. Annual pollutant exposures were estimated using a machine learning-based spatiotemporal model (space-time extremely randomized trees) based on residential addresses. Generalized linear models adjusted for sociodemographic, lifestyle, and meteorological covariates were employed to assess odds ratios (ORs) per interquartile range (IQR) increase in pollutants. Chronic exposure to particulate matter (PM) 10 demonstrated a consistent positive association with CMM prevalence across models. In fully adjusted analyses, each IQR increase in PM10 was associated with elevated CMM risk (OR = 1.01, 95% CI: 1.00-1.02, P = 0.039). Sensitivity analyses, including alternative exposure windows and adjustments for regional variations, reinforced PM10's robust association with CMM. Other pollutants (PM2.5, and sulfur dioxide) showed weaker or inconsistent associations. Long-term exposure to ambient particulate matter, particularly PM10, is significantly linked to increased CMM prevalence in China's aging population. The findings of this study provide epidemiological evidence, laying the foundation for future cohort studies and mechanistic investigations.

Machine learning has become an important tool in precision medicine and aging research. We introduce the

Cellular senescence is a state where cells permanently exit the cell cycle after a finite number of divisions, while maintaining metabolic activity. This phenomenon, initially described by Leonard Hayflick, plays a pivotal role in aging, contributing to the progressive decline in physiological function by promoting tissue dysfunction and restricting regenerative capacity. It is regulated by an array of factors, including DNA damage, telomere shortening, oxidative stress, mitochondrial dysfunction, and epigenetic modifications. Nesprins, a family of transmembrane proteins embedded in the nuclear envelope, are integral components of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, which connects the nucleus to the cytoskeleton, thus preserving structural integrity and facilitating mechanotransduction. Lamin proteins, which form the nuclear lamina beneath the inner nuclear membrane, provide support to nuclear envelope architecture, organize chromatin, and modulate gene expression. Lamin proteins also interact with nesprins to collectively sustain nuclear mechanics and maintain morphological stability. Understanding the molecular mechanisms by which nesprins and lamins influence cellular senescence provides valuable insights into the biology of aging and may offer novel therapeutic avenues to address age-related diseases. This review examines the interactions between nesprin and lamin proteins and their potential contributions to cellular senescence.

To investigate how mitochondria and telomeres evolve during early follicle growth in human preantral follicles, and how these changes relate to reproductive age.

The treatment of senescent wounds has been a hot topic of research, as the presence of chronic inflammation in senescent skin leads to diminished wound healing. While ongoing inflammation also impairs wound healing and leads to complications. As a kind of Chinese herbal medicine with the same source of food and medicine, Gastrodia elata has good biosafety and bioactivity. We discovered that hydrogel systems derived from Gastrodia elata polysaccharide (GEP) exhibit excellent stability and biosafety, suitable for application as a hydrogel dressing for skin wounds. We incorporated glycyrrhizic acid (GLY), an active component, into a GEP-prepared hydrogel. A senescent mouse model was established by in vivo injection of D-galactose. The hydrogel was administered continuously for 21 days after causing dorsal skin injury in mice. The results showed that the hydrogel had good swelling and degradation properties as well as anti-inflammatory, antioxidant and haemostatic activities, which could reduce lipopolysaccharide (LPS)-induced macrophage inflammation and accelerate wound healing by promoting the polarization of macrophages from the M1 phenotype to the M2 phenotype. Further mechanistic studies demonstrated that the glycyrrhizic acid microsphere-loaded hydrogel (GM-Gel) suppresses STAT3 phosphorylation and Bax/Caspase-3 expression, thereby inhibiting M1 polarization. In conclusion, GEP hydrogel is a promising biomaterial for the treatment of chronic wounds as it can significantly promote healing of aging skin wounds by inhibiting macrophage inflammation and accelerating wound repair.

This study introduces the 3E framework of volunteering-time exposure (e.g., volunteering hours), role engagement, and task essence (e.g., types of activities) - investigating how these dimensions and their interactions impact healthy aging outcomes in older adults.

Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging.

Investigating the interplay between mitochondrial DNA (mtDNA) variations and epigenetic aging metrics may elucidate biological mechanisms associated with age-related diseases. We estimated epigenetic age acceleration (EAA) metrics from DNA methylation data and derived mtDNA metrics, including heteroplasmic variants and mtDNA copy number (mtDNA CN) from whole genome sequencing. Linear regressions and meta-analyses were conducted to assess associations between EAA and mtDNA metrics, adjusting for chronological age, self-identified sex, and other covariates in 6,316 participants (58% female, 41% non-White Americans). Mediation analysis was conducted to examine whether EAA mediated the relationship between mtDNA CN and metabolic traits. A higher burden of rare heteroplasmic variants was associated with accelerations of first-generation EAA metrics, while a lower level mtDNA CN was associated with accelerations of second- and third-generation EAA metrics. For example, one standard deviation (SD) higher MSS, a score based on the predicted functions of rare heteroplasmic variants, was associated with a 0.22-year higher EAA by the Hannum method (p = 1.3E-6) among all participants, while one SD lower mtDNA CN was associated with higher DunedinPACE (β = -0.005, p = 6.0E-4). No significant association was observed between the heteroplasmy burden of common variants and EAAs. Furthermore, we observed DunedinPACE mediated 11.1% and 10.8% of the associations of mtDNA CN with obesity and T2DM in older FHS participants, respectively. Our analysis indicated that higher levels of heteroplasmy burden of rare variants and lower mtDNA CN were associated with accelerated epigenetic aging, and these associations showed stronger magnitudes among older participants.

Aging is a process characterized by the progressive decline in physiological function and increased susceptibility to disease. Many cellular functions, including unfolded protein responses (UPR, an endoplasmic reticulum (ER) stress coping mechanism), Ca2+ signaling, cellular signaling and inflammatory responses are affected by aging. These significantly impact Ca2+ handling by cardiac cells and the architecture of cardiomyocytes, leading to impaired contractility, and increased risk of arrhythmias. Cellular Ca2+ homeostasis and the UPR are interdependent, therefore, understanding and influencing these key cellular pathways should provide new therapeutic strategies for managing age-related cardiac diseases. Modulating Ca2+ handling and cellular stress pathways presents distinctive approaches to preventing molecular alterations linked to aging, while providing opportunities to reduce molecular damage and promote the effectiveness of cellular repair processes.

Circulating proteins provide insights into an individual's health and aging trajectory. However, little is known about their long-term temporal stability. We evaluated the five-year temporal stability of 7288 serum proteins in 3093 participants (mean age 75 years) of the AGES-Reykjavik study. We observe wide variability in protein temporal stability, independent of transcriptomic stability in tissues. Temporally stable proteins tend to be extracellular, secreted, and tissue-specific, while temporally variable proteins are typically involved in intracellular housekeeping functions. Generally, protein levels become more stable with age, and for some proteins, temporal stability differs by sex. Similar patterns and consistent temporal stability were observed for a subset of plasma proteins in the Cardiovascular Health Study. Genetic factors and disease state have widespread effects on the temporal stability of the proteome, while the co-regulatory structure of the proteome is largely retained over time. Our findings underscore the protein-specific differences in long-term temporal stability, which are particularly important to consider in the context of biomarker development and precision medicine.

Senescent cells contribute to tissue dysfunction and the progression of age-related diseases. Senolytic therapies, which selectively eliminate these cells, have demonstrated beneficial effects in preclinical models by restoring tissue function and delaying age-related decline. Naturally occurring compounds are gaining attention due to their structural diversity and low toxicity. Among these, triterpenes, plant-derived molecules with anti-inflammatory and protective properties, are emerging as therapeutic candidates for targeting cellular senescence. Here, we aimed to evaluate the senolytic activity of β-amyrin, a plant-derived triterpene, in established fibroblast models. Using senescent cells of murine and human origin, we found that β-amyrin selectively induced cell death in senescent cells. Mechanistic analyses suggest that this effect involves cannabinoid receptor 2 signaling and proceeds independently of caspase activation. These findings highlight β-amyrin as a promising senolytic compound with a potentially unique mechanism of action.

The goal of this study was to determine if measures of healthspan, which have been shown to decline with age, are associated with and predict mortality. We measured voluntary running activity, spontaneous activity, and cognition in male and female C57BL/6 mice at 26- to 28-months of age followed by analysis of the survival of each mouse. Voluntary running activity was positively associated with age at death in both male and female mice; however, only 14 to 21% of the variance in lifespan was explained by running wheel performance. In contrast, cognitive parameters assessed during a working memory paradigm were not predictive of lifespan, despite a negative correlation with day-time activity, suggesting an important relationship between quality of sleep and cognition. Finally, using a multiple regression model to identify the best predictors of longevity we found that a combination of various independent variables of activity and cognition predicted 55% and 21% of the lifespan of female and male mice, respectively. These data highlight the importance of movement parameters and day-time activity in mice that influence healthspan and lifespan.

Ageing is a major risk factor for developing vision loss diseases such as age-related macular degeneration (AMD). Unfortunately, we do not have the ability to effectively prevent, slow, or stop onset and progression of AMD long term. These challenges with therapeutic development result from poor understanding of disease mechanism and pathogenesis due to a lack of animal models that manifest the hallmark features of disease. Here, we investigated the rapidly ageing turquoise killifish (Nothobranchius furzeri) retina for features of human ageing and AMD. We report that the ageing killifish retina expresses genes associated with human retinal disease in the photoreceptors and retinal pigment epithelium (RPE). Our characterisation of the retina identified that killifish spontaneously develop many hallmark features of AMD and human ageing, including photoreceptor deterioration, lipid deposits, outer retinal inflammation, and ceramide accumulation in the RPE with advancing age. Further, we identify a sex-specific difference in the severity of phenotypes. We propose that the turquoise killifish is a highly suitable model for investigating ageing and AMD-related disease mechanisms across the lifespan.

Research on physical frailty has focused primarily on understanding the factors that lead to frailty development and on discovering strategies that might prevent or postpone the onset of frailty. In contrast, relatively little attention has focused on biological factors that may influence resilience to frailty once it occurs. It has been demonstrated that low serum testosterone and other markers of hypothalamic-pituitary-gonadal (HPG) axis deterioration may contribute significantly to frailty development in older men. Here, we test the hypothesis that lifetime HPG axis integrity provides a critical physiological context that can contribute to enhanced frailty resilience, i.e., buffer the adverse consequences of late-life frailty. Late-life frailty scores were generated using a 34-item clinical frailty index in a cohort of 87 geriatric male dogs with a broad range of lifetime testis exposure. These dogs were followed from time of frailty scoring until death. Mortality risk associated with frailty index was estimated using Cox proportional hazard models in the overall cohort and in three subgroups differing in lifetime testis exposure. Dogs with the shortest duration of testis exposure had a very high risk of mortality associated with late-life frailty, whereas the mortality consequence of increasing frailty was absent in males with the longest duration of intact HPG axis. The results suggest that disruption of the HPG axis early in life by gonadectomy can impact the lethality of late-life frailty. It follows from this new understanding that the adverse consequences of frailty are context-dependent and future studies of the timing of neutering in companion dogs may yield vital insights by applying a life course approach to assess the importance of early-life events as determinants of late-life frailty and lifelong health.

Many elements of an organism's behavior are intertwined with the organism's health. Over a long period of time, health status is also indicative of life span, with improved health correlating with a longer life. However, the relationship between longevity and behavior remains relatively unexplored. Here, we report that modification of a single longevity gene downstream of dietary restriction and hypoxia markedly alters behavior in

Living animals reach their end-of-life through a stereotypic set of fascinating but poorly understood processes. The discovery, first in flies and later in nematodes and zebrafish, of the "Smurf phenotype" has provided a valuable tool to investigate ageing and its associated physiological changes. Using the Smurfs, we have shown an evolutionarily conserved end-of-life transition across Drosophilids, nematodes, and zebrafish. This tool has been key to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype led us to propose a two-phase perspective of ageing: a first phase where individuals are apparently healthy and have low risk of mortality, but show an age-dependent and increasing risk of entering a second phase, marked by more pronounced hallmarks of ageing and a markedly increased risk of death. Here, we test whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the mammals using Mus musculus as a model. We performed a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic, and molecular measurements with the life history of approximately 150 mice. We show the existence of a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism allows better characterization of the high risk of imminent death and would extend its implications to a broader range of species for ageing research. The Stage 1 version of this Registered Report was submitted on 19th January 2022.

This study investigated the relationship between estimated glucose disposal rate (eGDR), aging acceleration (AgeAccel), and mortality in adults diagnosed with cardiovascular-kidney-metabolic (CKM) stages 1 to 4.

Cysteine sulfenylation (Cys-SOH) is a transient redox-sensitive post-translational modification that regulates protein activity and cellular stress responses, yet its in vivo dynamics remain difficult to capture due to short half-life and low abundance. Here, we report the design and application of BTD-Az, a cell-permeable probe that incorporates an azide handle into the benzothiazine scaffold, enabling rapid bioorthogonal labeling of Cys-SOH both in vivo and in vitro, followed by efficient enrichment through strain-promoted azide-alkyne cycloaddition. This approach streamlines the detection and analysis of Cys-SOH with exceptional specificity and convenience. BTD-Az exhibited negligible cytotoxicity, efficiently enriched sulfenylated proteins in vitro, and achieved direct in vivo labeling in mouse tissues through SPAAC-mediated pull-down. Coupling BTD-Az with 4D-DIA proteomics allowed global sulfenylome profiling, revealing >5000 labeled proteins across tissues. As a proof-of-concept biological application, we applied BTD-Az to aging cartilage and identified 95 proteins with differential sulfenylation, including the mitochondrial enzyme IDH2, whose Cys-SOH modification promoted proteasomal degradation and exacerbated redox imbalance. Collectively, this study establishes BTD-Az as a robust chemical tool for in vivo sulfenylation profiling, providing a broadly applicable platform for redox proteomics and the discovery of redox-sensitive regulatory mechanisms in health and disease.

Introduction Pathogenic variants in PKP2 are the most common cause of familial arrhythmogenic right ventricular cardiomyopathy (ARVC). Objective To test whether PKP2 deficiency only in cardiomyocytes is sufficient to provoke premature aging and pro-inflammatory senescence in non-myocytes, cardiac resident cells. Methods We studied mice with cardiomyocyte-specific, tamoxifen-activated loss of PKP2 (PKP2cKO) using conventional and multiplex imaging, cytokine arrays, epigenetic clocks, spatial transcriptomics, expansion and structured illumination microscopy, and correlative data analysis. We examined non-myocytes and cardiomyocytes for premature aging and senescence. Results We observed senescence-associated heterochromatin foci (SAHFs) and p21 staining in non-myocytes. Cytokines in media of non-myocyte cells were consistent with senescence-associated secretory phenotype (SASP). Epigenetic clocks identified premature aging. Multiplex immunohistochemistry showed non-myocyte cells in niches, intermingled with cardiomyocytes. Spatial transcriptomics showed over-representation of SASP-related transcripts, predominantly in myocyte-rich areas of the left ventricle. SAHFs, p21 staining and increased epigenetic age were not found in cardiomyocytes from PKP2cKO hearts, though we observed structural features associated to premature aging. Cross-reference analysis showed correlation between the PKP2cKO cardiac proteome and that of mice 5 or 6 times their chronological age, as well as transcriptional signatures of neurodegenerative diseases. Conclusion Loss of PKP2 expression only in adult cardiac myocytes is sufficient to induce pro-inflammatory senescence in non-myocytes, and overall premature cardiac aging. This is the first study to intersect cellular senescence and premature aging in desmosomal arrhythmogenic cardiomyopathies. We speculate that cell-agnostic molecular signatures, biomarkers, and pharmacology of senescence and of neurodegenerative diseases may be relevant to diagnose or treat PKP2-ARVC.

Inclusions of -Synuclein (Syn) characterize multiple age-related neurodegenerative diseases, including Parkinson's disease (PD) and Multiple System Atrophy (MSA). While interactions between Syn and lipids are known to contribute to Syn pathobiology, the precise cellular mechanisms that link lipids to Syn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we found that Syn progressively alters lipid metabolism in aging worms. Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on Syn's properties to condensate and form inclusions. Apart from lowering TAG levels, Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates Syn-induced loss of C. elegans motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the Syn-impaired mitochondrial response and rescues motility. These results link Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate Syn-induced toxicity in Parkinson's and other age-related synucleinopathies.

Frailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches.

Collagen, the most abundant protein in the mammalian extracellular matrix, is critical for skin structure and function, with Type I and Type III collagens being particularly important. Collagen degradation in skin is accelerated by aging and UV exposure, leading to structural and functional impairments. Exogenous collagen supplementation has been shown to restore skin structure and function. Traditional collagen extraction from animal tissues is limited by safety and quality concerns, while recombinant human collagen offers improved safety but faces challenges in solubility and production. This study aimed to construct a chimeric collagen derived from both Type I and Type III collagens and achieve its soluble expression in E. coli. Through translational pausing technology, a recombinant chimeric human collagen containing functional domains of both collagen types was successfully constructed and expressed with a yield of 1.36 g/L. A cysteine-rich C-propeptide domain was fused to enhance assembly and stability. The "dual-function" collagen significantly promoted fibroblast proliferation, migration, and adhesion, while stimulating endogenous Type I and Type III collagen production. Using the C. elegans model, the recombinant protein extended lifespan and enhanced oxidative aging resistance. Skin imaging confirmed its penetration into the dermis, and human skin efficacy tests demonstrated its ability to reduce periorbital wrinkles and crow's feet. This recombinant "dual" human collagen promotes endogenous collagen synthesis, accelerates skin repair, reduces aging signs, and shows no observed side effects, offering promising potential for anti-aging applications.

Skeletal muscle atrophy occurs in several diseases and is associated with chronic stress. Studies indicate that glucocorticoid receptor signalling is the major pathway that mediates stress-induced muscle degeneration. Although the glucocorticoid signalling pathway is relatively well characterized, there is a need to identify modulators of this pathway that may be useful for drug targeting. SIRT2 is a mammalian Sirtuin known to mediate the longevity benefits of calorie restriction and exercise. Currently, the role of SIRT2 in regulating stress-induced skeletal muscle atrophy is unclear. We found that SIRT2 is a critical regulator of muscle homeostasis and is required to protect against stress-induced muscle atrophy. SIRT2 levels are reduced during glucocorticoid-induced muscle atrophy. SIRT2 deficient mice are susceptible to glucocorticoid-induced muscle atrophy, while muscle-specific SIRT2-transgenic mice exhibit improved muscle function and are protected from glucocorticoid-induced atrophy. Mechanistically, SIRT2 binds and deacetylates critical residues in the DNA-binding domain of GR and negatively affects GR activity. Our findings suggest that SIRT2 activation may protect against glucocorticoid-induced skeletal muscle atrophy.

Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects but many of the underlying molecular cues remain unclear. Here, we build a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing ~1,500 mouse gut tissues profiled by spatial transcriptomics and ~400,000 single nucleus RNA-sequencing profiles. We develop a computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region and sex by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identify cellular and molecular gradients along the adult colonic tract and across the main crypt axis and multicellular programs associated with aging in the large intestine. Our multimodal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.

Research on the role of probiotics in maintaining locomotor function in aged Caenorhabditis elegans is limited. Therefore, we investigated whether a probiotic strain, Bacillus subtilis TO-A (BSTOA), which extends the lifespan of worms can prevent age-related declines in the locomotor functions of aged worms. This study revealed that aged worms fed BSTOA (BSTOA_day13) maintained better locomotor function than those fed Escherichia coli OP50 (OP50_day13). BSTOA_day13 exhibited better activity than OP50_day13 in maintaining actin structure during age-related changes in body wall muscles. Notably, the expression levels of oxidative stress-related genes fluctuated in BSTOA_day13; these worms also displayed high survival rates based on the paraquat assay. An examination of the locomotor function of aged gpx-7 mutants revealed that even worms fed BSTOA had a reduced thrashing rate. Therefore, consuming BSTOA may prevent the decline in age-related locomotor functions, such as symptoms of sarcopenia in humans, by inhibiting the decrease in gpx-7 expression in aged worms.

Mitochondrial DNA (mtDNA) copy number and telomere length are widely recognized as biomarkers of cellular aging and metabolic health. This study aimed to investigate the relationships between BMI, exercise modality, mtDNA copy number, and telomere length using saliva samples from Iranian adults. Participants (n = 96) were categorized into four groups: endurance athletes, strength athletes, overweight/obese individuals (BMI > 25), and healthy controls (BMI 18-25). Saliva samples were collected for DNA extraction, and mtDNA copy number and telomere length were quantified using real-time PCR. Statistical analyses included Kruskal-Wallis and Dunnett's post hoc tests, as well as linear regression to assess correlations among variables. The results indicated that endurance athletes exhibited a significantly higher mtDNA copy number compared to controls and strength athletes, reflecting enhanced mitochondrial biogenesis from aerobic training. No significant differences in telomere length were observed among groups. While BMI showed no significant correlation with telomere length or mtDNA copy number overall, a significant negative correlation between mtDNA copy number and BMI was found exclusively in endurance athletes. Additionally, a strong positive correlation between mtDNA copy number and telomere length was observed in all groups except strength athletes. No significant differences were found between saliva and blood samples for either biomarker, and women demonstrated longer telomeres than men. This study highlights the positive impact of endurance exercise on mitochondrial biogenesis while revealing complex relationships between BMI, exercise modality, and cellular aging biomarkers. These findings offer insights into exercise-specific effects on cellular aging.

In C. elegans hermaphrodites, the distal tip cells (DTCs) capping the distal gonad arms provide the niche signal, a Notch ligand, to maintain germline stem cell pools. Using fixed germlines, it was recently shown that the transcription of a Notch target gene decreased relatively early-on during adulthood. Here, we used the genetically encoded Notch Sensor Able to detect Lateral Signaling Activity (SALSA) to examine the pattern of GLP-1/Notch activity across the aging distal gonad in vivo. Interestingly, we find that the robust and progressively decreasing distal-proximal Notch activation gradient that is observed in young adults gets entirely lost during aging.

Muscle weakness and poor brain health both contribute to mobility limitations in older adults, but their respective contributions and interaction are not well-understood. This study examines the relationship between MRI-estimated brain-predicted age difference (brain-predicted age-chronological age), leg strength, and their interaction on mobility decline using Baltimore Longitudinal Study of Aging data (N = 645, 78.1 ± 7.54 years, 56% women). Partial Spearman correlations evaluated the relationships between leg strength, brain-predicted age difference (BPAD), gait speed, and time to complete 5 chair stands (5CS). Mixed-effects linear regression models examined associations of baseline BPAD, leg strength, and lifestyle factors with mobility change over time (5.74 ± 2.87 years). Logistic regression modeled predictors of success in a narrow course walking task. Leg strength significantly correlated with gait speed (r = 0.26, p < 0.001) and 5CS (r=-0.27, p < 0.001). BPAD was associated with decreased gait speed (β=-0.022, p = 0.011) and slower 5CS (β = 0.331, p = 0.012). Greater leg strength was associated with preserved gait speed (β = 0.023, p = 0.022) and faster 5CS (β=-0.552, p < 0.001). BPAD (OR = 0.712, 95% CI: 0.687, 0.940) and leg strength (OR = 0.805, 95% CI: 0.696, 0.964) predicted lower likelihood of narrow walk success. Interactions between BPAD and leg strength were not significant for any measure. These findings suggest accelerated brain aging and leg weakness independently contribute to mobility decline, highlighting the need for interventions targeting brain health and muscle strength to preserve mobility in aging populations.

Torquetenovirus (TTV) is a prevalent virus whose clinical significance remains unclear, potentially linked to immunosenescence. This study examines TTV species in relation to immune impairment, inflammation, and cellular stress response in aging. A subset of recruited age-stratified individuals (RASIG) from the MARK-AGE study was divided into three groups: Cohort 1 A (healthy young adults), Cohort 1B (older adults with mild immune decline), and Cohort 1 C (older adults with marked immune impairment). Analyses included TTV load, species diversity, lymphocyte subpopulations, inflammatory markers, Poly-(ADP-ribose) polymerase (PARP-1) expression/activity. Alpha- and beta-diversity analyses showed the highest TTV species diversity in Cohort 1 C, with significant cohort-dependent differences and partially cohort-specific clustering patterns. Increased TTV species number correlated with higher TTV load, elevated CMV IgG levels, and greater immune impairment risk. Specific TTV species were associated with CD4/CD8, and reduced T-cell receptor excision circles, suggesting impaired T-cell homeostasis. TTV viremia positively correlated with C-reactive protein (CRP) and α2-macroglobulin. PARP-1 expression and activity increased in individuals with higher TTV diversity, particularly in the presence of TTV9 and TTV20. TTV load and species diversity are associated with immunosenescence, inflammation, and PARP-1 activation suggesting their potential as biomarkers of age-related immune decline. Longitudinal studies are needed to clarify underlying mechanisms.

Age is the predominant risk factor for late-onset Alzheimer's disease, and interventions that reduce biological age may be therapeutic. We previously reported that bezisterim, a novel anti-inflammatory insulin sensitizer, modulated epigenetic age acceleration (EAA) in a randomized, placebo-controlled, 7-month Alzheimer's disease trial. Building on prior evidence linking bezisterim-induced EAA changes to improved cognitive and functional outcomes, we conducted integrative analyses to elucidate underlying molecular mechanisms. Bezisterim significantly reduced EAA across 12 independent biological clocks, reinforcing its impact on validated aging biomarkers, and identifying targets predominantly involved in inflammation and cognition, including transcriptional regulators that orchestrate broader gene networks. Genome-wide methylation profiling revealed 2,154 genes with significant differential promoter methylation between bezisterim and placebo groups. Treatment increased promoter methylation - suggesting transcriptional repression - in 433 genes known to be associated with aging and disease processes, including microglial neuroinflammation, pro-inflammatory kinase activity, cognitive decline, lipid metabolism, and transcriptional regulation. Conversely, treatment-decreased methylation of 15 genes potentially improved autophagy, and increased anti-inflammatory phosphatases and macrophage polarization. Analyses were conducted to search for correlations between promoter methylation and the 31 previous clinical measures in bezisterim and placebo subjects. Significant correlations (72 bezisterim, 13 placebo) suggest that methylation differences contribute to observed clinical differences. The majority of the correlations in bezisterim subjects were associated with neurologic and metabolic improvements, and 12 of 72 were correlated with 2-5 clinical measures each, potentially emphasizing their contribution to clinical benefit. Bezisterim appears to exert pleiotropic effects through coordinated modulation of aging-related epigenetic programs, potentially counteracting neurodegenerative processes at the intersection of inflammation, metabolism, and transcriptional control.

6-Shogaol is a natural dietary phenolic extensively rich in edible and medicinal plants such as Zingiber officinale Roscoe and Brassica spp., utilized as tumor inhibitor and a promising anti-aging drug. Our previous study has revealed that 6-shogaol significantly prolonged healthy life of C. elegans. However, the interactions of 6-shogaol with the microbiota, gut and brain during natural aging process remain largely unexplored.

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift. We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess amyloid-beta pathology and neuroinflammatory markers. Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters amyloid-beta plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.

Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the age effect on ptmAA levels. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

Aging is a complex, multifactorial process in which nutritional alterations, sedentary lifestyle, and chronic diseases can increase the risk of functional limitations, dependence, and disability in older adults. Identifying the degree of frailty is essential for designing programs to enhance their quality of life. The objective of the study was to determine the prevalence of frailty and its association with nutritional status, functionality, physical activity, and socioeconomic level in older adults in Azuay, a province in Ecuador, during post-pandemic period of 2023.

Research on healthy aging increasingly highlights the importance of muscle function, strength, and mass due to their pivotal roles in intrinsic capacity, frailty, sarcopenia, and overall health. Physical exercise remains a cornerstone strategy for enhancing these parameters. This study aimed to assess the impact of functional gait training using the sequential square mat (SSM) Fisior

Aging and its associated neurodegenerative diseases were increasingly recognized as one of the greatest global health threats. Brain aging involved a multitude of pathological changes, including immune inflammation and metabolic dysregulation.

Aging biomarkers play a vital role in understanding longevity, with the potential to improve clinical decisions and interventions. Existing aging clocks typically use blood, vitals, or imaging collected in a clinical setting. Wearables, in contrast, can make frequent and inexpensive measurements throughout daily living. Here we develop PpgAge, an aging clock using photoplethysmography at the wrist from a consumer wearable. Using the Apple Heart & Movement Study (n = 213,593 participants; >149 million participant-days), our observational analysis shows that this non-invasive and passively collected aging clock accurately predicts chronological age and captures signs of healthy aging. Participants with an elevated PpgAge gap (i.e., predicted age greater than chronological age) have significantly higher diagnosis rates of heart disease, heart failure, and diabetes. Elevated PpgAge gap is also a significant predictor of incident heart disease events (and new diagnoses) when controlling for relevant risk factors. PpgAge also associates with behavior, including smoking, exercise, and sleep. Longitudinally, PpgAge exhibits a sharp increase during pregnancy and concurrent with certain types of cardiac events.

Chronic hypertension with aging induces significant alterations in the structure and function of brain parenchyma and memory dysfunction. While therapeutic control of hypertension reduces risk, the functional changes in neural circuitry that underlie memory deficits are unknown. Identifying possible early onset changes in the hippocampal trisynaptic circuit (HTC) may reveal opportunities for therapeutic intervention. A large-scale clinical study revealed a direct relationship between reduced prospective memory score and reduced hippocampal functional connectivity in subjects with a history of chronic hypertension. Here, we report a potential mechanistic linkage between hypertension/aging and hippocampal neural circuitry dysfunction. We used chronically implanted multi-electrode silicon probes in awake freely behaving rats to monitor synchronous high frequency oscillations (at 140-200 Hz or the "ripple band") in the HTC CA1 subregion. This hippocampal subregion is known to participate in memory consolidation, in part via HTC ripples. The nootropic drug, α5IA, that inhibits α5GABA-A receptors, was administered orally, under conditions for target engagement, and ripple amplitude measured within subject in awake resting Sprague-Dawley (SD) rats. Significant HTC and memory dysfunction was observed in aged-hypertensive SD rats. The results reveal an hypertension/age-associated anomaly in ripple band activity in SD males, characterized by reductions in mean peak ripple amplitude and in the ability of α5IA to potentiate peak ripple amplitude, without effect upon ripple frequency or duration. Thus, the population of large peak amplitude sharp wave ripples is reduced and becomes insensitive to potentiation by α5IA. Having identified a specific change in peak ripple amplitude that is resistant to potentiation by α5IA, a nootropic probe-drug, this finding could lead to nuanced circuitry level approach for the treatment of memory dysfunction with aging and hypertension.

A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified Angiopoietin-like protein 8 (ANGPTL8), a newly found adipokine implicated in lipid metabolism, that influences the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs towards adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased bone marrow adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of bone marrow fat. ANGPTL8 influenced the bone marrow niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with Angptl8-Antisense Oligonucleotide (Angptl8-ASO) improved the phenotype of aging mice. The research proposes that ANGPTL8 is a critical regulator of senesence-related changes in the BM niche and the cell fate switch of MSCs.

Telomere damage can lead to senescence, aging and aging-related disorders, and cancer. Previously, we reported that cell-free chromatin particles (cfChPs) that circulate in human blood can readily enter healthy cells and damage their DNA. Herein, we show that dsDNA breaks inflicted by cfChPs selectively target telomeres, with the resulting DNA damage remaining unrepaired over time, whereas dsDNA breaks inflicted by γ-rays are not specific to telomeres and have a faster repair kinetics. We propose that cfChPs that are released from the billions of dying cells to enter the blood circulation are natural DNA damaging agents with a unique mechanism of action.

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis of these effects remains poorly understood. To define age-dependent cardiac transcriptional responses to isoflurane exposure and operative (ISO/OP) stress, we analyzed gene expression profiles across young adult (3m), late middle-aged (17m), and geriatric mice (27m) following short-term 2 h ISO/OP exposure. At 24 h after cessation, all age groups exhibited distinct cardiac transcriptional signatures separating ISO/OP from sham controls. In young adult hearts, transcriptional alterations 24 hours after cessation of ISO/OP were characterized by dysregulation of small molecule catabolic processes, fatty acid metabolism, disruptions to protein processing in endoplasmic reticulum and cytoskeletal organization. Late middle-aged mice displayed amplified perturbations in lipid metabolism alongside suppression of muscle system and calcium signaling pathways, while old mice showed robust activation of PPAR and AMPK signaling and downregulation of genes governing contractility and morphogenesis. In contrast, geriatric mice showed upregulation of fatty acid metabolic pathways, robust activation of PPAR and AMPK signaling, coupled with suppression of muscle differentiation and actin organization following ISO exposure, indicating a maladaptive metabolic reprogramming. Overlapping DEGs across all age groups converged on pathways regulating oxidative stress, Ca2+; handling, hypertrophy, and energy metabolism, suggesting a conserved but age-intensified cardiac stress response. Longitudinal profiling in aged mice revealed persistent transcriptomic remodeling five weeks after stress. Crucially, this remodeling was observed even after ISO exposure alone, indicating that general anesthesia is a primary driver of this long-term effect. This persistent signature was marked by mitochondrial dysfunction and dysregulation of genes associated with diabetic cardiomyopathy, extracellular matrix integrity, and neurodegenerative signaling. Together, these findings identify isoflurane exposure as a potent inducer of persistent, age-dependent metabolic and structural reprogramming in the heart, implicating impaired lipid utilization and mitochondrial homeostasis as central mechanisms linking the perioperative period, and specifically anesthetic exposure, to long-term cardiovascular vulnerability.

INTRODUCTION: While changes associated with age-related diseases, like oxidative stress, begin in midlife, most aging studies focused on older individuals. Our study assessed in vivo brain metabolites in healthy adults, including the understudied middle-age group. METHODS: 7T magnetic resonance spectroscopy data were acquired from 87 healthy adults (45 women) aged 20-79 years. Levels of eight metabolites were measured in posterior cingulate cortex (PCC) and centrum semiovale white matter (CSWM). RESULTS: With increasing age, we found (a) lower glutathione and glutamate, and higher myo-inositol in PCC, and (b) lower N-acetylaspartate and glutamate, and higher N-acetylaspartyl glutamate, myo-inositol, and total creatine in CSWM. Notably, these changes started in midlife and were largely driven by age-related changes in women. DISCUSSION: Overall, we found evidence that (a) oxidative stress, (b) neuroinflammation, and (c) neuronal loss begin in midlife of healthy adults. Targeting these mechanisms in midlife may slow brain aging and reduce the risks of developing age-related diseases.

Female reproductive aging is the earliest manifestation of aging in humans, with fertility declining due to reduced oocyte quality well before menopause. Menopause marks the definitive end of reproductive potential and the onset of increased risk for multiple age-related, chronic diseases. Emerging evidence links reproductive disorders, from infertility to widespread gynecological conditions such as polycystic ovarian syndrome, with elevated risks of premature morbidity and mortality. Indeed, it is increasingly evident that even normal reproductive transitions such as puberty, pregnancy, and menopause, act as physiological inflection points that shape long-term systemic health. Yet, fertility continues to be viewed primarily through the prism of procreation, with limited knowledge of the underlying biological mechanisms and scarce clinical focus on its broader health implications. Recent discoveries elucidating the genetic basis of reproductive traits combined with advances in our understanding of fundamental aging mechanisms offer a compelling framework to address these persistent knowledge gaps with far-reaching public-health consequences. This review synthesizes the current knowledge on how reproductive aging, normal reproductive phases and major reproductive dysfunctions influence long-term health trajectories and argues for a shift toward integrated, lifespan-based approaches to reproductive health in research and clinical care.

Macroautophagy (hereafter referred to as autophagy) is widely recognized as a central pathway for the clearance of protein aggregates and the maintenance of proteostasis. However, a recent study by Murley et al. challenges this conventional view. Using a

Members of the fragile X protein (FXP) family (FMR1, FXR1 and FXR2) are differentially expressed in most types of cancer and major neurodegenerative diseases. While increased expression of FXR1 in cancer has been linked to senescence evasion and consequently tumor initiation and progression, decreased expression of FXPs in neurodegeneration may contribute to pathogenic protein aggregation and death of vulnerable neurons. However, due the causal role in fragile x syndrome, most data are available about loss of FMR1 in neurons while functions of FXR1 and especially FXR2 remain largely unexplored. To address this knowledge gap, and to directly compare functions of the FXPs, we used proteomics of CRISPR/Cas9 edited HAP1 cells carrying knockouts of the individual FXPs for identification of cellular mechanisms associated with these proteins. Further exploration of proteomic findings suggests roles of the FXPs in ribosome biogenesis, autophagy and mitochondrial health linked to organismal aging, and cellular senescence. Validation of FXP induced defects relevant for neurodegenerative diseases in neuroblastoma cell line SH-SY5Y upon FXP knockdown revealed high cell type specificity of individual FXP functions. Overall, we provide a comprehensive overview and comparison of cellular mechanisms related to the individual FXPs, as well as starting points for further studying this protein family in respective cell types of FXP associated diseases, and in aging in general.

Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans.

In the context of rapid urbanization and escalating population aging, lifestyle factors play a critical role in sarcopenia development. This study aimed to clarify the prevalence of sarcopenia in elderly adults in the urban-rural transition zone of southern Pudong, Shanghai, and explore the association between lifestyle factors (with a focus on long-term farming history) and sarcopenia.

Fasting-based interventions are gaining momentum as strategies to modulate longevity. Conversely, the same metabolic adaptations that once ensured survival during starvation now contribute to the global obesity epidemic. While previous studies have characterized metabolic changes during fasting, few have examined the refeeding phase, and most lack an integrated analysis of key hormonal and metabolic regulators, including insulin, leptin, adiponectin, free T3, FGF21, and the plasma metabolome. To address this gap, we profiled 134 plasma metabolites using mass spectrometry, covering pathways involved in lipid, amino acid, and ketone metabolism, in a cohort of 20 adults (mean age 52.2 ± 11.8 years, 55% women, BMI 28.8 ± 6.4 kg/m

The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine. We highlight mechanistic parallels and distinctions between injury-induced dedifferentiation and OSKM-mediated reprogramming, emphasizing the roles of dedifferentiation, transient regenerative progenitors, and epigenetic remodeling. Critical safety considerations-such as teratoma formation, organ failure, and loss of cell identity-are discussed alongside strategies designed to mitigate these risks, like cyclic induction and targeted delivery. Finally, we briefly note the growing translational interest in this field, alongside directing readers to recent reviews for detailed coverage of biotech initiatives. Collectively, this work underscores the transformative potential of in vivo reprogramming for both tissue regeneration and rejuvenation, while stressing the importance of precise spatiotemporal control for its safe clinical application.

While the health effects of dietary copper intake have been widely studied, no research to date has specifically examined its association with biological aging. Here, we aim to explore the relationship between dietary copper intake and biological aging, while examining the mediating role of dietary inflammatory index (DII). This cross-sectional study included 18,160 adults from the 2003 to 2018 National Health and Nutrition Examination Survey (NHANES). Weighted multivariable linear regression models, subgroup analysis, trend tests, and restricted cubic spline (RCS) were used to analyze the relationship between dietary copper intake and biological aging. Biological aging was measured from different perspectives including phenotypic age (PhenoAge) and phenotypic age acceleration (PhenoAgeAccel). Additionally, mediation analysis explored the mediating role of DII in the above relationships. In this study, we found dietary copper intake was negatively associated with biological aging. Specifically, each 1-unit increase in dietary copper intake was associated with a 1.12-year decrease in PhenoAge and a 1.45-year decrease in PhenoAgeAccel. RCS models revealed a non-linear relationship between dietary copper intake and biological aging (p for nonlinear < 0.001). Specifically, the inverse association was stronger at lower intake levels, with the protective effect plateauing at higher values. Mediation analysis further indicated that DII mediated the above relationships. This study demonstrates a significant negative association between dietary copper intake and biological aging. Public health strategies that increase dietary copper intake may help reduce the burden of biological aging.

Autosomal dominant polycystic kidney disease leads to cyst formation and interstitial fibrosis in the kidney, with limited therapeutic options. A recent study demonstrates that polycystic kidney disease is characterized by the presence of senescence in the affected epithelial cells. This autosomal dominant polycystic kidney disease-associated senescence establishes a new perspective on disease progression and the paracrine impact of cystic epithelial cells. Most importantly, the senescence-associated secretory phenotype present in cystic kidney epithelial cells provides a novel therapeutic angle.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal genetic disorder caused by progerin, a mutant lamin A variant that disrupts nuclear architecture and drives systemic cellular dysfunction. Gastrointestinal (GI) involvement in HGPS remains poorly understood, despite growing evidence of gut abnormalities and microbial dysbiosis in progeroid mouse models. Here, we provide the first comprehensive characterization of colonic pathology in Lmna

Sequence variation in mitochondrial DNA was once considered neutral, but growing evidence indicates it can influence metabolic, physiological and life-history traits. Two hypotheses offer explanations for this non-neutral mtDNA variation: the mitochondrial climatic adaptation hypothesis, which posits that natural selection shapes mtDNA variation to match local environments, and the mother's curse hypothesis, which predicts the accumulation of male-harming variants due to maternal inheritance. We explored these hypotheses using genetic strains of Drosophila melanogaster bearing eight mtDNA haplotypes-nested within two distinct haplogroups (A1 and B1) that segregate along an Australian latitudinal cline. We measured the longevity of flies under cool (18 °C) and warm (28 °C) conditions, predicting that the A1 haplogroup-which has been reported to predominate at subtropical latitudes-would confer higher longevity in warm but reduced longevity in cool temperatures relative to the B1 counterpart. We also tested whether effects of mtDNA haplotype on longevity were larger in males, as predicted under the mother's curse hypothesis. We found mtDNA haplogroup and haplotype is associated with longevity, with the magnitude of effects varying with temperature, but not in a pattern consistent with either hypothesis. Haplogroup-by-environment interactions did not align with reported spatial distributions of the haplogroups, and haplotype effects on longevity were similar across sexes. Our findings add to the growing evidence that mtDNA variation contributes to thermal plasticity in longevity, but do not provide clear insight into whether this variation is adaptive or maladaptive.

Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.