Longevity Papers

Several dietary patterns are suggested to benefit health, potentially through DNA methylation changes. However, to what extent adherence to so-called healthy diets overlaps, whether these dietary patterns are equally beneficial, and whether they affect health outcomes through the same molecular mechanisms, remains unclear. Therefore, we investigated the overlap in adherence to ten diet quality scores, and examined the associations of these scores with both biological aging markers and DNA methylation profiles. We used data from the Rhineland Study, a large population-based cohort, and validated our findings using corresponding data from the independent EPIC-Potsdam cohort. Interestingly, we found minimal overlap of participants in the top 25% of adherence across different diet quality scores. Adherence to a healthy dietary pattern was associated with reduced epigenetic age acceleration regardless of the specific dietary pattern, except for the EAT-Lancet diet. Different dietary patterns were associated with distinct methylation profiles, which however largely converged onto the same biological pathways. Our research thus indicates that general adherence to a healthy dietary pattern promotes health through similar epigenetic mechanisms, despite variations in dietary composition.

Mitochondrial dysfunction is one of the important signs of cellular and even individual aging. Ganoderma lucidum is a common edible and medicinal mushroom, widely used as a functional food in Asia. This study investigated the potential anti-aging effects of Ganoderma lucidum extract (GLE). Our results demonstrated that GLE alleviated cellular oxidative stress, reduced the abnormal increase of mitochondrial ROS in aging cells, and maintained mitochondrial membrane integrity and inner membrane potential. Additionally, GLE affected mitochondrial biogenesis in aging cells. In a murine photoaging model, GLE treatment mitigated UVA-induced mitochondrial dysfunction while markedly attenuating UVA-triggered epidermal thickening and dermal protein depletion. These properties may be interrelated with the presence of abundant triterpenoids identified by LC-MS analysis.

Regulation of gene expression is fundamental for proper cellular function, and is constrained by the local chromatin environment of each gene, which varies spatially along the chromosome and is shaped by epigenetic modifications. Epigenetic modifications induce changes in the local chromatin structure, which can influence gene expression, by affecting the accessibility of DNA to transcription factors. Such changes are particularly relevant in aging and genetic disorders like Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WRN), where altered chromatin structure contributes to disease pathology. In this study, we analyze RNA-seq data using macroscopic metrics designed to be explicitly sensitive to chromatin modifications. The first metric, intra-chromosomal gene correlation length, measures spatial correlations in gene expressions along the chromosome. The second metric employs an energy landscape model based on the Arrhenius equation to estimate the energetic barriers associated with chromatin state transitions. We apply these metrics to various aging-related datasets, demonstrating their sensitivity to changes in the chromatin structure and the interpretability of the resulting outputs. The intra-chromosomal gene correlation length is particularly effective in quantifying changes in RNA-seq profiles due to increased chromatin accessibility during aging (and conversely, reduced accessibility due to treatment). This metric not only accurately distinguishes cell states, but also provides insight into the direction of aging. For instance, our observations on the effects of anti-sense oligonucleotide (ASO) treatment align with the existing literature, demonstrating that ASO partially restores chromatin structure in diseased cells. They additionally quantify the more pronounced effects in HGPS compared to WRN. The barrier energy landscape further extends this capability by offering a framework for understanding the progressive degradation of the regulatory mechanisms. Together, these metrics provide robust screening tools that enhance our ability to exploit common measurements such as RNA-seq to derive new phenotypes such as chromatin dynamics on aging and disease, offering an alternative perspective that complements traditional analytical techniques and enriches our understanding of cellular states.

Frailty, depression, and loneliness are significant risk factors that hinder successful aging. Physical exercise has been widely recognized as an effective intervention to improve both the physical and mental health of older adults. Guided by the integral conceptual model of frailty, this study aimed to explore the relationships among physical exercise, frailty, depression, and loneliness, providing theoretical support for designing targeted exercise interventions to alleviate loneliness in older adults.

Late-life diseases result from the poorly understood process of senescence (aging), which is largely genetically determined. According to a recently proposed evolutionary physiology-based account, the multifactorial model, senescence is largely caused by evolved but non-adaptive programmatic mechanisms specified by the wild-type (i.e. normal) genome. These act together with disruptions to wild-type function (due e.g. to infectious pathogens, mechanical injury and malnutrition) in a variety of combinations to generate diverse late-life diseases. Here, I explore the utility of this model by testing its capacity to provide an account of one complex, late-life disease, osteoarthritis (OA), and suggest a framework for understanding OA etiology. In this cartilage-focused framework, a core OA disease mechanism is a futile (non-adaptive) developmental program of endochondral ossification, in which hypertrophic articular cartilage chondrocytes alter joint architecture. Programmatic changes prime chondrocytes for futile program activation, which can be triggered by secondary causes of OA (e.g. joint mechanical injury). I suggest that an evolutionary cause of this priming, involving antagonistic pleiotropy, is selection to maximize early-life tissue repair benefits at the expense of late-life programmatic costs.

Drawing from the deep-rooted knowledge of traditional medicine, the Fabaceae family particularly Psoralea corylifolia has been esteemed for its natural remedies against aging. In this study Bakuchiol, a phenolic compound derived from P.corylifolia is explored for its potential to mitigate age-related deterioration through a close examination of its effects on Caenorhabditis elegans. Rather than seeing aging as mere decline, we investigate it as a dynamic process of molecular changes where Bakuchiol may play a pivotal role by influencing key genetic pathways to counter cellular damage and oxidative stress. Using a range of C. elegans strains including those with precise genetic modifications, this study probes Bakuchiol interaction with essential regulators of aging primarily the DAF-16 transcription factor, a counterpart to mammalian FOXO and the insulin/insulin-like growth factor (IIS) pathway. The findings show that Bakuchiol at an optimal concentration of 37.5 μM meaningfully extends lifespan and enhances resilience to stress independent of microbial influences. Notably, Bakuchiol promotes the nuclear translocation of DAF-16, up regulates stress-response genes and boosts the activity of superoxide dismutase (SOD-3) solidifying its role in modulating aging via conserved genetic mechanisms. This research highlights Bakuchiol potential as a powerful natural agent for aging intervention enriching the field of biogerontology and pointing toward the translational promise of plant derived compounds in developing advanced anti-aging therapies.

Leucine, a branched-chain amino acid (BCAA), is an effective nutritional strategy to enhance skeletal muscle mass in aging populations. This study aimed to evaluate the effects of oral leucine-enriched BCAA supplementation on muscle mass, muscle synthesis biomarkers, and physical performance in elderly patients with chronic kidney disease (CKD).

Sarcopenia is a prevalent age-related disorder characterized by progressive loss of muscle mass, strength, and physical performance. While genome-wide association studies (GWAS) have explored isolated traits, the multifactorial genetic architecture underlying sarcopenia remains poorly defined. In this study, we constructed a comprehensive genetic factor to explain the genetic architecture of sarcopenia, and explore causal associations, genetic comorbidities, and mediating pathways linking sarcopenia to 30 urological diseases.

The nervous system (NS) experiences morphological and functional changes during the aging process, where low-grade chronic inflammation, oxidative stress and senescence are key regulators. Sulforaphane (SFN) is an isothiocyanate that activates redox response and inhibits the inflammatory process, which could modify the pro-inflammatory components of senescent cells secretory phenotype (SASP). Here we aimed to determine if SFN long-term treatment was able to prevent age-associated damage in the NS of adult and old females and males Wistar rats. We evaluated cytokines and chemokines profile, senescent cells markers, and memory parameters of adult (15 m.o.) and old (21 m.o.) rats after three months of SFN treatment. Young rats (4 m.o.) were used as age controls. Differences between sexes were observed in the inflammatory profile. Our results showed that SFN-treatment diminished proinflammatory molecules, senescence markers and senescent cells number in brain cortex and hippocampus from males and females' adult rats, but no effects were observed in both sexes old groups compared with the same age control groups. SFN-dependent reduction in inflammatory and senescence parameters resulted in better scores in Barnes Maze Trial memory test when compared with same age non-treated group. Interestingly, adult females showed higher levels of proinflammatory cytokines and chemokines than adult males, which were prevented by SFN-treatment. No effects of SFN were observed in memory of old-treated groups.

Diabetes ranks as the ninth leading cause of death globally, and DNA-methylation age acceleration (DNAmAA) is closely linked to lifespan. However, the impact of DNAmAA on long-term outcomes in specific populations with diabetes and pre-diabetes has not yet been comprehensively studied.

Background: Mechanisms underlying Doxorubicin (Doxo) chemotherapy-induced aortic stiffening are incompletely understood. Objectives: Determine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating Doxo-induced aortic stiffening and the influence of senolytic therapy. Methods: Aortic stiffness (aortic pulse-wave velocity [PWV]), and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir [GCV]. Young (4-6 month) mice were injected with Doxo and subsequently treated with GCV or the senolytic ABT263. We evaluated the influence of SASP-associated circulating factors in plasma (the circulating SASP milieu) in mediating aortic stiffening ex vivo (aortic elastic modulus) and examined the contribution of glycation stress. Results: Doxo increased aortic PWV (425 vs. control, 353 cm/sec; P<0.05), an effect prevented by both GCV (348 cm/sec) and ABT263 (342 cm/sec; P<0.05 for both vs. Doxo). Plasma from Doxo-treated mice induced aortic stiffening ex vivo (P<0.05 vs. plasma from control mice), whereas plasma from Doxo-GCV and Doxo-ABT263 groups did not. Glycation stress was implicated in SASP-mediated aortic stiffening with Doxo, as inhibition of receptor mediated glycation stress signaling attenuated plasma-induced aortic stiffening. Conclusion: Cellular senescence and the circulating SASP milieu contribute to Doxo-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following Doxo exposure.

Large-scale genomic studies focusing on the genetic contribution to human aging have mostly relied on cross-sectional data. With the release of longitudinally curated aging phenotypes by the UK Biobank (UKBB), it is now possible to study aging over time at genome-wide scale. In this work, we evaluated the suitability of competing models of change in realistic simulation settings, performed genome-wide association scans on simulation-validated measures of age-related deweekcline, and followed up with LD-score regression and Mendelian Randomization (MR) analyses. Focusing on global cognitive and physical function, we observed marked differences between baseline function (θ) and accelerated decline (Δ). Both outcomes showed distinct heritability levels (e.g., 31.38%

Diversity Outbred (DO) mice are a powerful model system for mapping complex traits due to their high genetic diversity and mapping resolution. However, while there are extensive tools available for standard genetic analysis in DO mice, fewer techniques have been implemented to facilitate integrated, cross-study analysis. Here, we implement Haseman-Elston regression to estimate genetic correlations among 7,233 phenotypes measured across eleven independent DO mouse studies. We used this network of genetic correlations to cluster phenotypes according to shared genetics, which enhanced the power to detect quantitative trait loci (QTL). This approach empowered the detection of 884 QTL for 383 meta-phenotypes, explaining an average of 40.36% of the total genetic variance per mega-analysis. We leveraged this network for insights into specific areas of biology, including lifespan, frailty, immune composition, histological and functional lung phenotypes, and histological phenotypes of the aorta. We found the genetics of lifespan to share limited correlation with the genetics of frailty but stronger correlation with the genetics of immune cell composition. Additionally, mega-analyses driven by genetic correlations identified candidate genes (e.g. Cdkn2b) associated with degraded extracellular matrix in the aorta. Finally, an ensemble of genetic analyses implicated pulmonary neuroendocrine cell signaling and/or differentiation as a key driver of multiple lung pathophenotypes.

Background: Cardiovascular disease (CVD) is the leading cause of global mortality, with recent increases attributed to demographic shifts in age and rising rates of obesity. Diminished contractile reserve is a hallmark of a diseased heart; assessing contractile reserve is pivotal in prognosticating and monitoring CVD progression. The Frank-Starling mechanism and sympathetic stimulation are key to enhance contractile reserve but have not been explored in vivo in old and obese mouse models of CVD. This project aims to use speckle tracking echocardiography (STE) to characterize the function of the heart at baseline, with increased preload, and with sympathetic stimulation. We hypothesize that along with blunted systolic function, diastolic function, and contractility, old and obese mice will have a blunted contractile reserve. Methods: STE was obtained for control (4-month-old), aged (24-month-old), and obese mice (high fat diet-induced). Mice received an intravenous injection of 150L saline to increase preload to assess the Frank-Starling response, followed by injection of {beta}1adrenergic receptor agonist dobutamine to assess sympathetic response. Results: At baseline, aging and obese mice demonstrated blunted systolic, diastolic function, and contractility. Endocardial and epicardial wall displacement differed between aging and obese mice with contractile reserve, indicating that they have functionally distinct cardiac phenotypes. Conclusions: This study is the first to demonstrate blunted systolic function, diastolic function, and contractility through STE in aging and obese mice. Our novel method for investigating the contractile reserve of mice demonstrated aging and obese mice have dissimilar responses when assessing contractile reserve, which could contribute to their distinct functional phenotypes.

Leisure activities (LAs) are vital for healthy ageing and are linked to lower mortality risk in older adults. However, most previous longitudinal studies have assessed LAs at only one time point. We aimed to explore the impact of dynamic changes in LAs on subsequent all-cause mortality among older adults.

Epigenetic aging in early life remains poorly characterized, and patterns of gene expression can provide biologically meaningful insights. Blood DNA methylation was measured using the Illumina EPICv1.0 array and RNA sequencing was performed in blood in 174 adolescent participants (age range: 14-15 years) from the CHAMACOS cohort. Thirteen widely used epigenetic clocks were calculated, and their associations with transcriptome-wide RNA expression were tested using the

The disruption of renal cell homeostasis caused by aging has attracted considerable attention. A traditional Chinese medicine, ginseng, is a potential drug for treating aging-related diseases. The study investigates the effect and mechanism of ginsenoside Rg1, an active component of ginseng, on renal aging and injury.

Advances in understanding the mechanisms of aging and successful efforts in extending lifespan in laboratory animals have made enhancing human healthspan more attainable. A key factor in aging and many diseases is the decline in nicotinamide adenine dinucleotide (NAD+) levels. Preclinical studies demonstrate promising results for NAD+ boosting in improving conditions of disease or aging. However, limited human studies have shown clinically significant improvements in physiological function or quality of life with NAD+ boosting supplements. This randomized, double-blind, placebo-controlled study (Clinicaltrails.gov identifier: NCT06505967) investigated the impact of Qualia NAD+(R) on blood NAD+ levels and healthy aging, as assessed by quality of life surveys. Methods: Sixty-three healthy adults aged 35 - 76 (62% female) consumed Qualia NAD+ (n = 28) or placebo (n = 35) for 28 consecutive days and had NAD+ assessed. NAD+ levels were measured at baseline and study end using a self-administered, non-invasive blood spot assay, and quality of life measures were reported weekly. Qualia NAD+ increased NAD+ levels by an average of 67% compared to 4% with placebo (p < 0.001). Within-group changes for Qualia NAD+ and between-groups comparisons were also significant (p < 0.001). Qualia NAD+ improved emotional well-being on days 14, 21, and 28, and vitality on days 21 and 28, versus placebo (all p < 0.05). Aging female symptoms improved in overall and somatic categories at day 28 (all p < 0.05). No significant improvements in aging symptoms were observed for males. In conclusion, NAD+ boosting with Qualia NAD+ enhanced quality of life in all participants and alleviated some aging symptoms in females.

High-temperature requirement protein A1 (HTRA1) is a secreted serine protease with diverse substrates, including extracellular matrix proteins, proteins involved in amyloid deposition, and growth factors. Accordingly, HTRA1 has been implicated in a variety of neurodegenerative diseases including a leading cause of blindness in the elderly, age-related macular degeneration (AMD). In fact, genome wide association studies have identified that the 10q26 locus which contains HTRA1 confers the strongest genetic risk factor for AMD. A recent study has suggested that AMD-associated risk alleles in HTRA1 correlate with a significant age-related defect in HTRA1 synthesis in the retinal pigmented epithelium (RPE) within the eye, possibly accounting for AMD susceptibility. Thus, we sought to identify small molecule enhancers of HTRA1 transcription and/or protein abundance using an unbiased high-throughput screening approach. To accomplish this goal, we used CRISPR/Sp.Cas9 engineering to introduce an 11 amino acid luminescent peptide tag (HiBiT) onto the C-terminus of HTRA1 in immortalized ARPE-19 cells. Editing was very efficient (~88%), verified by genomic DNA analysis, short interfering RNA (siRNA), and HiBiT blotting. Nineteen-hundred and twenty compounds from two libraries were screened. An azo compound with reported anti-amyloidogenic and cardioprotective activity, Chicago Sky Blue 6B (CSB), was identified as an enhancer of endogenous HTRA1 secretion (2.0 +/1 0.3 fold) and intracellular levels (1.7 +/- 0.2 fold). These results were counter-screened using HiBiT complement factor H (CFH) edited ARPE-19 cells, verified using HiBiT blotting, and were not due to HTRA1 transcriptional changes. Importantly, serine hydrolase activity-based protein profiling (SH-ABPP) demonstrated that CSB does not affect HTRA1\'s specific activity. However, interestingly, in follow-up studies, Congo Red, another azo compound structurally similar to CSB, also substantially increased intracellular HTRA1 levels (up to 3.6 +/- 0.3 fold) but was found to significantly impair HTRA1 enzymatic reactivity (0.45 +/- 0.07 fold). Computational modeling of potential azo dye interaction with HTRA1 suggests that CSB and Congo Red can bind to the non-catalytic face of the trimer interface but with different orientation tolerances and interaction energies. These studies identify select azo dyes as HTRA1 chemical probes which may serve as starting points for future HTRA1-centered small molecule therapeutics.

Ants have been proposed as good models to study ageing and the effects of extrinsic mortality because of their long lifespans and plasticity of ageing within species. We discuss how age-dependent extrinsic mortality might influence queen lifespan, and how the effect of age-independent extrinsic mortality needs further study, accounting for different density-dependence scenarios. Based on a critical review of the available demographic data, we discuss the selective forces underlying ant ageing. We discuss differences and similarities between the life-history strategy of ants and the reproductive strategies iteroparity and semelparity. We consider how late-life fitness gains for the "superorganism" select for a delay of actuarial, and reproductive senescence, and we suggest future research directions.

"Biological aging clocks"-composite molecular markers thought to capture an individual's biological age-have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA-sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets in humans and mice, we develop and compare computational approaches for generating transcriptome-wide summaries from microglia to establish robust and applicable aging clocks. Our results reveal that unsupervised, frequency-based summarization approaches, which encode distributions of cells across molecular subtypes, strike a balance in accuracy, interpretability, and computational efficiency. Notably, our computationally derived microglia markers achieve strong accuracy in predicting chronological age across three diverse single-cell datasets, suggesting that microglia exhibit characteristic changes in gene expression during aging and development that can be computationally summarized to create robust markers of biological aging. We further extrapolate and demonstrate the applicability of single-cell-based microglia clocks to readily available bulk RNA-seq data with an environmental input (early life stress), indicating the potential for broad utility of our models across genomic modalities and for testing hypotheses about how environmental inputs affect brain age. Such single-cell-derived markers can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.

Sulforaphane, an organosulfur isothiocyanate derived from cruciferous vegetables, has been shown to inhibit inflammation, oxidative stress, and cancer cell growth. To explore the potential of sulforaphane as a candidate natural compound for promoting longevity more generally, we tested the dose and age-specific effects of sulforaphane on C. elegans longevity, finding that it can extend lifespan by more than 50% at the most efficacious doses, but that treatment must be initiated early in life to be effective. We then created a novel, gene-specific, transcriptional aging clock, which demonstrated that sulforaphane-treated individuals exhibited a "transcriptional age" that was approximately four days younger than age-matched controls, representing a nearly 20% reduction in biological age. The clearest transcriptional responses were detoxification pathways, which, together with the shape of the dose-response curve, indicates a likely hormetic response to sulforaphane. These results support the idea that robust longevity-extending interventions can act via global effects across the organism, as revealed by systems level changes in gene expression.

Aging negatively impacts central nervous system function; however, there is limited information about the cellular impact of aging on peripheral nervous system function. Importantly, injury to vulnerable peripheral axons of dorsal root ganglion (DRG) neurons results in somatosensory dysfunction, such as pain, at higher rates in aged individuals. Cellular senescence is common to both aging and injury and contributes to the aged pro-inflammatory environment. We discovered DRG neuron senescence in the context of aging and pain-inducing peripheral nerve injury in young (~3 months) and aged (~24 months) male and female mice. Senescent neurons were dynamic and heterogeneous in their expression of multiple senescence markers, including pro-inflammatory factor IL6. Senescence marker-expressing neurons had nociceptor-like profiles, included high-firing phenotypes and displayed increased excitability after IL6 application. Furthermore, elimination of senescent cells resulted in improvement of nociceptive behaviors in nerve-injured mice. Finally, male and female post-mortem human DRG contained senescent neurons that increased with age (~32 years old versus 65 years old). Overall, we describe a susceptibility of the peripheral nervous system to neuronal senescence-a potential targetable mechanism to treat sensory dysfunction, such as chronic pain, particularly in aged populations.

The genetic architecture underlying traits related to Human Musculoskeletal System Aging (MSA) remains largely unexplored. In this study, we conducted a large-scale multivariate genome-wide association study (GWAS) of MSA utilizing Genomic Structural Equation Modeling (Genomic SEM). We estimated causal single nucleotide polymorphisms (SNPs) associated with independent variation and identified 14 genome-wide significant loci (mean.PP > 0.95). We employed multiple transcriptome-wide association methods to analyze tissue, cellular levels, and genomic elements, identifying loci with high relevance to MSA susceptibility, along with associated element information. Our research represents the first comprehensive delineation of the genetic architecture of Musculoskeletal System Aging through a GWAS of unmeasured phenotype.

Oligodendrogenesis and myelin formation are important processes in the central nervous system (CNS) of jawed vertebrates, underpinning the highly efficient neural computation within the compact CNS architecture. Myelin, the dense lipid sheath wrapped around axons, enables rapid signal transmission and modulation of neural circuits. Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), which are widely distributed in the adult CNS and continue to produce new oligodendrocytes throughout life. Adult oligodendrogenesis is integral to adaptive myelination, which fine-tunes neural circuits in response to neuronal activity, contributing to neuroplasticity, learning, and memory. Emerging evidence also highlights the role of oligodendrogenesis in specialized brain regions, linking oligodendrocytes to metabolic and homeostatic functions. In the aging and diseased brain, dysregulated oligodendrogenesis exacerbates myelin loss and may contribute to pathogenesis. In addition, maladaptive myelination driven by aberrant neuronal activity could sustain a dysfunction in conditions such as epilepsy. This review summarizes the current understanding of oligodendrogenesis, with insights into its evolution, regulation, and impact on aging and disease.

Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to the development of age-related diseases. In the pursuit of slowing or even reversing the aging process, a prominent strategy of significant interest is calorie restriction (CR), also known as dietary restriction, and the potential influence of a drug called rapamycin (RM). Both CR and RM have demonstrated the capacity to extend healthspan and lifespan across a diverse array of species, including yeast, worms, flies, and mice. Nevertheless, their individual and combined effects on mitotic and postmitotic cells, as well as their comparative analysis, remain areas that demand a thorough investigation. In this study, we employ RNA-sequencing methodologies to comprehensively analyze the impact of CR, RM, and their combination (CR + RM) on gene expression in yeast cells. Our analysis uncovers distinctive, overlapping, and even contrasting patterns of gene regulation, illuminating the unique and shared effects of CR and RM. Furthermore, the transcriptional synergistic interaction of CR + RM is validated in extending the lifespan of both yeast and human cells.

Health status is closely linked to both healthcare access and utilization. While previous research has identified associations between health status and DNA methylation-based biomarkers of aging (epigenetic aging), studies exploring these relationships in the context of healthcare access and utilization remain limited. To address this gap, we analyzed cross-sectional associations in a representative sample of 2,343 U.S. adults from the 1999-2000 and 2001-2002 cycles of the National Health and Nutrition Examination Survey (NHANES). Our study examined the relationships of self-rated health status, healthcare access, and healthcare utilization with seven epigenetic aging biomarkers: HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge2, DNAm Telomere Length (DNAmTL), and DunedinPoAm.

To address the challenges of an ageing population, it is important to promote health by identifying factors for healthy ageing. The aim of this study was to investigate the bidirectional association between physical activity (PA) and sleep in healthy Japanese super-seniors over the age of 80. For approximately 1 year, 124 participants wore wearable devices and answered daily lifestyle questionnaires. PA was defined as daily step count and minutes in light activity. Sleep was measured using 24-h total sleep time (TST) and time in bed (TIB). Associations were analysed bidirectionally using multilevel mixed-effects linear regression models. Fully adjusted models revealed significant and inverse associations between sleep and PA from the same 24-h period. Similarly, the results were significant and inverse with PA from the day before as exposure and the next 24-h sleep measures as outcome. The between-individual associations between sleep measures and PA from the subsequent day were significant and inverse. However, there was a positive within-individual association between TST and step count from the subsequent day. The study suggests that associations between PA and sleep in super-seniors differ from patterns previously described in younger adults. Very old individuals with increasing 24-h total sleep time may compensate for a lower step count on one day by increasing their step count the following day.

Ageing is a gradual biological process marked by a decline in physiological function, increasing susceptibility to disease, and mortality. Transposable elements (TEs) are repetitive DNA sequences capable of moving within the genome, and thus potentially inducing mutations and disrupting normal cellular functions. Their mobile nature contributes to genomic variation, as transposition events can alter gene expression, chromosome structure, and the epigenetic landscape. To mitigate TE-induced damage, cells rely on epigenetic mechanisms, such as DNA methylation, histone modifications and small RNAs, to repress TE activity. However, these silencing mechanisms become less effective with age, leading to increased TE activation. This review explores the dual role of TEs as both a cause and consequence of ageing, suggesting a complex relationship between TEs and the ageing process.

Chronic infection with Toxoplasma gondii (T. gondii) results in severe damages to the integrity of intestinal barrier, however, both the underlying mechanism and feasible intervention strategies are still little known. Here, we found that both the chronic infection of T. gondii and transplanting gut microbiota from T. gondii-infected mice severely impaired the mice intestinal integrity, which was characterized by significantly decreased thickness of inner mucus layer and down-regulated expression of three tight junction proteins Occludin, ZO-1, and Claudin (p < 0.05). Moreover, T. gondii infection also led to mice intestinal microbiota dysbiosis, especially butyrate-producing bacteria, and significantly changed the expression of several senescence-associated markers, including 6- and 7- fold upregulation for P16, P21, and 6-fold downregulation for Lamin B1 at mRNA levels, and 2-fold downregulation for β-galactosidase at protein levels (p < 0.05). Interestingly, subsequent administration with dietary butyrate could alleviate T. gondii-induced intestinal integrity impairment and cell senescence, revealing a significant increase of the inner mucus layer thickness (p < 0.001), and a remarkable decrease in P16, P21, β-galactosidase expression levels while an upregulation of Lamin B1 expression (p < 0.05). Taken together, our study revealed that T. gondii-induced dysbiosis of gut microbiota, especially butyrate-producing bacteria, contributes to the intestinal impairment, potentially via promoting cell senescence. In addition, administration with the metabolite, butyrate, could be a promising therapeutic measure against T. gondii infection.

Age-associated changes to the intestinal microbiome may be linked to inflammageing and the development of age-related chronic diseases. Cynomolgus macaques, a common animal model in biomedical research, have strong genetic physiological similarities to humans and may serve as beneficial models for the effect of age on the human microbiome. However, age-associated changes to their intestinal microbiome have previously only been investigated in faecal samples. Here, we have characterised and investigated the effects of age in the cynomolgus macaque intestinal tract in luminal samples from both the small and large intestine.

Sex-biased longevity is observed across a wide range of animal taxa, including bats, for reasons not well understood. Patterns of cytosine methylation vary predictably with age in many organisms, offering a valuable means to investigate differences in patterns of aging at the molecular level. We tested sex differences in cytosine methylation across 14 bat species and compared patterns of age-associated variation. Sex differences were overrepresented on the X chromosome, showing a strong pattern of female hypermethylation within promoter regions. Sex and age-associated differences in methylation were non-randomly distributed with respect to proximity to putative sex hormone receptor binding sites, with sites hypermethylated in males and females tending to be underrepresented near androgen and estrogen receptor binding sites, respectively. Across species, we observed the relative steepness of male versus female slopes of age-associated variation was associated with the strength of precopulatory sexual selection, with especially strong trends towards male-biased age-associated slopes in two harem-polygynous species that exhibit female-biased longevity. Our results offer insights into how patterns of methylation differ across sexes and ages, and raise intriguing questions for future research, such as whether sex differences in molecular aging reflect sex-biased longevity, for which records in bats are sparse.

Aging-related retinal degeneration and vision loss have been severely affecting the elderly worldwide. Previously, we showed that the m

Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of sister chromatid cohesion. However, the mechanisms underlying age-dependent deterioration of cohesion are not well-defined. Autophagy, a cellular degradation process critical for cellular homeostasis, is known to decline with age in various organisms and cell types. Here we quantify basal autophagy in Drosophila oocytes and use GAL4/UAS inducible knockdown to ask whether disruption of autophagy in prophase oocytes impacts the fidelity of chromosome segregation. We find that individual knockdown of autophagy proteins in Drosophila oocytes during meiotic prophase causes a significant increase in segregation errors. In addition, Atg8a knockdown in prophase oocytes leads to premature loss of arm cohesion and missegregation of recombinant homologs during meiosis I. Using an oocyte aging paradigm that we have previously described, we show that basal autophagy decreases significantly when Drosophila oocytes undergo aging. Our data support the model that a decline in autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors.

Aging is a complex phenomenon involving oxidative stress, inflammation, and cellular damage subsequently leading to various disorders, such as cardiovascular diseases, neurodegenerative disorders, diabetes, and cancer. Sirtuin (SIRT) proteins are one of the major molecular factors that affect human aging. Sirtuins are a class of NAD

Intrinsic capacity (IC) refers to physical and mental capacities that determine healthy aging. IC is the central element of the World Health Organization care pathway 'Integrated Care for Older People' (ICOPE). However, the operationalization of a composite IC measurement in clinical settings remains to be defined. We used screening data from ICOPE implementation in a real-life population of 27,706 adults 60 years or older that were users of primary care services to elaborate and cross-validate IC scores and centile values for men and women. Here, we show that IC centiles were cross-sectionally associated with comorbidity, frailty and limitations in both activities of daily living and instrumental activities of daily living. External validation using populations from high-income (French INSPIRE-T cohort) and upper-middle-income (ICOPE Brazil) countries validated the associations between IC centiles and clinical outcomes. The IC centiles developed using ICOPE screening data constitute a standardized parameter to monitor individual and population IC through a clinically friendly approach.

Naked mole-rats (NMR;

The Bufei Yishen formula (BYF) has traditionally been employed to treat patients with COPD, demonstrating significant effectiveness. However, the underlying mechanisms through which BYF alleviates COPD remains unclear. Cellular senescence is crucial in the pathogenesis of COPD. This study aims to investigate whether the therapeutic mechanism of BYF is associated with the reduction of cellular senescence. To evaluate the anti-senescence effects of BYF, a COPD rat model and a cellular senescence model were established. The active compounds and underlying mechanisms of BYF were investigated in vitro. BYF treatment significantly mitigated lung function decline and pathological damage in COPD rats. It significantly inhibited senescence in lung tissue by decreasing the expression of the cell cycle inhibitor p21, DNA damage markers, pro-inflammatory cytokines, and matrix metalloproteinases. BYF4/5, isolated from BYF, demonstrated significant anti-senescence effects in bronchial epithelial cells. Additionally, 67 compounds were identified from BYF4/5, and 770 targets were predicted for these compounds. hesperidin and nobiletin, identified as key compounds in BYF, were found to inhibit cellular senescence and activate the AMPK-Sirt1-FoxO3a pathway and autophagy in 16HBE cells. The data indicate that BYF alleviates COPD by activating the AMPK-Sirt1-FoxO3a pathway and autophagy, thereby inhibiting bronchial epithelial cell senescence.

Few studies have examined the effects of self-managed lifestyle behavioral adjustment on cognitive status. This study aimed to explore the association between self-managed behavioral changes and transitions in cognitive status. The Hubei Memory and Aging Cohort Study was a prospective cohort study conducted from 2018-2023 in rural and urban areas. Home-dwelling adults aged ≥65 years completed neuropsychological, lifestyle, clinical, and cognitive assessments. The Cox regressions and cubic splines were used to assess the risk of incident cognitive impairment, and latent class analysis was used to group participants based on behavioral patterns and assess transitions in cognitive status. Among 2477 participants with a mean of 2.02 (SD, 1.25) years of follow-up were included in the study. Participants with low and intermediate compared with high baseline behavioral risk exhibited a reduced risk of incident cognitive impairment. At follow-up, those who maintained stable healthy behaviors or positively adjusted them had a 54% (HR, 0.46 [95% CI, 0.34-0.62]) and 84% (0.16 [0.07-0.35]) lower risk of developing cognitive impairment, respectively, compared with those who maintained unhealthy behaviors. The standard and reinforced behavioral adjustment patterns exhibited a 37% (0.63 [0.22-1.79]) and 77% (0.23 [0.05-0.97]) reduction in the risk of incident cognitive impairment, respectively, compared with the basic pattern. Optimal cognitive gains were attributed to positive adjustments in social networks, physical exercise, cognitive activity, and sleep health. Older adults who maintained healthy behaviors or positively adjusted their unhealthy behaviors exhibited a reduced risk of incident cognitive impairment. Positive behavior modification brought greater cognitive improvement to all participants and more pronounced effects for those with dementia.

Exercise interventions can reverse frailty. However, their scalability and sustainability are limited by manpower, which is reducing due to population aging. GrandMove is a program that combines healthy and productive aging strategies to (1) train and employ robust older adults as exercise coaches and (2) improve fitness and motivate the adoption of an exercise habit in older adults with frailty and prefrailty.

Since the conceptualization of early vascular aging (EVA) in 2008, significant efforts have been made to develop and improve its assessment. Initially lead by the investigation of arterial stiffness through pulse wave velocity (PWV), several additional vascular aging biomarkers have gained prominence in recent years. Despite expanding literature addressing methodological concerns associated with these biomarkers in youth, a standardized approach for clinical evaluation of EVA remains elusive, leaving pertinent gaps in understanding the optimal methodology. This article, resulting from international consensus efforts from the Youth Vascular Consortium, aims to provide an updated overview of methods available to measure EVA in youth and to discuss challenges in translating these methods into clinical practice.

Recent studies have suggested that gestational diabetes mellitus (GDM) can accelerate cellular aging in multiple cell types in offspring, but its impact on immune senescence remains uncertain. Our prior study reveals GDM increased the secretion of inflammatory factors by monocytes in offspring. This study discovered the transcriptome characteristics of aging monocytes at the single-cell level and explore the impact of GDM on the progression of monocyte aging in offspring.

The association between change in lifestyle in late-life and frailty mediated by genetic risk is yet to be elucidated. This study aimed to investigate the associations of change in lifestyle in late-life and genetic risk with frailty among older adults.

5-heptadecylresorcinol (AR-C17), a key bioactive component of whole grain (WG) wheat and rye, has been shown to exhibit anti-aging properties. However, the intestinal absorption dynamics of AR-C17 across different intestinal segments, as well as the aging-dependent differences in absorption between young and aging mice and their underlying mechanisms, remain poorly understood. In this study, we systematically evaluated AR-C17 absorption in various intestinal regions using an Ussing chamber system and elucidated potential contributing factors. Our results revealed that the jejunum and ileum served as the principal sites for AR-C17 absorption, with total absorption rates (TAR) reaching approximately 60 % in young mice. Conversely, aging mice exhibited significantly diminished AR-C17 absorption, with TAR values reduced to 20-45 % in these segments. Aging-associated alterations in key absorption parameters-including apparent permeability coefficient, transmucosal resistance, and short-circuit current-were observed during AR-C17 absorption, ultimately leading to reduced uptake in aging mice. Histopathological analysis demonstrated aging-associated structural deterioration, characterized by villus damage with irregular crypt architecture in the jejunum and villus vacuolization in the ileum. These morphological changes were accompanied by downregulated expression of Oct1 in the jejunum and Octn2 in the ileum, which collectively contributed to impaired AR-C17 absorption in aging mice. Further mechanistic investigations indicated that the differential absorption of AR-C17 between young and aging mice was closely associated with alterations in transmembrane transporters, inflammation, and tight junction. This study provided compelling evidence that aging-associated intestinal dysfunction significantly attenuated AR-C17 absorption, providing novel insights for optimizing the bioavailability of WG-derived bioactive compounds in the elderly.

Cell death mediated by the abnormal activation of autophagy has been observed in many neurodegenerative diseases. Dual leucine zipper kinase (DLK), a member of the mitogen-activated protein kinase cascade, plays a key role in regulating cellular autophagy and the progression of neurodegenerative diseases. However, its role in age-related hearing loss has not been reported. In this study, we found that DLK, phosphorylated c-Jun N-terminal kinase (p-JNK), and JNK3 expression increased in the cochleae of C57BL/6J mice during aging. The DLK/JNK pathway and autophagy are excessively activated in the House Ear Institute-Organ of Corti 1 (HEI-OC1) senescent hair cell line. After DLK was upregulated in HEI-OC1 cells, autophagy was activated, and cell aging was initiated. Inhibiting the DLK/JNK pathway in senescent HEI-OC1 cells can reduce autophagy activation and senescence, and inhibiting autophagy activation can also alleviate senescence. The inhibition of DLK or JNK3 in vivo significantly reduced age-related cochlear structural damage and hearing loss in C57BL/6J mice. The results of the present study showed that DLK/JNK3 may play a key role in cochlear hair cell senescence and age-related hearing loss through the abnormal activation of autophagy within cochlear hair cells, suggesting that DLK or JNK3 may be potential targets for alleviating age-related hearing loss.

Recent improvements in human longevity have highlighted the challenge of maintaining health throughout extended lifespans. This review examines how organisms regulate nutrient intake and metabolism, focusing on dietary protein's unique role in health and longevity. While caloric restriction enhances longevity, adherence to a low-calorie diet is challenging. Protein restriction represents an alternate nutritional intervention that improves longevity and health in model organisms and may be easier to translate to humans. However, its impacts are complex, and its mechanisms are poorly understood. The beneficial effects of protein restriction on metabolism and longevity may come at a cost to lean mass and physical resilience. Conversely, while public health recommendations often emphasize high protein intake, human epidemiological data and work on model organisms suggest that excessive protein consumption correlates with increased mortality. Understanding this paradox is crucial for developing evidence-based protein intake recommendations that balance longevity with physical performance.

Proper regulation of inflammatory responses is essential for organismal health. Dysregulation can lead to accelerated development of the diseases of aging and the aging process itself. Here, we identify a novel enzymatic activity of the mitochondrial sirtuin SIRT4 as a lysine deitaconylase that regulates macrophage inflammatory responses. Itaconate is a metabolite abundantly produced in activated macrophages. We find it forms a protein modification called lysine itaconylation. Using biochemical and proteomics approaches, we demonstrate that SIRT4 efficiently removes this modification from target proteins both in vitro and in vivo. In macrophages, elevated protein itaconylation increases upon LPS stimulation, coinciding with elevated SIRT4 expression. SIRT4-deficient macrophages exhibit significantly increased IL-1{beta} production in response to LPS stimulation. This phenotype is intrinsic to macrophages, as demonstrated by both lentiviral over-expression and acute SIRT4 knockdown models. Mechanistically, we identify key enzymes in branched-chain amino acid (BCAA) metabolism as targets of hyperitaconylation in SIRT4-deficient macrophages. The BCKDH complex component dihydrolipoamide branched chain transacylase E2 (DBT) is hyperitaconylated and has reduced BCKDH activity in SIRT4KO macrophages. Physiologically, SIRT4-deficient mice exhibit significantly delayed wound healing, demonstrating a consequence of dysregulated macrophage function. Our data reveal a novel protein modification pathway in immune cells and establish SIRT4 as a critical regulator at the intersection of metabolism and inflammation. These findings have implications for understanding immune dysregulation in aging and metabolic disease.

Biological age assessed by the Klemera and Doubal method (KDM) and phenotypic age (PhenoAge) was considered as a marker for ageing-related outcomes because it reflects different aspects of biological ageing and health, which are associated with increased risk of death. proBNPage based on N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a novel index for biological age estimation. However, the independence of its relationship with clinical outcomes from established risk factors, KDM or PhenoAge remains uncertain. Their identification could provide valuable information to prognosis.

The neuromuscular junction (NMJ) is a crucial peripheral synapse that controls muscle contraction. It consists of a presynaptic motor terminal, a postsynaptic muscle domain, and associated cells, such as terminal Schwann cells and kranocytes. Its larger size compared to central synapses has allowed detailed analyses of NMJ morphology that have been widely used as a reliable parameter of synaptic formation, maturation, function, and decline. Due to its high affinity for postsynaptic acetylcholine receptors (AChRs), the snake venom-derived α-bungarotoxin (BTX) has been pivotal in advancing our understanding of NMJ organization, enabling a detailed mapping of postsynaptic morphologies associated to distinct functional outcomes. Although certain morphological features are often associated with NMJ worsening, some of these cellular changes also occur in biological contexts where synaptic function remains intact. In this review, we draw on previous studies and our recent findings using BTX-based pulse-chase assays to suggest that combining morphological analyses with assessments of postsynaptic stability offers a more comprehensive understanding of NMJ function and regenerative potential. We propose that integrating diverse BTX-based tools into studies of NMJ morphology and stability will provide particularly valuable insights in contexts such as aging, injury, and neuromuscular diseases, where these combined parameters may serve as robust predictors of functional outcomes.

The need for efficient ATP production is predicted to result in the evolution of cooperation between the mitochondrial and nuclear encoded components of the electron transport system. Genotypes where mitochondrial and nuclear genomes from different geographic populations are combined (mismatched), are therefore predicted to result in negative fitness consequences. Such negative fitness effects are expected to be prominent in males, since maternal inheritance of mitochondria can lead to accumulation of male-harming mutations (the mother's curse hypothesis), and they may become more prevalent with ageing. To test these predictions, we measured fertility traits of females and males at different ages using a genetically diverse panel of 27 mitonuclear populations of Drosophila melanogaster with matched or experimentally mismatched mitonuclear genomes. We found no evidence that novel mitonuclear combinations had reduced fitness in females. In males, we found limited evidence of mitonuclear interactions affecting fitness in old age, however, not in the direction predicted. Novel mitonuclear combinations were associated with males that sired more offspring. Sex-specific advantages of mismatched males might arise if novel nuclear alleles compensate for deleterious mitochondrial alleles that have accumulated. If such compensatory effects of novel mitonuclear combinations increasing fitness occur in nature, they could represent a possible counterforce to the mother's curse.

Neurodegenerative diseases comprise a group of central nervous system disorders marked by progressive neuronal degeneration and dysfunction. Their pathogenesis is multifactorial, involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Recent research has highlighted the potential of exercise as a non-pharmacological intervention for both the prevention and treatment of these disorders. In particular, exercise has received growing attention for its capacity to upregulate the expression and activity of SIRT1, a critical mediator of neuroprotection via downstream signaling pathways. SIRT1, a key member of the Sirtuin family, is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. It plays an essential role in regulating cellular metabolism, energy homeostasis, gene expression, and cellular longevity. In the context of neurodegenerative diseases, SIRT1 confers neuroprotection by modulating multiple signaling cascades through deacetylation, suppressing neuronal apoptosis, and promoting neural repair and regeneration. Exercise enhances SIRT1 expression and activity by increasing NAD + synthesis and utilization, improving intracellular redox balance, alleviating oxidative stress-induced inhibition of SIRT1, and thereby promoting its activation. Moreover, exercise may indirectly modulate SIRT1 function by influencing interacting molecular networks. This review summarizes recent advances in the therapeutic application of exercise for neurodegenerative diseases, with a focus on SIRT1 as a central mechanism. It examines how exercise mediates neuroprotection through the regulation of SIRT1 and its associated molecular mechanisms and signaling pathways. Finally, the paper discusses the potential applications and challenges of integrating exercise and SIRT1-targeted strategies in the management of neurodegenerative diseases, offering novel perspectives for the development of innovative treatments and improvements in patients' quality of life.

Tests that can predict whether a drug is likely to extend mouse lifespan could speed up the search for anti-aging drugs. We have applied a machine learning algorithm, XGBoost regression, to seek sets of plasma metabolites that can discriminate control mice from mice treated with an anti-aging diet (caloric restriction) or any of four anti-aging drugs. When the model is trained on any four of these five interventions, it predicts significantly higher lifespan extension in mice exposed to the intervention which was not included in the training set. Plasma peptide data sets also succeed at this task. Models trained on drug-treated normal mice also discriminate long-lived mutant mice from their respective controls, and models trained on males can discriminate drug-treated from control females. Triglycerides are over-represented among the most influential features in the regression models. Triglycerides with longer fatty acid chains tend to be higher in the slow-aging mice, while triglycerides with shorter fatty acid chains tend to decrease. Plasma metabolite patterns may help to select the most promising anti-aging drugs in mice or in humans, and may give new leads into physiological and enzymatic targets relevant to discovery of new anti-aging drugs.

Objective: Investigate miR-486-3p's role in alleviating age-related angiogenic decline in Moyamoya disease (MMD) by regulating senescent endothelial cells. Methods: Clinical analysis of 151 MMD patients correlated age with postoperative angiogenesis (DSA grading). Senescent HUVECs (SA-{beta}-gal>80%) exhibited elevated SASP factors (IL-6/IL-8/MCP-1). Functional assays (EdU/Transwell/Matrigel) and bioinformatics identified miR-486-3p targets, validated via luciferase/Western blot. Results: Patients [≥]35 years had 3.67-fold higher risk of poor angiogenesis (OR=3.67). Senescent HUVECs showed 10-16-fold higher SASP secretion (p<0.01). miR-486-3p overexpression increased proliferation (EdU+25%), migration (1.7-fold), and tube formation (+40% branches) in senescent cells (p<0.01) and enhanced angiogenesis in vivo (p<0.001). miR-486-3p directly targeted FOXO4, reducing its luciferase activity (-35%) and protein levels (-37%) (p<0.01), suppressing SASP. Conclusion: miR-486-3p enhances post-revascularization angiogenesis in MMD by inhibiting FOXO4-mediated SASP, offering a therapeutic target and predictive biomarker.

Since the dawn of human civilisation, the pursuit of immortality has been a perennial quest. Over the past century, unprecedented advancements in medical science, public health initiatives, and social policies have significantly increased the global human lifespan. The debate between lifespan (the total number of years a person lives) and health span (the period of life free from chronic disease or disability) has gained considerable attention in both scientific and public discourse, with global focus now gradually shifting from merely living longer to living better. With this increase, a critical question has emerged: are these additional years truly spent in good health? As the global elderly population projected to reach 2.1 billion by 2050, this demographic shift is expected to place a substantial burden on health care systems, economic structures, and social frameworks. Emerging research in epigenetics, regenerative medicine, and lifestyle medicine suggests that preventive measures and personalised interventions can compress morbidity, promote healthier ageing trajectories, and ultimately increase health span. We review current lifespan and health span frameworks to foster dialogue among basic scientists, clinical specialists, social scientists, public health experts, and policymakers, advocating for a balanced approach that prioritises extending healthy, functional years of life over simply increasing lifespan.

Dried fruits have many advantages on condensed nutrients, food preservation, and availability through all seasons. This study investigated the longevity effects of five commercially available dried fruits (date, pineapple, fig, mango, and prune) on Caenorhabditis elegans. Each of the five dried fruits remarkably increased the lifespan compared with the control group. Especially, date fruit had the longest mean and maximum lifespan. In the analysis for the ratio of mean lifespan (MLS) to maximum lifespan in order to clarify their relationship, the ratio for date fruit was approximately 0.9, showing that it results in a longer MLS than other dried fruits. These results imply that date fruit consumption leads to a significantly greater increase in the MLS of C. elegans. The date fruit examined in this study did not contain syringic acid, a previously reported factor known to extend lifespan in date fruit, suggesting that other unidentified component(s) may contribute to its longevity-promoting effect.

Aging is a natural process that affects cellular function. In peritoneal dialysis (PD), chronic exposure to dialysate induces oxidative stress (OS) in peritoneal mesothelial cells (PMCs), leading to cellular aging, fibrosis, and reduced dialysis efficacy. Mesenchymal stem cells (MSCs) have shown potential in alleviating cellular aging. This study investigates the role of exosomes (hUMSC-Exos) derived from human umbilical cord MSCs (hUMSCs) in mitigating PMC senescence and explores the underlying mechanisms.

Sarcopenia, an age-related disease characterized by the loss of skeletal muscle mass and function, is a growing concern in the aging population. This study investigated the potential of Gromwell (Lithospermum erythrorhizon, LE) to ameliorate sarcopenia in aged mice and the effect of lithospermic acid (LA), a bioactive compound found in LE, on cellular senescence in aged human skeletal muscle myoblast (HSMM) cells. Nineteen-month-old male C57BL/6 mice were fed a diet supplemented with 0.05% LE for 9 weeks. LE supplementation mitigated age-related loss of muscle mass and function, promoted the transition of muscle fiber type from type I to type II, and reduced markers associated with muscle atrophy. In vitro, LA treatment decreased β-galactosidase activity and senescence marker expression in senescent HSMM cells. These findings suggest that LE may serve as a valuable food resource for the prevention and mitigation of sarcopenia, with LA contributing to its effectiveness.

Researches suggested a close connection between the gut microbiome homeostasis and skin health. Melatonin, as a multifunctional molecule, has the potential to regulate intestinal homeostasis and skin function. The study further explored the potential mechanism of melatonin in ameliorating skin barrier damage from the perspective of the association between intestinal microbiota and gut-skin axis in aging mice. We established a natural aging-induced skin barrier damage mouse model with or without melatonin supplementation and fecal microbiota transplantation (FMT) to clarify the crucial role of intestinal microbiota-mediated gut-skin axis in melatonin improving skin barrier damage. Furthermore, lipopolysaccharide (LPS)-treated mice and human keratinocytes cells (HaCaT) explored the modulation mechanism of melatonin. Our results suggested that aging induced skin barrier damage, including skin microbiota disorder and epidermal barrier structure disruption, and intestinal dysbiosis. Similarly, FMT from aging mice and LPS treatment rebuild the aging-like skin barrier damage. Whereas, melatonin or resatorvid (TAK242, the antagonist of LPS) supplementation restored all consequence in aging and LPS-treated mice. In vitro, melatonin restored LPS-induced skin barrier proteins deficiency in HaCaT via decreasing the expression level of TLR4 and MyD88 and increasing the content of p-ERK, p-GSK-3β and β-catenin proteins, while the improving effects was mimicked by pretreatment with a TLR4 antagonist but were blocked by GSK-3β agonists. Our study revealed that melatonin-mediated intestinal microbiota homeostasis suppresses LPS escape to restore the skin barrier function, including skin dysbiosis and epidermal structural disruption via LPS/TLR4/MyD88/ERK/GSK-3β/β-catenin loop, further improving skin aging in mice.

The prevalence of cognitive disorders such as Alzheimer's disease (AD) is increasing due to the global rise in longevity. The accumulation of amyloid β (Aβ) deposits and hyperphosphorylated Tau protein (p-Tau) are considered the main hallmarks of AD. A growing body of evidence suggests that the regular intake of flavonoid-rich foods could reduce the risk of developing AD or mitigate its progression. This study explores the potential of quercetin (Q) and epicatechin (EC) as effective molecules against AD-like pathology, using the Caenorhabditis elegans BR5270 strain, which expresses the pro-aggregant F3DK280 fragment of the human Tau protein. The results showed that after exposure to 150 µM of EC or Q, worms exhibited increased lifespan, improved chemotaxis, and delayed age-related decline in locomotion. To explore the molecular mechanisms involved, the expression of genes associated with the inhibition of p-Tau proteotoxicity were measured by RT-qPCR. It was found that Q and EC significantly increased the expression levels of autophagy-related genes and of a key gene for de novo synthesis of α- tubulin. EC and Q delay neurodegeneration in the C. elegans tauopathy model, suggesting their potential to reduce the risk of AD progression.