Longevity Papers

Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that primarily affects joints and causes pain, stiffness and swelling. The affected joints exhibit severe inflammation in the synovium and bone erosion, leading to joint deformity. Aging is an important factor facilitating the development of RA, as it is associated with an increase in the number of senescent cells and the production of the autoantibodies and proinflammatory cytokines in tissues. Given that CCN3 is highly expressed in RA joints and that its level is associated with the severity of the disease, we explored its molecular function in joints and therapeutic potential in RA. An analysis of public scRNA-seq data from the RA synovium revealed that CCN3 is expressed by an inflammatory fibroblast subset. Interestingly, stimulation with CCN3 resulted in the activation of the senescence pathway in synoviocytes and osteoclast differentiation in monocytes in vitro. Consistent with these results, the administration of CCN3 into the knee joint and onto the calvarial bone resulted in increased numbers of senescent synoviocytes in the joint and osteoclasts in the bone, respectively. Furthermore, the therapeutic potential of targeting CCN3 was evaluated in an experimental RA model. Administration of the CCN3 antibody significantly suppressed inflammation and osteoclast numbers in the joints of the RA model mice. Our findings suggest that CCN3 contributes to pathological processes in RA and represents a promising therapeutic target for the treatment of RA.

Plant-based diets are recognized for their health benefits. However, evidence on the association between plant-based diet quality and aging in the US population is limited. This study aimed to investigate the association between different plant-based diet indices, phenotypic age acceleration (PhenoAgeAccel), and biological age acceleration (BioAgeAccel). We hypothesized that healthful plant-based diets would negatively affect PhenoAgeAccel and BioAgeAccel in US adults. The cross-sectional analysis included 22,363 participants, and information was obtained from the National Health and Nutrition Examination Survey database. The quality of plant-based diet was assessed using 3 indices: overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). Phenotypic age (PA) and biological age (BA) was calculated based on a linear combination of chronological age and 12 multi-system clinical chemistry biomarkers in accordance with the previously established method. PhenoAgeAccel and BioAgeAccel are the residuals of the PA and BA. Weighted linear regression analyses were performed to evaluate the relationships between PDI, hPDI and uPDI, and PhenoAgeAccel and BioAgeAccel. After adjusting for all covariates, we observed that a 10-unit higher PDI score was associated with 0.80 years lower PhenoAgeAccel (β: -0.80, 95% confidence interval [CI]: -0.94, -0.67), and 1.91 years lower BioAgeAccel (β: -1.91, 95% CI: -2.42,-1.40). A 10-unit higher hPDI score was associated with 0.83 years lower PhenoAgeAccel (β: -0.83, 95% CI: -0.96, -0.70), and 1.76 years lower BioAgeAccel (β: -1.76, 95% CI: -2.18, -1.34). Conversely, a 10-unit higher uPDI score was associated with 0.77 years higher PhenoAgeAccel (β: 0.77, 95% CI: 0.66, 0.89) and 1.21 years higher BioAgeAccel (β: 1.21, 95% CI: 0.80, 1.62). These findings suggest that US adults may be able to slow the aging process by increasing adherence to a healthy plant-based diet.

Global aging heightens the risk of oral disorders, among which periodontitis is the major cause of tooth loss in the aging population. The regeneration of damaged periodontal hard tissue is highly challenging due to the existence of the refractory local inflammation. Owing to the potent anti-inflammatory capabilities, regulatory T cells hold great promise in immunotherapies for tissue regeneration. However, the transferred regulatory T cells can alter their phenotypes and functions in local inflammatory milieu, significantly impairing their therapeutic efficacy. Herein, we introduce a novel regulatory T cell-based nanobiohybrid system bearing polyphenol-functionalized rapamycin nanocomplexes. The sustained in situ release of immunosuppressant rapamycin from the cell-attached nanocomplexes maintains the anti-inflammatory phenotype of regulatory T cells in the inflammatory milieu. The synergistic actions of the anti-inflammatory cytokines secreted and the immunosuppressant released guide a pro-resolving polarization of macrophages and enhance osteogenic differentiation of bone marrow-derived stromal cells. The stabilized phenotype of the regulatory T cells dramatically promoted the resolution of periodontal inflammation and the repair of the hard tissue (alveolar bone) in vivo. Overall, these studies highlight a potent regulatory T cell-based nanobiohybrid therapy to treat periodontitis by modulating periodontal immune microenvironment.

Caenorhabditis elegans is highly important in current research, serving as a pivotal model organism that has greatly advanced the understanding of fundamental biological processes such as development, cellular biology, and neurobiology, helping to promote major advances in various fields of science. In this context, the survival of a nematode under various conditions is commonly investigated via statistical survival analysis, which is typically based on hypothesis testing, providing valuable insights into the factors influencing its longevity and response to various environmental factors. The extensive reliance on hypothesis testing is acknowledged as a concern in the scientific analysis process, emphasizing the need for a comprehensive evaluation of alternative statistical approaches to ensure a rigorous and unbiased interpretation of research findings. In this work, we propose an alternative method to hypothesis testing for evaluating differences in nematode survival. Our approach relies on a clustering technique that takes into account the complete structure of survival curves, enabling a more comprehensive assessment of survival dynamics. The proposed methodology helps to identify complex effects on nematode survival and enables us to derive the probability that treatment induces a specific effect. To highlight the application and benefits of the proposed methodology, it is applied to two different datasets, one simple and one more complex.

Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8

The intestinal epithelium serves as a physical and functional barrier against harmful substances, preventing their entry into the circulation and subsequent induction of a systemic immune response. Gut barrier dysfunction has recently emerged as a feature of ageing linked to declining health, and increased intestinal membrane permeability has been shown to promote heightened systemic inflammation in aged hosts. Concurrent with age-related changes in the gut microbiome, the thymic microenvironment undergoes a series of morphological, phenotypical and architectural alterations with age, including disorganisation of the corticomedullary junction, increased fibrosis, increased thymic adiposity and the accumulation of senescent cells. However, a direct link between gut barrier dysbiosis and thymic involution leading to features of immune ageing has not been explored thus far. Herein, we reveal strong associations between enhanced microbial translocation and the peripheral accumulation of terminally differentiated, senescent and exhausted T cells and the compensatory expansion of regulatory T cells in older adults. Crucially, we demonstrate that aged germ-free mice are protected from age-related increases in intestinal permeability, highlighting the direct impact of mucosal permeability on thymic ageing. Together, these findings establish a novel mechanism by which gut barrier dysfunction drives systemic activation of the immune system during ageing through thymic involution. This enhances our understanding of drivers of T cell ageing and opens up the possibility for the use of microbiome-based interventions to restore immune homeostasis and promote healthy ageing in older adults.

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD. Beagles naturally develop Aβ plaques and cognitive dysfunction. We evaluated the impact of FDA-approved CN inhibitor, tacrolimus, and experimental NFAT inhibitor, Q134R, on cognitive outcomes during a three-year prevention study in 37 middle-aged beagles. While beagles treated with CN/NFAT inhibitors showed differences in the pattern of cognitive maintenance and duration of their effect, there was improvement in spatial learning, as well as maintenance of memory, attention, and working memory relative to placebo dogs. CN/NFAT inhibition is a promising target for prevention of cognitive decline that may be rapidly implemented in human clinical trials.

Hypertension affects 1 in 2 U.S. adults and hypertension prevalence increases with aging. Both hypertension and aging can cause arterial remodeling. We investigated the hypothesis that aortic remodeling contributes to age-dependent hypertension in male Sprague Dawley (SD) rats. Compared to young 3-month-old rats 16-month-old male SD rats developed age-dependent hypertension that associated with increased sympathetic tone to the vasculature, elastin disarray and blood pressure variability. Our quantitative proteomic/phosphoproteomic workflow of the aorta identified 2366 proteins and 226 phosphoproteins, from which 58 proteins and 39 phosphoproteins were differentially expressed or phosphorylated respectively between young normotensive controls and aged hypertensive animals. Analysis of the proteome highlighted significant changes in the extracellular matrix, actin cytoskeleton and inflammatory pathways. Analysis of the differential phosphoproteome revealed significant differences in synapse and neuron projection and vascular smooth muscle cell (VSMC) function including actin remodeling and focal adhesions. STRING hypertension network analysis identified 13 differentially expressed and 10 differentially phosphorylated proteins associated with hypertension. Within the STRING analysis we observed 2 major areas of correlation of alterations in the aorta proteome with increased hypertension risk score - vascular inflammation and VSMC function. The majority of the identified phosphorylation sites (78.57%) in hypertension-relevant hyperphosphorylated proteins were located at serine residues. Collectively, we report that arterial remodeling in age-dependent hypertension is associated with an altered extracellular matrix and actin cytoskeleton and modulation of VSMC focal adhesion networks and neuron/synapse interactions.

Epigenetic clocks, DNA methylation-based predictive models of chronological age, are often utilized to study aging associated biology. Despite their widespread use, these methods do not account for other factors that also contribute to the variability of DNA methylation data. For example, many CpG sites show strong sex-specific or cell-type-specific patterns that likely impact the predictions of epigenetic age. To overcome these limitations, we developed a multidimensional extension of the Epigenetic Pacemaker, the Multi-state Epigenetic Pacemaker (MSEPM). We show that the MSEPM is capable of accurately modeling multiple methylation-associated factors simultaneously, while also providing site-specific models that describe the per site relationship between methylation and these factors. We utilized the MSEPM with a large aggregate cohort of blood methylation data to construct models of the effects of age-, sex-, and cell-type heterogeneity on DNA methylation. We found that these models capture a large faction of the variability at thousands of DNA methylation sites. Moreover, this approach allows us to identify sites that are primarily affected by aging and no other factors. An analysis of these sites reveals that those that lose methylation over time are enriched for CTCF transcription factor chip peaks, while those that gain methylation over time are associated with bivalent promoters of genes that are not expressed in blood. These observations suggest mechanisms that underlie age-associated methylation changes and suggest that age-associated increases in methylation may not have strong functional consequences on cell states. In conclusion, the MSEPM is capable of accurately modeling multiple methylation-associated factors, and the models produced can illuminate site-specific combinations of factors that affect methylation dynamics.

Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.

Protein-rich diets shorten lifespan but increase fecundity in many organisms. Animals actively adjust their feeding behavior to meet their nutritional requirements. However, the neural mechanisms underlying the dynamic regulation of protein consumption remain unclear. Here we find that both sexes of fruit flies exhibit a preference for protein food before mating to prepare for reproduction. Mated female flies display an increased appetite for yeast to benefit their offspring, albeit at the cost of stress resistance and lifespan. In contrast, males show a momentarily reduced yeast appetite after mating likely to restore their fitness. This mating state-dependent switch between sexes is mediated by a sexually dimorphic neural circuit labeled with leucokinin in the anterior brain. Furthermore, intermittent yeast consumption benefits both the lifespan and fecundity of males, while maximizing female fecundity without compromising lifespan.

Geese are susceptible to oxidative stress during breeding, leading to senescence of granulosa cells (GCs) and reduced egg production. Adiponectin (ADPN) is a cytokine secreted by adipose tissue that functions to regulate metabolism and antioxidants. However, its role in the regulation of goose GCs is unclear. To investigate this, senescence in primary goose GCs was induced by D-gal and assessed via RT‒qPCR, senescence-associated β-galactosidase (SA-β-gal) staining, immunofluorescence, flow cytometry, and transcriptomics. The effect of ADPN on GC senescence was investigated by overexpressing and knocking down ADPN expression. The results showed that ADPN could alleviate oxidative stress and cell cycle arrest in GCs, reduce the expression of the senescence-associated secretory phenotype (SASP)-related genes IL-6 and IL-8, regulate the metabolic capacity of GCs, reduce the accumulation of SA-β-gal, maintain telomere length, and alleviate the senescence of GCs induced by D-gal. The RNA-seq results provided further evidence for the regulatory effect of ADPN on GC senescence. ADPN was shown to attenuate oxidative stress-induced GC senescence through the AGE (Advanced glycation end products)-RAGE (Receptor of advanced glycation end products) and NOD-like receptor pathways. These findings may contribute to the development of improved theoretical references for improving egg-laying performance and prolonging the service life of geese.

The aging of the immune system substantially impacts individual immune responses, yet accurately quantifying immune age remains a complex challenge. Here we developed IMMClock, a novel immune aging clock that uses gene expression data to predict the biological age of individual CD8 T cells, CD4 T cells, and NK cells. The accuracy of IMMClock is first validated across multiple independent datasets, demonstrating its robustness. Second, utilizing the IMMClock, we find that intrinsic cellular aging processes are more strongly altered during immune aging than differentiation processes. Thirdly, our analysis confirms the strong associations between immune aging and established processes such as cellular senescence, exhaustion, and telomere length at the single cell level. Furthermore, immune aging is accelerated under several disease conditions such as type 2 diabetes, heart disease, and cancer. Finally, we apply IMMClock to analyze a perturb-seq gene activation screen of T cell functionality. We find that the post-perturbation immune age of individual T cells is strongly correlated with their pre-perturbation immune age. Furthermore, the immune age at resting state of individual T cells is strongly predictive of their post-stimulation activation state. Overall, IMMClock advances our understanding of immune aging by providing precise, single-cell level age estimations. Its future applications hold promise for identifying interventions that concomitantly rejuvenate and activate T cells, potentially enhancing efforts to counteract age-related immune decline.

Aging, the predominant risk factor for numerous diseases, manifests in various forms across the structure and architecture of tissues of the human body, offering the opportunity to quantify and interpret tissue-specific aging. To address this, we present a comprehensive assessment of tissue changes occurring during human aging, utilizing a vast array of whole slide histopathological images from the Genotype-Tissue Expression Project (GTEx). We analyzed 25,712 images from 40 distinct tissue types across 983 individuals, applying deep learning to quantify the nuanced morphological changes that tissues undergo with age. We developed tissue clocks--predictors of biological age based on tissue images--which achieved a mean prediction error of 4.9 years and were associated with telomere attrition, the incidence of subclinical pathologies, and comorbidities. In a systematic assessment of biological age rates across organs, we identified pervasive non-uniform rates of aging across the human lifespan, with some organs exhibiting earlier changes (20-40 years old) and others showing bimodal patterns of age-related changes. We also uncovered several associations between demographic, lifestyle, and medical history factors and tissue-specific acceleration or deceleration of biological age, highlighting potential modifiable risk factors that influenced the aging process at the tissue level. Finally, by combining paired histological images and gene expression data, we developed a strategy to predict tissue-specific age gaps from blood samples. This approach was validated in external cohorts of both healthy individuals and those with chronic diseases, revealing the organs most differentially affected by aging in disease contexts. This work offers a new perspective on the aging process by positioning tissue structure as an integrator of cellular and molecular changes that reflect the physiological state of organs. These findings underscore the value of histopathological imaging as a tool for understanding human aging and provide a foundation for the exploration of tissue-specific aging processes in age-associated diseases.

Innate host defense mechanisms require posttranslational modifications (PTM) to protect against viral infection. Age-associated immunosenescence results in increased pathogenesis and mortality in the elderly, but the contribution of altered PTM regulation to immunosenescence is unknown. SUMOylation is a rapid and reversible post-translational modification that has been implicated in age-associated disease and plays conflicting roles in viral replication and antiviral defenses in mammals. We have discovered in Caenorhabditis elegans that induction of antiviral defense is regulated through SUMOylation of DRH-1, the ortholog of the DEAD/H-box helicase and cytosolic pattern recognition receptor RIG-I, and that this regulation breaks down during aging. We find the SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV), a natural enteric C. elegans pathogen. ULP-4 promotes stabilization of DRH-1, which translocates to the mitochondria to activate the IPR in young animals exposed to virus. Loss of either drh-1 or ulp-4 compromises antiviral defense resulting in a failure to clear the virus and signs of intestinal pathogenesis. During aging, expression of ulp-4 decreases, which results in increased proteosomal degradation of DRH-1 and loss of the IPR. Mutating the DRH-1 SUMOylated lysines resulted in the constitutive activation of the IPR in young animals and partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.

Understanding the pathophysiology of neurological symptoms observed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is essential to optimizing outcomes and therapeutics. To date, small sample sizes and narrow molecular profiling have limited the generalizability of findings. In this study, we profiled multiple cortical and subcortical regions in postmortem brains of patients with coronavirus disease 2019 (COVID-19) and controls with matched pulmonary pathology (total n = 42) using spatial transcriptomics, bulk gene expression and proteomics. We observed a multi-regional antiviral response without direct active SARS-CoV2 infection. We identified dysregulation of mitochondrial and synaptic pathways in deep-layer excitatory neurons and upregulation of neuroinflammation in glia, consistent across both mRNA and protein. Remarkably, these alterations overlapped substantially with changes in age-related neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Our work, combining multiple experimental and analytical methods, demonstrates the brain-wide impact of severe acute/subacute COVID-19, involving both cortical and subcortical regions, shedding light on potential therapeutic targets within pathways typically associated with pathological aging and neurodegeneration.

Biological age reflects actual aging and overall health, but current aging clocks are often complex and difficult to interpret, limiting their clinical application. In this study, we introduced a Gompertz law-based biological age (GOLD BioAge) model that simplified aging assessment. We estimated GOLD BioAge using clinical biomarkers and found significant associations of the difference from chronological age (BioAgeDiff) with risks of morbidity and mortality in NHANES. Moreover, we developed GOLD ProtAge and MetAge using proteomics and metabolomics data, which outperformed the clinical-only model in predicting mortality and chronic disease risks in UK Biobank. Benchmark analysis illustrated that our models exceeded common aging clocks in predicting mortality across diverse age groups in both NHANES and UK Biobank. The results demonstrated that the GOLD BioAge algorithm effectively applied to both clinical and omics data, showing excellent performance in predicting age-related outcomes. Additionally, we created a simplified version called the Light BioAge, which used three biomarkers for aging assessment. The Light model reliably captured mortality risks in three validation cohorts (CHARLS, RuLAS, CLHLS). It significantly predicted the onset of frailty, stratified frail individuals, and collectively identified individuals at high risk of mortality. In summary, the algorithm of GOLD BioAge could provide a valuable framework for aging assessment in public health and clinical practice. HighlightsO_LIThe algorithm of Gompertz law based biological age (GOLD BioAge) was proposed to construct biological aging clocks with convenient and interpretable calculations, which had better performance in predicting mortality risks. C_LIO_LIOur approach was applicable to proteomics and metabolomics, yielding ProtAge and MetAge with great clinical prospect to improve accuracy of aging assessment and prevent age-related diseases. C_LIO_LIThe Light BioAge, a simplified version, was developed using age and three biomarkers, and it independently predicted mortality in three cohorts. C_LIO_LIThe Light BioAgeDiff significantly predicted the onset of frailty, stratified frail individuals, and collectively identified individuals at high risk of mortality. C_LI

Changes in the sperm epigenome induced by age and/or stressors often follow common unexplained patterns affecting genes responsible for embryonic development and neurodevelopment. The stochastic epigenetic variation (SEV) hypothesis proposes that in response to stressors naturally variable methylation regions (VMRs) associated with morphogenic genes increase in methylation variation to diversify phenotypes and improve chances of survival of the genetic lineage. Here, we test predictions from the SEV hypothesis using mouse and rat sperm DNA methylation and other -omics data. We demonstrate that the context of DNA regions determines the response of sperm methylome to various factors rather than the stressors and/or timing of these factors. We propose a model explaining age/stress-dependent shifts in methylation in VMRs by an asymmetric increase in methylation variation of these regions. Because methylation variation in VMRs increases with age, sperm methylome response to stressors may be characterized as an acceleration of epigenetic aging.

Low physical activity (PA) levels are associated with increased mortality. Improved measurement has resulted in stronger proven associations between PA and mortality, but this has not yet translated to improved estimates of the disease burden attributable to low PA. This study estimated how much low PA reduces life expectancy, and how much life expectancy could be improved by increasing PA levels for both populations and individuals.

Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age-related bone loss. Overexpression of Nampt ameliorates the senescence-associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT-OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP.

Current hypertension treatments rely on chronological age, which may not reflect individual differences in aging and its impact on cardiovascular health. This study aimed to determine whether biological age can predict adverse outcomes in older adults with hypertension, independent of traditional risk factors including chronological age.

Several crucial acceleration periods exist during aging process. Epigenetic clocks, serving as indicators of aging, are influenced by genetic factors. Investigating how the genetic contributions on these clocks change with age may provide novel insights into the aging process. In this study, based on 1084 adult twins from the Chinese National Twin Registry (CNTR), we established structural equation models (SEMs) to evaluate the trends in genetic influence with aging for epigenetic clocks, which include PC-Horvath, PC-Hannum, PC-PhenoAge, PC-GrimAge, and DunedinPACE. A decline in overall heritability was observed for all five clocks from ages 31 to 70, with a relatively stable trend at first. Subsequently, apart from PC-GrimAge, the other four clocks displayed a more evident drop in heritability: DunedinPACE and PC-PhenoAge experienced a clear decline between 55 and 65 years, while PC-Horvath and PC-Hannum showed a similar decrease between 60 and 70 years. In contrast, the heritability of PC-GrimAge remained stable throughout. An analysis of methylation sites (CpGs) from these clocks identified 41, 26, 4, and 36 CpG sites potentially underlying heritability changes in DunedinPACE, PC-Horvath, PC-Hannum, and PC-PhenoAge, respectively. Data from the CNTR were collected through two surveys in 2013 and 2018. Based on 308 twins with longitudinal data, declines in genetic components were observed at follow-up compared to baseline, with significant decreases in the four PC-clocks. DunedinPACE peaked in 5-year longitudinal genetic contribution changes at age 55-60, while PC-clocks consistently peaked at age 50-55. These findings may offer novel insights into the role of genetic variations in aging.

Age-related cognitive impairment is a prevalent issue in developed societies. Gamma oscil2lations at 40 Hz have been identified as a potential therapeutic approach for age-related cognitive decline and can be induced through various modalities, including auditory, visual, electrical, and magnetic stimulation. In this study, we investigated a novel modality of stimulation: whole-body vibration at 40 Hz. We examined the effects of 40 Hz vibration on cognitive performance and associated neuronal activity in the brains of aged male rats. Our findings revealed that only vibration at 40 Hz, rather than 20 Hz or 80 Hz, elicited cortical gamma oscillations in aged male rats. Additionally, following 8 weeks of prolonged treatment, the implementation of 40 Hz whole-body vibration significantly augmented the cognitive function of aged male rats as evidenced by behavioral assessments. Mechanistic studies demonstrated that these beneficial effects were attributed to the reduction of neuronal apoptosis in hippocampal CA1 through regulation of synaptic connections between astrocytes and neurons via 40 Hz gamma oscillations. Collectively, this suggests a promising intervention for age-related cognitive decline and identifies neuron-astrocyte synapses as potential therapeutic targets.

For the optimal survival of a species, an organism coordinates its reproductive decisions with the nutrient availability of its niche. Thus, nutrient-sensing pathways like insulin-IGF-1 signaling (IIS) play an important role in modulating cell division, oogenesis, and reproductive aging. Lowering of the IIS leads to the activation of the downstream FOXO transcription factor (TF) DAF-16 in Caenorhabditis elegans which promotes oocyte quality and delays reproductive aging. However, less is known about how the IIS axis responds to changes in cell cycle proteins, particularly in the somatic tissues. Here, we show a new aspect of the regulation of the germline by this nutrient-sensing axis. First, we show that the canonical G1-S cyclin, Cyclin D/CYD-1, regulates reproductive fidelity from the uterine tissue of wild-type worms. Then, we show that knocking down cyd-1 in the uterine tissue of an IIS receptor mutant arrests oogenesis at the pachytene stage of meiosis-1 in a DAF-16-dependent manner. We observe activated DAF-16-dependent deterioration of the somatic gonadal tissues like the sheath cells, and transcriptional de-regulation of the sperm-to-oocyte switch genes which may be the underlying reason for the absence of oogenesis. Deleting DAF-16 releases the arrest and leads to restoration of the somatic gonad but poor-quality oocytes are produced. Together, our study reveals the unrecognized cell non-autonomous interaction of Cyclin D/CYD-1 and FOXO/DAF-16 in the regulation of oogenesis and reproductive fidelity.

Aging is a process that accompanies a decline in the function of various tissues and organs, especially affecting intestinal health. Agarose oligosaccharide (AOS) can prolong the lifespan of organisms and protect the intestine in the previous study. It was examined to evaluate the effects of AOS on intestinal health, and the potential associations between intestinal homeostasis and health status were further validated.

Ageing is an inevitable and multifaceted biological process that impacts a wide range of cellular and molecular mechanisms, leading to the development of various diseases, such as liver fibrosis. Liver fibrosis progresses to cirrhosis, which is an advanced form due to high amounts of extracellular matrix and restoration of normal liver structure with failure to repair damaged tissue and cells, marking the end of liver function and total liver failure, ultimately death. The most important factors are reactive oxygen species (ROS) and cellular senescence. Oxidative stress is defined as an impairment by ROS, which are by-products of the mitochondrial electron transport chain and other key molecular pathways that induce cell damage and can activate cellular senescence pathways. Cellular senescence is characterized by pro-inflammatory cytokines, growth factors, and proteases secreted by senescent cells, collectively known as the senescence-associated secretory phenotype (SASP). The presence of senescent cells, which disrupt tissue architecture and function and increase senescent cell production in liver tissues, contributes to fibrogenesis. Hepatic stellate cells (HSCs) are activated in response to chronic liver injury, oxidative stress, and senescence signals that drive excessive production and deposition of extracellular matrix. This review article aims to provide a comprehensive overview of the pathogenic role of ROS and cellular senescence in the aging liver and their contribution to fibrosis.

The suprachiasmatic nucleus (SCN) in the hypothalamus regulates circadian timing system (CTS) by co-ordinating peripheral tissue clocks and extra-SCN oscillators in the brain. Aging disrupts the CTS, impairing physiological functions and reducing antioxidant defences, which contribute to neurodegeneration. The brain is vulnerable to oxidative damage due to its high metabolic activity, oxygen consumption, and levels of iron and lipids. Antioxidant enzymes, such as catalase (CAT), glutathione S-transferase (GST), superoxide dismutase (SOD), and lipid peroxidation (LPO), help against oxidative damage. In this study, we examined the temporal patterns of these antioxidant stress indicators in the SCN and extra-SCN brain regions (frontal cortex, cerebellum, and hippocampus) at various time points in male Wistar rats 3, 12, and 24 months. The rhythmicity of GST and LPO levels persisted across brain regions with aging, while CAT rhythmicity was lost in the SCN and hippocampus of older rats. SOD rhythmicity persisted in cortex, cerebellum, and hippocampus but was lost in the SCN. The daily rhythm parameters of CAT were affected most significantly, followed by SOD, GST, and LPO. Our findings demonstrate that aging leads to desynchronization of oxidative stress indicators potentially contributing to neurodegeneration and circadian dysfunction with varying effects across different brain tissues.

The aging of pancreatic beta cells is closely associated with various diseases, such as impaired glucose tolerance, yet the underlying regulatory mechanisms remain unclear. In this study, we screened young and aged mouse pancreatic beta cells' high-throughput sequencing data from the GEO public database. Utilizing bioinformatics techniques, we identified the key regulatory factor YY1 in the aging process of pancreatic islets. We observed a significant decrease in the expression of YY1 in a D-gal-induced mouse model of pancreatic aging and an H

Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

During aging, in addition to increased oxidative stress, inflammation also occurs. A chronic and low-grade inflammation - called "inflammaging" - develops, which contributes to the etiology of diseases related to aging. Resveratrol (Resv.) is a polyphenol well known for its biologically active properties, such as antioxidant and anti-inflammatory properties. This balance can be regulated by Nrf2 - a transcription factor that regulates cellular defense against oxidative agents through the expression or inhibition of certain genes. The objective was to evaluate the effect of Nrf2 on the production of cytokines in leukocytes of different ages treated with resveratrol (5µm). The subjects were divided into three groups: 20-39, 40-59 and 60-80 years old. After separation of the leukocytes, a 24-hour treatment was carried out with and without ML385 inhibitor with the treatments: Control, Resv, Peroxide and Peroxide+Resv. 150 µM peroxide was set to develop an oxidative environment. Cytokines were measured by ELISA (*p < 0.05). In general, there was an increase in TNF and IL-6 in cells stimulated with peroxide compared to controls. A decrease in these two cytokines was also observed in cells treated with resveratrol, both at basal levels and in an oxidizing environment (with peroxide). The polyphenol was able to increase IL-10 only in the youngest age groups. The same profile was observed comparing the same groups when the Nrf2 pathway was inhibited with ML385. It is concluded that resveratrol may have a better effect on preventing oxidation and inflammation present in aging, especially through the antioxidant and anti-inflammatory Nrf2 pathway.

Cochlear hair cell senescence is one of the major causes of age-related hearing loss (ARHL) and is significantly related to reactive oxygen species (ROS) accumulation. Research shows that vitamin C (VC) can inhibit ROS accumulation; however, its association with cochlear hair cell senescence remains elusive.

Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway.

Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

Cardiometabolic multimorbidity (CMM) and aging are increasing public health concerns. This prospective study used UK Biobank cohort to investigate the relationship between biological aging and the trajectory of CMM to dementia and mortality.

Preservation of dendritic spines is a putative mechanism of protection against cognitive impairment despite development of Alzheimer Disease (AD)-related pathologies. Aging, the chief late-onset AD risk factor, is associated with dendritic spine loss in select brain areas. However, no study to our knowledge has observed this effect in precuneus, an area selectively vulnerable to early accumulation of AD-related pathology. We therefore quantified dendritic spine density in precuneus from 98 subjects without evidence of neurocognitive decline, spanning ages 20-96, and found a significant negative correlation between age and large dendritic spine density. In these same subjects, we conducted liquid chromatography-tandem mass spectrometry of >5000 proteins and identified 203 proteins which statistically mediate the effect of age on large dendritic spine density. Using computational pharmacology, we identified ten drugs which are predicted to target these mediators, informing future studies designed to test their effects on age-related dendritic spine loss and cognitive decline.

While senescent cells have detrimental roles in several contexts, they are highly heterogeneous. p16 highly expressing senescent cells have been reported to exert beneficial functions in wound healing. Here we use Xenium spatial transcriptomics to identify a distinct p21 highly expressing senescent population induced on wounding, with a pro-inflammatory profile. We find that clearing p21 highly expressing cells expedites wound closure and is partially mediated by NF-κB inhibition, thus enhancing our understanding of the multifaceted functions of senescence in tissue remodeling.

As the population aging progresses, age-related osteoporosis has become one of the most common and severe chronic degenerative diseases. Due to insufficient understanding of its complex pathomechanisms, current clinical treatments often suffer from many negative effects. Type H vessels play critical role in bone remodeling owing to their specialized function in coupling angiogenesis and osteogenesis. Increasing evidences have shown a close association between the age-related decline of type H vessels and bone loss. However, the underlying mechanisms whereby the regression of type H vessels with aging remain largely unknown.

To explore the regulatory mechanism of lncRNA UCA1 and NRF2 in cardiomyocyte aging. In this study, we explored how lncRNA UCA1 regulates NRF2 and its effect on cardiomyocyte aging. H9c2 cardiomyocytes were cultured and treated with H2O2 to simulate cardiomyocyte aging in vitro. The expression levels of lncRNA UCA1 and NRF2 in cells were detected using qRT-PCR. Cell viability was assessed using the CCK8 assay, and cell aging was detected via Sa-β-gal staining. The levels of oxidative stress markers (SOD, MDA, ROS) and the expressions of ferroptosis-related proteins (ACSL4, TFR1, FTH1, GPX4) were measured. The regulatory mechanism between UCA1 and NRF2 was investigated using RIP-qPCR. Additionally, changes in m6A modification levels and the expression of m6A modification-related proteins in cells after UCA1 overexpression were analyzed by western blot. Our results indicate that H2O2 treatment significantly downregulated the expression of lncRNA UCA1 and NRF2. UCA1 overexpression promoted H9c2 cell proliferation, inhibited cell aging, increased SOD activity and the expression of FTH1 and GPX4 proteins, and decreased MDA and ROS content as well as ACSL4 and TFR1 protein expression. RIP-qPCR verified that UCA1 can promote the expression of NRF2 in cells. Overexpression of UCA1 significantly increased the expression of the demethylase FTO, leading to a reduction in m6A modification levels. Furthermore, there was significant enrichment between FTO and NRF2, and overexpression of FTO improved the expression of NRF2 protein in cells. Taken together, lncRNA UCA1 inhibits oxidative stress and ferroptosis, thereby preventing cardiomyocyte aging. This protective effect is likely mediated by increasing the expression of demethylase FTO and reducing m

Normal aging in humans and non-human primates is associated with a decline in cognitive functions. Subject-wise differences in cognitive decline can be attributed to different degrees of damage to cortical white matter (WM) which is largely affected by neuroinflammation during aging. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have recently been identified as a potential immunomodulatory therapeutic for brain damage and Alzheimers disease (AD) and related dementias by suppressing neuroinflammation. Here, we evaluated the efficacy of MSC-EVs for slowing or ameliorating cognitive decline during aging in rhesus monkeys, a well-studied model of normal aging that is free of extensive AD pathology. We report that late middle-aged monkeys treated with MSC-EVs every two weeks for 18 months showed improved performance on a task of spatial working memory relative to vehicle control monkeys. In addition, we used diffusion magnetic resonance imaging (MRI) and resting state functional MRI to evaluate structural white matter and functional network changes in vivo. Imaging data revealed that MSC-EV treatment preserved prefrontal and temporal WM structural integrity and large-scale functional network connectivity that are correlated with early, increased CSF levels of amyloid beta protein. Amyloid beta levels at 12 months are also correlated with improved cognitive performance at the end of the 18 months of treatment. These findings suggest that MSC-EVs can mitigate age-related cognitive decline by potentially enhancing the CSF clearance of neurodegenerative proteins, which correlates with greater WM integrity and functional brain connectivity.

Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging; however, the contribution of immune aging to regenerative failure is just starting to be explored. Here, we apply a strategy combining single-cell RNA sequencing with flow cytometry, histological analysis, and functional assays to perform a complete analysis of the immune environment of the aged regenerating skeletal muscle on a time course following injury with single-cell resolution. Our results reveal an unanticipated complexity and functional heterogeneity in immune populations within the skeletal muscle that have been regarded as homogeneous. Furthermore, we uncover a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a set of potential targets to improve skeletal muscle health and regenerative capacity in aging.

6-PPD quinone (6-PPDQ) could accelerate aging process. However, the underlying mechanism for the acceleration in aging process remains largely unclear. We aimed to examine the role of immunosuppression in 6-PPDQ in causing accelerated aging process in Caenorhabditis elegans. 6-PPDQ (0.1-10 μg/L) could decrease locomotion and increase reactive oxygen species (ROS) generation at both adult day-8 and day-12. 6-PPDQ at adult day-12 induced more severe immunosuppression reflected by decrease in expression of antimicrobial genes (lys-1, lys-7, spp-1, and dod-6) compared to that at adult day-8. Meanwhile, 6-PPDQ (10 μg/L) affected expressions of some transcriptional factor genes during the aging. Among them, at adult day-8, susceptibility to 6-PPDQ toxicity was caused by RNAi of daf-16, bar-1, elt-2, atf-7, skn-1, and nhr-8, and resistance to 6-PPDQ toxicity was induced by RNAi of daf-5, daf-3, and daf-12. Additionally, RNAi of daf-16, bar-1, elt-2, atf-7, skn-1, and nhr-8 caused more severe decrease in lys-1 and lys-7 expressions in 6-PPDQ exposed nematodes, whereas decrease in lys-1 and lys-7 expressions in 6-PPDQ exposed nematodes was inhibited by RNAi of daf-5, daf-3, and daf-12. The 6-PPDQ toxicity and 6-PPDQ induced decrease in lys-1 and lys-7 expressions were further suppressed by RNAi of insulin ligand genes (ins-6, ins-7, and daf-28) and receptor gene daf-2. Therefore, immunosuppression-caused immunosenescenece mediated the acceleration in aging process in 6-PPDQ exposed nematodes, which was under the control of certain transcriptional factors.

Exposure to solar ultraviolet-B (UV-B) radiation significantly accelerates skin aging by inducing the expression of matrix metalloproteinases (MMPs) such as MMP-1, leading to alterations in the extracellular matrix and consequent photoaging. Some plant components, renowned for their UV-absorbing and antioxidative properties, show potential for mitigating photoaging by reducing UV-B-induced MMP levels. In this context, we explored the inhibitory effects of Clerodendrum trichotomum extract (CTE) on UV-B-induced skin damage.

Age is an important risk factor of stroke, cognitive decline, and dementia. Senescent endothelial cells (ECs) accumulate with advancing age through exposure to cellular stress, such as that exerted by hypertension and diabetes. These senescent ECs have altered characteristics, such as altered tight junction proteins, use of a more indiscriminate transcellular transport system, increased inflammation, and increased immune cell interactions. ECs are the main component of the blood-brain barrier (BBB), separating the brain from systemic circulation. As senescent ECs accumulate in the BBB, their altered functioning results in the disruption of the barrier. They have inadequate barrier-forming properties, disrupted extracellular matrix, and increased transcytosis, resulting in an overly permeable barrier. This disruption of the BBB can have important effects in stroke and cognitive impairment, as presented in this review. Besides increasing the permeability of the BBB, senescent ECs can also impair angiogenesis and vascular remodeling, which in ischemic stroke may increase risk of hemorrhagic transformation and worsen outcomes. Senescent ECs may also contribute to microvascular dysfunction, with disruption of cerebral perfusion and autoregulation. These may contribute to vascular cognitive impairment along with increased permeability. With an aging population, there is growing interest in targeting senescence. Several ongoing trials have been evaluating whether senolytics can slow aging, improve vascular health, and reduce the risk of stroke and cognitive decline.

Oocyte aging is a significant factor in the negative reproductive outcomes of older women. However, the pathogenesis of oocyte aging remains unclear. This study aimed to identify the hub genes involved in oocyte aging via bioinformatics methods.

It has been previously demonstrated that intestinal barrier damage is one of the underlying mechanisms leading to frailty in non-HIV-infected aging populations. However, there is a paucity of direct evidence which demonstrates the association between intestinal barrier damage and frailty in people living with HIV (PLWH).

Aging tendons undergo disruptions in homeostasis, increased susceptibility to injury, and reduced capacity for healing. Exploring the mechanisms behind this disruption in homeostasis is essential for developing therapeutics aimed at maintaining tendon health through the lifespan. We have previously identified that the extracellular matrix protein, Cochlin, which is highly expressed in healthy flexor tendon, is consistently lost during both natural aging and upon depletion of Scleraxis-lineage cells in young animals, which recapitulates many aging-associated homeostatic disruptions. Therefore, we hypothesized that loss of Cochlin would disrupt tendon homeostasis, including alterations in collagen fibril organization, and impaired tendon mechanics. By 3-months of age, Cochlin-/- flexor tendons exhibited altered collagen structure, with these changes persisting through at least 9-months. In addition, Cochlin-/- tendons demonstrated significant declines in structural and material properties at 6-months, and structural properties at 9-months. While Cochlin-/- did not drastically change the overall tendon proteome, consistent decreases in proteins associated with RNA metabolism, extracellular matrix production and the cytoskeleton were observed in Cochlin-/-. Interestingly, homeostatic disruption via Cochlin-/- did not impair the tendon healing process. Taken together, these data define a critical role for Cochlin in maintaining tendon homeostasis and suggest retention or restoration of Cochlin as a potential therapeutic approach to retain tendon structure and function through the lifespan.

Entropy trajectories remain unclear for the aging process of human brain system due to the lacking of longitudinal neuroimaging resource. We used open data from an accelerated longitudinal cohort (PREVENT-AD) that included 24 healthy aging participants followed by 4 years with 5 visits per participant to establish cortical entropy aging curves and distinguish with the effects of age and cohort. This reveals that global cortical entropy decreased with aging, while a significant cohort effect was detectable that people who were born earlier showed higher cortical entropy. Such entropy reductions were also evident for large-scale cortical networks, although with different rates of reduction for different networks. Specifically, the primary and intermediate networks reduce their entropy faster than the higher-order association networks. We conclude two specific characteristics of the entropy of the human cortex with aging: the shift of the complexity hierarchy and the diversity of complexity strengthen.

Predation, a major cause of natural selection, is classically thought to target the weak and sick. However, predators can target animals with condition-dependent sexual traits, and therefore, high-quality individuals can also be the focus of predation. Thus, it is not always clear which individuals are the foci of predators or how this affects trait evolution. Here, we tested for evolutionary effects of sex-specific predation on male and female longevity using replicate populations of the broad-horned flour beetle

Cognitive decline poses one of the greatest global challenges for health and social care, particularly in China, where the burden on the older adult population is most pronounced. Despite the rapid expansion of internet access, there is still limited understanding of the long-term cognitive impacts of internet use among middle-aged and older adults.

Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells) reaches the limit of its ability to replicate, known as cellular or replicative senescence, and consequently, the organs lose their physiological functions, resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary lifestyle, and genetic abnormalities. These stress factors can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of the effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and the gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome, and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related cellular composition and function changes across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. Using our atlas, we have identified basal stem cells as a highly variable population across aging, more so than other skin cell populations such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we have developed an innovative mRNA-based treatment to mitigate the effects of skin aging. Cell senescence decreased 25% in skin cells treated with ATF3 mRNA, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found crosstalk between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%. We conclude that ATF3-targeted mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.

Inflammation plays a crucial role in tissue injury, repair and disease, orchestrating a complex interplay of immune responses and cellular processes. Recent studies have uncovered the intricate connection between inflammation and stem cell dynamics, shedding light on the central role of stem cells in tissue regeneration. This Review highlights the significance of inflammation in shaping epithelial stem cell dynamics and its implications for tissue repair, regeneration and aging. We explore the multifaceted interactions between inflammation and stem cells, focusing on how inflammatory signals affect stem cell behavior and fate as well as the remodeling of their niche in the respiratory tract. We also discuss the concept of 'inflammatory memory' in epithelial stem cells, where prior inflammatory stimuli endow these cells with enhanced regenerative potential and confer long-lasting protective mechanisms for maintaining tissue integrity and function. Furthermore, we review the impact of cell senescence induced by inflammation on tissue regeneration and aging, delving into the molecular mechanisms underlying the modulation of signaling pathways, epigenetic modifications and cellular crosstalk. Understanding these dynamic processes not only deepens our knowledge of tissue homeostasis and repair but also holds profound implications for regenerative medicine strategies aimed at preventing pulmonary diseases.

Cellular senescence occurs through the accumulation of many kinds of stresses. Senescent cells in tissues also cause various age-related disorders. Therefore, detecting them without labeling is beneficial for medical research and developing diagnostic methods. However, existing biomarkers have limitations of requiring fixation and labeling, or their molecular backgrounds are uncertain. Coherent anti-Stokes Raman scattering (CARS) spectroscopic imaging is a novel option because it can assess and visualize molecular structures based on their molecular fingerprint. Here, we present a new label-free method to visualize cellular senescence using CARS imaging in nucleoli. We found the peak of the nucleolar amide I band shifted to a higher wavenumber in binuclear senescent cells, which reflects changes in the protein secondary structure from predominant α-helices to β-sheets originating from amyloid-like aggregates. Following this, we developed a procedure that can visualize the senescent cells by providing the ratios and subtractions of these two components. We also confirmed that the procedure can visualize nucleolar aggregates due to unfolded/misfolded proteins produced by proteasome inhibition. Finally, we found that this method can help visualize the nucleolar defects in naïve cells even before binucleation. Thus, our method is beneficial to evaluate ongoing cellular senescence through label-free imaging of nucleolar defects.

Dementia prevention in Africa is critically underexplored, despite the continent's high prevalence of modifiable risk factors. With a predominantly young and middle-aged population, Africa presents a prime opportunity to implement evidence-based strategies that could significantly reduce future dementia cases and mitigate its economic impact. The multinational Africa-FINGERS program offers an innovative solution, pioneering culturally sensitive, multidomain interventions tailored to the unique challenges of the region.  Leveraging insights from landmark global studies such as Worldwide-FINGERS and Alzheimer's Disease Neuroimaging Initiative, the program employs a multideterminant precision prevention framework, grounded in community based systems dynamics. Africa-FINGERS further integrates cutting-edge state-of-the-art multimodal biomarker evaluations tailored to regional contexts, with the goal of advancing brain health and establishing a global standard for dementia prevention. This groundbreaking initiative highlights the potential for scalableand sustainable interventions, thus is poised to transform dementia risk reduction efforts across the continent. HIGHLIGHTS: Dementia rates are escalating in Africa, largely due to longer life spans and increased prevalence of modifiable risk factors. Yet, few regional interventions have directly targeted lifestyle factors to reduce dementia risk. The multinational Africa-FINGERS study will address this gap by adapting the successful FINGERS lifestyle intervention to African populations. Africa-FINGERS will pioneer a culturally informed, multidomain dementia risk reduction intervention in the African region through feasibility dementia prevention trials in rural and urban sites across Kenya and Nigeria in the first instance, enrolling 600 at-risk adults (≥ 50 years). The program adopts participatory research methods to develop culturally appropriate interventions and build infrastructure to evaluate dementia biomarkers from ante and post mortem samples. A cost-effectiveness analysis will be conducted to guide the strategic implementation of Africa-FINGERS into regional health systems. The Africa-FINGERS strategy aligns with the Worldwide-FINGERS framework and integrates the global Alzheimer's Disease Neuroimaging Initiative approach, emphasizing multimodal analysis.

Various dietary supplements have been shown to extend the life span of

An altered gut microbiome is a feature of many multifactorial diseases, and microbiome effects on host metabolism, immune function, and possibly neurological function are implicated. Increased biological age is accompanied by a change in the gut microbiome. However, age-related health loss does not occur uniformly across all subjects but rather depends on differential loss of gut commensals and gain of pathobionts. In this article, we summarize the known and possible effects of the gut microbiome on the hallmarks of aging and describe the most plausible mechanisms. Understanding and targeting these factors could lead to prolonging health span by rationally maintaining the gut microbiome.

In cells, TDP-43 is a crucial protein that can form harmful amyloid aggregates linked to fatal and incurable human neurodegenerative disorders. Normally, TDP-43 exists in a smaller soluble native state that prevents aggregation. However, aging and stress can destabilize this native state, leading to the formation of disease-causing amyloid aggregates via the formation of partially unfolded, high-energy intermediates with a greater tendency to aggregate. These intermediates are crucial in the early stages of amyloid formation and are challenging to study due to their low stability. Understanding the structure of these early aggregation-prone states of TDP-43 is essential for designing effective treatments for TDP-43 proteinopathies. Targeting these initial intermediates could be more effective than focusing on fully formed amyloid aggregates. By disrupting the aggregation process at this early stage, we may be able to prevent the progression of diseases related to TDP-43 aggregation. Hence, we decided to uncover the hidden, high-energy intermediates in equilibrium with the native states of TDP-43 by modulating the thermodynamic stability of the soluble native dimer (N form) and monomeric molten globular state (MG form) of full-length TDP-43. The thermodynamic modulation performed in the current study successfully revealed the highly aggregation-prone intermediate of full-length TDP-43, i.e., PUF. Moreover, we observed that along with high aggregation propensity, the aggregation kinetics and mechanisms of PUF differ from previously identified intermediates of full-length TDP-43 (the MG and I forms). The information regarding the initial aggregation-prone state of full-length TDP-43 could lead to therapies for amyloid diseases by halting early protein aggregation.

Inflammaging, characterized by persistent chronic inflammation in older adults, has emerged as a critical factor linked to age-related diseases such as cardiovascular diseases (CVDs), metabolic disorders, and cognitive decline, which collectively contribute to the leading causes of death globally. Elevated levels of cytokines, chemokines, and others inflammatory mediators characterize inflammaging and serve as indicators of biological age. Among the causes of inflammaging, deterioration of the immune system, mitochondrial dysfunction, dysbiosis, accumulation of DAMPs, together with genetic or epigenetic factors, contribute to inflammaging not only in CVD but also in other age-related conditions. This review examines the causes and consequences of inflammaging, particularly its implications for atherosclerosis and heart failure with preserved ejection fraction (HFpEF) and explores potential strategies to mitigate it in the onset of CVD.

Ageing is a major risk factor for various chronic diseases and offers a potential target for developing novel and broadly effective preventatives or therapeutics for age-related conditions, including those affecting the brain. Mechanisms contributing to ageing have been summarized as the hallmarks of ageing, with iron imbalance being one of the major factors. Ferroptosis, an iron-mediated lipid peroxidation-induced programmed cell death, has recently been implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Addressing ferroptosis offers both opportunities and challenges for treating neurodegenerative diseases, though the specific mechanisms remain unclear. This research explores the key processes behind how ferroptosis contributes to brain ageing, with a focus on the complex signaling networks that are involved. The current article aims to uncover that how ferroptosis, a specific type of cell death, may drive age-related changes in the brain. Additionally, the article also unveils its role in neurodegenerative diseases, discussing how understanding these mechanisms could open up new therapeutic avenues.

Reliable predictors of long-term all-cause mortality are needed for middle-aged and older populations. Previous metabolomics mortality studies have limitations: a low number of participants and metabolites measured, measurements mainly using nuclear magnetic spectroscopy, and the use only of conventional statistical methods. To overcome these challenges, we applied liquid chromatography-tandem mass spectrometry and measured >1000 metabolites in the METSIM study including 10,197 men. We applied the machine learning approach together with conventional statistical methods to identify metabolites associated with all-cause mortality. The three independent machine learning methods (logistic regression, XGBoost, and Welch's

Nicotinamide adenine dinucleotide (NAD

The C. elegans Argonaute protein PRG-1/Piwi and associated piRNAs protect metazoan genomes by silencing transposons and other types of foreign DNA. As prg-1 mutants are propagated, their fertility deteriorates prior to the onset of a reproductive arrest phenotype that resembles a starvation-induced stress response. We found that late-generation prg-1 mutants with substantially reduced fertility were long-lived, whereas early- or mid-generation prg-1 mutants had normal lifespans. Loss of the stress response transcription factor DAF-16 caused mid- or late-generation prg-1 mutants to live very short lives, whereas overexpression of DAF-16 enabled both mid- and late-generation prg-1 mutants to live long. Cytoplasmic P-bodies that respond to stress increased in long-lived late-generation prg-1 mutants and were transmitted to F1 but not F2 cross-progeny. Moreover, moderate levels of heritable stress shorten late-generation prg-1 mutant longevity when DAF-16 or P bodies are deficient. Together, these results suggest that the longevity of late-generation prg-1 mutants is a hormetic stress response. However, dauer larvae that occur in response to stress were not observed in late-generation prg-1 mutants. Small germ cell nucleoli that depended on germline DAF-16 were present in late-generation prg-1 mutants but were not necessary for their longevity. We propose that prg-1 mutant germ cells transmit a form of heritable stress, high levels of which promote longevity and strongly reduce fertility. The heritable stress transmitted by prg-1/Piwi mutant germ cells may be generally relevant to epigenetic inheritance of longevity.

Investigating brain-enriched proteins with machine learning methods may enable a brain-specific understanding of brain aging and provide insights into the molecular mechanisms and pathological pathways of dementia. The study aims to analyze associations of brain-specific plasma proteomic aging signature with risks of incident dementia. In 45,429 dementia-free UK Biobank participants at baseline, we generated a brain-specific biological age using 63 brain-enriched plasma proteins with machine learning methods. The brain age gap was estimated, and Cox proportional hazards models were used to study the association with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia. Per-unit increment in the brain age gap z-score was associated with significantly higher risks of all-cause dementia (hazard ratio [95% confidence interval], 1.67 [1.56-1.79], P < 0.001), AD (1.85 [1.66-2.08], P < 0.001), and vascular dementia (1.86 [1.55-2.24], P < 0.001), respectively. Notably, 2.1% of the study population exhibited extreme old brain aging defined as brain age gap z-score > 2, correlating with over threefold increased risks of all-cause dementia and vascular dementia (3.42 [2.25-5.20], P < 0.001, and 3.41 [1.05-11.13], P = 0.042, respectively), and fourfold increased risk of AD (4.45 [2.32-8.54], P < 0.001). The associations were stronger among participants with healthier lifestyle factors (all P-interaction < 0.05). These findings were corroborated by magnetic resonance imaging assessments showing that a higher brain age gap aligns global pathophysiology of dementia, including global and regional atrophy in gray matter, and white matter lesions (P < 0.001). The brain-specific proteomic age gap is a powerful biomarker of brain aging, indicative of dementia risk and neurodegeneration.

We employed an untargeted proteo-metabolomic approach to profile circulating biomarkers in plasma samples from the I-Lan Longitudinal Aging Study, aiming to identify biomarkers and pathways associated with physio-cognitive decline syndrome (PCDS). In 115 propensity score-matched PCDS case-control pairs, pathway analyses implicated dysregulation of fatty acid metabolism and inflammation in PCDS pathogenesis. Sex-specific associations were observed, with disruptions in central carbon metabolism (elevated PKM, MDH1, and GAPDH; decreased MINPP1) and tyrosine metabolism (decreased MIF, DBH; increased thyroxine) characterizing in men. In contrast, perturbations in glutathione and phenylalanine metabolism, including increased ANPEP, GSTP1, and decreased pyroglutamic acid, were identified in women. Results suggest that dysregulated energy and redox homeostasis likely contribute to PCDS development. Notably, ANPEP, PKM, and MIF emerged as potential biomarkers, elucidating the muscle-brain crosstalk framework. Our findings provide insights into potential molecular mechanisms underlying PCDS and the muscle-brain crosstalk, marking progress toward elucidating biomarkers in the journey of healthy aging.

Oxidants produced through endogenous metabolism or encountered in the environment react directly with reactive sites in biological macromolecules. Many proteins, in particular, are susceptible to oxidative damage, which can lead to their altered structure and function. Such structural and functional changes trigger a cascade of events that influence key components of the proteostasis network. Here, we highlight recent advances in our understanding of how cells respond to the challenges of protein folding and metabolic alterations that occur during oxidative stress. Immediately after an oxidative insult, cells selectively block the translation of most new proteins and shift molecular chaperones from folding to a holding role to prevent wholesale protein aggregation. At the same time, adaptive responses in gene expression are induced, allowing for increased expression of antioxidant enzymes, enzymes that carry out the reduction of oxidized proteins, and molecular chaperones, all of which serve to mitigate oxidative damage and rebalance proteostasis. Likewise, concomitant activation of protein clearance mechanisms, namely proteasomal degradation and particular autophagic pathways, promotes the degradation of irreparably damaged proteins. As oxidative stress is associated with inflammation, aging, and numerous age-related disorders, the molecular events described herein are therefore major determinants of health and disease.

Somatic stem cell pools are comprised of diverse, highly specialized subsets whose individual contribution is critical for the overall regenerative function. In the bone marrow, myeloid-biased HSC (myHSC) are indispensable for replenishment of myeloid cells and platelets during inflammatory response but at the same time, become irreversibly damaged during inflammation and aging. Here, we identify an extrinsic factor, Semaphorin 4A (Sema4A), which non cell-autonomously confers myHSC resilience to inflammatory stress. We show that the absence of Sema4A, myHSC inflammatory hyper-responsiveness in young mice drives excessive myHSC expansion, myeloid bias and profound loss of regenerative function with age. Mechanistically, Sema4A is mainly produced by neutrophils, signals via a cell surface receptor Plexin D1 and safeguards myHSC epigenetic state. Our study shows that by selectively protecting a distinct stem cell subset, an extrinsic factor preserves functional diversity of somatic stem cell pool throughout organismal lifespan.

In modern human societies, social interactions and pro-social behaviours are associated with better individual and collective health, reduced mortality, and increased longevity. Conversely, social isolation is a predictor of shorter lifespan. The biological processes through which sociality affects the ageing process, as well as healthspan and lifespan, are still poorly understood. Unveiling the physiological, neurological, genomic, epigenomic, and evolutionary mechanisms underlying the association between sociality and longevity may open new perspectives to understand how lifespan is determined in a broader socio/evolutionary outlook. Here we summarize evidence showing how social dynamics can shape the evolution of life history traits through physiological and genetic processes directly or indirectly related to ageing and lifespan. We start by reviewing theories of ageing that incorporate social interactions into their model. Then, we address the link between sociality and lifespan from two separate points of view: (i) considering evidences from comparative evolutionary biology and bioanthropology that demonstrates how sociality contributes to natural variation in lifespan over the course of human evolution and among different human groups in both pre-industrial and post-industrial society, and (ii) discussing the main physiological, neurological, genetic, and epigenetic molecular processes at the interface between sociality and ageing. We highlight that the exposure to chronic social stressors deregulates neurophysiological and immunological pathways and promotes accelerated ageing and thereby reducing lifespan. In conclusion, we describe how sociality and social dynamics are intimately embedded in human biology, influencing healthy ageing and lifespan, and we highlight the need to foster interdisciplinary approaches including social sciences, biological anthropology, human ecology, physiology, and genetics.

Targeting cellular senescence, one of the hallmarks of aging and aging-related pathologies emerges as an effective strategy for anti-aging and cancer chemotherapy. Here, a switch from TBK1-OPTN axis to TBK1-ATAD3A axis to promote cellular senescence is shown. Mechanically, TBK1 protein is abnormally activated and localized to the mitochondria during senescence, which directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A is significantly elevated in cellular senescence as well as in physiological and pathological aging and is essential for suppressing Pink1-mediated mitophagy by facilitating Pink1 mitochondrial import. Inhibition of ATAD3A phosphorylation at Ser321 by either TBK1 deficiency or by a Ser321A mutation rescues the cellular senescence. A blocking peptide, TAT-PEP, specifically abrogating ATAD3A phosphorylation, results in elevated cell death by preventing doxorubicin-induced senescence, thus leading to enhanced tumor sensitivity to chemotherapy. TAT-PEP treatment also ameliorates various phenotypes associated with physiological aging. Collectively, these results reveal the TBK1-ATAD3A-Pink1 axis as a driving force in cellular senescence and suggest a potential mitochondrial target for anti-aging therapy.

Progress in understanding the causes of physiological and behavioral changes in post-menopausal women is hampered by the paucity of animal models that accurately recapitulate these age-associated changes. Here we evaluate the translational potential of female rhesus macaques (Macaca mulatta). Like women, these long-lived diurnal primates show marked neuroendocrine changes during aging, as well as perturbed sleep-wake cycles and cognitive decline. Furthermore, the brains of old rhesus macaques show some of the same pathological hallmarks of Alzheimer's disease as do humans, including amyloidosis and tauopathology. Importantly, unlike humans, rhesus macaques can be maintained under tightly controlled environmental conditions, such as photoperiod, temperature and diet, and tissues can be collected with zero postmortem interval; this makes them especially suitable for studies aimed at elucidating underlying molecular mechanisms. Recent findings from female macaques are helping to elucidate how sex-steroids influence gene expression within the brain and contribute to the maintenance of cognitive function and amelioration of age-associated pathologies. Taken together, these findings emphasize the translational value of female rhesus macaques as a model for elucidating causal mechanisms that underlie normative and pathological changes in post-menopausal women. They also provide a pragmatic platform upon which to develop safe and effective therapies.

Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR.

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.

Intrinsic capacity (IC), as a comprehensive measure of an individual's functional ability, has gained prominence in the framework for healthy aging introduced by the World Health Organization (WHO). As internet usage continues to integrate into daily life, it is imperative to scrutinize the association between internet use and IC to effectively promote healthy aging among the middle-aged and older population.

Both changes in body composition and increased fall risk occur with increasing age. While weight management may be considered a component of falls prevention, the long-term consequences of changes in weight, however, remain uncertain. This prospective study aimed to evaluate the relationship between weight and body composition changes over 5 years with fall occurrence.

Aging is a dynamic and progressive process characterized by the gradual accumulation of cellular damage. The continuous functional decline in the intrinsic capacity of living organisms to precisely regulate homeostasis leads to an increased susceptibility and vulnerability to diseases. Among the factors contributing to these changes, body composition-comprised of fat mass and lean mass deposits-plays a crucial role in the trajectory of a disability. Particularly, visceral and intermuscular fat deposits increase with aging and are associated with adverse health outcomes, having been linked to the pathogenesis of sarcopenia. Adipose tissue is involved in the secretion of bioactive factors that can ultimately mediate inter-organ pathology, including skeletal muscle pathology, through the induction of a pro-inflammatory profile such as a SASP, cellular senescence, and immunosenescence, among other events. Extensive research has shown that natural compounds have the ability to modulate the mechanisms associated with cellular senescence, in addition to exhibiting anti-inflammatory, antioxidant, and immunomodulatory potential, making them interesting strategies for promoting healthy aging. In this review, we will discuss how factors such as cellular senescence and the presence of a pro-inflammatory phenotype can negatively impact body composition and lead to the development of age-related diseases, as well as how the use of polyphenols can be a functional measure for restoring balance, maintaining tissue quality and composition, and promoting health.

Senescent cells are defined as normal cells that have undergone irreversible division arrest due to various factors. These cells have been found to play a pivotal role in aging and the development of chronic diseases. Numerous studies demonstrated that physical exercise is effective in anti-aging and anti-chronic diseases. Furthermore, the combination of exercise and hypoxia has been shown to optimize the stimulus of oxygen deprivation and extend cellular lifespan.

Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence-a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21

In order to find early selection criteria to improve the longevity of show jumping horses, a specific protocol was designed.

In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging.

Aging is widely regarded as an irreversible physiological process throughout the mammalian lifespan, characterized by functional tissue deterioration and increased disease incidence. One hallmark of mammalian aging is reduced tissue regeneration, primarily attributed to the declining function of tissue-specific stem cells. In recent years, various strategies aimed at rejuvenating stem cells through drug-delivery systems have been extensively explored. Here we describe a method for the long-term, controlled, systemic delivery of drugs using subcutaneous implantations of osmotic pumps.

The female reproductive system ages before any other physiological system, making it a sensitive indicator of aging. Early reproductive aging is associated with the early onset of infertility and an increased risk of several diseases. During aging, systemic and reproductive oxidative stress and inflammation levels increase through inflammasome activation, leading to ovarian follicle loss. Other markers of reproductive aging include increased fibrosis and shortening of telomeres in ovarian cells. The factors that accelerate reproductive aging are unclear, but likely involve exposure to endocrine-disrupting chemicals such as phthalates. Di(2-ethylhexyl) phthalate (DEHP) is a widely used phthalate and humans are exposed to it daily. Several studies show that DEHP induces reproductive toxicity by affecting estrous cyclicity, follicle numbers, and hormone levels. However, little is known about the mechanisms underlying DEHP-induced early onset of reproductive aging. Thus, this study tested the hypothesis that dietary exposure to DEHP induces early reproductive aging by affecting inflammation, fibrosis, and the expression of telomere regulators and antioxidant enzymes. Adult CD-1 female mice were exposed to vehicle (corn oil) or DEHP (0.5, 1.5, or 1500 ppm) via the chow for six months. Exposure to DEHP increased the expression of antioxidant enzymes and Casp3, increased expression of telomere-associated genes, and increased fibrosis levels in the ovary. In addition, DEHP exposure for 6 months altered ovarian and systemic inflammatory status. Collectively, our novel data suggest that 6-month dietary exposure to DEHP may accelerate reproductive aging by affecting several reproductive aging markers in female mice.

Emerging studies have suggested the association of ambient air pollution with worse cognitive function; however, causal evidence remains scarce. We aimed to estimate the effect of particulate matter (PM) exposure on overall and domain-specific cognitive function. A total of 14,205 participants aged 45 years and above were drawn from the 2015 wave of the China Health and Retirement Longitudinal Study (CHARLS). Cognitive function was assessed using a standardized questionnaire consisting of two domains: episodic memory and mental status. Participants' exposure to city-level PM (PM

Ergothioneine (EGT) is a sulfur-containing amino acid with strong antioxidant activity. In this study, a D-galactose induced mouse aging model was used to investigate the anti-aging effects of EGT. EGT intervention could significantly improve the recognition memory of aging mice. Additionally, it improved the D-galactose induced decrease in the number of neurones, enhanced the levels of cAMP and BDNF in the brain, and increased the density and expression of PSD95 in aging mice. Meanwhile, EGT could attenuate oxidative stress by reducing the content of MDA and enhancing T-SOD activity

Cognitive reserve (CR) explains the varying trajectories of cognitive decline in healthy and pathological ageing. CR is often operationalized in terms of socio-behavioural proxies that modulate cognitive performance. Individuals with higher CR are known to maintain better cognitive functions, but evidence on the underlying brain activity remains scattered. Here we review CR studies using functional MRI in young, healthy and pathologically elderly individuals. We focus on the two potential neural mechanisms of CR, neural reserve (efficiency of brain networks) and neural compensation (recruitment of additional brain regions), and the effect of different proxies on them. The results suggest increased task-related activity in different cognitive domains with age and compensation in case of difficult task and pathology. The effects of proxies lead to increased neural reserve (reduced brain activity) in both older and younger individuals. Their relationship with compensation remains unclear, largely due to the lack of young adult samples, particularly in clinical studies. These findings underscore the critical role of lifelong engagement in mentally enriching activities for preserving cognitive function during aging. New studies are encouraged to refine the CR theoretical and empirical framework, particularly regarding the measurement of socio-behavioral proxies and their relationship with cognitive decline and neural underpinning.

Bats are becoming recognised as new model species to study naturally evolved mammalian extended healthspan and disease tolerance. However, this research is limited by the lack of bat specific cellular resources. Here we describe an optimised protocol to develop both primary and immortalised fibroblast cell-lines from wing biopsy punches from the Egyptian fruit bat, Rousettus aegyptiacus. We show that the immortalised cell lines and primary cells show similar characteristics in their proliferative capacity and response to oxidative stress. They also exhibited a similar response in their NF-κB immune response to TLR agonists including SARS-CoV2. As wing punches can be acquired non-lethally, these methods can be used to develop primary and immortalised cells, from potentially any bat species, including those of conservation concern that cannot be sacrificed. This can expand the scope of bat species that can be studied in the future, and the development of key cellular resources required to functionally validate the regulators of bats' unique longevity.

Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and cerebral waste clearance by examining the association between MRI-visible PVS, tear fluid total-tau, and IOP. Thirty cognitively healthy participants, all aged over 55 years, underwent 7 Tesla MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear fluid-wetting length, and hemispheric region of interest volume. Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear fluid total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear fluid total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to the cerebral waste clearance system. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases.

Time-restricted feeding (TRF) is known to promote longevity and brain function, and potentially prevent neurological diseases. Animal studies show that TRF enhances brain-derived neurotrophic factor (BDNF) signaling and regulates autophagy and neuroinflammation, supporting synaptic plasticity, neurogenesis and neuroprotection. Feeding/fasting paradigms influence the circadian cycle, with TRF aligning circadian cycle-related gene expression, and thus altering physiological processes. Emerging evidence highlights the role of gut microbiota in neuronal plasticity, based on the observation that TRF significantly alters gut microbiota composition. Hence, the gut-brain axis may be crucial for maintaining cognitive functions and presents a potential therapeutic target for TRF-mediated neuroprotection. In the context of ischemic stroke where neuronal damage is extensive, TRF can be a preconditioning strategy to enhance synaptic plasticity and neuronal resilience, thus improving outcomes after stroke. This review discussed the link between TRF and circadian regulation in neuronal plasticity and its implications for recovery after stroke.

Neuroinflammation, a low-grade chronic inflammation of the central nervous system, is linked to age-related neuropsychiatric disorders such as senile depression and Alzheimer's disease. Recent studies have explored controlling neuroinflammation as a novel treatment strategy. Molecular hydrogen shows anti-inflammatory effects. However, its impacts on neuroinflammation and age-related neuropsychiatric disorders remain unelucidated. We investigated molecular hydrogen's effects on microglial activation, neuroinflammation, depressive-like behavior, and short-term cognitive decline in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Aged heart is defined via structural and mitochondrial dysfunction of the heart. However, there is still no potent compound to improve cardiac function abnormalities in aged individuals. Olive oil (OLO), as an oil with monounsaturated fatty acids, has diverse protective effects on the cardiovascular system, including anti-inflammatory, anti-diabetic, and mitigating effects on blood pressure. In the present study, we evaluated the protective effects of OLO against aging-related cardiac dysfunction.

Frailty is common among older adults with chronic pain, and early identification is crucial in preventing adverse outcomes like falls, disability, and dementia. However, effective tools for identifying frailty in this population remain limited. This study aimed to explore frailty risk factors in older adults with chronic pain and to develop 9 machine learning models for frailty identification. The Shapley Additive Explanations (SHAP) method was used to explain the models. The Random Forest (RF) model performed best with 0.822 accuracy, 0.797 precision, and an AUC of 0.881. The variables in the RF model included: age, BMI, education level, pain duration, number of pain sites, pain level, depression, and Activity of Daily Living (ADL). Pain level, depression, and ADL were the 3 most important variables in the RF model. This model helps healthcare providers to identify frailty early, enabling timely interventions to improve patient outcomes and promote healthy aging.

The mechanisms responsible for increased metabolic cost of walking in older adults are poorly understood. We recently proposed a theoretical premise by which age-related reductions in Achilles tendon stiffness (k

Sarcopenia and frailty are common among elderly individuals and present substantial health hazards. Exploring their relationship is essential for optimizing geriatric healthcare, particularly within the context of China.

This meta-analysis aimed to qualitatively analyze the different aspects of the successful aging (SA) criteria and quantitatively assess the rate of SA and its different dimensions among people aged ≥60 years globally to provide a basis for constructing criteria for SA.

Maintaining healthy brain function during ageing is of great importance, especially for the self-sufficiency of older adults. The main aim of this study was to determine the effects of dance and martial arts on exerkines Brain Derived Neurotrophic Factor (BDNF) and irisin blood serum levels.

Non-resolving, chronic inflammation (inflammaging) is believed to play an important role in aging and age-related diseases. The goal of this study was to determine if inflammation induced by necroptosis arising from the liver plays a role in chronic liver disease (CLD) and liver cancer in mice fed a western diet (WD). Necroptosis was induced in liver using two knockin (KI) mouse models that overexpress genes involved in necroptosis (Ripk3 or Mlkl) specifically in liver (i.e., hRipk3-KI and hMlkl-KI mice). These mice and control mice (not overexpressing Ripk3 or Mlkl) were fed a WD (high in fat, sucrose, and cholesterol) starting at 2 months of age for 3, 6, and 12 months. Feeding the WD induced necroptosis in the control mice, which was further elevated in the hRipk3-KI and hMlkl-KI mice and was associated with a significant increase in inflammation in the livers of the hRipk3-KI and hMlkl-KI mice compared to control mice fed the WD. Overexpressing Ripk3 or Mlkl significantly increased steatosis and fibrosis compared to control mice fed the WD. Mice fed the WD for 12 months developed liver tumors (hepatocellular adenomas): 28% of the control mice developing tumors compared to 62% of the hRipk3-KI and hMlkl-KI mice. The hRipk3-KI and hMlkl-KI mice showed significantly more and larger tumor nodules. Our study provides the first direct evidence that inflammation induced by necroptosis arising from hepatocytes can lead to the progression of hepatic steatosis to fibrosis in obese mice that eventually results in an increased incidence in hepatocellular adenomas.

There are limited data describing the epidemiology of vertebral fractures (VF) from resource-limited settings, where the ageing population is growing most rapidly. We aimed to determine the prevalence, incidence, and risk factors for VF in The Gambia, West Africa. The Gambian Bone and Muscle Ageing Study is a prospective observational study in men and women aged 40 years and over. Rural participants had baseline measurements and plasma samples collected and were followed up 6-8 years later; urban participants had a single measurement. DXA scans were obtained to assess areal bone mineral density (aBMD), body composition and VF. Prevalence and incidence were calculated. Risk factors for prevalent and incident fracture were tested using logistic regression, in men and women separately, with and without adjustment for age and BMI. At baseline, 581 individuals (298 women) had useable scans, 214 (127 women) at follow-up. Prevalence of VF was 14.8%. Those with VF were older (65.6(11.2) vs 61.7(12.3) years, P=.01) and had lower aBMD Z-scores. For example, in women, a 1SD increase in femoral neck Z-score resulted in a lower risk of having a prevalent VF (OR [95% CI]) 0.51 [0.38, 0.73]. In men, lumbar spine Z-scores were predictive of prevalent fracture; (0.71 [0.53, 0.97]). The incidence of VF over follow-up was 12.1%. Low BMD and grip strength were associated with the odds of having an incident VF. Given the importance of prevalent VF in predicting future VF and other fragility fractures in other populations, our findings are a major cause for concern. VF prevalence in Gambian older adults is similar to elsewhere despite fractures not being a perceived issue. Risk factors were like those identified elsewhere including age, aBMD and bone resorption. Understanding the impact of these fractures is important in a region where health of the ageing population needs to be prioritized.

Type H vessels have been proven to couple angiogenesis and osteogenesis. The decline of type H vessels contributes to bone loss in the aging process. Aging is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, whether AOPP accumulation is involved in age-related decline of type H vessels is unclear. Here, we show that the increase of AOPP levels in plasma and bone was correlated with the decline of type H vessels and loss of bone mass in old mice. Exposure of microvascular endothelial cells to AOPPs significantly inhibited cell proliferation, migration, and tube formation; increased NADPH oxidase activity and excessive reactive oxygen species generation; upregulated the expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1; and eventually impaired angiogenesis, which was alleviated by redox modulator N-acetylcysteine and NADPH oxidase inhibitor apocynin. Furthermore, reduced AOPP accumulation by NAC treatment was able to alleviate significantly the decline of type H vessels, bone mass loss, and deterioration of bone microstructure in old mice. Collectively, these findings suggest that AOPPs accumulation contributes to the decline of type H vessels in the aging process, and illuminate a novel potential mechanism underlying age-related bone loss.

Circular RNAs (circRNAs) represent a novel class of RNA molecules characterized by a circular structure and enhanced stability. Emerging evidence indicates that circRNAs play pivotal regulatory roles in the aging process. Despite this, there is a lack of a systematic resource that integrates aging-associated circRNA data. Therefore, we developed a comprehensive database named circAge, which encompasses 689 aging-related samples from 7 species and 21 tissue types. We also generated 47 new tissue samples from mice and rhesus monkeys through high-throughput sequencing. Integrating predictions from multiple bioinformatics tools, we identified over 413,378 unique circRNAs. Our data analysis revealed a general increase in circRNA expression levels with age, with approximately 22% of circRNAs demonstrating sequence conservation across species. The circAge database systematically predicts potential interactions between circRNAs and miRNAs, RNA-binding proteins, and assesses the coding potential of circRNAs. This resource lays a foundation for elucidating the regulatory mechanisms of circRNAs in aging. As a comprehensive repository of aging-associated circRNAs, circAge will significantly accelerate research in this field, facilitating the discovery of novel biomarkers and therapeutic targets for aging biology and developing diagnostic and therapeutic strategies for aging and age-related diseases. CircAge is publicly available at https://circage.kiz.ac.cn.

To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism.

Physical activity (PA) is associated with higher gait speed. We aimed to examine the associations between PA and change in spatial and temporal gait measures as well as fall risk in community-dwelling individuals free of dementia.

Mosaic loss of the Y chromosome (mLOY) is the most common somatic event in men, strongly associated with aging and various health conditions. Current methods for detecting mLOY primarily rely on DNA genotyping arrays. Here, we present MosCoverY, a novel method for estimating mLOY from NGS sequencing data that can be applied to both exome and genome sequencing. MosCoverY addresses the challenges posed by the structure of the Y chromosome by focusing on single-copy genes and normalizing their coverage against autosomal exons matched by length and GC content. We validated MosCoverY using data from 212,062 male participants in the UK Biobank, comparing its results to those obtained using genotyping- or whole genome sequencing-based methods. MosCoverY identified mLOY in 5.6% of men, demonstrating performance that was comparable to the other methods. MosCoverY also replicated known associations between mLOY, age, smoking, all-cause mortality, and germline genetic loci, showing the strongest associations in many cases. MosCoverY offers a valuable tool for detecting mLOY from exome data in population-scale studies.

Mutation of the daf-2 insulin/IGF-1 receptor activates the DAF-16/Foxo transcription factor to suppress the transgenerational sterility phenotype of prg-1/piRNA mutants that are deficient for piRNA-mediated genome silencing. As with PRG-1/piRNAs, mutations in the nuclear RNA interference gene nrde-1 compromised germ cell immortality, but deficiency for daf-2 did not suppress the transgenerational sterility of nrde-1 or nrde-4 single mutants or of prg-1; nrde-4 or prg-1; hrde-1 double mutants. NRDE-1 and NRDE-4 promote transcriptional silencing in somatic cells via the nuclear Argonaute protein NRDE-3, which was dispensable for germ cell immortality. However, daf-2 deficiency failed to promote germ cell immortality in prg-1; nrde-3 mutants. Consistently, we found that DAF-16 activity in somatic cells suppressed the transgenerational sterility of prg-1 mutants via the SID-1 dsRNA transmembrane channel that promotes systemic RNAi as well as Dicer, the dsRNA binding protein RDE-4 and the RDRP RRF-3. We conclude that DAF-16 activates a cell-non-autonomous systemic RNAi pathway that promotes small RNA-mediated genome silencing in germ cells to suppress loss of the genomic immune surveillance factor Piwi/PRG-1. Author SummarySmall RNAs can promote genome silencing. The Argonaute protein Piwi interacts with thousands of small RNAs termed piRNAs in germ cells to suppress expression of transposons and foreign genetic elements. However, the Piwi silencing system may be commonly targeted by viral or transposon genomic parasites that seek to suppress the endogenous defences against their expression and replication. Activation of the DAF-16 stress response pathway promotes adult longevity and can also abolish the transgenerational sterility of C. elegans Piwi mutants. We found that DAF-16 accomplishes this by activating a somatic small RNA pathway where small RNAs are initially produced in the soma and are then transported into the germline to suppress expression of a toxic genetic locus in Piwi mutants. Thus, the DAF-16 stress response pathway activates a systemic small RNA cascade to suppress defects in the Piwi/piRNA genome silencing system.