Longevity Papers

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of patients with prostate cancer after chemotherapy. Global chromatin accessibility mapping via assay for transposase-accessible chromatin with high-throughput sequencing, and expression profiling through RNA sequencing, reveals global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment, and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.

Early life stress (ELS) and enrichment often have opposing effects on long-term cognitive abilities. Deprivation, such as institutionalized care during early childhood neurodevelopmental periods, results in lifelong working memory and recall deficits. In contrast, enrichment facilitates new learning and slows cognitive decline due to aging and neurodegenerative diseases. Similarly, in rodent models, enrichment facilitates learning whereas ELS induces prominent spatial memory deficits. Environmental enrichment (EE) and ELS can cause opposing changes in hippocampal structure (e.g. shifts in synaptic density) that largely depend on experimental conditions. However, it remains untested whether EE can rescue the behavioral disruptions caused by ELS and how this would impact the hippocampus at advanced ages. To address this, we conducted a longitudinal study on ELS mice, extensively training them on a cognitive enrichment track (ET) or an exercise alone control track (CT). After this, the mice underwent repeated memory testing followed by brain extraction for anatomical analysis of their hippocampus. We found that ET reversed spatial memory deficits at 6, 13 and 20 months and reduced the number of dentate gyrus (DG) to CA3 synapses. Surprisingly, this reduction occurred at excitatory MF synapses surrounding CA3 somas in the stratum pyramidale, a layer not typically associated with MF terminals. Collectively, these findings suggest that cognitive enrichment during early adulthood may reverse ELS-induced spatial memory deficits by adjusting synaptic connectivity between the DG and CA3.

Young blood or plasma improves cognitive function in aged animals but has limited availability. The current study generates a subtype of young blood cells from easily expandable induced pluripotent stem cells and evaluates their effects on age- and Alzheimer's disease (AD)-associated cognitive and neural decline. In aging mice, intravenous delivery of induced mononuclear phagocytes (iMPs) improves performance in hippocampus-dependent cognitive tasks, increases neural health, and reduces neuroinflammation. Hippocampal single nucleus RNA-sequencing shows that iMPs improve the health of a subpopulation of mossy cells that are critically involved in the type of cognitive task in which iMPs improve performance, and shows that iMPs decrease the transcriptional age of several hippocampal cell types. Plasma proteomic analyses reveal that iMPs can also reverse age-associated increases in serum amyloid levels. This is verified in vitro, where iMP-conditioned media isshown to protect human microglia against cell death induced by serum amyloids. Finally, iMPs improve cognition in both young and aging 5×FAD mice, highlighting their potential as a prevention as well as an intervention strategy. Together, these findings suggest that iMPs provide a novel therapeutic strategy to target both age- and AD-related cognitive decline.

Pharmacological modulation of monoaminergic signaling, a process targeted by many therapeutic and recreational drugs via receptors, transporters, degradation enzymes, or reuptake mechanisms, is emerging as a promising aging intervention and as a strategy to treat various maladies. Monoamines (including dopamine, serotonin, and norepinephrine) are central to the regulation of mood, movement, sleep, memory, and systemic physiology. Here, we demonstrate that Reserpine, chronic inhibitor of the vesicular monoamine transporter (VMAT), robustly extends lifespan in Drosophila melanogaster in a dose-dependent manner. However, reserpine-treated flies also exhibit reduced locomotor activity and impaired survival under acute heat stress, indicating a context-dependent trade-off between lifespan extension and stress resilience. Transcriptomic profiling revealed that reserpine induces a transcriptionally repressed, low-energy state characterized by downregulation of metabolic, immune, and stress-response genes in treated aged animals. Notably, under heat stress, reserpine blunts the induction of canonical protective genes, including heat shock proteins and antioxidant genes, resulting in increased proteotoxic vulnerability. These findings highlight the potential trade-offs of monoaminergic modulation and support further investigation of VMAT inhibitors, monoamine modulators and other hypertension drugs as geroprotective agents.

Aging involves changes in the gut microbiome impacting health and longevity; however, the roles of specific microbial metabolites remain understudied. Here, we examine the microbial contribution to the metabolic profile in aged mice. Fecal samples were collected from female Swiss-Webster mice raised conventionally (Conv) or germ free (GF), at 8 weeks (young) and 18 (aged) months of age, and the microbiome and metabolome were characterized. Significant differences were observed in bacterial composition and its predicted functional activity between young and aged mice. Interestingly, we found more age-related differences in metabolite abundances among Conv mice than GF mice, highlighting the contribution of the microbiome to aging. Moreover, microbiome-associated metabolites, predominantly lipids, were higher in aged mice, with linoleic acid metabolism enriched in this group. Our study underscores a microbiome-dependent component to age-related metabolic changes in mice, particularly in lipid-associated pathways, and contributes to the growing body of literature linking gut microbiota to host metabolism in aging.

The cerebellum supports higher-order cognition, such as working memory and executive function (EF) both directly and through connection with prefrontal areas via cortical loops. Thus, age-related degradation to white matter connectivity comprising cerebello-thalamo-cortical (CTC) loops may underlie age-related differences in EF. In 190 healthy adults (aged 20-94 years) we collected diffusion tensor imaging scans and multiple tests of working memory and EF. Deterministic tractography was used to generate CTC tracts from which white matter metrics (mean, radial, axial diffusivities) were extracted. General linear model results indicated that reduced white matter integrity (i.e., higher diffusivity) was associated with significantly poorer EF performance in an age-dependent fashion. Higher mean, radial, and axial diffusivities in fronto-cerebellar white matter was associated with lower EF scores in older, but not younger, adults. These findings suggest CTC white matter connectivity is important for executive function performance and lend mechanistic evidence to the role of the cerebellum in age-related differences in higher-order cognitive operations.

Changes in microRNA (miRNA) play a role in brain aging. They are considered potential therapeutic targets. Regular long-term exercise benefits brain health. However, its exact mechanism is not fully understood. This study explored how moderate-intensity intermittent training (MIIT) improves cognitive function and reduces apoptosis in the aging brain. This study induced aging in rats by giving them D-gal injections (150 mg/kg/day) for 6 weeks. After confirming the model, the rats underwent MIIT. They exercised 45 minutes a day, 5 days a week, for 8 weeks. The results from behavioral, morphological, and molecular tests showed that 8 weeks of MIIT significantly slowed the decline in spatial learning and memory in D-gal aging rats. The exercise also improved the structure of the prefrontal cortex (PFC) and reduced apoptosis. Aging caused an overexpression of miR-34a-5p in the prefrontal cortex. MIIT reduced this overexpression. It also up-regulated Notch1 and inhibited excessive apoptosis by regulating Bcl-2 and Bax expression. In conclusion, MIIT may improve brain health by targeting miR-34a-5p and regulating apoptosis-related pathways.

With the growing demand for adult orthodontic treatment, age-related changes in clinical outcomes have emerged as significant challenges. However, effective strategies to improve outcomes in aging patients remain limited. Periodontal ligament stem cells (PDLSCs), a mechanosensitive subpopulation of mesenchymal stem cells, play a significant role in bone remodeling during orthodontic tooth movement (OTM) and are increasingly recognized as key contributors to the decline in orthodontic responsiveness with age. This review highlights the multifaceted role of PDLSCs in OTM, encompassing mechanosensation, mechanotransduction, and subsequent bone remodeling. It further examines how aging impairs PDLSC biology and potentially contributes to reduced orthodontic responsiveness in older individuals. Key aging-related mechanisms are described, including increased oxidative stress, disrupted mitochondrial homeostasis, impaired autophagy, loss of proteostasis, and epigenetic modifications. Dysregulation of intracellular signaling pathways further underscores the complexity of age-related functional decline. Based on these insights, emerging strategies for rescuing aged PDLSCs are summarized, offering a theoretical foundation for developing targeted interventions to enhance orthodontic outcomes in the aging population.

Age-related arterial stiffening is a hallmark of vascular ageing and a key driver of cardiovascular disease. Oxidative stress, impaired autophagy, and extracellular matrix remodelling play an important role in the progression of aortic stiffening. Hydroxytyrosol (HT), a phenolic compound in olives, has demonstrated antioxidant properties and the ability to modulate autophagy, positioning it as a potential therapeutic for vascular ageing. In this study, we investigated the effects of HT on autophagy flux and antioxidant protein expression in human aortic endothelial cells (HAoECs). In parallel, we examined the impact of HT on arterial stiffness

Age-associated atrial myopathy results in structural remodeling and a disturbance of atrial conductance. Atrial myopathy often precedes atrial fibrillation (AF) and can facilitate AF progression. However, the molecular mechanism linking aging to atrial deterioration remains elusive. CDGSH iron-sulfur domain-containing protein 2 (CISD2) is a mammalian pro-longevity gene. We used Cisd2 knockout (Cisd2KO) and Cisd2 transgenic (Cisd2TG) mice to investigate pathophysiological mechanisms underlying age-related atrial myopathy. Four findings are pinpointed. Firstly, in both humans and mice, the level of atrial CISD2 declines during natural aging; this correlates with age-associated damage, namely degeneration of intercalated discs, mitochondria, sarcoplasmic reticulum (SR) and myofibrils. Secondly, in Cisd2KO and naturally aged wild-type mice, Cisd2 deficiency causes atrial electrical dysfunction and structural deterioration; conversely, sustained Cisd2 levels protect Cisd2TG mice against age-related atrial myopathy. Thirdly, Cisd2 plays a vital role in maintaining Ca²⁺ homeostasis in atrial cardiomyocytes. Cisd2 deficiency disrupts Ca²⁺ regulation, leading to elevated cytosolic Ca²⁺, reduced SR Ca²⁺, impaired store-operated calcium entry, and mitochondrial Ca²⁺ overload; these compromise mitochondrial function and attenuate antioxidant capability. Finally, transcriptomic analysis reveals that Cisd2 protects the atrium from metabolic reprogramming and preserves into old age a transcriptomic profile resembling a youthful pattern, thereby safeguarding the atrium from age-related injury. This study highlights Cisd2's crucial role in preventing atrial aging and underscores the therapeutic potential of targeting Cisd2 when combating age-associated atrial dysfunction, which may lead to the development of strategies for improving cardiac health in aging populations.

The H/ACA ribonucleoprotein complex component dyskerin is essential for the biogenesis of H/ACA RNAs, including the human telomerase RNA (hTR). The N-terminal extension and 2' helix of dyskerin are hotspots for disease-associated mutations linked to X-linked dyskeratosis congenita (X-DC), a premature aging disorder. Some of these mutations disrupt dyskerin-hTR interactions, leading to hTR destabilization and reduced telomerase activity. Cryo-EM structures of human telomerase have shown that the N-terminal extension and 2' helix participate in dyskerin dimerization. However, biochemical evidence for dyskerin dimerization is still lacking, and it remains unclear whether mutations in these regions impair hTR binding by disrupting dimerization. Here, we provide the first biochemical evidence that dyskerin undergoes dimerization. We further demonstrate that dimerization is RNA independent and not abolished by disease mutations in the N-terminal extension or 2' helix. Instead, these mutations impair hTR binding. Our findings offer new mechanistic insight into how mutations in the dyskerin N-terminal extension and 2' helix contribute to the pathogenesis of X-DC.

Age is the most important risk factor for the majority human diseases, leading to the exploration of innovative approaches, including the development of predictors to estimate biological age (BA). These predictors offer promising insights into the ageing process and age-related diseases. With real-time, multi-modal data streams and continuous patient monitoring, these BA can also inform the construction of 'human digital twins', quantifying how age-related changes impact health trajectories. This study highlights the significance of BA within a deeply phenotyped longitudinal cohort, using omics-based approaches alongside gold-standard clinical risk predictors. BA and health traits predictions were computed from 29 epigenetics, 4 clinical-biochemistry, 2 proteomics, and 3 metabolomics clocks. The study reveals that ageing is different between individuals but relatively stable within individuals. We suggest that BA should be considered crucial biomarkers complementing routine clinical tests. Regular updates of BA predictions within digital twin frameworks can also help guiding individualised treatment plans.

Arsenic, a widespread environmental contaminant, threatens millions globally through contaminated water, soil, and food. While arsenic compounds are used to treat acute promyelocytic leukemia, their toxic legacy includes cancers, cardiovascular disease, diabetes, and neurodegeneration, primarily driven by oxidative stress, mitochondrial dysfunction, and epigenetic instability. Sirtuins, a family of NAD⁺-dependent enzymes, are central to cellular defense, orchestrating metabolism, stress resistance, DNA repair, and longevity. Arsenic disrupts sirtuin function, particularly SIRT1, SIRT2, and SIRT3, via microRNA-mediated silencing and post-translational modifications, impairing antioxidant defenses, disturbing energy metabolism, and accelerating cellular injury across organ systems. However, activating sirtuins with agents like resveratrol, metformin, or berberine, as well as through lifestyle interventions, can counteract arsenic toxicity, restore cellular resilience, and provide new therapeutic strategies. This review synthesizes current knowledge on the interplay between arsenic exposure and sirtuin biology, examining how arsenic alters sirtuin expression and activity, the downstream consequences for cellular signaling and organ health, and emerging interventions targeting sirtuin pathways. By bridging molecular insights with translational potential, we highlight the promise of sirtuins as therapeutic targets in combating arsenic toxicity and guide future research directions.

One of the major challenges in modern biogerontology is understanding the accumulation of molecular damage and the manifestation of phenotypic heterogeneity during aging. Notably, genomic instability caused by impaired DNA damage repair along with telomere attrition are primary drivers of aging. However, how these aging-related characteristics differ in individuals who age healthily without developing major age-associated diseases remains unclear. Here, whole genome sequencing (WGS) was performed on 100 healthy agers (≥ 60 years old, no age-related diseases) and 100 unhealthy agers (≥ 60 years old, at least one age-related disease/condition) based on a case-control study. Telomere length was measured using TelSeq and Computel. High-functional impact germline variant (gHFI) burden and alteration pattern at the pathway level were also analyzed. The GTEx dataset including 751 individuals was used to observe the functional impact of identified germline variants at the molecular level. Telomere length showed minimal differences before 65 years of age but declined rapidly in unhealthy agers beyond this age. Additionally, healthy agers had lower gHFI burden, particularly in DNA repair genes such as BLM. Pathway analysis revealed enrichment of oxidative stress-related mutations in healthy agers, correlated with reduced oxidative stress and upregulated antioxidant enzymes (SOD1 and SOD2). Overall, genomic instability preserved through slow telomere attrition and reduced DNA repair defects plays a key role in healthy aging. Improved oxidative stress resistance may contribute to healthier aging, highlighting the role of genetic factors in reducing age-related decline and supporting overall well-being in later life.

Cellular senescence is a critical process involved in aging and related disorders, yet the molecular triggers of early senescence remain elusive. Here, we identify DNA methyltransferase 1 (DNMT1) downregulation as a key trigger of early senescence and establish serine protease inhibitor Kunitz type 2 (SPINT2) as its critical downstream effector. Using replicative and oxidative stress-induced senescence models of primary human diploid fibroblast, we observed persistent upregulation of SPINT2 and inverse downregulation of DNMT1, preceding senescence-associated β-galactosidase activity, a conventional senescence marker. Pharmacological inhibition and siRNA-mediated knockdown of DNMT1 significantly increased SPINT2 expression and induced senescence, showing mitigated effects by SPINT2 knockdown. Furthermore, SPINT2 overexpression alone induced senescence. Methylation-specific sequencing identified four CpG sites in SPINT2 promoter, that became hypomethylated at early transition of senescence and upon DNMT1 suppression. Functional analyses revealed that DNMT1-mediated SPINT2 expression induced c-Met inhibition, triggering senescence. Transcriptomic profiling identified 17 commonly deregulated c-Met signaling genes in both senescence models, with COL27A1, STAM2, and CBL validated as key downstream targets of SPINT2/c-Met signaling. These findings establish DNMT1-mediated SPINT2 upregulation as a novel epigenetic mechanism driving senescence initiation via c-Met inhibition, providing insights into the early stage of senescence and potential therapeutic targets for aging-related diseases.

Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging

Pancreatic β-cell function declines with age, but the underlying mechanism is poorly understood. In this study, we attempted to address how to reverse β-cell aging. Our data showed that sirtuin 6 (SIRT6) overexpression can reduce age-associated DNA damage, cell death, and functional decline in β-cells. Our findings suggest that improving Sirt6 gene expression and function may slow down β-cell decline in older patients.

Chronic respiratory diseases impart a huge global disease burden. Many cases of adult chronic respiratory disorders are recognised to originate early in life during critical phases of lung growth and development. We therefore reviewed the longitudinal evolution of common childhood respiratory diseases across the lifespan. We included studies relating childhood respiratory health (preterm birth, asthma, low lung function or bronchiectasis) to respiratory health in adolescents and adults, including COPD.The negative impact of preterm birth (with or without bronchopulmonary dysplasia) on future respiratory health has now been quantified, with many having increasing deviation of lung function from the norm over their life course. While previous studies report children with asthma frequently "outgrow their disease" by adolescence or early adulthood, recent data describe asthma trajectories that include relapse, early-onset adult-remitting, and early-onset persistent childhood asthma. Evidence is emerging in adults of the negative impact of chronic productive cough, breathlessness and lower lung function on future respiratory and cardiovascular health and all-cause mortality. In addition, we found that in general, childhood respiratory health and adverse lung function trajectories are inextricably linked to adult respiratory health and cardiovascular events, as well as cardiovascular and all-cause mortality. Thus, we highlight the importance of pulmonary assessments in high-risk groups during childhood (

This study explores the relationships between biochemical phenotypes identified using machine learning, and key health outcomes, including body composition, physical function, and mortality risk. Data were collected from 536 physically active Spanish participants aged over 65 years (76.5% women) enrolled in the EXERNET cohort (2017-2018), with a 6-year mortality follow-up. Principal component analysis, and hierarchical and k-means clustering was used to identify distinct biochemical profiles. Associations between clusters and health outcomes were assessed using analysis of covariance and Cox proportional hazards models. Three distinct clusters emerged: 'Healthy', characterized by biochemical values within the normal range and used as the reference group; 'Metabolic', marked by dysregulated metabolic parameters; and 'Hepatic', which exhibited impaired liver function markers. Notably, all clusters showed subclinical levels of dysfunction. The 'Healthy Cluster' demonstrated the highest levels of organized physical activity (90%, p < 0.001), whereas the 'Metabolic Cluster' showed poorer body composition and reduced physical performance. Both the 'Metabolic' and 'Hepatic' clusters demonstrated a higher mortality risk, as confirmed through Cox regression analyses. Adjusted hazard ratios were significantly elevated when considering physical activity and adiposity, with values of 3.45 and 3.71 for the 'Metabolic Cluster', and 3.01 and 3.85 for the 'Hepatic Cluster' (p < 0.05). This study underscores the strong link between metabolic health, physical activity, body composition and 6-years mortality risk in older adults. Machine learning techniques for identifying phenotypic clusters offers a promising tool for early detection and targeted interventions to improve aging outcomes.

Energy restriction is closely related to cellular senescence and species longevity. Here, based on the structure and function of ATP synthase, a key enzyme for energy generation, we develop energy metabolism-engaged nanomedicines (EM-eNMs) to rejuvenate aged stromal/stem cells, and help to prevent skeletal ageing. We show that EM-eNMs infiltrate the mitochondria of aged bone marrow mesenchymal stromal/stem cells (BMMSCs), driving mitochondrial fission, mitophagy, glycolysis and maintaining BMMSC stemness and multifunction. The EM-eNMs directly bind to the ATP synthase and promote mitophagy through induction of the dynamin-related protein 1 (DRP1) gene. Remarkably, EM-eNMs selectively target bone tissues through systemic delivery and significantly reverse osteoporotic bone loss in aged mice by enhancing mitochondrial fission and mitophagy, while simultaneously restoring the stemness and osteogenic potential of aged BMMSCs in situ. Taken together, our findings highlight the potential of the EM-eNMs as a targeted therapy to alleviate cellular senescence and age-related diseases.

Aging is a multi-modal process, leaving distinct signatures across molecular layers, including the epigenome. DNA methylation changes are among the most robust markers of biological aging. Yet, most studies rely on models assuming linear relationships with age and often analyze mixed-sex cohorts, overlooking well-known sex differences in the timing and nature of aging phases. Such approaches risk obscuring critical, non-linear transitions and sex-specific trajectories that may better capture the biology of aging. We developed a computational approach to detect complex, non-linear trajectories and disentangle shared from sex-divergent patterns. Applied to whole-blood deconvoluted methylomes from 252 females and 246 males spanning ages 19-90 years, this analysis revealed convergent and divergent epigenetic aging pathways independent of immune cell composition. These non-linear trajectories were enriched for developmental transcription factor binding motifs, including NF1/CTF and REST, which are known for their oncogenic potential. Strikingly, a female-specific non-linear cluster was robustly associated with cancer onset and systemic inflammation. Our results uncover sex-specific, non-linear aging programs that better capture the dynamics of epigenetic change than linear models. These findings nominate candidate biomarkers for early disease risk and offer mechanistic insight into how aging trajectories diverge between the sexes.

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline. Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.

Caloric restriction (CR) can enhance human health, though underlying mechanisms, particularly related to energy expenditure, remain unclear. This ancillary investigation of the only randomized controlled trial of long-term CR in normal-weight adults, aimed to quantify metabolic adaptation following weight loss by assessing changes in energy-expending tissues and organs using magnetic resonance imaging (MRI). Participants in the CR group were prescribed 24-month 25% CR causing a ~ 13% weight loss at 12 months followed by 12 month weight maintenance, whereas the control group maintained ad libitum food intake throughout. The CR group experienced reductions in adipose tissue and skeletal muscle mass compared to the control group. Sleeping energy expenditure decreased more than predicted at 12 months, regardless of whether predictions were based on body mass, dual x-ray absorptiometry (DXA)-derived body composition, or MRI-derived tissue mass. MRI-derived models explained slightly more variation in energy expenditure at baseline and detected greater metabolic adaptation than simpler models based on body mass only. At 24 months, only the models based on DXA and MRI were indicative of persistent metabolic adaptation. These findings highlight the complexity of metabolic responses to CR. Further, advanced imaging techniques hold potential to provide insight into organ-specific contributions to energy metabolism during CR.

The gut microbiota of centenarians plays a vital role in promoting healthy longevity. We performed a cross-sectional study of 224 people from Jiaoling, China, which is globally recognised for the longevity of its residents. Compared with younger people, centenarians showed significantly increased alpha-diversity, enrichment of the beneficial bacteria Lactobacillus, Akkermansia, and Christensenella, and increased redox capacity in the gut microbiota. Serum metabolomics of centenarians showed significant enrichment of antioxidant metabolites, including L-ascorbic acid 2-sulphate and lipoic acid. Finally, we isolated and screened a strain of Lactobacillus plantarum 124 (LP124) with a good antioxidant effect on the gut microbiota of centenarians. Animal experiments further verified that mesaconic acid from LP124 regulates the gut microbiota, is anti-inflammatory, relieves oxidative stress, maintains the intestinal barrier, and is the best-known anti-aging molecule. LP124 derived from the gut microbiota of centenarians and its metabolite mesaconic acid, have a significant positive effect on health and longevity.

Aging is characterized by a progressive decline in physiological functions and an increased susceptibility to age-related diseases, yet effective interventions remain limited. Recent advancements in understanding the molecular mechanisms of aging have highlighted pathways such as insulin-like signaling, mTOR, and sirtuins. Meanwhile, traditional medicinal herbs are increasingly recognized for their potential to modulate these pathways. However, comprehensive analyses investigating how these herbs influence multiple aging-related metabolic pathways simultaneously remain scarce. This study examines the anti-aging and antioxidant effects of Radix Saposhnikoviae (Fangfeng) through metabolomic analysis using Drosophila melanogaster as a model organism. Our findings indicate that different Fangfeng preparations significantly extended the lifespan of Drosophila to varying extents. Utilizing nuclear magnetic resonance (NMR) metabolomics, we identified key metabolic pathways modulated by Fangfeng, including those related to energy metabolism, oxidative stress response, lipid metabolism, protein homeostasis, and inflammatory processes-each closely associated with aging. The results revealed significant regulation of these pathways, particularly those involved in oxidative stress and energy homeostasis, which are central to the aging process. These findings underscore the potential of Radix Saposhnikoviae as a promising medicinal herb for modulating key biochemical pathways associated with aging and oxidative stress. This study provides a scientific basis for the integration of traditional herbal medicine into contemporary anti-aging strategies, contributing to the expanding field of aging research.

A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in aging biology. Here, we showed that phosphorylation of the Mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathogenesis.

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, have also been linked to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we performed a genome-wide CRISPR knockout screen using HCoV-229E and identified Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a potent restriction factor. Mechanistically, UHRF1 suppressed HCoV-229E infection by downregulating the expression of its cell entry receptor, aminopeptidase N (APN), through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirmed the critical role of APN in HCoV-229E infection and identified additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis revealed that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 was further validated in primary alveolar macrophages isolated from elderly individuals, which exhibited heightened susceptibility to HCoV-229E infection compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus infection and provide novel insights into the epigenetic regulation of viral entry receptors.

Cell cycle progression presents a fundamental challenge to genome integrity, particularly due to the need to reestablish post-translational histone modifications (PTMs) following DNA replication. Although proliferative and differentiating tissues exhibit markedly different cell cycle dynamics, how these differences shape the histone modification landscape in vivo remains largely unexplored. Here, we show that levels of H3K27ac, H3K27me3, and H3K9me3 are tightly linked to cell cycle dynamics in the Drosophila wing imaginal disc. We demonstrate that both physiological and pathological elongation of the cell cycle led to an accumulation of H3K9me3 and H3K27me3, whereas cell cycle acceleration reduces their levels. In contrast, H3K27ac exhibits the opposite pattern: levels decrease in arrested cells and increase with faster cycling. Genome-wide CUT&Tag analysis reveals that these changes predominantly affect genomic loci already modified in normally proliferating tissue. Importantly, the regulation of methylation levels at H3K9 and H3K27 is not solely mediated by the cell cycle machinery but reflects a metabolically guided process in which the rate of methylation is coupled to the rate of cell proliferation through metabolic activity, including signaling via the Insulin/PI3K/Akt pathway. Our study thus reveals key principles for understanding histone methylation in proliferating, senescent, and differentiating cells. In contrast, H3K27 acetylation is regulated through a distinct, cell cycle-coupled mechanism. We find that CBP/Nejire-mediated acetylation of H3K27 peaks during S-phase and is reversed by HDAC1, as cells exit replication. Disruption of this acetylation cycle leads to replication stress and a G2 cell cycle arrest via a DNA damage checkpoint. Notably, this genome-protective function of CBP/Nejire depends specifically on acetylation of the H3K27 residue itself, revealing a novel role for H3K27ac beyond its well-established function in transcriptional activation. Together, our findings establish a robust link between cell cycle progression and histone modification dynamics, highlighting the necessity of maintaining balanced PTM levels under varying proliferative states. These insights have broad implications for our understanding of development, aging, and tumor growth.

Aging disrupts physiological and behavioral homeostasis, largely driven by one-carbon metabolism, mitochondrial, and metabolic imbalance. To elucidate the roles of conserved metabolic and mitochondrial genes in age-related decline, we employed genetic manipulations in vivo using Drosophila melanogaster models, in a cell-autonomous and non-cell-autonomous manner. By using panneuronal and indirect flight muscle (IFM) specific drivers, we assessed the impact of gene knockdown (KD) or overexpression (OE) on sleep-circadian rhythms, locomotion, and lipid metabolism in a cell-autonomous and non-cell-autonomous manner to address bidirectional neuro-muscle communications. KD of genes such as SdhD and Gnmt leads to a decrease in flight performance, especially in 6 weeks with both drivers. Panneuronal knockdown of genes did not impact the locomotory performance. Whereas knockdown of mAcon1, LSD2, Ampkα, Ald, and Adsl genes showed reduced flight performance, with only IFM-specific driver emphasizing the cell-autonomous role of metabolic genes. Panneuronal KD of Ald, GlyP, mAcon1, and Gnmt genes showed increased total sleep, reduced activity, while Adsl and Ogdh knockdown led to sleep fragmentation, in a mid-age suggests cell-autonomous impact. Functional analysis of AMPK signaling via overexpression and knockdown of Ampkα, as well as expression of the mutant overexpression SNF1A and its kinase-dead mutant, revealed kinase-dependent, age- and tissue-specific modulation of sleep and activity rhythms. Lipid analysis showed that panneuronal overexpression of Ampkα altered lipid droplet number and size in the brain, indicating disrupted lipid homeostasis during aging. These findings on various genes provide us with an understanding of their diverse effects on sleep-activity rhythms, locomotor effects, and communication in cell and non-cell-autonomous roles. Our study emphasizes Ampkα as a central regulator of behavioral and metabolic aging, linking neuronal energy sensing, motor function, and lipid dynamics, and offers mechanistic insights into tissue-specific metabolic regulation with potential relevance for interventions targeting age-related decline and neurodegeneration.

Brain aging significantly impairs cognitive and behavioral functions. While some nonlinear aging studies have identified age-specific aging peaks at certain ages, the influence of different cell types on brain aging fluctuations across the lifespan remains unclear. This study, approaching from the interdisciplinary perspective of brain aging and systems dynamics, extends the nonlinear aging analysis to the cellular level, using single-cell transcriptomic data to analyze 45 healthy elderly brain samples aged 29-94 years. Describing cellular and molecular differences in the aging process, neuron proportion is downregulated but relatively stable with low variability after aging, while glial cells are significantly upregulated and highly unstable. Notably, peaks in nonlinear molecular fluctuations are observed in aging at ages 60, 70, and 79. The nonlinear features prompted the introduction of a dynamic network biomarker and the identification of 56-60 years as the tipping point in the brain's healthy aging process, then suggesting that glia predominantly mediate this process and exploring the underlying features and mechanisms. This work investigates the tipping point of aging at single-cell resolution and provides new research strategies for early diagnosis and intervention of aging-related neurological diseases.

Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), a transition driven by cellular senescence, a state of irreversible cell-cycle arrest. However, the molecular mechanisms promoting this pathological process remain unclear. Here we show that the channel protein Pannexin1 (Panx1) promotes this detrimental senescence and subsequent kidney fibrosis. We found that Panx1 functions in a noncanonical role as a calcium (Ca

This review summarizes the latest advancements in stem cell (SC) mitochondrial proteomics. With the rapid development of biotechnology, mitochondrial proteomics has emerged as a pivotal area in SC research. The research methods used in mitochondrial proteomics include mass spectrometry (MS), with pre-MS sample processing, MS data acquisition employing both qualitative and quantitative approaches, and bioinformatics analysis to annotate and explore protein functions. In recent years, mitochondrial proteomics research has contributed to the establishment and expansion of our understanding of the roles of various mitochondrial proteins involved in regulating SC differentiation, metabolism and aging, including Drp1, Mfn1/2, OPA1, SIRT3, Bcl-2, YME1L, and PGC-1α. This multidisciplinary approach, combining qualitative and quantitative proteomics with bioinformatics, sheds light on the intricate regulatory mechanisms of mitochondrial proteins in SC. These findings provide a scientific basis for developing novel therapeutic targets and strategies, thereby advancing the field of regenerative medicine and personalized treatment paradigms.

Given that age is a significant risk factor for multiple neurodegenerative diseases, investigating normal brain aging may help identify molecular events that may contribute to increased disease risk over time. Single-nucleus RNA sequencing (snRNA-seq) enables analysis of gene expression changes within specific cell-types, potentially offering insights into the molecular mechanisms underlying aging. However, most brain snRNA-seq datasets used age-matched controls from studies focused on pathological processes and have largely been limited to cortical regions. Therefore, there is a need to investigate the non-pathological aging process in brain regions that are vulnerable to age-related diseases. Here, we report a snRNA-seq study of 6 young (20-30 years) and 7 aged (60-85 years) encompassing four different brain regions: the entorhinal cortex, middle temporal gyrus, subventricular zone, and putamen. We captured over 150,000 nuclei that represented 10 broad cell-types. While we did not find statistically significant differences in cell-type proportions with age, region- and cell-type-specific differential expression analyses identified over 8,000 age-associated genes. Notably, within a given cell-type, most of these associations were region-specific. Functional enrichment analyses of the gene sets for each cell-type-region combination revealed diverse biological processes, including multiple hallmarks of aging, such as proteostasis, interactions with cytokines, vesicular trafficking, metabolism, inflammation, and metal ion homeostasis. Overall, our findings suggest that unique cell-types exhibit distinct transcriptional aging profiles both at the cell-type level and across different brain regions.

The search for drugs that extend lifespan in human-like biological models is a frontier area in biomedical research. In this study, we report a novel electrochemical approach using flufenamic acid (FFA), a widely known nonsteroidal anti-inflammatory drug (NSAID), to generate and detect its pharmacologically active metabolites. Electrochemical oxidation of FFA on multi-walled carbon nanotubes(MWCNT)-modified electrode yielded hydroxylated derivatives, primarily 4-hydroxy FFA (m/z 297.05 g/mol) and a polyhydroxylated product termed FFA-Redox (m/z 243.05 g/mol), as surface-confined species (MWCNT@FFA-Redox). To establish biological relevance, Caenorhabditis elegans (C. elegans) were exposed to FFA, resulting in in vivo formation of metabolites identical to those generated electrochemically. This confirmed the physiological significance of the electrosynthesized compounds. Lifespan assays demonstrated that FFA-Redox prolonged the survival of C. elegans by up to 40% under Klebsiella pneumoniae infection and by up to 80% under Staphylococcus aureus infection. This protective effect was attributed to reduced levels of intracellular reactive oxygen species (ROS). Mechanistic insights suggest that FFA-Redox induces a "de-aging" response by enhancing the expression of superoxide dismutase (SOD), a key antioxidant enzyme activated during oxidative stress.

Altered neuromuscular strategies are suggested to contribute to age-related decreases in postural stability. Current approaches tend to overlook global (whole body) neuromuscular postural control strategies, potentially due to methodological constraints or residual influence from a longstanding, but outdated, biomechanical view in which postural sway is represented by a single-jointed inverted pendulum. In this study, we investigate age-related differences in postural strategies during upright static balance maintenance by assessing global neuromuscular control. We collected simultaneous posturography and electromyography (EMG) data from young (18-35 years, n = 32) and older (65-85 years, n = 33) participants while they stood upright on a force plate or on foam pads thereon, with eyes open or closed. Postural instability was assessed by the standard deviation and velocity of the center of pressure. EMG sensors recorded the activity of thirty muscles (15 on each hemibody). Co-contraction across all muscle pairs was measured with Falconer's co-contraction index (CCI), and muscle synergy with non-negative matrix factorization. The older group possessed increased global co-contraction intensity, marked by more frequent use of a knee extensor synergy, and was more unstable than the younger group. Notably, advancing age modulated the variability of co-contraction intensity, where the oldest individuals consistently adopted a pure co-contraction strategy marked by the highest CCI values and lowest variability. Age-corrected correlations revealed that knee extensor CCI values were significantly related to postural instability. Taken together, global co-contraction appears to be a signature of elderly postural strategy and age-related instability may be directly related to the extent of knee extensor co-contraction. These results stress the importance of zooming out from classical agonist-antagonist muscle pair investigations in the endeavor to understand elderly postural control strategy.

Senescent cardiac fibroblasts (CFs), which are activated and acquire a pro-fibrotic phenotype, exacerbate age-related interstitial fibrosis and cardiac dysfunction by unclear mechanisms. Traditionally regarded as a central organ involved in regulating aging, the small intestine (SI) communicates with remote organs. However, the mechanisms underlying its role in CFs senescence remain undefined. We aimed to clarify whether the SI epithelium-derived exosomes (SI-exos) and their contained microRNAs could regulate CFs senescence and participate in deteriorating cardiac fibrosis during aging. Systemic administration of aged SI-exos exerted deleterious effects on the hearts of young recipient mice, as evidenced by exacerbated cardiac aging, inflammation, fibrosis, and the resulting poorer cardiac function. In vitro studies revealed that aged SI-exos could induce the activation and senescence of young CFs, while treatment with young SI-exos mitigated the activation and senescence of aged CFs. Mechanistic investigation identified that miR-223-3p was a common molecule significantly increased both in aged SI-exos and aged serum-exos. Incubation of young CFs with miR-223-3p mimics exacerbated cellular activation and senescence by cooperatively suppressing target genes: RASA1 and KLF15. In contrast, miR-223-3p inhibitor could rescue D-gal-induced CFs activation and senescence. Over-expression of RASA1 or KLF15 significantly rescued miR-223-3p-induced CFs activation and senescence. Summarily, our findings demonstrate for the first time that miR-223-3p enrichment in aged SI-exos, and its suppression of RASA1 and KLF15 in CFs, is a novel potential mechanism exacerbating cardiac aging and fibrosis. Targeting miR-223-3p mediated pathological communication between the aged SI epithelium and CFs might be an effective strategy for cardioprotection during aging.

Astrocytes play a critical role in neuroinflammation and the pathogenesis of neurodegenerative diseases. Here we found that human induced pluripotent stem cell (iPSC)-derived astrocytes responded differently to inflammatory triggers compared to rodent astrocytes, showing increased neurotoxicity when exposed to TNF- and IFN-{gamma}. Furthermore, astrocytes with senescent features showed even higher levels of neurotoxicity in the presence of TNF- and IFN-{gamma}, suggesting a potential link between aging and neurodegenerative diseases. It was also demonstrated that LPS-activated neuron/astrocyte/microglia tri-culture produced TNF-, leading to neurotoxicity in the tri-culture when IFN-{gamma} was present. Through compound screening, we identified Janus kinase inhibitors capable of preventing neurotoxicity in astrocytes induced by TNF- and IFN-{gamma}, demonstrating the potential use of neurotoxic astrocytes as a platform for drug screening. These results provide insight into the complex relationship between aging, inflammation, and neurodegenerative diseases, emphasizing the potential of targeting astrocytes as a novel therapeutic approach for addressing neurodegenerative diseases.

The thymus is a primary lymphoid organ generating self-restricted and self-tolerant naïve T cells. Early in life the thymus starts to involute, resulting in decreased naïve T cell output which may be more self-reactive, leading to an increased prevalence of autoimmunity. A decrease in the transcription factor FOXN1 is an early event in thymic involution. Using the Foxn1lacz model, we studied how premature thymic involution affects the thymic microenvironment, thymocytes, and peripheral T cell immunity. We found that early thymic involution led to aged-like thymic epithelial cells that resulted in aged-like thymocyte phenotypes, with a significant decrease in CD4+ single-positive T cells. We also observed severe lymphopenia in Foxn1lacz mice caused by the premature decrease in T cell production, resulting in a peripheral T cell phenotype similar to de novo aged peripheral T cells. Moreover, following T cell receptor stimulation, Foxn1lacz peripheral T cells had reduced IL-2 secretion and strong initial IFN-γ responses, resembling aged wild-type peripheral T cell responses. Lastly, influenza response in Foxn1lacz had a reduction in some aspects of T cell responses to influenza infection. Our study shows an independent and direct impact of premature thymic involution on both thymopoiesis and peripheral immune niches likely contributing to immunosenescence and inflammaging as observed in the elderly population.