With the aging of the population, frailty has become a common syndrome that severely affects the quality of life of older adults. This study aims to analyze the correlation between cognition and frailty, physical activity and frailty, and elucidate the potential pharmacological targets of cognitive frailty and physical frailty.We conducted logistic regression analyses using data from the China Health and Retirement Longitudinal Study (CHARLS) to examine the associations between total cognition and frailty, physical activity and frailty. Furthermore, summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (TSMR) were employed to explore potential pharmacological targets for frailty. Genes associated with physical frailty and cognitive frailty were identified, followed by analysis via colocalization analysis, phenome-wide association studies (PheWAS), and DsigDB drug prediction. Cross-sectional analysis of CHARLs revealed that total cognition(OR 0.93, 95% CI 0.92-0.95) and middle physical activity(OR 0.95, 95% CI 0.92-0.97) were negatively correlated with frailty. SMR identified 41 drug genes associated with frailty, and subsequent TSMR validation and co-localization analysis showed that 11 candidate genes exhibited strong colocalization (PP.H4 > 0.8). GRPEL 1, PABPC 4, and WBP 2NL were ultimately identified as potential drug targets associated with physical frailty, while LANCL1, LRPPRC, FADS1, and WBP2NL were identified as potential drug targets associated with cognitive frailty. Phenome-wide association analysis(PheWAS) did not reveal any significant associations between these genes and other phenotypes at the genome-wide significance threshold. Laudanosine, 25-hydroxycholesterol, and hexadecanal emerged as the top three candidate compounds for therapeutic intervention. We identified potential drug targets for physical frailty and cognitive frailty through comprehensive analysis and elucidated drugs associated with potentially relevant genetic markers, thereby laying the foundation for a deeper understanding of the mechanisms of frailty.

Aging is a progressive and irreversible biological process that contributes to the pathogenesis of numerous age-related diseases. Elucidating the molecular mechanisms of aging is crucial for promoting healthy aging and extending healthspan. RNA-binding proteins (RBPs) are pivotal regulators of post-transcriptional gene expression and play essential roles in diverse biological processes. RBPs interact with both coding and non-coding RNAs to regulate RNA metabolism, stability, localization, and translation. Dysregulated RBP-RNA interactions have been closely associated with aging and age-related diseases. This review systematically summarizes the structural characteristics of RBPs and the evolution of methods used to study them. We focus on the molecular mechanisms of six key RBPs, namely HuR, AUF1, TTP, IGF2BP2, QKI, and LARP7, in the context of aging and age-related diseases. In addition, we discuss the regulatory functions of post-translational modifications of RBPs. Furthermore, we provide a multidimensional overview of RBP involvement in aging and age-related diseases through large language model (LLM)-based text-mining analysis. Our study provides a foundation for the comprehensive characterization of RBPs in aging and age-related diseases.

Maternal sleep deprivation (MSD) is a common but usually unnoticed issue during pregnancy, and in recent years, it has been increasingly recognised as an important prenatal stressor that may adversely influence maternal physiology, placental function, and fetal neurodevelopment. Sleep disturbances during pregnancy, including reduced sleep duration, fragmented sleep, poor sleep quality, circadian disruption, and rapid eye movement sleep restriction, have been associated with altered hypothalamic-pituitary-adrenal axis activity, systemic inflammation, oxidative stress, and impaired circadian regulation. Emerging evidence from clinical and preclinical studies suggests that these alterations may affect fetal neurogenesis, synaptic development, neuroimmune signaling, and maturation of brain circuits involved in cognition and emotional regulations. Within the framework of the Developmental Origins of Health and Disease, maternal sleep disturbances may contribute to epigenetic modifications, mitochondrial dysfunction, microglial activation, and altered neuroplasticity-related pathways, which are increasingly implicated in long-term neurological vulnerability. Experimental findings further indicate that prenatal sleep disruption may impair offspring cognitive performance, emotional behavior, and stress responsiveness, while potentially influencing biological pathways associated with brain aging-related processes. However, the extent to which MSD directly contributes to pathological brain aging in humans remains incompletely understood. Factors such as timing and duration of exposure, sex-specific responses, and postnatal environmental conditions may further influence offspring outcomes. Therefore, this narrative review critically summarizes current evidence regarding MSD and examines the molecular, cellular, and neurodevelopmental mechanisms through which prenatal sleep disturbances may influence long-term neurological health and vulnerability to brain aging-associated alterations in offspring.This graphical abstract illustrates the mechanistic framework connecting maternal sleep deprivation to the developmental programming of brain aging in offspring. [ MSD: maternal sleep deprivation; DOHaD: Developmental Origins of Health and Disease; 11β HSD2: 11β hydroxysteroid dehydrogenase type 2; ROS: reactive oxygen species; REM: rapid eye movement; HPA axis: hypothalamic pituitary adrenal axis; BDNF: brain derived neurotrophic factor].

Kaempferol (KMP) is a dietary compound found in a wide range of foods. The therapeutic capabilities of these foods are associated with the phenolic compounds present in their structures, particularly their antioxidant activity. Remarkable medical care areas linked to KMP include pain relief, anti-aging, antiallergic, anticancer, antidiabetic, anti-inflammatory, antioxidant, antipyretic, central nervous system regulation, wound healing, and hepatoprotective characteristics. KMP has attracted considerable attention in the examination of its possible roles in dealing with a range of age-related diseases. These conditions include cardiovascular diseases (CVDs), immunoinflammatory diseases, neurodegenerative diseases (NDs), and cancer. It can delay oocyte aging, thereby enhancing the subsequent embryonic growth cascade. Delaying oocyte aging is mainly accomplished by reducing apoptosis and reactive oxygen species (ROS) levels. Furthermore, KMP has antioxidant effects on age-related diminished ovarian reserve (AR-DOR) by reducing HSP90 expression, thereby boosting NRF2 expression. KMP treatment influences multiple processes in aging oocytes, including peroxisome function, oxidative stress, cAMP signaling, TNF signaling, and gap junction pathways. Additionally, KMP improved negative pregnancy outcomes associated with fertilized aged oocytes.

This study aims to investigate the mechanism by which extract of Dendrobium officinale leaves (EDL) extends the lifespan of Caenorhabditis elegans. Untargeted metabolomics and network pharmacology analyses revealed that EDL primarily contains active components such as fatty acids, flavonoids, and polyphenols, which are predicted to potentially modulate pathways including MAPK, AMPK, mTOR, and longevity-related signaling pathways. Experimental results showed that 2mg/mL EDL significantly extended the mean lifespan of nematodes by 11.4%, enhanced pharyngeal pumping rate and muscular endurance, but reduced brood size. EDL treatment also significantly decreased lipid droplet accumulation, cell apoptosis, and lipofuscin levels. Transcriptomic analysis indicated that EDL regulated the expression of multiple genes related to energy metabolism, particularly activating longevity-regulating pathways and the AMPK signaling pathway. RT-qPCR results demonstrated that EDL significantly increased the mRNA level of sod-3 in C.elegans. In conclusion, EDL may upregulate the expression of the sod-3 gene via the DAF-16/SOD-3 axis, thereby extending lifespan in C. elegans, providing a scientific basis for the high-value utilization of Dendrobium officinale leaves.

The ageing population and the increasing prevalence of age-related diseases underscore the urgent need for targeted therapeutic strategies. Accumulating evidence indicates that quinolinic acid (QA), a neuroinflammatory neurotoxin, contributes to the pathogenesis of neurodegenerative disorders. In this study, using Caenorhabditis elegans as a model organism, we demonstrate that chronic QA exposure acts as a robust driver of accelerated aging, significantly reducing overall healthspan. This pro-aging effect is accompanied by the premature onset of decreased locomotor function, enhanced lipofuscin accumulation, and decreased thermotolerance. Beyond these systemic aging phenotypes, QA induced pronounced cognitive deficits, including impaired short- and long-term associative memory and structural damage to dopaminergic neurons.Using this QA-induced injury model, we investigated the therapeutic potential of the clinical compound dimethyl fumarate (DMF), a derivative of a tricarboxylic acid cycle intermediate, and revealed that DMF's protective effects are partially dependent on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In summary, our results demonstrate the therapeutic efficacy of DMF as a highly effective geroprotector and neuroprotector against QA-induced toxicity and define the Nrf2 pathway as a crucial mediator of the cognitive benefits of DMF, thus establishing its therapeutic repurposing potential for age-related neurodegenerative diseases.

Aging research has made remarkable progress in describing aging through the genetic architecture of longevity, epigenetic clocks, proteomic signatures, and systems-level analyses. Yet a critical dimension remains underrepresented: the role of genome integrity, germline and somatic mutation accumulation in individual-specific vulnerability, frailty, and multimorbidity across the life course. The need for individual-level thinking has deep roots, from Darwin's emphasis on individual variation in natural selection, to Garrod's chemical individuality, to Lewontin's genotype-phenotype (G-P) map and reaction norms. This tradition in evolutionary biology and medicine treats the individual as a primary unit of both selection and intervention. Here, we argue for an N-of-1 framework in aging research. Population-level epidemiology and genetics of aging based on means and variances can produce a "curse of the average," obscuring the individual genetic variation that impacts relative aging among individuals. The individual-centered N-of-1 framework would integrate longitudinal tracking of mutation accumulation ranging from individual cells, tissues, and organs into comprehensive individual aging profiles aligned with the G-P map concept. The emerging idea of "mosaic aging" further emphasizes that cells, cell types, tissues, organs, and organ systems within an individual reflect heterogeneous aging trajectories. We discuss how somatic mutations, operating through Muller's ratchet-like dynamics in stem cell populations, generate hierarchical vulnerabilities across biological scales. The extreme rarity of centenarians who may maintain superior genome integrity illustrates the relevance of this framework. We suggest that an integrated G-P map approach, grounded in evolutionary genetics, would advance both precision medicine and geroscience.

As the challenges posed by an aging population become increasingly apparent, the prevention and treatment of age-related diseases have become key research priorities. This study hypothesizes that Zhizi Baipi Decoction exhibits aging modulatory effects. Traditional Chinese Medicine Decoction that has been passed down for generations and remains widely used in contemporary clinical practice. Due to their short lifespan, well-defined genetic backgrounds, and ease of manipulation, model organisms such as Drosophila and C. elegans are commonly employed in aging modulatory research. This study evaluated the aging modulatory potential of Zhizi Baipi Decoction using Drosophila and C. elegans as model organisms, and used a Nuclear Magnetic Resonance-based metabolomics approach to explore the aging modulatory potential of Zhizi Baipi Decoction and its intrinsic mechanism. It was found that Zhizi Baipi Decoction could prolong the lifespan of Drosophila and C. elegans, improve locomotor activity, delay intestinal aging and so on, establishing a foundational framework for the future research and development of this traditional remedy.

Epigenetic aging clocks offer precise measures of biological age, yet the causal contributions of immune gene expression within specific cell subtypes to epigenetic aging remain poorly understood. By integrating single-cell eQTL data from the OneK1K cohort with GWAS summary statistics for four epigenetic clocks (HannumAge Acceleration, IEAA, PhenoAge Acceleration, and GrimAge Acceleration), we performed two-sample Mendelian randomization across diverse immune cell subtypes, followed by colocalization analysis and gene-level phenome-wide association studies. We identified 11 eGene-cell type pairs surviving Bonferroni correction, including NUCKS1 in CD4 NC T cells and NCR3 in Classic Monocytes as risk-increasing eGenes for HannumAge Acceleration, and HSPA1B in Classic Monocytes as protective across multiple clocks. ANP32E in Classic Monocytes represented the strongest risk signal for GrimAge Acceleration (OR = 2.683), while BCAS4 in CD8 EM T cells was the strongest protective association (OR = 0.683). Colocalization confirmed NUCKS1 (PP.H4 = 87%) and NCR3 (PP.H4 = 69%) as high-confidence causal eGenes, and PheWAS revealed no genome-wide significant off-target associations for the prioritized targets, supporting their specificity. These findings establish cell subtype-specific causal roles for immune gene expression in epigenetic aging and prioritize NUCKS1, NCR3, and ANP32E as candidate targets for interventions aimed at promoting healthy aging.

Oxidative stress and DNA damage caused by hydroquinone (HQ) increases the aging process, whereas antioxidants encourage longer lifespan by decreasing oxidative stress, making it ideal for research on mitigation of oxidative stress induced toxicity. Our study, explored 2'-hydroxyflavanone (2HF) and quercetin (QE) effects on HQ exposed Drosophila through gut toxicity assays (trypan blue) and survivorship (Kaplan-Meier plots) along with fertility and fecundity of female flies. Effects of the compounds on DNA methyltransferase 2 (DNMT2) and P-element Induced Wimpy testis (Piwi) protein were predicted through molecular docking and molecular dynamics simulation. QE and 2HF, individually and in combination, significantly enhanced lifespans, fertility, fecundity and reduced gut toxicity in Drosophila exposed to HQ. QE exhibited the strongest binding affinity to the proteins and greater stabilizing effect on both proteins followed by 2HF as implicated in the computational studies. This data supports the results of the lifespan and developmental assays performed in vivo, indicating that QE and 2HF, when administered alone or in combination serve as natural therapeutics for mitigating toxic effects and modulate longevity. Elaborate research on how these flavonoids act in preventing age related diseases and enhancing lifespan in humans is required.