Biogerontology最新文献

Traditional Chinese Medicine (TCM), as a globally recognized phytomedicinal approach, has made significant contributions to healthcare and anti-aging research worldwide. Jingfang Granule (JFG), an established TCM preparation in China, was demonstrated to exert effects on prolonging lifespan and healthspan via the Caenorhabditis elegans model in this study. We employed RNA-seq analysis to investigate the complex genetic interactions through which JFG extends the lifespan of C. elegans. We observed that administering JFG to adult nematodes increased the transcription levels of extracellular matrix (ECM)-related genes (including collagen genes), reproduction-related genes (e.g., egg-1, lin-41), and stress-activated transcription factor-1 (atfs-1). JFG treatment slowed down the functional degradation of organs, such as the cuticle, reproductive system, and mitochondria, leading to enhanced innate immunity and fecundity. Our findings demonstrate that JFG protects nematodes from age-related physiological decline and extends both lifespan and healthspan. This study not only highlights the effects of JFG on delaying aging but also provides a deep understanding of the genetic interactions underlying its anti-aging benefits.

Aging is a complex biochemical phenomenon that considerably impacts both individual health and societal dynamics. Recent researches have emphasized the essential function of metabolism in the processes of aging and longevity. Metabolites-chemical byproducts produced by the host organism and its symbiotic partners, including the microbiota, are generated through numerous metabolic pathways. In the last fifteen years, major progress has been made in elucidating the metabolism of BCAAs and the detailed molecular mechanisms that connect BCAAs homeostasis to the aging process. The growing body of literature presents a comprehensive view of the tissue- and disease-specific regulatory mechanisms governing BCAAs and their activation of various molecular pathways. These pathways link fluctuations in BCAA levels to the onset and progression of age-related diseases. This review seeks to consolidate current knowledge on the factors influencing BCAA levels and their metabolic pathways. It further aims to elucidate the molecular mechanisms linking dysregulated BCAA homeostasis to age-related diseases, evaluate epidemiological evidence correlating BCAAs with various cardiovascular conditions, and identify gaps in current understanding that warrant further investigation.

Reproductive aging is an emerging global health concern, projected to become the third most significant health issue in the near future, according to the World Health Organization. This complex process is driven by molecular and cellular changes, including alterations in DNA, RNA, and protein expression. Among non-coding RNAs (ncRNAs), long non-coding RNAs (lncRNAs) have been increasingly recognized for their regulatory roles in spermatogenesis and their potential contributions to aging and testicular diseases. This review examines the functions of lncRNAs in testicular biology, focusing on their gene-regulatory roles, isoform diversity, subcellular localization, and interactions with key molecular components. While research has historically prioritized protein-coding genes, the extensive ncRNA landscape suggests a broader regulatory network influencing reproductive health. Many testis-specific lncRNAs exhibit conserved sequences, modular structures, and repeat-rich elements, which contribute to their functional significance. Dysregulation of these lncRNAs has been implicated in pathological conditions such as testicular cancer, highlighting their potential as biomarkers and therapeutic targets. Understanding the dynamic roles of lncRNAs in testicular function, aging, and disease is essential for advancing reproductive medicine. This study provides insights into the complex interplay between lncRNAs and reproductive aging, emphasizing their significance in testis-specific processes and associated disorders.

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.

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.

Cortisol has been widely used as biomarker of stress and aging, but confounding effects and disruption of the hypothalamic-pituitary-adrenal axis can lead to misinterpretation of results based on a single measurement. A possible alternative is the co-measurement of cortisol and the adrenal hormone dehydroepiandrosterone-sulfate (DHEAS), a glucocorticoid antagonist that modulates the stress response. Using data from 969 individuals from the Midlife in the United States study, this study aimed to investigate the influence of age, sex, and self-identified biosocial group (SIBG) on DHEAS, cortisol, and the cortisol/DHEAS ratio, to test whether these hormones add predictive power to epigenetic age estimates, and to compare the performance of these three hormonal measures in predicting epigenetic age acceleration (EAA) using sex epigenetic clocks: Horvath, Horvath's skin & blood (Horvath2), Hannum, PhenoAge, GrimAge, and DunedinPACE. Our findings revealed that age, sex and SIBG significantly influenced all three hormonal measures. Controlling for these biodemographic factors, we found that the cortisol/DHEAS was the best predictor of epigenetic clocks. There was a significant and positive correlation between cortisol and Hannum epigenetic age, and between cortisol/DHEAS ratio in three out of the six clocks (Hannum, Horvath2, PhenoAge), but no significant associations between DHEAS and epigenetic age. The cortisol/DHEAS ratio also had a significant and positive correlation with Hannum EAA. DHEAS and cortisol were not significantly associated with EAA for any epigenetic clock. Our results reinforce the importance of co-measuring cortisol and DHEAS in studies investigating the effect of stress in aging processes.

During aging, the decline in ovarian hormone levels in women is associated with increased weight gain, fat accumulation, and alterations in the circadian timing system. Aligning eating with the activity phase improves metabolic outcomes. In contrast, misalignment entrains the circadian clock in peripheral organs and raises spontaneous locomotor activity (SLA) before mealtime. Given that ovarian estradiol (E2) modulates both metabolism and circadian function, this study aimed to investigate the role of ovariectomy (OVX) on the time-restricted (TR) feeding effects on metabolism. Two-month-old female rats underwent OVX and were fed with TR during either the light or dark phases. TR-DARK feeding did not reverse the weight and fat gain observed in OVX rats under ad libitum (AD) feeding, likely because it did not change the food intake pattern in OVX rats. Conversely, TR-LIGHT reversed the OVX-induced metabolic effects. Next, we test if OVX affects food-entrainment of circadian clocks. TR-LIGHT, regardless of OVX, abolished the peak Per1, Bmal1, Cry2, and Reverb-ɑ expression in the liver. It also increased SLA at food onset independently of OVX. In contrast, OVX elevated liver expression of Per1, Bmal1, and Cry2 at baseline (zeitgeber time, ZT1), and of Reverb-ɑ at peak (ZT6 and ZT13) compared to SHAM-AD rats. To assess the role of E2, OVX rats received a daily injection of E2 at ZT1 for 3 days, and the expression of clock genes was evaluated on the fourth day. In a different group of E2-treated OVX rats, the daily rhythm of SLA was also monitored. E2 treatment reversed the OVX-induced increase in both weight and fat gain, as well as in Per1, Bmal1, and Cry2. However, it did not affect the Reverb-α. E2 promotes an increase in SLA at ZT1 and ZT2. In conclusion, TR-DARK neither alleviates the lack of ovarian hormones in OVX-induced metabolic changes, nor do ovarian hormones participate in food-entrainment of circadian clocks. However, E2 seems to modulate clock gene expression in the liver.

Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline-features often missed by classical malnutrition criteria. We propose a unifying framework-Respond → Adapt → Resolve-to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms-including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress-that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan-via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.

Cytoskeleton-Associated Protein 4 (CKAP4) is a multifunctional protein implicated in diverse cellular processes, including cytoskeletal organization, signal transduction, and extracellular matrix remodeling. Recent studies have highlighted the dual role of CKAP4 in regulating cell growth and aging. On one hand, CKAP4 can promote cell proliferation and survival by activating signaling pathways such as PI3K/Akt, thereby delaying cellular senescence under physiological conditions. On the other hand, under chronic stress or pathological stimuli, CKAP4 may induce cell cycle arrest and accelerate aging by interacting with ligands such as antiproliferative factor (APF) and Dickkopf-1 (DKK1), leading to the upregulation of cell cycle inhibitors and the suppression of autophagy. Moreover, CKAP4 has emerged as a key mediator linking extracellular matrix remodeling to inflammatory responses, which are closely associated with age-related diseases. This review comprehensively summarizes the current understanding of CKAP4's molecular mechanisms in cell longevity and aging, discusses its involvement in inflammation and tissue homeostasis, and explores its potential as a therapeutic target for aging-related disorders.

Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.