Biogerontology最新文献

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.

Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies. We showed that CBD extended the period of locomotor activity in a dose-dependent manner, suggesting its influence on the circadian clock. Additionally, CBD improved sleep quality and extended lifespan under starvation conditions. The study also revealed enhanced rhythmicity in Close Proximity (CP) rhythm and increased eggs reproduction with dietary CBD supplementation. Furthermor, CBD attenuates age-related motor dysfunction in wild-type and Parkinson's disease (PD) model in Drosophila. These findings strongly suggest that appropriate amount of CBD affects the circadian rhythms, sleep, life span, CP rhythm, egg reproduction and motor function of Drosophila melanogaster, and providing a basic data for exploring its potential applications in managing circadian-related disorders in other animals.

Cognitive aging, a pivotal domain at the intersection of neuroscience and psychology, exhibits a strong association with neurodegenerative disorders; however, its comprehensive underlying mechanisms remain incompletely elucidated. This review aims to provide a thorough synthesis of recent advancements in the investigation of cognitive aging in the brain, highlighting multidimensional assessment techniques, neurobiological foundations, molecular regulatory pathways, systemic changes, environmental-gene interactions, and intervention strategies. Evidence suggests that cognitive aging is marked not only by widespread neuronal loss but also by subtle modifications within neural networks, protein homeostasis, mitochondrial functionality, and epigenetic regulation. The integration of various technological methodologies has shed light on the continuum that exists between cognitive aging and neurodegenerative disorders. Concurrently, multidimensional intervention strategies are being proposed; however, current research frameworks face challenges due to limitations in biomarker systems, indicating a need for a paradigm shift. Future investigations should leverage emerging technologies to develop more precise regulatory frameworks and personalized intervention strategies aimed at addressing the global challenges associated with aging, thereby enhancing the prevention and treatment of related pathologies.

Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms, the underlying driver of period change is more general. We show that it arises from an inherent property of a positively skewed frequency distribution, which naturally follows from a symmetric Gaussian distribution of intrinsic periods. Using a Kuramoto framework with a time-dependent coupling strength and age-related widening of period variability, we map the geometry of synchronization and macroscopic period and trace a developmental trajectory across this surface. Strong coupling in early adulthood pulls the synchronized period below the mean, matching data from C57BL/6 mice, whereas declining coupling and greater heterogeneity in late life lengthen the period and reduce amplitude. The same mechanism explains the negative correlation between amplitude and macroscopic period when period variability is high. This "circadian geometry" reveals that age-dependent variations in the macroscopic period are sufficiently explained by coupling and the width of the period distribution, and provides a parsimonious framework applicable to the SCN and other oscillator populations for understanding long-term changes in circadian dynamics during development and aging.

The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.