Biogerontology最新文献

The hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, synchronizing peripheral clocks through oscillations in core clock genes and proteins. Circadian disruption contributes to immunosenescence, aging, and neurodegenerative disorders such as Parkinson's disease (PD). Previous work from our group demonstrated age-related changes in circadian rhythms of clock genes, protein levels, and serotonin metabolism in the SCN and substantia nigra (SN) of male Wistar rats. This study examined the age of onset for circadian misalignment in clock (rBmal1, rCry1, rCry2, rPer1, rPer2), immune (rCox2, rIl1β, rIl4, rTgfβ1), and PD-associated (rLrrk2, rPark2, rPark7, rSnca) genes in SCN and SN. Male Wistar rats aged 3 (adult), 12 (middle-aged), and 24 (aged) months were studied. In SCN, rPark2 decreased and rSnca increased in 12 months and 24 months, while rCry1 and rPer2 were elevated in 12 months. Rhythmicity of rTgfβ1 declined in 24 months. In SN, rBmal1 rhythmicity was abolished in 24 months, while rPark2 lost rhythmicity in 12 months and 24 months. rSnca and rIl1β were elevated in 24 months. Misalignments in rCry1, rPer2, rIl4, rIl1β, rTgfβ1, and rLrrk2 in SCN, and rCry2, rIl4, rLrrk2, rPark2, and rSnca in SN appeared by middle age. A ketogenic diet intervention (KDI) resulted in modulation of rhythmic expression of rPer2, rSnca, rCry1, rTgfβ1, and rPark2 in SCN and improved rPark2, rSnca, and rIl1β in SN. These findings indicate that translationally, circadian misalignment in PD-related genes emerges early, suggesting its potential as a biomarker for preclinical PD. Moreover, dietary strategies such as KDI highlight promising non-pharmacological approaches to preserve circadian integrity, delay neurodegeneration, and guide personalized interventions in at-risk individuals.

Myostatin and follistatin are the regulators of muscle growth and pivotal proteins that regulate muscle tissue function. An integrated approach is HIIT and resistance training provides a holistic strategy for promoting healthy aging and maintaining functional abilities, potentially through the modulation of myostatin and follistatin levels. This study aims to assess the effect of high-intensity interval training and resistance training on myostatin and follistatin protein concentrations in aged rats' serum and muscle tissue. In this study, 20-month-old female Sprague-Dawley rats were used in three groups: (1) Control (Con), (2) Resistance training (RT), and (3) High-intensity interval training (HIIT). The HIIT and resistance training protocols were carried out for 8 weeks and three sessions per week. The results showed serum levels and muscle tissue content of myostatin increased in the RT compared to the control group (p = 0.0001 and p = 0.04). The muscle tissue content of follistatin increased in the HIIT compared to the control group (p = 0.03). There is a significant difference in serum levels and muscle tissue content of follistatin between HIIT and RT groups (p = 0.0001 and p = 0.001). According to the roles of myostatin and follistatin in regulating muscle hypertrophy, present research shows HIIT has more effects on follistatin levels and resistance training has more effects on myostatin levels. This can indicate that according to the number of training sessions, HIIT can be a better and newer treatment method for older people.

Extracellular vesicles (EVs) contribute to the maintenance of organism-wide proteostasis by mediating intercellular communication. Loss of proteostasis and altered intercellular communication are associated with aging and age-related diseases, suggesting key roles for EVs. However, it is unclear how the proteome of the EVs changes with age. To identify EV-associated proteins (EVAPs) and their fate with age, we curated publicly available EV proteome data from C. elegans model organism and human. Our analysis reveals that EVs carry proteins with diverse functions, including those involved in protein quality control. We found that abundance of the EVAPs changes significantly with age, heat stress, pathogen infections and diseases. Many of these EVAPs also aggregate with age and overlap with Aβ-driven protein aggregates. Further, we identified human orthologs of C. elegans EVAPs from human brain tissues affected with Alzheimer's disease and breast cancer. This meta-analysis highlights EVs proteome composition, their abundance changes, and aggregation during aging, stress, infection and disease conditions. Overall, this study provides new insights into the dynamics of EV proteins during aging and may possibly help in identifying potential biomarkers for age-related diseases.

The SARS-CoV-2 pandemic has affected millions worldwide, with aging being a key risk factor for severe disease outcomes. This study examines the rate of epigenetic aging, as measured by DNA methylation-based aging markers, in COVID-19 patients versus healthy individuals. We found that PCGrimAge, a next-generation epigenetic clock associated with immune dysregulation and inflammation, showed the strongest correlation with the chronological age of the European COVID-19 patients. Several other next-generation epigenetic clocks, including PCGrimAge, DunedinPACE, and ZhangY2017, also exhibited accelerated aging in both older and female COVID-19 patients. Interestingly, first-generation clocks, such as Hannum2013, indicated a significant reduction in epigenetic aging, likely reflecting limitations in their sensitivity to infection-related biological changes rather than an actual deceleration of the aging process. Our results also showed that immune dysregulation, rather than intrinsic cellular aging, may be the primary driver of accelerated epigenetic aging in COVID-19. This is supported by stronger associations observed in Age Acceleration (AA) and Extrinsic Epigenetic Age Acceleration (EEAA) compared to Intrinsic Epigenetic Age Acceleration (IEAA). Furthermore, immune dysregulation may be linked to CpG site demethylation, which in turn influences epigenetic clock dynamics. We also identified disparities between European and non-European populations, characterized by significantly higher IEAA for PCPhenoAge and DunedinPACE among non-European patients with COVID-19. In summary, our results underscore the differential sensitivity of epigenetic clocks to COVID-19-related biological changes.

Amyloid-β (Aβ) plaques are one of the primary biomarkers of Alzheimer's Disease (AD). Other publications have reported various mechanisms regarding the clearance of Aβ, and recent studies have also investigated the relationship between daily rhythms of Aβ and AD. The intent of this study was to determine if the circadian rhythm of Aβ differed between a region that was more vulnerable to AD-related pathology (the olfactory bulbs; OB) compared to a region that is less vulnerable (the cerebellum; CER). We chose to utilize an APPxPS1 knock-in (KI) mouse strain as this strain expresses amyloid precursor protein (APP) and Aβ under control of its normal promoter as opposed to AD transgenic models that overexpress APP and, as a consequence, Aβ. Mice (N = 128, equally divided between male and female, wild type and KI) were acclimated to a 12:12 light cycle for two weeks, and tissue was collected over a 24-h period in constant darkness. Using a unique immunoassay designed to measure human or rodent Aβ side-by-side, we confirmed a robust circadian Aβ rhythm in the mouse brain and that the OB contains more overall Aβ accumulation than the CER. The circadian Aβ rhythm was not present in the OB of the KI as compared to the WT mice. In contrast, the Aβ rhythm in the CER did not differ between genotypes. These results suggest that the loss of Aβ rhythm in disease-affected brain regions may be associated with the development of AD pathology and could have important implications for therapy.

Bone marrow exhibits functional decline, yet cellular heterogeneity and molecular mechanisms remain unclear due to limitations of traditional research methods. This study aims to characterize age-related changes and identify key drivers in bone marrow. Integrated multi-omics analysis was performed using scRNA-seq, proteomics, pseudo-bulk transcriptomics, weighted gene co-expression network analysis (WGCNA)-based transcription factor (TF) network modeling, and CellChat analysis. Samples included 6 young and aged bone marrow specimens. Statistical validation involved differential expression analysis, Cox regression modeling, and receiver operating characteristic (ROC) curve analysis. A novel hematopoietic subpopulation (3.19% of aged samples) was identified, activating the cellular senescence pathway (KEGG) and enhancing inflammatory crosstalk with CD8⁺ T cells via NMU signaling (|avg_log2FC|> 0.58, p < 0.001). Pseudo-bulk and proteomic analyses identified CAPN1, MAP2K1, and JUND as potential signal modules. Immunohistochemistry and Western blot confirmed their co-expression, while molecular docking revealed interaction interfaces. In two independent bulk-RNA cohorts (n = 58), a Cox model based on the CAPN1-MAP2K1-JUND module showed robust predictive value for aging, with AUCs of 0.7507 (p = 0.0154) and 0.90 (p = 0.0274). This study identifies a pivotal molecular module linking single-cell dynamics to tissue-level senescence in bone marrow, providing new insights into aging mechanisms and potential therapeutic targets.

High-intensity interval training (HIIT) is capable of reversing many aging-related metabolic differences in the proteome, but studies using proteomics to investigate the mechanism of the effects of HIIT on hepatic metabolic function in aged rats have not been reported. In this study, we investigated the effects of 8 months of HIIT on mitochondrial oxidative function, oxidative stress, and inflammation in the liver of aged rats, and further explored the possible mechanisms of the metabolic effects of HIIT in aged rats by proteomics. The results of the study revealed that HIIT improved liver morphology, enhanced mitochondrial oxidative function, decreased inflammation and apoptosis levels, increased intrahepatic antioxidant function and inhibited ferroptosis in aged rats. Proteomics showed that HIIT altered changes in glycine, serine and threonine metabolic pathways in the liver, and further use of targeted amino acid metabolomics revealed that HIIT markedly increased glycine and serine content in aged livers. In vitro cells demonstrated that exogenous glycine supplementation significantly enhanced the intracellular antioxidant capacity of oxidatively stressed hepatocytes, while decreasing the level of inflammatory factor expression and significantly inhibiting the occurrence of ferroptosis. Our findings suggest that the improvement of metabolic function in aged liver tissue by HIIT may be associated with elevated glycine content, and that glycine within aged livers elevated by HIIT may mediate the maintenance of metabolic homeostasis within liver tissue.

Aging may be conceptualized as a wound that fails to heal, characterized by persistent, unresolved inflammation. Building on Ogrodnik's "unhealed wound" model, this Perspective extends the Exposure-Related Malnutrition (ERM) framework to propose a bioenergetic interpretation of aging. ERM links chronic stress adaptation, nutrient misallocation, and mitochondrial insufficiency to sustained bioenergetic debt that impedes the transition from catabolic containment to anabolic repair. Across tissues, this energetic shortfall manifests as metabolic inflexibility, lipid-droplet accumulation, and a continuum of adaptive mitochondrial dysfunction that remains reversible until the threshold of senescence-the terminal stage of unresolved adaptation. Recognizing bioenergetic availability as the principal determinant of regenerative success reframes mitochondrial dysfunction and senescence not as primary causes of aging but as downstream consequences of chronic energetic exhaustion. Within this continuum, aging reflects a progressive loss of rhythmic catabolic-anabolic cycling that supports metabolic adaptation. Transient metabolic stress normally induces hormetic activation followed by anabolic recovery, but when this oscillation fails, adaptive hormesis gives way to maladaptive exhaustion. Aging thus emerges from the erosion of bioenergetic rhythm-a transition from recovery with renewal to endurance without repair.

Aging involves progressive accumulation of molecular and cellular damage, leading to functional decline and increased susceptibility to age-related diseases. Natural low-molecular-weight geroprotectors are substances of plant and food origin capable of modulating key mechanisms of aging. Based on current scientific data, sixteen fundamental mechanisms of aging are analyzed, and compounds from food that demonstrate potential in slowing age-related changes are presented. Special attention is paid to the mechanisms of action of these substances at the molecular and cellular levels, as well as their availability in common food products. This review summarizes the current understanding of the interaction between natural nutrients and fundamental aging processes and opens perspectives for developing dietary strategies for healthy longevity.

Vocal fold fibroblasts play an important role in the production of the extracellular matrix in the vocal folds. Myofibroblasts increase in the aging vocal fold lamina propria with increased alpha-smooth muscle actin. In addition to alpha-smooth muscle actin, various sarcomeric genes are expressed in myofibroblasts. However, there have been no studies on sarcomeric genes with myofibroblast differentiation in aging vocal folds. The purpose of this study was to analyze the changes and functions of sarcomeric genes related to myofibroblast differentiation in aging vocal folds using next-generation sequencing (NGS). Young (6-month-old, 22 rats) and old (22-month-old, 22 rats) male Sprague-Dawley rats were used for this study. NGS was performed on the harvested lamina propria of the vocal folds in each group. NGS data were analyzed using functional annotation, gene ontology, network pathways, and network analysis methods. After identifying the increased expression of sarcomeric genes in aging vocal folds, we evaluated the expression of sarcomeric genes in the normal human vocal fold lamina propria removed after surgery for various vocal fold lesions. The functions of sarcomeric genes in fibroblast senescence, proliferation, differentiation, contraction, and stiffness were investigated. Among the four sarcomeric genes identified through network cluster analysis of the NGS results, the expression levels of myosin light chain kinase 2 (Mylk2) and myomesin 2 (Myom2) were significantly higher in the lamina propria of old rats than in young rats. The increase in Mylk2 and Myom2 expression was associated with cellular senescence but not with the proliferative ability of fibroblasts. However, the expression of Mylk2 and Myom2 increased with myofibroblast differentiation. Inhibition of Mylk2 and Myom2 affects cellular contraction, leading to reduced stiffness. Our results suggest that Mylk2 and Myom2 are novel biomarkers of vocal fold myofibroblasts and are involved in the regulation of vocal fold stiffness in aging rats and humans.