Biogerontology最新文献

Homeostatic systems (nervous, immune, and endocrine) are crucial for maintaining health throughout life and, consequently, relevant for the rate of aging and the longevity achieved. In many species, male and female mammals show different lifespans, attributed to distinct redox states, but it is scarcely known whether sex differences in the functioning of these systems are involved. This study investigated, in an integrative view, sex differences in the nervous and immune systems of Swiss strain mice by analyzing behavior, immune function, and redox biomarkers across aging, to determine whether possible sex differences in homeostatic systems affect longevity. A longitudinal study was conducted on 20 female and male Swiss mice. At their young (2 mon), adult (7 mon), and old (18 mon) ages, subjects were subjected to a battery of behavioral tests, and peritoneal leukocytes were extracted to assess immune function and redox biomarkers. The natural deaths of animals were recorded for a longevity study. Our results indicate that sexual differences begin at a young age, and several are maintained until old age. Females, in general, show better behavior, immune function, and redox biomarkers, contributing to their higher longevity compared to males. The enhanced longevity in females may be attributable, in part, to the preservation of robust immune competence, with emphasis on innate immune functions and lower oxidative stress. The integration of behavioral and immunological profiles, together with redox biomarkers, underscores the critical importance of incorporating both sex as a biological variable in the design of aging-related research.

Healthspan, the disease-free period of life, has become a central focus in aging research. Cuscuta chinensis seed and Eucommia ulmoides bark extracts, two traditional Chinese medicine (TCM) remedies, have shown promising healthspan-extending effects in Caenorhabditis elegans. In this study, RNA-seq analysis of aged worms treated with these extracts revealed significant transcriptomic alterations. Gene ontology and KEGG pathway analyses indicated upregulation of genes involved in immune defense, lysosomal function, and protein homeostasis, which may underlie the shared phenotype of enhanced stress resistance and lifespan extension. Beyond these effects, C. chinensis further improved multiple health parameters. Consistent with its broad spectrum of phenotypes, C. chinensis induced extensive transcriptomic remodeling involving over 3000 differentially expressed genes. Modulating collagen-, unc-, and muscle-related genes may explain improved locomotion, while upregulation of mec genes could contribute to enhanced mechanosensation. Notably, far-3, encoding a fatty acid- and retinol-binding protein, was upregulated more than 150-fold, and RNA interference assays demonstrated that FAR-3 is necessary for C. chinensis-induced healthspan improvement. Furthermore, C. chinensis influenced genes linked to antagonistic pleiotropy and insulin-like signaling, suggesting a systemic, hormesis-driven reprogramming of aging processes. Together, these findings uncover both shared and distinct molecular mechanisms through which C. chinensis and E. ulmoides promote healthspan in C. elegans.

The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised > 35% to youthful levels. Our results suggest miRNAs upregulated with age to downregulate proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results suggest miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity as well as the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein-coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in cultured C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide novel information regarding how miRNA expression changes in skeletal muscle, as well as the potential functional consequences of these changes and how they are ameliorated by CR.

Age-related functional decline has emerged as a major challenge to human health and societal development. Safe and effective anti-aging interventions, particularly those involving natural products, offer promising strategies to delay aging and promote healthy longevity. In this study, we used Caenorhabditis elegans (C. elegans) models to investigate the anti-aging effects and underlying mechanisms of Liu Jun Zi Decoction (LJZD), a traditional Chinese herbal formula. The results showed that LJZD extended lifespan and enhanced stress resistance and locomotion in C. elegans. Serum pharmacochemistry, network pharmacology, and molecular docking identified key bioactive compounds that target the IIS/mTOR and p16/p21 pathways. Furthermore, we found that LJZD promoted longevity by improving mitochondrial function via the IIS-mTOR axis. Notably, LJZD also conferred neuroprotection in Aβ-/tau-expressing models. These findings provide mechanistic insights into multi-target herbal interventions for aging and neurodegeneration.

Cellular and molecular mechanisms that drive a perturbed wound microenvironment and impaired healing in aged skin have not been fully delineated. To obtain a comprehensive understanding of cell-intrinsic changes acquired during ageing that impact early responses to injury, we performed single-cell RNA sequencing in young and aged intact female murine skin and wounds 3 days post-injury. We observed that substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged, but not young, tissues accompany a global increase in basal inflammation. This is driven by an altered signalling environment leading to impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we show that ageing-induced changes in skin resident cells persist after injury, resulting in increased expression of senescence-related genes in wound fibroblasts and aberrant monocyte-to-macrophage transitioning coupled to an enhanced inflammatory signature and defective intercellular signalling in comparison to wounds in young mice. In summary, our data highlights a contribution of both cell-intrinsic changes and an altered tissue microenvironment to poor wound healing responses in aged mice.

One of the key hallmarks of aging is the breakdown of proteostasis-the finely tuned balance of protein synthesis, folding, trafficking, and degradation that maintains proteome integrity and cellular function. In this study, we employed ¹⁵N metabolic labeling to assess protein turnover in young and aged mice. Among the proteins examined, cystatin C exhibited the largest age-related reduction in turnover, alongside decreases in other proteins involved in neuroprotection, structural stability, and neurotransmission, including transthyretin, proteolipid protein 1, and the astrocytic glutamate transporter SLC1A3. Reduced proteostatic capacity is likely to increase neuronal susceptibility to proteotoxic stress, protein aggregation, and excitotoxic injury. Immunohistochemical analysis revealed a punctate accumulation of cystatin C in cortical layer IV, a region particularly vulnerable to age-related pathology. Moreover, gene expression profiling showed region-specific upregulation of inflammatory markers (Cd11b, Fcgr1, and Cr3), suggesting enhanced degradation of brain structures through phagocytic activity. Together, these findings demonstrate that aging disrupts proteostasis in a protein- and region-specific manner, with cystatin C emerging as a central mediator linking impaired clearance to neuroinflammation and cortical vulnerability. Interventions aimed at enhancing autophagy, proteasome function, or chaperone activity may represent promising strategies to counteract proteostasis collapse and mitigate neurodegeneration in the aging brain.

Aging is a complex process that includes chronological aging and cellular aging. Although chronological aging is irreversible, cellular aging, which is reversible, is closely associated with chronological aging. Understanding the complexity of the impact and mechanisms of aging on the male reproductive function is crucial in maintaining male fertility. This study reviews the effects and mechanisms associated with aging in males on male reproductive health. It also provides potential therapeutic strategies for alleviating the reproductive consequences of aging in males. Evidence from the literature revealed that aging suppresses testicular steroidogenesis and circulating testosterone, lowers spermatogenesis and sperm quality, and induces erectile dysfunction. These adverse events are mediated by mitochondrial dysfunction and reduced ATP production, oxidative stress, inflammation, apoptosis, and DNA damage. More so, telomere shortening, cellular senescence, and epigenetic modification play crucial roles. Modulation of these processes with antioxidants such as vitamin C, vitamin E, CoQ10, and zinc attenuates cellular aging and promotes male reproductive health.

Aging reduces testicular function by lowering sperm quality and testosterone, worsened by diseases. Morphine addiction harms male reproduction by disrupting hormonal balance and increasing testicular oxidative stress and inflammation. Regular physical exercise can help counteract these effects by boosting antioxidants and supporting sperm production. This study explores how exercise mitigates inflammaging and testosterone decline by modulating the NF-κB signaling pathway in aged male rats with morphine addiction. A total of 56 male Wistar rats were divided into eight groups, with four groups for each age category (young and old). The experimental groups were as follows: 1) Control, 2) Trained, 3) Addicted, and 4) Trained + Addicted. Rats in the addicted groups received morphine treatment for 28 days, while the trained groups underwent treadmill exercise sessions for 4 weeks. The gene expression levels of NF-κB and Nrf2 in testis tissue were quantified using RT-PCR. Additionally, the concentrations of the cytokines TNF-α and IL-10 were measured in testis tissue by ELISA. Furthermore, the levels of MDA, TAC, and testosterone were assessed using specific assay kits. Our results demonstrated that morphine exposure in both young and old rats significantly decreased IL-10, TAC, and testosterone levels, while it increased TNF-α, MDA, and NF-κB gene expression. Exercise in both young and old groups resulted in a reduction of NF-κB gene expression, as well as decreased levels of TNF-α and MDA. Additionally, exercise increased testosterone, interleukin-10, and total antioxidant capacity in both serum and testicular tissue. Our results demonstrated that exercise mitigates testicular impairments following morphine exposure in young and old rats via reducing inflammation and oxidative stress while increasing testosterone levels and modulating NF-κB expression.

To verify whether DNA repair is regulated by FOXO3a, a tet-on flag-h-FOXO3a transgenic mice were used. RT-q-PCR and western blot analysis showed that the mRNA and protein levels of flag-h-FOXO3a, XRCC4, XPC, APE1 and MSH2 increased dose dependently by doxycycline. DNA repair activities like non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) also increased in a doxycycline dose dependent manner. MEF (mouse embryonic fibroblast) cells of the transgenic mouse were transfected with human XRCC4/XPC/APE1/MSH2 promoter-pGL3 basic vectors. Promoter assay and ChIP (chromatin immunoprecipitation) assay showed increased promoter activity and interactions of FOXO3a to FOXO consensus sites. The results indicate that XRCC4, XPC, APE1, and MSH2 are transcriptional target genes of FOXO3a and activities of NHEJ, NER, BER and MMR are regulated probably via transcriptional activation of XRCC4, XPC, APE1 and MSH2 by FOXO3a. FOXO3a overexpression in MEF cells and tet-on flag-h-FOXO3a transgenic mouse exhibited high resistance to gamma radiation. Small intestine showed less damage and apoptosis in doxycycline-treated mice. The median and maximum lifespan of the doxycycline-treated transgenic mice increased by about 30%. The results suggest that FOXO3a overexpression provide protection against gamma radiation and lifespan extension possibly via activation of DNA repair.