Biogerontology最新文献

Aging not only significantly reduces the quality of life for the elderly but also poses multifaceted challenges to society. Its progression involves the synergistic interaction of multidimensional, multipathway molecular mechanisms, including mitochondrial dysfunction, oxidative stress accumulation, chronic inflammation, and genomic damage. Quercetagetin (QG), as a natural flavanol monomer, exhibits significant potential in anti-aging due to its simultaneous targeting of key aging pathways such as oxidative stress and chronic inflammation. We first evaluated QG's safety profile, finding that 0.02 mg/ml QG did not adversely affect motility, feeding, growth, and reproductive capacity in Caenorhabditis elegans (C. elegans). At this concentration, in vivo experiments using wild-type C. elegans confirmed QG's ability to extend lifespan and enhance oxidative stress resistance. The antioxidant and anti-aging effects of QG were further validated using the daf-16 mutant C. elegans DR26. Subsequently, observation of QG's impact on C. elegans mitochondrial morphology revealed significant reductions in area/perimeter and mitochondria coverage ratio following treatment. This indicates that QG treatment shifts the mitochondrial network from fusion toward fission and reduces overall mitochondrial content. QG can also improve age-related dopaminergic, 5-hydroxytryptaminergic and cholinergic neuron degeneration. Mass spectrometry metabolome analysis revealed that QG significantly affected citrate cycle and glycerophospholipid metabolism. Collectively, QG extends C. elegans lifespan by regulating redox homeostasis, DAF-16/FOXO pathways, mitochondrial homeostasis and metabolic reprogramming. This multi-target regulatory capacity positions QG as an ideal candidate molecule for anti-aging drug development.

This two part study on the afferent connectivity of lumbar spinal motor neurons in normal ageing mice investigates; Study 1: time course analysis of age-related changes in the synaptic coverage of lumbar spinal cords of male C57BL/BJ mice at 4,15,18 and 24 months of age and Study 2: the effect of long term 8-month resistance wheel exercise (RWE) on lumbar spinal cords of male C57BL/6J mice exercised from 15 to 23 months of age. Uniquely, each study used spinal cords obtained from the same mice that had previously been analysed for changes in skeletal muscles and sciatic nerves in a parallel series of time course and exercise studies. Input to presumed alpha motor neurons was investigated by quantifying VGLUT1 immunoreactive synaptic contacts known to be derived from proprioceptive muscle afferents. Here we found no significant changes in the percentage of synaptic VGLUT1 coverage of motor neurons from 4 to 24 months. Importantly, this differs from our previous results (Krishnan et al., Biogerontology 19:385-399, 2018) where there was about 50% decrease in VGLUT1 innervation of motor neurons in older mice aged 27 months, indicating a rapid deterioration in proprioceptive feedback in late ageing. In the exercise study, 8 months of voluntary wheel running (beginning at 15 months), had no impact on VGLUT1 synaptic connectivity in spinal cords, consistent with our previous report of no effect on peripheral nerves obtained from this same ageing and exercised cohort of mice. Nonetheless there was a significant amount of sarcopenia in these animals. Overall, these studies highlight the variable impact of ageing on different motor-related tissues.

An accumulation of senescent cells within tissues is a hallmark of the aging process. Cellular senescence is associated with an increased level of cytosolic dsDNA which primarily originates from a leakage of mitochondrial DNA (mtDNA) and a loss of genomic DNA integrity. Cytosolic dsDNA is an important alarming factor for cytosolic dsDNA sensors which trigger the remodeling of the immune system through diverse signaling pathways. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) signaling is a major defence mechanism induced by an accumulation of cytosolic dsDNA in senescent cells. The cGAS-STING pathway stimulates immune responses via the interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB)-driven pathways. The activation of cGAS-STING signaling in senescent cells generates pleiotropic immune responses in a context-dependent manner. For instance, cGAS-STING signaling induces proinflammatory responses by enhancing the secretion of cytokines, chemokines, and colony-stimulating factors. The secretion of many chemokines and colony-stimulating factors can remodel hematopoiesis and enhance thymic involution with aging. Moreover, cGAS-STING signaling promotes proinflammatory responses by stimulating the NLRP3 inflammasomes. On the other hand, cGAS-STING signaling aids in the resolution of inflammation by recruiting immunosuppressive cells into tissues and suppressing the pathogenic activity of T helper 17 cells. In addition, an increased cGAS-STING signaling in senescent cells stimulates the expression of inhibitory immune checkpoint ligands, such as PD-L1, and thus prevents their elimination by immune cells. Recent studies have clearly revealed that cGAS-STING signaling not only induces cellular senescence but it can also promote the aging process.

While immune system involvement in aging is increasingly recognized, causal relationships between specific immune cell populations and biological aging indicators remain unclear. We aimed to identify immune targets influencing aging trajectories to inform future immunomodulatory interventions. We conducted two-sample Mendelian randomization (MR) analysis using immunophenotype GWAS data (3,757 Sardinian participants) and aging phenotype statistics (PhenoAgeAccel: n = 107,460; BioAgeAccel: n = 98,446). Analysis employed IVW methodology with sensitivity analyses including weighted median estimation, MR-Egger regression, MR-PRESSO, and Cochran's Q statistic. Significance was determined using False Discovery Rate (FDR) correction (P_FDR < 0.05). After FDR correction, seventeen immune cell phenotypes showed significant associations with PhenoAgeAccel: two cDCs, one monocyte subtype, ten myeloid cells, three TBNK cells, and one Treg population. Key findings included protective effects of FSC-A on granulocyte (β = -0.24, 95% CI:-0.37 to -0.10, P_FDR = 1.81 × 10^-2) and risk associations of CD14⁺ CD16^- monocyte (β = 0.41, 95% CI:0.24-0.58, P_FDR = 6.84 × 10^-4). Among TBNK cells, CD8⁺ T cell (β = 0.32, 95% CI: 0.16-0.47, P_FDR = 6.44 × 10^-3) and CD28^- CD8⁺ T cell (β = 0.40, 95% CI: 0.23-0.58, P_FDR = 8.14 × 10^-4) emerged as risk factors. For BioAgeAccel, four phenotypes showed suggestive relationships, with Unswitched Memory B Cell showing the strongest protective effect (β =  - 0.32, 95% CI:-0.52 to-0.12, p = 1.75 × 10^-3). Our study revealed causal relationships between specific immune cell phenotypes and biological aging acceleration, identifying potential therapeutic targets for age-modulation and suggesting immune signatures as crucial regulators in aging-related processes.

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.