Microbial diets and their metabolites can influence host aging, yet identifying geroprotective compounds from complex culture matrices remains challenging. Here, a diet supplemented with the human gut-derived Enterococcus faecium SI194 extended the mean lifespan of Caenorhabditis elegans by 23.24%, improved aging-associated phenotypes, and enhanced SKN-1-responsive signaling. No lifespan extension was detected in skn-1(zu67) mutants, consistent with the involvement of SKN-1. To prioritize metabolites for independent phenotypic evaluation, we integrated untargeted metabolomics with structure-based virtual screening against glycogen synthase kinase-3 (GSK-3), a negative regulator of SKN-1. Among 71 structurally annotated features enriched in the OP50-SI194 liquid-culture preparation, the feature annotated as obtusifolin had the most favorable Vina docking score. A single 100-ns molecular dynamics trajectory supported the conformational persistence of the modeled GSK-3-Obt complex under the simulated conditions. Exogenous obtusifolin (Obt; 30μM) extended mean lifespan by 14.55%, reduced DCFH-DA-derived fluorescence and age-associated intestinal autofluorescence, and increased gst-4p::GFP fluorescence. These findings support the geroprotective effects of the SI194-supplemented diet and exogenous Obt as distinct interventions and illustrate the workflow's utility for candidate prioritization. Future studies should clarify Obt's contribution to SI194-associated lifespan extension and its relationship with SKN-1 and GSK-3.
Heat shock factors (HSF1 and HSF2) maintain proteostasis under stress, yet their activation across the continuum of rising temperatures is incompletely understood. Furthermore, how age impacts thermally driven rheostatic changes in stress responses is not fully elucidated. Here, we investigate how different temperature levels impact HSF1 and HSF2 in Jurkat T cells and splenocytes from young and aged mice. Using Western blotting, EMSA, RT-qPCR, immunofluorescence, and co-immunoprecipitation, we examined heat shock response changes across a range of thermal conditions. Unlike most cell types that require 42°C for HSF1 activation, Jurkat cells maximally responded at 41°C and splenocytes at 40°C. Optimal HSF1 activation coincided with maximal nuclear translocation, Ser326 phosphorylation, SIRT1 protein levels, and HSP RNA levels. By contrast, HSF2 nuclear translocation required a higher temperature (42°C) than HSF1. Age reduced HSF1 protein levels and nuclear translocation during thermal stress, while HSF2 protein levels were significantly elevated. These findings reveal distinct temperature-sensitive patterns of HSF1 and HSF2 activation of immunocytes during heat stress and identify age-associated alterations in this response.
Background Psychological stress and health behaviors are associated with oxidative status and telomere biology, but evidence from multidomain interventions in breast cancer survivors remains limited. Objective To evaluate the effects of the Pythagorean Self-Awareness Intervention (PSAI) on biological, behavioral, and psychosocial outcomes following breast cancer treatment. Methods In this randomized controlled trial, 120 women were randomized to an eight-week PSAI program or education-only control condition (n = 60 each); 118 were included in the modified intention-to-treat analysis. Primary biological outcomes were serum total oxidant status and PBMC relative telomere T/S ratio. Linear mixed-effects models estimated group × time effects, between-group differences in change, 95% confidence intervals (CIs), and Hedges’ g. Results Total oxidant status decreased more in the intervention group (difference in change, −3.83 μmol/L; 95% CI −7.03 to −0.63; p = 0.020; g = −0.13). Telomere-length change did not differ significantly between groups (−0.170 log₂[T/S] units; 95% CI −0.554–0.214; p = 0.382; g = −0.23). PSAI also improved physical activity, body weight, sleep, perceived stress, anxiety, and depression. Conclusion PSAI improved total oxidant status and several patient-relevant outcomes but did not significantly affect telomere-length change. Longer, adequately powered trials with repeated biomarker assessments are required.
Atherosclerotic cardiovascular disease remains a leading global cause of the cardiovascular mortality burden, yet traditional lipid-centric models fail to explain the residual cardiovascular risk observed in older populations. This review, synthesising contemporary literature from 2020 onwards alongside foundational studies, explores the paradigm shift towards the 'geroscience hypothesis', positing that intrinsic biological ageing of the vascular wall is a potent amplifier and primary driver of atherogenesis acting in synergy with circulating lipids. We delineate a pathogenic triad: cellular senescence, systemic inflammaging, and epigenetic dysregulation. At the cellular level, mechanical and metabolic stressors force endothelial and vascular smooth muscle cells into a usually stable senescent state, triggering the Senescence-Associated Secretory Phenotype. Immunologically, ASCVD in the elderly is driven by metabolically exhausted macrophages, the emergence of clonal haematopoiesis of indeterminate potential, and cytotoxic memory T cells. Crucially, metabolic stressors such as hyperglycaemia induce long-lasting alterations to the chromatin landscape of haematopoietic stem cells, establishing 'trained immunity' and a persistent pro-inflammatory metabolic memory. These processes are deeply governed by an altered epigenetic landscape, including the loss of protective sirtuins and aberrant RNA methylation, which dynamically accelerate biological clocks like GrimAge. Clinically, vascular ageing trajectories are highly sexually dimorphic and heavily influenced by midlife metabolic clustering and endocrine shifts and murine models suggest highly sexually dimorphic plaque immunophenotypes. Finally, we evaluate the translational frontier of precision senotherapeutics. We contrast senomorphics, such as repurposed metformin and natural polyphenols that suppress the SASP, with targeted senolytics. Emerging nanotechnology—including in vivo CAR-T lipid nanoparticles and responsive peptide nanoassemblies—offers preclinical proof-of-concept strategies to selectively clear senescent cells without systemic toxicity. Ultimately, mitigating ASCVD requires moving beyond lipid management to integratively target the biological clock of the artery.
