How diet shapes aging and age-related diseases marked by senescent cell accumulation remains unclear. Here we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS ameliorates phenotypes of aging and diverse age-related disorders and extends lifespan in male mice. Integrated functional omics analyses show that senescent cells exhibit globally reduced proteome cysteine reactivity but increased expression and apparent cysteine reactivity of proteins essential for endoplasmic reticulum proteostasis. This redox–proteostasis state is linked to glutathione disulfide (GSSG) accumulation and can be recapitulated by GSSG delivery in nonsenescent cells. Mechanistically, VS inactivates reactive cysteines and promotes disulfide bond formation in senescent cells, leading to protein misfolding, aggregation and ultimately cell death. Glutathione reductase downregulation promotes GSSG accumulation, distinguishing senescent from nonsenescent cells and conferring selective susceptibility to VS. Our findings reveal an exploitable redox–proteostasis vulnerability of senescent cells with therapeutic potential to ameliorate aging. Wu, Yang, Li and colleagues identify vanadyl sulfate, a dietary supplement, as a senolytic that targets altered cysteine reactivity in senescent cells, improving age-related conditions and extending lifespan in mice.
Liang and colleagues show that, in mice, activated oocytes can persist for almost a year within ovarian secondary follicles by adopting a state of reduced biosynthetic and metabolic activity. Improved understanding of the mechanism that underpins how and when ovarian follicles persist has implications for the dynamics of female reproductive aging.
Assessing and validating circulating biomarkers is essential for developing preclinical measures of biological aging in mice. However, comprehensive serum proteomics are limited by technical challenges and low sample volumes. Here we present a quantitative nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry for deep proteomic profiling of low-volume mouse serum. This approach increased proteomic coverage by 3–6-fold with median coefficient of variation <10%. In 30 mice aged 12, 24 and 30 months, we uncovered 3,992 protein groups from 20 µl of serum and revealed age- and sex-specific changes, and capturing senescence-associated circulating proteins. With 1 µl additional serum,the proximity extension assay quantified 43 cytokines not detected by mass spectrometry. Comparison with plasma proteomics from the Baltimore Longitudinal Study of Aging identified conserved age-associated circulating proteins, several of which were linked to frailty in humans, notably COL6A3. These results establish a scalable approach for discovering aging biomarkers in sample-limited mouse studies with translational relevance to human health. To address the technically challenging task of profiling the age-associated blood proteome in sample-limited mouse studies, the authors present a quantitative nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry to identify key age-associated circulating proteins with relevance to human health.
