Diet profoundly shapes human physiology and health, including aging and age-related diseases marked by senescent cell accumulation. However, the underlying mechanisms remain unclear. Here, we report vanadyl sulfate (VS), a mineral dietary supplement, as a senolytic agent. Oral VS extends lifespan and ameliorates phenotypes of aging and diverse age-related disorders. Integrated functional-omics analyses show that senescent cells exhibit globally reduced proteome cysteine reactivity, but upregulated expression of proteins essential for endoplasmic reticulum (ER) proteostasis, accompanied by increased apparent cysteine reactivity. This redox-proteostasis state is linked to glutathione disulfide (GSSG) accumulation that can be recapitulated by GSSG delivery in non-senescent 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 (GSR) downregulation promotes GSSG accumulation, distinguishing senescent from non-senescent cells and conferring selective susceptibility to VS. Our findings reveal an exploitable redox-proteostasis vulnerability of senescent cells with therapeutic potential to ameliorate aging.