Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate

Lifestyles including dietary choices have a major impact on shaping of human physiology and health, including aging. However, the underlying mechanisms remain largely unknown. Here, we use a blood nutrient compound library-based screening approach to demonstrate that vanadyl sulfate (VS), a mineral dietary supplement, selectively induces cell death in senescent cells, thus extends lifespan and ameliorates phenotypes of aging and age-related disorders in vivo. Integrated functional omics strategies including activity-based protein profiling reveal that senescent cells accumulate glutathione disulfide, leading to overall reduced cysteine reactivity of the proteome but elevated cysteine reactivity of proteins that are crucial for endoplasmic reticulum (ER) proteostasis, which licenses VS to effectuate senolysis. VS inactivates reactive cysteines on proteins to form incorrect disulfide bonds, causing aberrant protein misfolding and aggregation that sabotage ER proteostasis, leading to senescent cell death. Our findings uncover a unique vulnerability of senescent cells for therapeutic exploration to treat aging and age-related disorders.