Altered protein cysteine reactivity in senescent cells is a vulnerability for senolysis to ameliorate aging.

Rong Wu, Fan Yang, Jiacheng Li, Tong Wu, Ruitu Lyu, Junhong Xiang, Xue Gao, Rukang Zhang, Hao Fan, Chunzhao Yin, Jiayi Tu, Zhicheng Xie, Chufan Cai, Freya Q Zhang, Kelly Xue, Jeronimo Najarro, Lei Dong, Rui Su, Angelo Y Meliton, Em Lundberg, Jonah K Chen, Janane Rahbani, Nickolai O Dulin, Nicole Arellano, Jun-Wei B Hughes, Shannon E Elf, Yu-Ying He, Bruce M Bissonnette, Robert B Hamanaka, Gökhan M Mutlu, Judith Campisi, Chuan He, Jing Chen

Department of Medicine, The University of Chicago, Chicago, IL, USA. · pubmed

Paper

Abstract

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.

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Research summary

Vanadyl sulfate acts as a senolytic agent by exploiting a specific redox-proteostasis vulnerability in senescent cells, characterized by glutathione disulfide accumulation and altered cysteine reactivity, to induce cell death and extend lifespan in mice. This paper is relevant because it identifies a novel mechanism for senolysis and demonstrates that a dietary supplement can target the accumulation of senescent cells, a key driver of aging, thereby directly addressing a root cause of age-related decline rather than just treating symptoms.

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