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

Year: 2026
Type: article
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.
Source: Nature Aging
DOI: 10.1038/s43587-026-01253-5
Authors: 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
Institutions: University of Chicago, Shanghai Medical College of Fudan University, Fudan University, The University of Texas Southwestern Medical Center, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, University of Utah, Buck Institute for Research on Aging
Language: English
Subfield: Cell Biology
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: University of Chicago, Westlake University, University of Tokyo, National Institutes of Health, Ludwig Center at Harvard, National Heart, Lung, and Blood Institute, National Human Genome Research Institute
OpenAlex ID: W7225389363
FWCI:
Cites: 100
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Related to: 10