Altered protein cysteine reactivity in senescent cells is a vulnerability for senolysis to ameliorate aging
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.
Authors
- Judith Campisi (ORCID: https://orcid.org/0000-0001-6858-9462)
- Ruitu Lyu (ORCID: https://orcid.org/0000-0003-4597-1604)
- Jeronimo Najarro (ORCID: https://orcid.org/0009-0001-2600-7871)
- Marc Bissonnette (ORCID: https://orcid.org/0000-0001-8420-4294)
- Chufan Cai (ORCID: https://orcid.org/0000-0001-6209-0820)
- Janane F. Rahbani (ORCID: https://orcid.org/0000-0003-4598-4683)
- Tong Wu (ORCID: https://orcid.org/0000-0001-9968-9909)
- Rong Wu (ORCID: https://orcid.org/0000-0001-6091-8364)
- Zhicheng Xie (ORCID: https://orcid.org/0009-0003-3990-0508)
- Jiacheng Li (ORCID: https://orcid.org/0000-0003-3730-3534)
- Jun‐Wei B. Hughes (ORCID: https://orcid.org/0000-0003-1887-0242)
- Freya Q. Zhang (ORCID: https://orcid.org/0000-0002-2596-0433)
- Hao Fan (ORCID: https://orcid.org/0000-0001-5245-9698)
- Jiayi Tu (ORCID: https://orcid.org/0000-0002-2626-0084)
- Nickolai O. Dulin (ORCID: https://orcid.org/0000-0001-6096-5822)
- Nicole Arellano (ORCID: https://orcid.org/0000-0003-1618-0467)
- Robert B. Hamanaka (ORCID: https://orcid.org/0000-0002-8909-356X)
- Junhong Xiang (ORCID: https://orcid.org/0000-0002-6556-4435)
- Lei Dong (ORCID: https://orcid.org/0000-0001-9574-0148)
- Chuan He (ORCID: https://orcid.org/0000-0003-4319-7424)
- Shannon Elf (ORCID: https://orcid.org/0000-0002-8845-3818)
- Jing Chen (ORCID: https://orcid.org/0000-0002-5376-9062)
- Chunzhao Yin
- Angelo Y. Meliton
- Yu-Ying He
- Em Lundberg
- Xue Gao
- Gökhan M. Mutlu
- Rukang ZHANG
- Rui Su
- Jonah K. Chen
- Fan Yang
- Kelly Xue
Institutions
- City Of Hope National Medical Center (US)
- Buck Institute for Research on Aging (US)
- University of Utah (US)
- University of Chicago (US)
- City of Hope (US)
- Beckman Research Institute (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2026-11-06
- DOI
- https://doi.org/10.1038/s43587-026-01253-5
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Chicago
- Westlake University
- University of Tokyo
- National Institutes of Health
- Ludwig Center at Harvard