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Oxidative, metal, and hypoxia stresses are largely associated with these phenotypes. Whereas drug development and disease therapeutics have advanced remarkably in last 3 decades, there are still limited options for stress management. Because the latter can effectively decrease the disease burden, we performed cell-based screening of antistress compounds by recruiting 3 chemical models of oxidative (paraquat), metal (cadmium nitrate), or hypoxia (cobalt chloride) stresses. The screening of 70 compounds for their ability to offer protection against oxidative, metal, and hypoxia stresses resulted in the selection of 5 compounds: Withaferin-A (Wi-A), methoxy Withaferin-A (mWi-A), Withanone (Wi-N), triethylene glycol (TEG), and Ashwagandha (Withania somnifera) leaf M2-DMSO extract (M2DM). Molecular assays revealed that whereas stress caused increase in (a) apoptosis, (b) reactive oxygen species accumulation coupled with mitochondrial depolarization, (c) DNA double-strand breaks, and (d) protein aggregation, low nontoxic doses of the selected compounds caused considerable protection. Furthermore, Wi-N, TEG, and their mixture-treated normal human fibroblasts (at young, mature, and senescent stages representing progressively increasing accumulation of stress) showed increase in proliferation. Taken together, these results suggested 3-way (oxidative, metal, and hypoxia) antistress potential of Wi-N and TEG that may be useful for management of environmental and old-age\u2013related pathologies.<\/jats:p>","DOI":"10.1093\/gerona\/glad103","type":"journal-article","created":{"date-parts":[[2023,4,16]],"date-time":"2023-04-16T03:04:03Z","timestamp":1681614243000},"page":"1569-1577","source":"Crossref","is-referenced-by-count":5,"title":["Three-Way Cell-Based Screening of Antistress Compounds: Identification, Validation, and Relevance to Old-Age-Related Pathologies"],"prefix":"10.1093","volume":"78","author":[{"given":"Huayue","family":"Zhang","sequence":"first","affiliation":[{"name":"Graduate School of Science and Technology, University of Tsukuba , Tsukuba , Ibaraki ,","place":["Japan"]},{"name":"AIST-INDIA DAILAB, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science & Technology (AIST) , Tsukuba 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