High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

David B. Lombard*, William J. Kohler, Angela H. Guo, Christi Gendron, Melissa Han, Weiqiao Ding, Yang Lyu, Tsui Ting Ching, Feng Yung Wang, Tuhin S. Chakraborty, Zaneta Nikolovska-Coleska, Yuzhu Duan, Thomas Girke, Ao Lin Hsu, Scott D. Pletcher, Richard A. Miller

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

Original languageEnglish
Article numbereaaz7628
JournalScience Advances
Issue number40
StatePublished - 30 Sep 2020


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