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Title: High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance
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.  more » « less
Award ID(s):
1661152
PAR ID:
10223459
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Date Published:
Journal Name:
Science Advances
Volume:
6
Issue:
40
ISSN:
2375-2548
Page Range / eLocation ID:
eaaz7628
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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