RT Journal Article
SR Electronic
T1 High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaaz7628
DO 10.1126/sciadv.aaz7628
VO 6
IS 40
A1 Lombard, David B.
A1 Kohler, William J.
A1 Guo, Angela H.
A1 Gendron, Christi
A1 Han, Melissa
A1 Ding, Weiqiao
A1 Lyu, Yang
A1 Ching, Tsui-Ting
A1 Wang, Feng-Yung
A1 Chakraborty, Tuhin S.
A1 Nikolovska-Coleska, Zaneta
A1 Duan, Yuzhu
A1 Girke, Thomas
A1 Hsu, Ao-Lin
A1 Pletcher, Scott D.
A1 Miller, Richard A.
YR 2020
UL http://advances.sciencemag.org/content/6/40/eaaz7628.abstract
AB 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.