RT Journal Article
SR Electronic
T1 High throughput small molecule screening reveals NRF2-dependent and - independent pathways of cellular stress resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 778548
DO 10.1101/778548
A1 Lombard, David B.
A1 Kohler, William
A1 Guo, Angela H.
A1 Gendron, Christi
A1 Han, Melissa
A1 Ding, Weiqiao
A1 Lyu, Yang
A1 Li, Xinna
A1 Shi, Xiaofang
A1 Nikolovska-Coleska, Zaneta
A1 Duan, Yuzhu
A1 Girke, Thomas
A1 Hsu, Ao-Lin
A1 Pletcher, Scott D.
A1 Miller, Richard A.
YR 2019
UL http://biorxiv.org/content/early/2019/09/22/778548.abstract
AB Biological aging is the dominant risk factor for most chronic diseases. Development of anti-aging 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 C. elegans. Transcriptomic analysis implicated Nrf2 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Molecules that conferred stress resistance also induced cellular inflammatory pathways, and other core pathways such as AMPK signaling. Small molecules identified in this work may represent attractive candidates to evaluate for their potential pro-health and pro-longevity effects in mammals.