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

doi:10.1126/sciadv.aaz7628

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 journal › Article › peer-review

13 Scopus citations

Abstract

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 language	English
Article number	eaaz7628
Journal	Science Advances
Volume	6
Issue number	40
DOIs	https://doi.org/10.1126/sciadv.aaz7628
State	Published - 30 Sep 2020

Access to Document

10.1126/sciadv.aaz7628

Cite this

Lombard, D. B., Kohler, W. J., Guo, A. H., Gendron, C., Han, M., Ding, W., Lyu, Y., Ching, T. T., Wang, F. Y., Chakraborty, T. S., Nikolovska-Coleska, Z., Duan, Y., Girke, T., Hsu, A. L., Pletcher, S. D., & Miller, R. A. (2020). High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance. Science Advances, 6(40), Article eaaz7628. https://doi.org/10.1126/sciadv.aaz7628

@article{e1b1c9f2e80e4974ab6794ac1287127c,

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

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).",

year = "2020",

month = sep,

day = "30",

doi = "10.1126/sciadv.aaz7628",

language = "English",

volume = "6",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "40",

}

Lombard, DB, Kohler, WJ, Guo, AH, Gendron, C, Han, M, Ding, W, Lyu, Y, Ching, TT, Wang, FY, Chakraborty, TS, Nikolovska-Coleska, Z, Duan, Y, Girke, T, Hsu, AL, Pletcher, SD & Miller, RA 2020, 'High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance', Science Advances, vol. 6, no. 40, eaaz7628. https://doi.org/10.1126/sciadv.aaz7628

TY - JOUR

T1 - High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance

AU - Lombard, David B.

AU - Kohler, William J.

AU - Guo, Angela H.

AU - Gendron, Christi

AU - Han, Melissa

AU - Ding, Weiqiao

AU - Lyu, Yang

AU - Ching, Tsui Ting

AU - Wang, Feng Yung

AU - Chakraborty, Tuhin S.

AU - Nikolovska-Coleska, Zaneta

AU - Duan, Yuzhu

AU - Girke, Thomas

AU - Hsu, Ao Lin

AU - Pletcher, Scott D.

AU - Miller, Richard A.

N1 - Publisher Copyright: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2020/9/30

Y1 - 2020/9/30

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85092677543&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aaz7628

DO - 10.1126/sciadv.aaz7628

M3 - Article

C2 - 33008901

AN - SCOPUS:85092677543

SN - 2375-2548

VL - 6

JO - Science Advances

JF - Science Advances

IS - 40

M1 - eaaz7628

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this