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Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan

Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small mol...

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Autores principales: Zhang, Peichuan, Zhai, Yuying, Cregg, James, Ang, Kenny Kean-Hooi, Arkin, Michelle, Kenyon, Cynthia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003076/
https://www.ncbi.nlm.nih.gov/pubmed/31879284
http://dx.doi.org/10.1534/g3.119.400618
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author Zhang, Peichuan
Zhai, Yuying
Cregg, James
Ang, Kenny Kean-Hooi
Arkin, Michelle
Kenyon, Cynthia
author_facet Zhang, Peichuan
Zhai, Yuying
Cregg, James
Ang, Kenny Kean-Hooi
Arkin, Michelle
Kenyon, Cynthia
author_sort Zhang, Peichuan
collection PubMed
description Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened ∼100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans’ stress resistance, and at least 9 extended their lifespan by ∼10–50%. We further evaluated a chalcone that produced relatively large effects on lifespan and were able to implicate the activity of two, stress-response regulators, NRF2/skn-1 and SESN/sesn-1, in its mechanism of action. Our findings suggest that screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds may reveal new ways to extend healthy human lifespan.
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spelling pubmed-70030762020-02-14 Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan Zhang, Peichuan Zhai, Yuying Cregg, James Ang, Kenny Kean-Hooi Arkin, Michelle Kenyon, Cynthia G3 (Bethesda) Investigations Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened ∼100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans’ stress resistance, and at least 9 extended their lifespan by ∼10–50%. We further evaluated a chalcone that produced relatively large effects on lifespan and were able to implicate the activity of two, stress-response regulators, NRF2/skn-1 and SESN/sesn-1, in its mechanism of action. Our findings suggest that screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds may reveal new ways to extend healthy human lifespan. Genetics Society of America 2019-12-26 /pmc/articles/PMC7003076/ /pubmed/31879284 http://dx.doi.org/10.1534/g3.119.400618 Text en Copyright © 2020 Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigations
Zhang, Peichuan
Zhai, Yuying
Cregg, James
Ang, Kenny Kean-Hooi
Arkin, Michelle
Kenyon, Cynthia
Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title_full Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title_fullStr Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title_full_unstemmed Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title_short Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans’ Lifespan
title_sort stress resistance screen in a human primary cell line identifies small molecules that affect aging pathways and extend caenorhabditis elegans’ lifespan
topic Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003076/
https://www.ncbi.nlm.nih.gov/pubmed/31879284
http://dx.doi.org/10.1534/g3.119.400618
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