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

• Published in: G3 : genes - genomes - genetics Vol. 10; no. 2; pp. 849 - 862
• Main Authors: Zhang, Peichuan, Zhai, Yuying, Cregg, James, Ang, Kenny Kean-Hooi, Arkin, Michelle, Kenyon, Cynthia
• Format: Journal Article
• Language: English
• Published: United States Genetics Society of America 01.02.2020; Oxford University Press
• Subjects: aging; Aging - drug effects; Aging - genetics; Aging - metabolism; Animals; Biomarkers; c. elegans; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - physiology; Cell Line; Computational Biology - methods; Drug Discovery; Drug Screening Assays, Antitumor; Gene Expression Profiling; Humans; Investigations; Longevity - drug effects; Molecular Imaging; nrf2; oxidative stress; Oxidative Stress - drug effects; Signal Transduction - drug effects; Small Molecule Libraries; small molecule screen; stress resistance; Stress, Physiological - drug effects; Stress, Physiological - genetics; Transcriptome; wi-38; stress resistance; C. elegans; NRF2; Small molecule screen; WI-38; aging; oxidative stress
• ISSN: 2160-1836; 2160-1836
• DOI: 10.1534/g3.119.400618

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 ' 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, / and / , 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.