Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.72410
Keywords
crotamiton derivative; lifespan; OSM-9; proteostasis; C; elegans
Categories
Funding
- National Natural Science Foundation of China [22037002]
- Shanghai Institutions of Higher Learning
- Natural Science Foundation of Shanghai [21ZR1416700]
- Innovation Program of Shanghai Municipal Education Commission [2021 01 07 00 02 E00104]
- Chinese Special Fund for State Key Laboratory of Bioreactor Engineering [2060204]
- Program for Professor of Special Appointment
- Natural Science Foundation of Shanghai
- Innovation Program of Shanghai Municipal Education Commission
- Chinese Special Fund for Special Key Laboratory of Bioreactor Rngineering
- [TP2018025]
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This study discovered a new small molecule derived from crotamiton, named JM03, which exhibits antioxidant, anti-hypertonic, and anti-aging effects. JM03 extends the lifespan of C. elegans by modulating the OSM-9 and SKN-1 signaling pathways.
While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects.
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