Fmo induction as a tool to screen for pro-longevity drugs.

Autor: Huang S; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA. shijiaoh@ksu.edu., Cox RL; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Tuckowski A; Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109, USA., Beydoun S; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Bhat A; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Howington MB; Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, 48109, USA., Sarker M; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Miller H; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Ruwe E; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Wang E; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA., Li X; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 316048109-2200, USA., Gardea EA; Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA., DeNicola D; Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA., Peterson W; Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA., Carrier JM; Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA., Miller RA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, 316048109-2200, USA.; University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA., Sutphin GL; Department of Molecular & Cellular Biology, University of Arizona, Tucson, AZ, 85721, USA., Leiser SF; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA. leiser@umich.edu.; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA. leiser@umich.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2024 Oct; Vol. 46 (5), pp. 4689-4706. Date of Electronic Publication: 2024 May 24.
DOI: 10.1007/s11357-024-01207-y
Abstrakt: Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds.
(© 2024. The Author(s), under exclusive licence to American Aging Association.)
Databáze: MEDLINE
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