期刊
AGING CELL
卷 20, 期 10, 页码 -出版社
WILEY
DOI: 10.1111/acel.13476
关键词
aging; complex III; diet; drosophila; intestine; intestinal permeability; leaky gut; metabolism; mitochondria; oxidative stress; superoxide
资金
- American Federation for Aging Research
- Glenn Foundation
- NIH [R01 AG045835, R56 AG038688]
- Calico Life Sciences LLC
- Larry L. Hillblom Foundation
The study demonstrates that inhibiting the production of free radicals can reduce the increase in intestinal permeability, apoptosis, and lifespan shortening in fruit flies and mice fed with high-nutrient or high-fat diets.
The underlying causes of aging remain elusive, but may include decreased intestinal homeostasis followed by disruption of the intestinal barrier, which can be mimicked by nutrient-rich diets. S3QELs are small-molecule suppressors of site IIIQo electron leak; they suppress superoxide generation at complex III of the mitochondrial electron transport chain without inhibiting oxidative phosphorylation. Here we show that feeding different S3QELs to Drosophila on a high-nutrient diet protects against greater intestinal permeability, greater enterocyte apoptotic cell number, and shorter median lifespan. Hif-1 alpha knockdown in enterocytes also protects, and blunts any further protection by S3QELs. Feeding S3QELs to mice on a high-fat diet also protects against the diet-induced increase in intestinal permeability. Our results demonstrate by inference of S3QEL use that superoxide produced by complex III in enterocytes contributes to diet-induced intestinal barrier disruption in both flies and mice.
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