期刊
AGING CELL
卷 12, 期 1, 页码 121-129出版社
WILEY
DOI: 10.1111/acel.12027
关键词
aging; Drosophila; endocrinology; genetics; insulin; IGF-1signaling; longevity; neuroscience; signaling
资金
- Ellison Medical Foundation
- NIH National Institute on Aging [R01 AG037962]
Ubiquitously reduced signaling via Methuselah (MTH), a G-protein-coupled receptor (GPCR) required for neurosecretion, has previously been reported to extend life and enhance stress resistance in flies. Whether these effects are due to reduced MTH signalling in specific tissues remains unknown. We determined that reduced expression of mth targeted to the insulin-producing cells (IPCs) of the fly brain was sufficient to extend life and enhance oxidative stress resistance. Paradoxically, we discovered that overexpression of mth targeted to the same cells has similar phenotypic effects to reduced expression due to MTH's interaction with beta-arrestin, which uncouples GPCRs from their G-proteins. We confirmed the functional relationship between MTH and beta-arrestin by finding that IPC-targeted overexpression of beta-arrestin alone mimics the longevity phenotype of reduced MTH signaling. As reduced MTH signaling also inhibits insulin secretion from the IPCs, the most parsimonious mechanistic explanation of its longevity and stress-resistance enhancement might be through reduced insulin/IGF signaling (IIS). However, examination of phenotypic features of long-lived IPC-mth modulated flies as well as several downstream IIS targets implicates enhanced activity of the JNK stress-resistance pathway more directly than insulin signaling in the longevity and stress-resistance phenotypes.
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