Metabolic Signatures of Life Span Regulated by Mating, Sex Peptide, and Mifepristone/RU486 in Female Drosophila melanogaster

Metabolic Signatures of Life Span Regulated by Mating, Sex Peptide, and Mifepristone/RU486 in Female Drosophila melanogaster

Abstract Mating and transfer of male sex peptide (SP), or transgenic expression of SP, causes inflammation and decreased life span in female Drosophila. Mifepristone rescues these effects, yielding dramatic increases in life span. Here targeted metabolomics data were integrated with further analysis...

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Published in:The journals of gerontology. Series A, Biological sciences and medical sciences Vol. 76; no. 2; pp. 195 - 204
Main Authors: Landis, Gary N, Doherty, Devon V, Yen, Chia-An, Wang, Lu, Fan, Yang, Wang, Ina, Vroegop, Jonah, Wang, Tianyi, Wu, Jimmy, Patel, Palak, Lee, Shinwoo, Abdelmesieh, Mina, Shen, Jie, Promislow, Daniel E L, Curran, Sean P, Tower, John
Format: Journal Article
Language:English
Published: US Oxford University Press 01-02-2021
Subjects:
Amino acids
Drug therapy
Ecdysone
Evolutionary conservation
Gene expression
Immune response
Juvenile hormones
Kynurenic acid
Life expectancy
Life span
Lipids
Metabolism
Metabolomics
Methoprene
Midgut
Mifepristone
Peptides
Protein turnover
Sexual intercourse
THE JOURNAL OF GERONTOLOGY: Biological Sciences
Tryptophan
Uric acid
Aging
1/3-methylhistidine
Urate
Juvenile hormone
Kynurenine pathway
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Summary:Abstract Mating and transfer of male sex peptide (SP), or transgenic expression of SP, causes inflammation and decreased life span in female Drosophila. Mifepristone rescues these effects, yielding dramatic increases in life span. Here targeted metabolomics data were integrated with further analysis of extant transcriptomic data. Each of 7 genes positively correlated with life span were expressed in the brain or eye and involved regulation of gene expression and signaling. Genes negatively correlated with life span were preferentially expressed in midgut and involved protein degradation, amino acid metabolism, and immune response. Across all conditions, life span was positively correlated with muscle breakdown product 1/3-methylhistidine and purine breakdown product urate, and negatively correlated with tryptophan breakdown product kynurenic acid, suggesting a SP-induced shift from somatic maintenance/turnover pathways to the costly production of energy and lipids from dietary amino acids. Some limited overlap was observed between genes regulated by mifepristone and genes known to be regulated by ecdysone; however, mifepristone was unable to compete with ecdysone for activation of an ecdysone-responsive transgenic reporter. In contrast, genes regulated by mifepristone were highly enriched for genes regulated by juvenile hormone (JH), and mifepristone rescued the negative effect of JH analog methoprene on life span in adult virgin females. The data indicate that mifepristone increases life span and decreases inflammation in mated females by antagonizing JH signaling downstream of male SP. Finally, mifepristone increased life span of mated, but not unmated, Caenorhabditis elegans, in 2 of 3 trials, suggesting possible evolutionary conservation of mifepristone mechanisms.
ISSN:1079-5006
1758-535X
DOI:10.1093/gerona/glaa164