Sex bias in human disease is common, however underlying mechanisms remain unclear. Women have immune advantage relative to men, but also greater auto-immune disease and Alzheimer's Disease. Women's immune advantage is modulated by pregnancy and correlates with escape from X-chromosome inactivation of several key immune regulatory genes. In Drosophila females, mating and male Sex Peptide cause increased reproduction but also inflammation and shortened life span. We have shown that these effects can be reversed by feeding the human drug mifepristone/RU486, yielding +70% increase in median life span, and correlated with altered X-linked gene expression, metabolic re-programming, and altered microbiome. We will test the hypothesis that female reproductive metabolism makes mitochondria more susceptible to bacterial toxins, thereby reducing healthspan and life span. We test conserved genes and pathways, including catecholamine signaling, cholesterol metabolism, and the role of specific microbial metabolites. Methods include florescent transgenic reporter constructs, high- throughput sequencing of microbial genomes and fly transcriptomes, 3D video tracking of fly gene expression and behavior, and testing conserved genes and small molecules for ability to increase life span and reduce inflammation.
AIM 1 investigates mechanisms including signaling pathway genes and small molecules.
AIM 2 investigates metabolome regulation, and AIM 3 identifies the relevant microbe(s) and metabolites. If successful this research will identify mechanisms for female-specific aging that might be partly conserved in humans, and may identify promising genetic targets and drugs for sex- specific interventions in human inflammation and aging-related disease.

Public Health Relevance

We are using the laboratory fruit fly Drosophila to test the hypothesis that sexual differentiation inhibits the long-term maintenance of tissues, and thereby promotes aging and disease. These studies may identify promising drugs to test for human diseases such as Parkinson?s disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Guo, Max
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University of Southern California
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Los Angeles
United States
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Pomatto, Laura C D; Tower, John; Davies, Kelvin J A (2018) Sexual Dimorphism and Aging Differentially Regulate Adaptive Homeostasis. J Gerontol A Biol Sci Med Sci 73:141-149
Li, Zewei; Lyu, Runhe; Tower, John (2018) Models of Replicator Proliferation Involving Differential Replicator Subunit Stability. Orig Life Evol Biosph 48:331-342
Tower, John; Landis, Gary N; Shen, Jie et al. (2017) Mifepristone/RU486 acts in Drosophila melanogaster females to counteract the life span-shortening and pro-inflammatory effects of male Sex Peptide. Biogerontology 18:413-427
Pomatto, Laura C D; Wong, Sarah; Carney, Caroline et al. (2017) The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster. Aging (Albany NY) 9:1153-1185
Tower, John (2017) Sex-Specific Gene Expression and Life Span Regulation. Trends Endocrinol Metab 28:735-747