Our analysis of gene expression changes during Drosophila aging reveals down- regulation of mitochondrial genes and induction of innate immune response, oxidative stress response, and proteotoxicity response. We will test the hypothesis that sexual differentiation inhibits mitochondrial turnover, and this synergizes with mitochondrial mutations to cause an accumulation of abnormal mitochondria that promote the mitochondrial unfolded protein response (UPRmt), inflammation and aging. We test conserved genes including p53, the dosage compensation (DC) machinery, and dopamine signaling. The methods include florescent transgenic reporter constructs, high-throughput sequencing of mitochondrial genomes and cell 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 for the trade-off between reproduction and life span, including the DC machinery, p53 and small molecules.
AIM 2 addresses mechanisms for cell-specific patterns of aging in oenocytes (liver-like cells), including the UPRmt, MnSOD and mitochondrial mutations. These studies may yield a model system for disease-causing mitochondrial heteroplasmy and mutations in humans.
AIM 3 tests possible mechanisms for sex-specific effects of p53 on life span, including autophagy. If successful this research may identify mechanisms for mitochondrial maintenance failure during aging that are (partly) conserved with 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)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-CB-T (02)M)
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Fridell, Yih-Woei
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University of Southern California
Schools of Arts and Sciences
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
Pomatto, Laura C D; Wong, Sarah; Tower, John et al. (2018) Sex-specific adaptive homeostasis in D. melanogaster depends on increased proteolysis by the 20S Proteasome: Data-in-Brief. Data Brief 17:653-661
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