Insulin signaling regulates aging in many organisms, including the fruit fly Drosophila melanogaster. The adult fly produces four insulin like peptides (DILP) in specialized neurons of the brain. Knocking out these neurons extends lifespan, as do systemic mutations of the insulin signal transduction system. Activated insulin receptor represses the transcription factor FOXO. FOXO is thus thought to be a key modulator of the insulin control of lifespan and as expected its overexpression extends fly lifespan. This renewal aims to understand how particular insulin peptides work through a single insulin receptor to direct FOXO to genes that regulate aging. It will identify which of the adult insulin is most responsible for control of aging by knocking out each insulin encoding gene individually and in combination. Through the method of chromatin immunoprecipitation and full genome microarray analysis it will identify the genes that are directly regulated by FOXO when low insulin signaling slows aging. It will test the relevance of pathways involving these genes in the control of aging by conducting epistasis tests between their loss-of-function genotypes and insulin signaling mutants. Finally, the project will use a very unique resource of synthetic, recombinant Drosophila insulin peptides DILP1, DILP2 and DILP5 to study how these proteins individually and together affect signal transduction and FOXO targeting in a fly cell culture system. Together these studies will discover how specific insulin like peptides modulate aging through their control of FOXO.

Public Health Relevance

The work proposed in this renewal aims to understand how the several different insulin like proteins of Drosophila work to regulate aging and alternatively, metabolism. It will use new, advanced genetic methods to individually knockout each of the fly's insulin genes and study how this affects life span. It will also study how each of these insulin proteins controls the binding of the essential transcription factor FOXO to downstream genes and test whether these specific genes are required for reduced insulin signaling to slow aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Guo, Max
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Brown University
Schools of Medicine
United States
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Post, Stephanie; Karashchuk, Galina; Wade, John D et al. (2018) Drosophila Insulin-Like Peptides DILP2 and DILP5 Differentially Stimulate Cell Signaling and Glycogen Phosphorylase to Regulate Longevity. Front Endocrinol (Lausanne) 9:245
Zheng, Wenjing; Rus, Florentina; Hernandez, Ana et al. (2018) Dehydration triggers ecdysone-mediated recognition-protein priming and elevated anti-bacterial immune responses in Drosophila Malpighian tubule renal cells. BMC Biol 16:60
Lin, Feng; Hossain, Mohammed Akhter; Post, Stephanie et al. (2017) Total Solid-Phase Synthesis of Biologically Active Drosophila Insulin-Like Peptide 2 (DILP2). Aust J Chem 70:208-212
Kang, Ping; Chang, Kai; Liu, Ying et al. (2017) Drosophila Kruppel homolog 1 represses lipolysis through interaction with dFOXO. Sci Rep 7:16369
Post, Stephanie; Tatar, Marc (2016) Nutritional Geometric Profiles of Insulin/IGF Expression in Drosophila melanogaster. PLoS One 11:e0155628
Bowman, Elizabeth; Tatar, Marc (2016) Reproduction regulates Drosophila nutrient intake through independent effects of egg production and sex peptide: Implications for aging. Nutr Healthy Aging 4:55-61
Tatar, Marc; Sedivy, John M (2016) Mitochondria: Masters of Epigenetics. Cell 165:1052-1054
Bai, Hua; Post, Stephanie; Kang, Ping et al. (2015) Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP. PLoS One 10:e0134415
Tatar, Marc; Post, Stephanie; Yu, Kweon (2014) Nutrient control of Drosophila longevity. Trends Endocrinol Metab 25:509-17
Ding, Feifei; Gil, M Pilar; Franklin, Michael et al. (2014) Transcriptional response to dietary restriction in Drosophila melanogaster. J Insect Physiol 69:101-6

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