Pioneering work in the genetically tractable organism, C. elegans, has shown that single gene mutations potently extend life span. Phyleticallly conserved endocrine systems figure prominently, revealing that aging is hormonally regulated. Notably, reduction of Insulin/IGF signaling doubles worm life span, with similar influences in flies and mice. More recently, nuclear hormone receptors (NHR), transcription factors regulated by fat soluble hormones, have emerged as regulators of development and aging in worms and flies. Our long-term goal is to understand how such endocrine systems govern these processes. In C. elegans, the NHR, DAF-12, retards reproductive development and aging. NHR and Insulin/IGF signaling somehow work together during development, and have complex interactions for life span. DAF-12's molecular identity suggests regulation by lipophilic hormones, but such hormones remain unidentified. Accordingly.our previous work identified DAF-9, a cytochrome P450 (CYP450) related to steroidogenic hydroxylases, as a proximal regulator of DAF-12, suggesting a sterol hormone controls development and aging. However, the extent of the lipophilic hormone pathway and the relationship with insulin/IGF signaling are largely unknown. The goals of this proposal are to: 1) molecularly dissect the DAF-12 lipophilic hormone pathway 2) understand how the pathway is linked to insulin/IGF signaling 3) test hormonal hypotheses of development and aging. Our preliminary RNAi screens identified 4 new genes putatively involved in hormone metabolism. We propose to characterize these genes and identify more. For the genes in hand, we will generate mutant alleles, determine larval developmental and adult aging phenotypes, and associated traits of stress resistance. We will also elucidate the cellular localization to pinpoint endocrine cells, and test regulation by insulin/IGF signaling in vivo. Finally, we will order the genes within pathways by genetic epistasis and synergy, as well as by using phenotypic rescue by lipid extracts. Further genetic screens will focus on novel genes involved in hormone metabolism, sterol transport, and transcriptional activation. Our work comprises the first broad studies of lipophilic hormone signals and their regulation of nuclear receptor biology in a key model systemfor aging. Such studies should illuminate endocrine networks in humans that control development, lipid metabolism and aging, and their dysregulation in diabetes, obesity, and cardiovascular 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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Finkelstein, David B
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Mahanti, Parag; Bose, Neelanjan; Bethke, Axel et al. (2014) Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan. Cell Metab 19:73-83
Heestand, Bree N; Shen, Yidong; Liu, Wei et al. (2013) Dietary restriction induced longevity is mediated by nuclear receptor NHR-62 in Caenorhabditis elegans. PLoS Genet 9:e1003651
Antebi, Adam (2013) Regulation of longevity by the reproductive system. Exp Gerontol 48:596-602
Magner, Daniel B; Wollam, Joshua; Shen, Yidong et al. (2013) The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans. Cell Metab 18:212-24
Wiese, Mary; Antebi, Adam; Zheng, Hui (2012) Regulation of neuronal APL-1 expression by cholesterol starvation. PLoS One 7:e32038
Shen, Yidong; Wollam, Joshua; Magner, Daniel et al. (2012) A steroid receptor-microRNA switch regulates life span in response to signals from the gonad. Science 338:1472-6
Wollam, Joshua; Magner, Daniel B; Magomedova, Lilia et al. (2012) A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity. PLoS Biol 10:e1001305
Schaedel, Oren N; Gerisch, Birgit; Antebi, Adam et al. (2012) Hormonal signal amplification mediates environmental conditions during development and controls an irreversible commitment to adulthood. PLoS Biol 10:e1001306
Wollam, Joshua; Antebi, Adam (2011) Sterol regulation of metabolism, homeostasis, and development. Annu Rev Biochem 80:885-916
Wollam, Joshua; Magomedova, Lilia; Magner, Daniel B et al. (2011) The Rieske oxygenase DAF-36 functions as a cholesterol 7-desaturase in steroidogenic pathways governing longevity. Aging Cell 10:879-84

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