For a broad range of taxonomically diverse organisms, nutrient availability acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. In mammals, longevity through diet restriction is accompanied by a broad-spectrum improvement in health during aging. We and others have used genetic and environmental manipulations in invertebrate model systems to establish that nutrient- mediated longevity is a regulated response that activates specific neurons and that involves neuroendocrine systems targeting conserved pathways in peripheral tissues. These target pathways have since been manipulated in mammalian systems to improve longevity or other health-related phenotypes, which reinforces the effectiveness of simple model systems for aging research. Nevertheless, the development of successful human interventions requires a much better mechanistic understanding of how neuronal inputs are integrated and how critical metabolic processes implement the changes that underlie the effects of diet-restriction. In this renewal, we build upon the results from the parent award to continue our dissection of the molecular mechanisms of DR. First, neuronal control of the DR response will be examined by elucidating the mechanisms through which a newly described gene that we call ponchik modulates obesity, feeding behavior, and longevity. We will also take advantage of a completed genetic screen to identify new modulators of dietary restriction that act exclusively in the fly brain. Second, we have discovered that the transsulfuration pathway (TSP), which controls the metabolism of sulfur-containing amino acids, actively promotes survival and metabolic homeostasis in response to nutritional and hormonal signals. We will test a model involving the TSP as an energy sensor that affects protein synthesis, xenobiotic and antioxidative responses, and the production of key signaling molecules that promote health and longevity, specifically under conditions of dietary restriction. The contributions of this project are two-fold. First, we will continue to elucidate the basic principles of how aging is controlled by the nervous system. Second, we will determine how the evolutionarily conserved process of transsulfuration promotes lifespan and influences energy balance. These contributions are significant because understanding the molecular details of how nutrient- and energy-sensitive neural circuits direct changes in peripheral tissues to alter lipid metabolism, behavior, and overall lifespan in a complex organism will illuminate basic principles of aging that can be applied to develop novel intervention strategies in human aging.

Public Health Relevance

Dietary restriction is the most potent way to extend lifespan and ameliorate aging-related disease in mammals. Our studies will identify how diet orchestrates changes in the brain and throughout different tissues in the fruit fly, Drosophila melanogaster, to influence health and aging. Because the focus of our work is on biological processes that are evolutionarily conserved, our discoveries will illuminate mammalian studies in these areas and foster new ideas for medical intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023166-08
Application #
8310982
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Finkelstein, David B
Project Start
2003-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$306,407
Indirect Cost
$109,361
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Waterson, Michael J; Chung, Brian Y; Harvanek, Zachary M et al. (2014) Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling. Proc Natl Acad Sci U S A 111:8137-42
Ro, Jennifer; Harvanek, Zachary M; Pletcher, Scott D (2014) FLIC: high-throughput, continuous analysis of feeding behaviors in Drosophila. PLoS One 9:e101107
Ostojic, Ivan; Boll, Werner; Waterson, Michael J et al. (2014) Positive and negative gustatory inputs affect Drosophila lifespan partly in parallel to dFOXO signaling. Proc Natl Acad Sci U S A 111:8143-8
Piper, Matthew D W; Blanc, Eric; Leitao-Goncalves, Ricardo et al. (2014) A holidic medium for Drosophila melanogaster. Nat Methods 11:100-5
Gendron, Christi M; Kuo, Tsung-Han; Harvanek, Zachary M et al. (2014) Drosophila life span and physiology are modulated by sexual perception and reward. Science 343:544-8
Kuo, Tsung-Han; Yew, Joanne Y; Fedina, Tatyana Y et al. (2012) Aging modulates cuticular hydrocarbons and sexual attractiveness in Drosophila melanogaster. J Exp Biol 215:814-21
Kabil, Hadise; Kabil, Omer; Banerjee, Ruma et al. (2011) Increased transsulfuration mediates longevity and dietary restriction in Drosophila. Proc Natl Acad Sci U S A 108:16831-6
Linford, Nancy J; Kuo, Tsung-Han; Chan, Tammy P et al. (2011) Sensory perception and aging in model systems: from the outside in. Annu Rev Cell Dev Biol 27:759-85
Poon, Peter C; Kuo, Tsung-Han; Linford, Nancy J et al. (2010) Carbon dioxide sensing modulates lifespan and physiology in Drosophila. PLoS Biol 8:e1000356
Pletcher, Scott D (2009) The modulation of lifespan by perceptual systems. Ann N Y Acad Sci 1170:693-7

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