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 #
5R01AG023166-10
Application #
8719889
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Finkelstein, David B
Project Start
2003-09-30
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
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
Shell, Brandon C; Schmitt, Rebecca E; Lee, Kristen M et al. (2018) Measurement of solid food intake in Drosophila via consumption-excretion of a dye tracer. Sci Rep 8:11536
Chung, Brian Y; Ro, Jennifer; Hutter, Sabine A et al. (2017) Drosophila Neuropeptide F Signaling Independently Regulates Feeding and Sleep-Wake Behavior. Cell Rep 19:2441-2450
Lee, Jung-Eun; Rayyan, Morsi; Liao, Allison et al. (2017) Acute Dietary Restriction Acts via TOR, PP2A, and Myc Signaling to Boost Innate Immunity in Drosophila. Cell Rep 20:479-490
Gendron, Christi M; Pletcher, Scott D (2017) MicroRNAs mir-184 and let-7 alter Drosophila metabolism and longevity. Aging Cell 16:1434-1438
Ro, Jennifer; Pak, Gloria; Malec, Paige A et al. (2016) Serotonin signaling mediates protein valuation and aging. Elife 5:
Xie, Zhongyu; Zhang, Di; Chung, Dongjun et al. (2016) Metabolic Regulation of Gene Expression by Histone Lysine ?-Hydroxybutyrylation. Mol Cell 62:194-206
Harvanek, Zachary M; Mourão, Márcio A; Schnell, Santiago et al. (2016) A computational approach to studying ageing at the individual level. Proc Biol Sci 283:
Wong, Jenny-Marie T; Malec, Paige A; Mabrouk, Omar S et al. (2016) Benzoyl chloride derivatization with liquid chromatography-mass spectrometry for targeted metabolomics of neurochemicals in biological samples. J Chromatogr A 1446:78-90
Waterson, Michael J; Chan, Tammy P; Pletcher, Scott D (2015) Adaptive Physiological Response to Perceived Scarcity as a Mechanism of Sensory Modulation of Life Span. J Gerontol A Biol Sci Med Sci 70:1088-91
Ro, Jennifer; Harvanek, Zachary M; Pletcher, Scott D (2014) FLIC: high-throughput, continuous analysis of feeding behaviors in Drosophila. PLoS One 9:e101107

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