Dietary restriction (DR) provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. Reduction of nutrients in the diet by DR not only extends lifespan but also protects against a number of age related diseases including neurodegeneration, cancer, diabetes and cardiovascular diseases. It is therefore likely that investigation of the molecular mechanisms underlying DR will promote a greater understanding of the pathogenesis of various human age related diseases and help advance the development of therapeutics for these disorders. Due to their short lifespan and ease of genetic manipulation;invertebrate models continue to be useful as models for understanding aging and disease. Our laboratory has previously identified the nutrient sensing TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway now appears to play a conserved role in lifespan extension in yeast, worms, flies and mice. We have previously demonstrated that 4E-BP (eukaryotic initiation factor 4E binding protein) plays a key role in mediating lifespan extension by DR. We have also described the genome-wide translational changes that result from DR using a method that combines polysomal profiling with microarrays. Using this method we have identified a subset of mRNAs that are preferentially translated upon DR, despite a decrease in global translation which included genes involved in mitochondrial functions, protein folding, fat metabolism and calcium signaling [1]. We have shown that upon DR there is an increase in mitochondrial function which is required for the DR mediated longevity. We hypothesize that the increase in mitochondrial function is part of a metabolic switch towards enhanced fatty acid metabolism which extends lifespan in the fly. We observe that enhanced fat metabolism increases muscle activity which plays a critical role in lifespan extension upon DR. Here we address the mechanisms by which changes in fat metabolism and increased muscle activity play a causal role in mediating the lifespan extension effects due to DR. Our findings will have a significant impact on understanding the role of nutrition in aging and age related diseases in humans. We wish to comprehensively address the mechanism of DR in D. melanogaster by addressing the following specific aims: 1) To characterize the role of fat metabolism in lifespan extension upon DR. 2) To investigate the mechanisms by which enhanced fat turnover enhances activity and extends lifespan upon DR and 3) To examine the role of fat metabolism and enhanced activity in lifespan extension in long-lived strains. We believe that understanding the basic process of DR by conserved signaling pathways in D. melanogaster will help unravel some of the mysteries of aging and age-related diseases in humans.

Public Health Relevance

Dietary restriction is the most robust environmental method of lifespan extension in various species and has been shown to protect against various age related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the mechanism by which muscle activity and fat metabolism mediate the lifespan extension effects by dietary restriction using Drosophila. Our findings will have a significant effect on understanding the role of the target of rapamycin (TOR) pathway and nutrition in aging and age related diseases in humans. )

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038688-03
Application #
8523727
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2011-09-30
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$442,598
Indirect Cost
$214,454
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
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Chaudhuri, Jyotiska; Bose, Neelanjan; Gong, Jianke et al. (2016) A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive α-Dicarbonyl Detoxification. Curr Biol 26:3014-3025
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Luis, Nuno Miguel; Wang, Lifen; Ortega, Mauricio et al. (2016) Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction. Cell Rep 17:1207-1216
Kumar, Jitendra; Barhydt, Tracy; Awasthi, Anjali et al. (2016) Zinc Levels Modulate Lifespan through Multiple Longevity Pathways in Caenorhabditis elegans. PLoS One 11:e0153513
Laye, Matthew J; Tran, ViLinh; Jones, Dean P et al. (2015) The effects of age and dietary restriction on the tissue-specific metabolome of Drosophila. Aging Cell 14:797-808
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Chi, Thomas; Kim, Man Su; Lang, Sven et al. (2015) A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease. PLoS One 10:e0124150
Kaul, Tiffany K; Reis Rodrigues, Pedro; Ogungbe, Ifedayo V et al. (2014) Bacterial fatty acids enhance recovery from the dauer larva in Caenorhabditis elegans. PLoS One 9:e86979
Katewa, Subhash D; Khanna, Amit; Kapahi, Pankaj (2014) Mitobolites: the elixir of life. Cell Metab 20:8-9

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