Dietary restriction (DR), or reduced food intake without malnutrition, is highly beneficial in a variety of experimental organisms using a number of endpoints, including glucose homeostasis, acute stress resistance and longevity. While energy restriction is commonly thought to the key to a successful DR regimen, a small but growing body of literature points to the dominant role of nutrient restriction. Long-term restriction of dietary methionine, an essential amino acid, results in increased lifespan, health span and acute stress resistance in experimental rodents. Although the phenotype resembles that of DR, it occurs in the absence of energy restriction. The benefits of methionine restriction are thought to involve perturbation of one or more methionine-requiring pathways, such as DNA methylation or glutathione biosynthesis. Our preliminary data indicate that short-term restriction of dietary methionine improves glucose homeostasis and stress resistance within as little as six days. Importantly, we have also found that restriction of two other essential amino acids - tryptophan and leucine - lend similar benefits. We hypothesize that restriction of any essential amino acid will rapidly trigger changes in animal physiology resulting in improved glucose homeostasis and increased stress resistance.
Our aim i s to elucidate relevant upstream amino acid sensing pathways and downstream effectors of oxidative stress resistance with the ultimate goal of translating these benefits to the clinic.

Public Health Relevance

Long-term methionine restriction increases lifespan, health span and stress resistance in experimental rodents. Here we propose to test the ability of short-term methionine restriction to increase stress resistance and improve insulin sensitivity in mice. Our aim is to elucidate upstream nutrient sensing pathways and downstream effectors with the ultimate goal of translating these benefits to the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090629-04
Application #
8585053
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Silva, Corinne M
Project Start
2010-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$327,038
Indirect Cost
$124,538
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Hine, Christopher; Kim, Hyo-Jeong; Zhu, Yan et al. (2017) Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. Cell Metab 25:1320-1333.e5
Hine, Christopher; Mitchell, James R (2017) Endpoint or Kinetic Measurement of Hydrogen Sulfide Production Capacity in Tissue Extracts. Bio Protoc 7:
Longchamp, Alban; Harputlugil, Eylul; Corpataux, Jean-Marc et al. (2017) Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review. Gerontology 63:228-237
Brandhorst, Sebastian; Harputlugil, Eylul; Mitchell, James R et al. (2017) Protective effects of short-term dietary restriction in surgical stress and chemotherapy. Ageing Res Rev 39:68-77
MacArthur, Michael R; Mitchell, James R (2017) Feeding the Genome: In Silico Optimization of Dietary Amino Acid Composition. Cell Metab 25:486-488
Brace, Lear E; Vose, Sarah C; Stanya, Kristopher et al. (2016) Increased oxidative phosphorylation in response to acute and chronic DNA damage. NPJ Aging Mech Dis 2:16022
Mauro, Christine R; Tao, Ming; Yu, Peng et al. (2016) Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. J Vasc Surg 63:500-9.e1
Hine, Christopher; Harputlugil, Eylul; Zhang, Yue et al. (2015) Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160:132-44
Robertson, Lauren T; Treviño-Villarreal, J Humberto; Mejia, Pedro et al. (2015) Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. J Nutr 145:1717-27
Mejia, Pedro; Treviño-Villarreal, J Humberto; Hine, Christopher et al. (2015) Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression. Nat Commun 6:6050

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