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 i s 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 #
5R01DK090629-02
Application #
8225340
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
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$363,375
Indirect Cost
$138,375
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Hine, Christopher; Mitchell, James R (2015) Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Exp Gerontol 68:26-32
Hine, Christopher; Mitchell, James R (2014) Saying no to drugs: fasting protects hematopoietic stem cells from chemotherapy and aging. Cell Stem Cell 14:704-5
Varendi, Kärt; Airavaara, Mikko; Anttila, Jenni et al. (2014) Short-term preoperative dietary restriction is neuroprotective in a rat focal stroke model. PLoS One 9:e93911
Mauro, Christine R; Tao, Ming; Yu, Peng et al. (2014) Preoperative dietary restriction reduces intimal hyperplasia and protects from ischemia-reperfusion injury. J Vasc Surg :
Harputlugil, Eylul; Hine, Christopher; Vargas, Dorathy et al. (2014) The TSC complex is required for the benefits of dietary protein restriction on stress resistance in vivo. Cell Rep 8:1160-70
Mitchell, James R; Beckman, Joshua A; Nguyen, Louis L et al. (2013) Reducing elective vascular surgery perioperative risk with brief preoperative dietary restriction. Surgery 153:594-8
Robertson, Lauren T; Mitchell, James R (2013) Benefits of short-term dietary restriction in mammals. Exp Gerontol 48:1043-8
Gallinetti, Jordan; Harputlugil, Eylul; Mitchell, James R (2013) Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J 449:1-10
Peng, Wei; Robertson, Lauren; Gallinetti, Jordan et al. (2012) Surgical stress resistance induced by single amino acid deprivation requires Gcn2 in mice. Sci Transl Med 4:118ra11