Title: Dietary restriction promotes vascular health through hydrogen sulfide-mediated angiogenesis Aging is a prime risk factor for cardiovascular disease, neurodegenerative disease and type II diabetes, all of which involve progressive dysfunction of the vasculature, the system of blood vessels and capillaries that deliver blood throughout the body. Maintenance of vascular health is expected to have major beneficial effects on healthspan and lifespan. Angiogenesis, or the growth of new blood vessels from endothelial cells in existing vessels, is a process by which vascular health and function can be maintained or improved. Angiogenesis is triggered under normal physiological situations such as exercise, but also by pathophysiological stimuli including ischemia due to blockage of a blood vessel. In both cases, oxygen deprivation is a major trigger of angiogenesis through activation of a genetic program controlled by the hypoxia inducible factor 1 alpha (HIF1?) transcription factor. Dietary restriction, generally defined as reduced food intake without malnutrition, increases lifespan, healthspan and stress resistance in experimental organisms, but the underlying cellular and molecular mechanisms remain largely unknown, particularly in mammals. Our surprising preliminary data indicate that nutrient restriction can promote angiogenesis via a novel mechanism independent of hypoxia or HIF1 ?. Specifically, we found that restriction of just the sulfur-containing amino acids methionine and cysteine, a regimen also known as methionine restriction, strongly increased muscle capillary density in mice. This occurred through the activation of the amino acid deprivation sensor GCN2 and the downstream transcription factor ATF4. It also required another downstream ATF4 target, the transsulfuration pathway gene CGL, a major producer of endogenous hydrogen sulfide (H2S). Increased H2S was in turn required for angiogenesis through a novel mechanism involving a metabolic switch from oxidative to glycolytic metabolism. Here, we propose to test the hypothesis that dietary restriction in general, and methionine restriction in particular, increases lifespan and healthspan of rodents in part by increasing angiogenesis via a novel mechanism requiring CGL and H2S. We will test the functional consequences of increased angiogenesis in standard rodent preclinical models of vascular function/dysfunction, as well as its contribution to lifespan extension by dietary restriction. Taken together, we expect to uncover novel pathways controlling angiogenesis and vascular function with the potential to translate to humans in the context of aging and aging-related disorders.

Public Health Relevance

Vascular dysfunction plays a major role in aging-related disease, but efficient strategies to mitigate morbidity and mortality due to vascular disease are lacking. We have found that brief periods of dietary restriction promote angiogenesis, or the growth of new blood vessels. We propose to study the molecular mechanisms underlying this phenomenon, and its functional implications in preclinical models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AG036712-06A1
Application #
9547695
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kerr, Candace L
Project Start
2010-08-15
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Mejia, Pedro; TreviƱo-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
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