Caloric Restriction (CR) is the only well-established protocol in mammals that consistently increases lifespan and delays age-related physiological declines. The recent finding that the health benefits of CR apply to rhesus monkeys has increased interest in developing interventions that can mimic the health benefits of CR. However, the molecular basis of the CR effects in aging is poorly understood. We and others have postulated that a profound metabolic reprogramming underlies the health benefits of CR. Recent studies suggest that the mitochondrial sirtuin Sirt3 plays a major role in mitochondrial metabolic control, and we have shown that the ability of CR to prevent age-related hearing loss is completely dependent on Sirt3. Based on these and other observations, our central hypothesis is that Sirt3 mediated deacetylation of key metabolic targets in response to CR increases resistance to oxidative stress and as a consequence prevents age-related mitochondrial dysfunction. Within this application we propose to extensively and mechanistically investigate one of the major processes underlying the effects of CR at the organismal level, the mitochondrial adaptations in response to reduced caloric intake. The proposed studies will address the effects of Sirt3-mediated mitochondrial adaptations in response to CR at the biochemical level through the analysis of Sirt3 targets in mitochondria, at the cellular level through the analysis of age-related mitochondrial dysfunction, and at the tissue-specific level through cardiac and skeletal muscle functional assays of aged animals. We will also determine if the ability of CR to increase lifespan and prevent age-related pathology requires Sirt3. Results from the study will provide a detailed molecular understanding of mitochondrial adaptation to CR and the role of sirtuins in these pathways; Knowledge of the molecular mechanisms and key pathways regulated has potential for significantly improving health outcomes through the development of novel therapeutics that specifically target these pathways.

Public Health Relevance

A reduction in caloric intake retards aging parameters and improves general health. The main goal of the proposed studies is to determine if and how the protein Sirt3 mediates the beneficial effects of caloric restriction. These studies will generate novel opportunities for age-related therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG038679-05S1
Application #
9306622
Study Section
Program Officer
Fridell, Yih-Woei
Project Start
2016-06-29
Project End
2017-05-31
Budget Start
2016-09-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
$68,500
Indirect Cost
$23,729
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Barger, Jamie L; Vann, James M; Cray, Nicole L et al. (2017) Identification of tissue-specific transcriptional markers of caloric restriction in the mouse and their use to evaluate caloric restriction mimetics. Aging Cell 16:750-760
Yu, Wei; Denu, Ryan A; Krautkramer, Kimberly A et al. (2016) Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. J Biol Chem 291:3268-79
Dittenhafer-Reed, Kristin E; Richards, Alicia L; Fan, Jing et al. (2015) SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metab 21:637-46
Barger, Jamie L; Anderson, Rozalyn M; Newton, Michael A et al. (2015) A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PLoS One 10:e0120738
Prolla, Tomas A; Denu, John M (2014) NAD+ deficiency in age-related mitochondrial dysfunction. Cell Metab 19:178-80
Peek, Clara Bien; Affinati, Alison H; Ramsey, Kathryn Moynihan et al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417
Still, Amelia J; Floyd, Brendan J; Hebert, Alexander S et al. (2013) Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. J Biol Chem 288:26209-19
Hebert, Alexander S; Dittenhafer-Reed, Kristin E; Yu, Wei et al. (2013) Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell 49:186-99