Nutrient signaling is central and evolutionarily conserved in pathways that modulate aging and lifespan, as our Program Project investigators have demonstrated in preliminary studies of yeast and worms. The mTOR (mammalian target of rapamycin) signaling pathway monitors Intracellular amino add levels and regulates protein synthesis, cell growth, and ribosomal biogenesis. We hypothesize that reduced signaling through the mTOR pathway has positive effects on aging and lifespan, which are mediated by translational regulation. Furthermore, signaling through mTOR may be intimately linked to mitochondrial metabolism and reactive oxygen species (ROS), thus providing a mechanistic connection between the paradigms of ROS and dietary restriction in aging. Evidence, including our preliminary data, suggests that these effects may be particularly important in cardiac aging, an important cause of human morbidity and mortality. The focus of the research in Project 2 derives from these key findings. We will use knockout, conditional knockout and transgenic mice to delineate the effects of reduced signaling through the TORCl arm of the mTOR pathway and the interactions of this signaling with dietary restriction and reactive oxygen species (ROS).
Specific Aim 1 is to establish whether reduced TORCl signaling enhances cardiac resistance to aging. We will determine whether this mechanism can account for the cardiac benefits of dietary restriction, whether it is mediated by alterations in protein translation and whether reduced levels of ROS are a significant part of this mechanism.
In Aim 2, we will extend these studies to effects on mouse lifespan to confirm that reduced TORCl signaling Increases mouse longevity. These genetic approaches will lead to fundamental insights into key regulators of longevity and determinants of health span, and that with this knowledge, pharmacologic interventions can be designed to confer similar health benefits to humans. Cardiac aging Is a significant cause of late-life mortality and diastolic dysfunction is a major contributor to the physiological declines in the aging heart. The proposed studies may reveal novel therapeutic interventions for diastolic dysfunction which currently are sorely lacking.

Public Health Relevance

These genetic approaches will lead to fundamental insights into key regulators of longevity and determinants of health span, and that with this knowledge, pharmacologic interventions can be designed to confer similar health benefits to humans. Cardiac aging is a significant cause of late-life mortality and diastolic dysfunction is a major contributor to the physiological declines In the aging heart. The proposed studies may reveal novel therapeutic interventions for diastolic dysfunction which currently are sorely lacking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038550-05
Application #
8677676
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Finkelstein, David B
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Hsieh, Edward J; Shulman, Nicholas J; Dai, Dao-Fu et al. (2012) Topograph, a software platform for precursor enrichment corrected global protein turnover measurements. Mol Cell Proteomics 11:1468-74

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