The importance of mTOR signaling in cardiac aging and lifespan in mammals

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant) Nutrient signaling is central and evolutionarily conserved in pathways that modulate aging and lifespan, as our Program Project invesfigators 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 translafional regulafion. Furthermore, signaling through mTOR may be infimately linked to mitochondrial metabolism and reactive oxygen species (ROS), thus providing a mechanisfic connection between the paradigms of ROS and dietary restricfion 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, condlfional knockout and transgenic mice to delineate the effects of reduced signaling through the TORCl arm ofthe mTOR pathway and the interactions ofthis signaling with dietary restricfion 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 alterafions in protein translation and whether reduced levels of ROS are a significant part ofthis mechanism. In Aim 2, we will extend these studies to effects on mouse lifespan to confirm that reduced TORCl signaling Increases mouse longevity. These genefic approaches will lead to fundamental insights into key regulators of longevity and determinants of health span, and that with this knowledge, pharmacologic intervenfions can be designed to confer similar health benefits to humans. Cardiac aging Is a significant cause of late-life mortality and diastolic dysfuncfion is a major contributor to the physiological declines in the aging heart. The proposed studies may reveal novel therapeutic interventions for diastolic dysfunction which currenfiy are sorely lacking.