The overall theme of this project is to test the hypothesis that life span extension, longevity and stress resistance are mediated by common mechanisms. Growing lines of evidence suggest that the longevity of a wide variety of organisms, from yeast to worms and flies to mammals, is regulated by defined molecular mechanisms, including Sir2, an NAD-dependent histone deacetylase, and the adenylyl cyclase-protein kinase A pathway. A major limitation to understanding the key regulatory mechanisms responsible for causing the adverse effects of aging, or conversely, those that extend longevity, is the lack of animal models which exhibit prolonged lifespan and which do not develop cardiomyopathy or osteoporosis or other end- points, which are normally observed with aging. The model, which is accepted best for increasing longevity from yeast to primates, is caloric restriction. Relatively few other models for longevity are available. In this connection, we have recently identified a novel, genetically engineered animal model, which lives longer than wild type animals and does not exhibit many of the cardiac and osteoporotic features of old age, i.e., mice with the adenylyl cyclase (AC) type 5 """"""""knocked out"""""""" (ACS KO). It is our contention that examining mechanisms that are unique to the ACS KO model will provide important insight into the aging process and, potentially, mechanisms which might be utilized to reverse this process. Projects 1 and 2 examine these mechanisms in this mouse model. In addition, Project 3 has developed and will study other mouse models of aging and stress resistance, related to Sir2alpha. The central hypothesis in that project is that Sir2alpha mediates anti-aging as well as cell protective effects in the heart in vivo. These 3 projects are supported by 5 cores: Administration/Physiology;Animal Care;Genomics/Proteomics;Bioinformatics/Biostatistics;Pathology. This Program Project has major implications for public health. The disability associated with aging has a major impact on the public health and the U.S. economy. Finding molecular switches, such as the ones described in this project, could ameliorate disability with aging and would be a major step forward.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-6 (O2))
Program Officer
Kohanski, Ronald A
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University of Medicine & Dentistry of NJ
Anatomy/Cell Biology
Schools of Medicine
United States
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Vatner, Dorothy E; Zhang, Jie; Oydanich, Marko et al. (2018) Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell :e12751
Guers, John J; Zhang, Jie; Campbell, Sara C et al. (2017) Disruption of adenylyl cyclase type 5 mimics exercise training. Basic Res Cardiol 112:59
Vatner, Stephen F (2016) Why So Few New Cardiovascular Drugs Translate to the Clinics. Circ Res 119:714-7
Bravo, Claudio A; Vatner, Dorothy E; Pachon, Ronald et al. (2016) A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. J Pharmacol Exp Ther 357:331-6
Sciarretta, Sebastiano; Yee, Derek; Ammann, Paul et al. (2015) Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes. Clin Sci (Lond) 128:387-403
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
Ho, David; Zhao, Xin; Yan, Lin et al. (2015) Adenylyl Cyclase Type 5 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance. Diabetes 64:2636-45
Yan, Lin; Kudej, Raymond K; Vatner, Dorothy E et al. (2015) Myocardial ischemic protection in natural mammalian hibernation. Basic Res Cardiol 110:9
Lee, Grace J; Yan, Lin; Vatner, Dorothy E et al. (2015) Mst1 inhibition rescues ?1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis. Basic Res Cardiol 110:7
Zhao, Zhenghang; Babu, Gopal J; Wen, Hairuo et al. (2015) Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart. Am J Physiol Heart Circ Physiol 308:H240-9

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