Advancing age is associated with the development of arterial dysfunction characterized by endothelial dysfunction and large artery stiffness. One hypothesis is that the chronic reduction of caloric intake (Caloric Restriction;CR) can activate cellular and molecular events that prevent age-related arterial dysfunction. This proposal aims to determine if lifelong caloric restriction (40%) and/or a pharmacological caloric restriction mimetic can prevent the age-related arterial dysfunction and the cellular and molecular mechanisms by which this may occur. Specifically, we will examine the effect of lifelong CR on the regulation and modulation of nuclear transcription factors, by acetylation, involved in the regulation of arterial oxidative stress, inflammation and apoptosis in middle-aged (MA) and older (O) mice.
The specific aims are (1) to measure endothelium dependent dilation (EDD), nitric oxide (NO) bioavailability and stiffness in large arteries of MA/O mice and to determine if advancing age is associated with a pro-oxidative, -inflammatory, -apoptotic phenotype, (2) to determine if CR attenuates the activation and acetylation of the pro- oxidative, -inflammatory and -apoptotic signaling molecules;nuclear factor kappa B (NFkB), p53, and forkhead foxO (FoxO3a) via an increase a nuclear deacetylase SIRT-1 in MA/O mice and (3) to determine if activation of the nuclear deacetylase SIRT-1 can prevent the aged arterial phenotype and dysfunction. To do so, we will study young (Y: 4-6 mo), MA (18-20 mo) and O (29-31 mo) male B6D2F1 mice. Endothelial function, nitric oxide bioavailability, and larger artery stiffness will be measured. Oxidative stress, inflammatory cytokines, markers of apoptosis and activation/acetylation of NFkB, p53 and FoxO3a will be assessed in aortic lysates and endothelial cells. Lastly, we will utilize pharmacological inhibition of the nuclear deacetylase SIRT-1 to determine its role in age and caloric restriction-associated arterial function, oxidative stress, inflammation and apoptosis. The expected results will provide novel insight into the cellular and molecular mechanisms by which CR and CR mimetics preserve age-associated arterial function.

Public Health Relevance

Advancing age is associated with arterial dysfunction. This proposal aims to determine if life-long caloric restriction and/or a pharmacological caloric restriction mimetic can prevent the age-related arterial function and the cellular and molecular mechanisms by which this may occur.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040297-03
Application #
8517535
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2011-09-01
Project End
2016-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$289,619
Indirect Cost
$95,894
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Trinity, Joel D; Barrett-O'Keefe, Zachary; Ives, Stephen J et al. (2016) Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis. J Hypertens 34:266-73
Beyer, Andreas M; Freed, Julie K; Durand, Matthew J et al. (2016) Critical Role for Telomerase in the Mechanism of Flow-Mediated Dilation in the Human Microcirculation. Circ Res 118:856-66
Walker, Ashley E; Morgan, R Garrett; Ives, Stephen J et al. (2016) Age-related arterial telomere uncapping and senescence is greater in women compared with men. Exp Gerontol 73:65-71
Hazra, Sugata; Henson, Grant D; Morgan, R Garrett et al. (2016) Experimental reduction of miR-92a mimics arterial aging. Exp Gerontol 83:165-70
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99
Walker, Ashley E; Henson, Grant D; Reihl, Kelly D et al. (2015) Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness. J Physiol 593:1931-43
Ghosh, Payal; Mora Solis, Fredy R; Dominguez 2nd, James M et al. (2015) Exercise training reverses aging-induced impairment of myogenic constriction in skeletal muscle arterioles. J Appl Physiol (1985) 118:904-11
Frech, Tracy; Walker, Ashley E; Barrett-O'Keefe, Zachary et al. (2015) Systemic sclerosis induces pronounced peripheral vascular dysfunction characterized by blunted peripheral vasoreactivity and endothelial dysfunction. Clin Rheumatol 34:905-13
Barrett-O'Keefe, Zachary; Ives, Stephen J; Trinity, Joel D et al. (2015) Endothelin-A-mediated vasoconstriction during exercise with advancing age. J Gerontol A Biol Sci Med Sci 70:554-65
Donato, Anthony J; Morgan, R Garrett; Walker, Ashley E et al. (2015) Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol 89:122-35

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