Cardiovascular disease (CVD) is the leading cause of death in the United States. Aging is the major risk factor for development of CVD. The major age-related arterial phenotypes, which are thought to be responsible for the development of CVD in older adults, are reduced endothelial function and enhanced large artery stiffness. Recently, it has been demonstrated that inhibition of the mTOR signaling pathway, via rapamycin or genetic manipulation, extends lifespan and reduces age-related physiological dysfunction. The proposed studies aim to determine (a) if increased mTOR signaling is responsible for age-related arterial dysfunction and (b) whether dietary rapamycin treatment and activation of AMPK, a putative """"""""rapalog"""""""", can reverse age-related arterial dysfunction. Our laboratory has performed preliminary studies suggesting that arterial activation of mTOR is increased with advancing age and that this is concomitant with age-associated endothelial dysfunction and large artery stiffening known to result from increases in oxidative stress and inflammation. Furthermore, dietary treatment of old mice with mTOR inhibitor, rapamycin, can reverse this age-associated arterial phenotype and improve arterial function. In the present application, by utilizing dietary rapamycin treatment, we will directly assess the role that mTOR plays in modulating transcription factor activity and downstream gene/protein expression and the subsequent effects on arterial phenotype and function. In addition, we will determine if pharmacological activation of AMPK by AICAR will act as a """"""""rapalog,"""""""" mimicking the effects of rapamycin-induced mTOR inhibition on arterial function and phenotype.

Public Health Relevance

Advancing age is associated with arterial dysfunction. The proposed studies aim to determine if elevated arterial mTOR signaling contributes to dysfunction. In addition, we will determine if rapamycin or a rapalog, the AMPK activator AICAR, can reverse age-related arterial dysfunction and the cellular and molecular mechanisms involved.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG043952-01A1
Application #
8583560
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2013-09-01
Project End
2015-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$186,250
Indirect Cost
$61,250
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
Lesniewski, Lisa A; Seals, Douglas R; Walker, Ashley E et al. (2017) Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 16:17-26
Machin, Daniel R; Clifton, Heather L; Richardson, Russell S et al. (2017) Acute oral tetrahydrobiopterin administration ameliorates endothelial dysfunction in systemic sclerosis. Clin Exp Rheumatol 35 Suppl 106:167-172
Machin, Daniel R; Leary, Miriam E; He, Yuxia et al. (2016) Ultrasound Assessment of Flow-Mediated Dilation of the Brachial and Superficial Femoral Arteries in Rats. J Vis Exp :
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
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
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
Machin, Daniel R; Clifton, Heather L; Garten, Ryan S et al. (2016) Exercise-induced brachial artery blood flow and vascular function is impaired in systemic sclerosis. Am J Physiol Heart Circ Physiol 311:H1375-H1381
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
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
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

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