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 #
3R01AG040297-02S1
Application #
8528913
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$36,921
Indirect Cost
$12,211
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; Gates, Phillip E; Vink, Hans et al. (2017) Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study. J Rheumatol 44:1603-1611
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
Trott, Daniel W; Lesniewski, Lisa A; Donato, Anthony J (2017) Selected life-extending interventions reduce arterial CXCL10 and macrophage colony-stimulating factor in aged mouse arteries. Cytokine 96:102-106
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
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 :
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
Trott, Daniel W; Henson, Grant D; Ho, Mi H T et al. (2016) Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. Exp Gerontol :
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
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

Showing the most recent 10 out of 33 publications