Advancing age is the primary risk factor for cardiovascular diseases, and arterial dysfunction is a critical contributor to this increased disease risk. The proposed studies will explore the novel hypothesis that age- associated arterial telomere dysfunction is an underlying mechanism for increased arterial inflammation and dysfunction with aging. We hypothesize that telomere dysfunction, characterized by telomere uncapping, triggers cell senescence via the p53/p21 pathway that results in increased inflammatory signaling and ultimately leading to augmented large artery stiffness and endothelial dysfunction. We will address these hypotheses by utilizing mouse and endothelial cell culture models of aging, as well as inducible systemic and endothelial specific models of telomere uncapping. Additionally, using a transgenic mouse model of greater systolic blood pressure and pulse pressure and in vitro arterial and tissue culture models of circumferential stress, we will determine if increases in circumferential wall stretch is a critical stimulus for te induction of telomere uncapping. These results will reveal a novel mechanism underlying age-associated arterial dysfunction and disease risk, as well as provide critical evidence for future studies to determine therapeutic targets to reduce chronic arterial inflammation. This is a clinically relevant and important goal given the prevalence of cardiovascular disease among older adults, the increasing age of our population and its associated morbidity, mortality, and health care burden.

Public Health Relevance

Advancing age is a risk factor for cardiovascular diseases. The aim of the proposed project is to determine the mechanism(s) leading to age-related inflammation and subsequent arterial dysfunction. Specifically, we will examine the roles of systemic and endothelial-specific telomere dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG050238-03
Application #
9459816
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kerr, Candace L
Project Start
2016-09-01
Project End
2021-03-31
Budget Start
2018-05-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
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
Machin, Daniel R; Bloom, Samuel I; Campbell, Robert A et al. (2018) Advanced age results in a diminished endothelial glycocalyx. Am J Physiol Heart Circ Physiol 315:H531-H539
Ungvari, Zoltan; Tarantini, Stefano; Donato, Anthony J et al. (2018) Mechanisms of Vascular Aging. Circ Res 123:849-867
Donato, Anthony J; Machin, Daniel R; Lesniewski, Lisa A (2018) Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circ Res 123:825-848
Trott, Daniel W; Henson, Grant D; Ho, Mi H T et al. (2018) Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. Exp Gerontol 109:99-107
Clifton, Heather L; Machin, Daniel R; Groot, H Jonathan et al. (2018) Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement. Exp Physiol 103:1412-1424
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