This proposal seeks renewal of R01 AG006537 for years 20-24 to provide continuing support for our work in the integrative physiology of human aging. The proposed research will determine if caloric restriction- induced weight loss improves vascular endothelium-dependent dilation (EDD), a clinically important marker of endothelial function and atherosclerotic disease risk, in overweight and mildly obese middle-aged and older adults. We also will determine the role of reduced inflammation, oxidative stress and visceral adiposity in mediating these beneficial effects of weight loss on EDD. Our integrative working hypothesis is that: --EDD will be improved following weight-loss -these improvements will be associated with reduced systemic inflammation, a reduced inflammatory vascular endothelial phenotype, and reduced levels of nuclear factor kappa B (NFKB), a key pro- inflammatory transcription factor -the reduced inflammation-related improvements in EDD will be associated with decreased oxidative stress mediated suppression of EDD -these integrative physiological adaptations to weight loss will be more closely related to reductions in abdominal visceral adiposity than to decreases in total or abdominal subcutaneous fat. To test this hypothesis we will conduct a 12-week weight loss intervention (randomized attention control design). The tonic influence of inflammation on EDD will be determined before and after the intervention period using short-term blockade of NFKB with orally administered Salsalate. Intravenous infusion of ascorbic acid, a potent antioxidant, will be used to determine the effects of oxidative stress on EDD. Key outcomes will include brachial artery flow-mediated dilation (i.e., EDD);cytokines (plasma levels;whole- blood cell production and protein/mRNA gene expression);blood cell NFKB protein/mRNA gene expression;vascular endothelial expression of inflammation- and oxidant-related proteins;and dual x-ray absorptiometry (total fat)- and computed tomography (abdominal visceral and subcutaneous fat)-measured adiposity. The proposed study should provide the first insight into the role of reduced inflammation, oxidative stress and visceral adiposity in weight loss-mediated improvements in EDD in overweight/obese older adults.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG006537-24
Application #
7928915
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Dutta, Chhanda
Project Start
1986-08-01
Project End
2013-06-30
Budget Start
2010-07-15
Budget End
2013-06-30
Support Year
24
Fiscal Year
2010
Total Cost
$476,094
Indirect Cost
Name
University of Colorado at Boulder
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
LaRocca, Thomas J; Martens, Christopher R; Seals, Douglas R (2017) Nutrition and other lifestyle influences on arterial aging. Ageing Res Rev 39:106-119
Martens, Christopher R; Seals, Douglas R (2016) Practical alternatives to chronic caloric restriction for optimizing vascular function with ageing. J Physiol 594:7177-7195
Jablonski, Kristen L; Klawitter, Jelena; Chonchol, Michel et al. (2015) Effect of dietary sodium restriction on human urinary metabolomic profiles. Clin J Am Soc Nephrol 10:1227-34
Jablonski, Kristen L; Donato, Anthony J; Fleenor, Bradley S et al. (2015) Reduced large elastic artery stiffness with regular aerobic exercise in middle-aged and older adults: potential role of suppressed nuclear factor ? B signalling. J Hypertens 33:2477-82
Kaplon, Rachelle E; Gano, Lindsey B; Seals, Douglas R (2014) Vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults. J Appl Physiol (1985) 116:156-63
Seals, Douglas R (2014) Edward F. Adolph Distinguished Lecture: The remarkable anti-aging effects of aerobic exercise on systemic arteries. J Appl Physiol (1985) 117:425-39
Walker, Ashley E; Kaplon, Rachelle E; Pierce, Gary L et al. (2014) Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor ?B. Clin Sci (Lond) 127:645-54
Santos-Parker, Jessica R; LaRocca, Thomas J; Seals, Douglas R (2014) Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv Physiol Educ 38:296-307
Jablonski, Kristen L; Fedorova, Olga V; Racine, Matthew L et al. (2013) Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness. Clin J Am Soc Nephrol 8:1952-9
Jablonski, Kristen L; Racine, Matthew L; Geolfos, Candace J et al. (2013) Dietary sodium restriction reverses vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure. J Am Coll Cardiol 61:335-43

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