Aging is associated with enhanced inflammation. An altered ratio between angiotensin receptors AT1R and AT2R results in induction of inflammation in animal models. The effects of aging on the expression of AT1R and AT2R in humans and the contribution of changes in AT1R and AT2R to increased inflammation in the older have not been previously studied. Our preliminary evidence suggests that frail older adults have up-regulation of AT1R, down-regulation of AT2R expression and implicate for IL6 in this imbalance. We hypothesize that human frail aging is associated with up-regulation of AT1R and down-regulation of AT2R expression and function in immune system cells. We hypothesize that these receptor changes contribute to decreased immune system cells phagocytic capacity and to the increased production of inflammatory cytokines in older individuals which will further heighten the divergence in AT1R and AT2R expression. In order to test these hypotheses, we propose a comprehensive study of AT1R and AT2R using immune system cells (lymphocytes and monocytes) from young, healthy adults (age 20-30) and four comparison groups that consist of (1) robust, older adults (age 70-90), (2) robust, older adults (age 70-90) treated with AT1R blockers, (3) frail, older adults (age 70-90), (4) frail, older adults (age 70-90) treated with AT1R blockers. From these subjects we will collect lymphocytes and monocytes that will be utilized for the following proposed studies: 1. Measure changes in gene expression, protein synthesis, and signaling pathways of AT1R and AT2R in immune system cells from young control (20-30Y) and the four comparison groups (N=33 in each group) using Q-PCR, western blot, confocal microscopy, flow cytometry and Bio-Plex Phosphoprotein Cellular Signaling Assays. 2. Evaluate age-related difference and contribution of Angiotensin receptors blockade to monocytes phagocytic function by incubating immune system cells from the same individuals with specific AT1R and/or AT2R blockers and measuring changes in monocytes phagocytic function with Phagocytosis Assay at baseline and in response to treatment(s). 3. Evaluate contribution of AT1R and AT2R to cytokine production in the older individuals by incubating immune system cells from the same individuals with specific AT1R and/or AT2R blockers and measuring cytokines with ELISA and Bio-Plex cytokine assays at baseline and in response to treatment(s). 4. Assess the feedback of inflammation on AT1R and AT2R expression and function by incubating immune system cells from the same subjects with IL-6. Q-PCR and western blot will be used to quantify the change in expression of AT1R and AT2R in response to IL-6 treatment.

Public Health Relevance

This study is designed to evaluate specific factors that may play a role in late life weakness, increased morbidity and mortality. Angiotensin receptors 1 and 2 (AT1R and AT2R) are found on the surface and on the inside of virtually all human cells. This study will evaluate the relationships among these receptors in immune system cells as people age, and determine how these changes might influence chronic inflammation, frailty and late life vulnerability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AG035005-05
Application #
8728716
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Fuldner, Rebecca A
Project Start
2010-09-30
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$161,325
Indirect Cost
$11,950
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Campbell, Jean Y; Durso, Samuel C; Brandt, Lynsey E et al. (2013) The unknown profession: a geriatrician. J Am Geriatr Soc 61:447-9
Abadir, Peter M; Foster, D Brian; Crow, Michael et al. (2011) Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A 108:14849-54