Aging is associated with dramatic alterations in immune function, resulting in reduced immunologic responsiveness and increased mortality from infections. The underlying mechanisms remain poorly understood, however. Currently, most information is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes (the key effectors of adaptive immunity). This compartment demonstrates a profound age-associated alteration in function and composition of the memory CD8+ T lymphocyte pool that is due, in large part, to the increasingly disproportionate accumulation of blood immune cells with features of replicative senescence. These are defined as cells with short telomeres, inability to proliferate and associated phenotypic changes. There are no reliable data on the age-related changes in T lymphocytes in the human gastrointestinal tract, which is the major reservoir of total body lymphocytes and an anatomical region of high antigenic exposure. However, our preliminary studies on a cohort of young individuals document significant differences in T cell phenotypes between the gut and blood from the same individual. The overarching goal of the proposed studies is to determine the effect of aging on gut-associated lymphoid tissue (GALT) and to analyze the impact of chronic antigenic stimulation on these changes. Based on data suggesting that CD8+ T lymphocyte aging is largely driven by chronic viral infections, such as cytomegalovirus, we will assess the impact of chronic antigenic stimulation by also including persons infected with the human immunodeficiency virus. This treatable chronic viral infection allows us to test whether lowering the antigenic burden, via direct viral suppression, retards the age-related accumulation of senescent cells in the gut by reducing the impact of the chronic viral infection.
Aim 1 a will compare phenotypic and functional parameters of gut and blood samples from healthy young (20-35 yrs) and older (50-65 yrs) individuals.
Aim 1 b will determine the additive impact of vigorous persistent antigenic stimulation on the normative age-related changes in the CD8+ T lymphocyte compartments within blood and gastrointestinal mucosa of individuals in the same age groups, and Aim 2 will evaluate whether the altered GALT rate of senescent CD8+ T lymphocyte accumulation is retarded by treatment that reduces the viral load, and thus the level of chronic antigenic stimulation. The proposed research, will, therefore provide the first comprehensive analysis of age-associated changes in the human gut, the largest lymphoid organ in the body. The results will have significant clinical implications in terms of age- appropriate treatments and vaccine development for the ever-increasing older U.S. population.

Public Health Relevance

The proposed research will provide the first comprehensive analysis of age-associated immune changes in the human gut, the largest lymphoid organ in the body. The results will have significant clinical implications in terms of age-appropriate treatments and vaccine development for the ever-increasing older population. In addition, if our research shows that accelerated aging of the immune cells in the gut is reversible, this will stimulate efforts to identify novel therapeutic approaches for enhancing immune function in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032422-04
Application #
8309195
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$993,364
Indirect Cost
$339,165
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dock, Jeffrey; Hultin, Lance; Hultin, Patricia et al. (2017) Human immune compartment comparisons: Optimization of proliferative assays for blood and gut T lymphocytes. J Immunol Methods 445:77-87
Dock, Jeffrey; Ramirez, Christina M; Hultin, Lance et al. (2017) Distinct aging profiles of CD8+ T cells in blood versus gastrointestinal mucosal compartments. PLoS One 12:e0182498
Effros, Rita B (2016) The silent war of CMV in aging and HIV infection. Mech Ageing Dev 158:46-52
Carroll, Judith E; Esquivel, Stephanie; Goldberg, Alyssa et al. (2016) Insomnia and Telomere Length in Older Adults. Sleep 39:559-64
Preza, Gloria Cuevas; Yang, Otto O; Elliott, Julie et al. (2015) T lymphocyte density and distribution in human colorectal mucosa, and inefficiency of current cell isolation protocols. PLoS One 10:e0122723
Chou, Jennifer P; Ramirez, Christina M; Wu, Jennifer E et al. (2013) Accelerated aging in HIV/AIDS: novel biomarkers of senescent human CD8+ T cells. PLoS One 8:e64702
Chou, Jennifer P; Effros, Rita B (2013) T cell replicative senescence in human aging. Curr Pharm Des 19:1680-98
Effros, Rita B (2012) Editorial: T cell memory, bone marrow, and aging: the good news. J Leukoc Biol 91:185-7
Rickabaugh, Tammy M; Kilpatrick, Ryan D; Hultin, Lance E et al. (2011) The dual impact of HIV-1 infection and aging on naïve CD4 T-cells: additive and distinct patterns of impairment. PLoS One 6:e16459
Dock, Jeffrey N; Effros, Rita B (2011) Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence. Aging Dis 2:382-397

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