Immune senescence is a state of diminished immune competence manifested by reduced ability to respond to and clear pathogens and tumors, and it is believed to significantly contribute to morbidity and mortality in older individuals. Caloric restriction (CR) is the only intervention that consistently and significantly prolongs lifespan and delays the age-associated morbidity and mortality in experimental animals, but its mechanism of action is incompletely understood. CR appears to exert beneficial effects on the aging rodent immune system. However, it is not known whether CR can reverse immune senescence, or whether CR would similarly impact the immune system of primates. ? ? In this proposal, we shall elucidate the effects of aging upon the immune system of Rhesus Macaques, and test the hypothesis that CR acts to maintain T-cell subset balance and preserve T-cell responsiveness in aged Rhesus Macaques. To that ene, we shall measure key immunological parameters known to be affected by aging in other species. Cross-sectional studies will be performed in young and old animals fed regular or CR diets.
Specific aims will examine the effects of aging and CR on T-cell subset frequencies and function (Aim 1), thymic output and peripheral T-cell homeostasis (Aim 2), TCR diversity of T-cell subsets (Aim 3), and T-cell subset gene expression patterns (Aim 4). ? ? These studies will comprehensively and precisely characterize the effects of aging and CR in a real-life, outbred primate model. This will not only test the validity of observations in rodents, but also put limits on current hypotheses and allow for the rational setting of new ones.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG021384-02
Application #
6651516
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M4))
Program Officer
Fuldner, Rebecca A
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
2
Fiscal Year
2003
Total Cost
$381,466
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Nikolich-Žugich, Janko (2012) The aging immune system: challenges for the 21st century. Semin Immunol 24:301-2
Cicin-Sain, Luka; Smyk-Pearson, Susan; Smyk-Paerson, Sue et al. (2010) Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J Immunol 184:6739-45
Messaoudi, Ilhem; Fischer, Miranda; Warner, Jessica et al. (2008) Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates. Aging Cell 7:908-19
Nikolich-Zugich, Janko (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8:512-22
Nikolich-Zugich, Janko (2007) Non-human primate models of T-cell reconstitution. Semin Immunol 19:310-7
Cicin-Sain, Luka; Messaoudi, Ilhem; Park, Byung et al. (2007) Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 104:19960-5
Messaoudi, Ilhem; Warner, Jessica; Fischer, Miranda et al. (2006) Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci U S A 103:19448-53
Nikolich-Zugich, Janko (2005) T cell aging: naive but not young. J Exp Med 201:837-40
Nikolich-Zugich, Janko; Messaoudi, Ilhem (2005) Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol 40:884-93
Jankovic, Vladimir; Messaoudi, Ilhem; Nikolich-Zugich, Janko (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets. Blood 102:3244-51