Our long-term goal is to elucidate the mechanisms whereby moderate food restriction (FR) increases immune function, delays the appearance of age- associated disease processes and significantly prolongs life span. We observed higher lymphocyte proliferative responses, higher anti- inflammatory lymphokine production, changes in long-chain fatty acids in lymphocyte membranes and age-related changes in gene expression in aging food-restricted rats. Our recent studies revealed that FR delays the rise of memory T-cells and also the loss of CD4+ T-cell proliferative response to superantigens (staphylococcal enterotoxin-B) indicting that changes in rat Vbeta+ subsets may occur with age. We propose that age- related changes in both T-cell subsets and membrane integrity may modulate various cellular functions and transmembrane signaling apparatus.
The aim of this proposal is to test the hypothesis that FR modifies T-cell functions, including virgin and memory T-cell subset functions, and suppresses the rise in pro-inflammatory cytokines released by T-cells and macrophages (Mphis). Our proposal will address the following: 1) The mechanism(s) underlying T-cell defects with age: analyze the functional changes in purified T-cell subsets obtained from spleens of both ad libitum and food-restricted rats at 6, 18 and 36 months of age, as well as the frequency and functional loss of alloreactive CD4+ and CD8+ T-cell subsets, their lymphokine production (IL-2, gamma-IFN, IL-4) and also mRNA expression. 2) The characteristics of age-associated functional and quantitative changes in virgin (CD45RChigh) and memory (CD45RClow) T-cells within CD4+ and CD8+ T-cell subsets: measure pro- and anti-inflammatory lymphokine production, and the proliferative response to various stimulatory agents including bacterial superantigens and recall antigens. 3) Determine if age- associated proliferative responses in T-cell subsets correlate with increased release of pro-inflammatory cytokines by Mphis: measure PGE2, IL-1, IL-6 and TNF-alpha by activating in vitro, both resident and elicited peritoneal Mphis. Finally, the correlation between T-cell immunological dysfunction and changes in membrane phospholipid composition and fluidity with age and diet will be determined. to achieve the above specific aims, we will use female Fischer-344 x Brown Norway F1 rats as these rats live relatively long and are free of common diseases. these studies should enable us to understand the fundamental mechanisms involved in maintaining an active immune system during aging through reduced caloric intake and may thus provide valuable information on maintaining a healthy life span for our rapidly growing aging population.
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