Macrophage (Mphi) responsiveness to activating signals like interferon- gamma (IFN-gamma), lipopolysaccharide (LPS), and Propionibacterium acnes (p. Acnes) declines with age in human and animals as assessed by decreased anti-tumor activity, and nitric oxide (NO), H2O, and tumor necrosis factor-alpha (TNF-alpha) production. Recent epidemiological evidence suggests that chronic exercise can protect against cancer and infectious disease. In young mice, we have shown that exercise increases murine Mphi anti-tumor activity medicated by increased TNF- alpha and NO production and perhaps increased sensitivity to IFN- gamma. Growth hormone (GH) and PRL (PRL) can increase Mphi function and it is likely that GH deficiency contributes to Mphi dysregulation in the aged. Unfortunately, the extent to which chronic exercise, which increases GA and PRL and attenuates glucocorticoid (CORT) secretion and sensitivity, affects depressed Mphi function in the aged is unknown. We hypothesize that chronic exercise will reverse the age-related decrease in Mphi function by increasing the GH/PRL: CORT ratio and decreasing Mphi sensitivity to CORT. We will test this hypothesis by chronically (16 was) exercising young (6 month), mature (12 month), and senescent (24 month) Balb/cByJNia mice in experiments designed to answer the following critical questions; (1) Does chronic exercise increase Mphi function and responsiveness to classical activating signals in aged mice as it does in young mice. We will inject P. Acnes in vivo and culture thioglycollate (TG)-elicited peritoneal Mphi's with IFN-gamma and LPS in vitro to determine the role of chronic exercise in Mphi priming and activation for anti-tumor activity, MHC II expression, and effector molecule production. We will explore potential mechanisms for this effect by measuring Mphi IFN-gamma and LPS (CD14) receptor density and signaling through mitogen activated protein kinases (MAPK's). We will also measure P. acnes-induced IFN-gamma production. (2) Is the exercise induced increase in Mphi function due to an increase in the GH/PRL:CORT ration and decreased Mphi CORT sensitivity? In vivo, we will address this by treating aged mice with bromocriptine (a dopamine agonist that suppresses PRL), and octreotide (somatostatin analog that inhibits GH). In vitro TG-elicited Mphi'S will be incubated with varying concentrations of IFN-gamma. And effector molecule production assays. Mechanism will be determined by measuring Mphi CORT receptor number and affinity and CORT induced expression of the NfkappaB antagonist IkappaB. Lastly, (3) Can GH an dPRL substitute for, or synergize with IFN-gamma, in priming Mphi's for activation by LPS in aged mice for activation. We will prime TG- elicited Mphi's from exercised mice of different ages with GH, PRL, and IFN-gamma activate them with LPS and measure anti-tumor activity and effector molecule production. We believe that GH and PRL and prime Mphi's from aged mice for activation. We will explore the mechanism for this effect by GH/PRL receptor and MAPK blockade and measurement of MAPK activity. These experiments will be the first to describe and mechanistically address how chronic exercise affects the aging immune system in an attempt to explore the potential use of exercise in enhancing age-associated declines in immune infection.
