Jeffrey A. Woods, Ph.D. - US grants

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.

The extent to which exercise training or long-term physical activity influences dysregulated immune function in the elderly is unclear. Preliminary evidence suggests that exercise training may improve various dysregulated immune function measures in older adults. Although such findings have the potential to be of substantial public health importance, the majority of studies have suffered from small sample sizes, inadequate measurement of physical fitness, and weak research designs. .The proposed study is designed to overcome these limitations by employing a longitudinal randomized controlled trial examining the effect of exercise training on clinically relevant immune function measures in older adults (65-80 years). Moreover, relationships between several factors known to be altered by exercise training and changes in immune function will be assessed. As such, there are two specific aims to be addressed. In Aim 1, a one-year exercise trial is proposed to determine whether moderate intensity aerobic exercise training can improve immune function in previously sedentary older adults. In Aim 2, the role played by physiological, behavioral, and psychosocial factors in the relationship between exercise training and improved immune function will be examined. Employing a randomized controlled trial, sedentary subjects (n=150) will be randomly assigned to either a one year moderate aerobic exercise training program (n = 75) or a sedentary control group (n = 75). Clinically relevant measures of immune function including the delayed-type hypersensitivity response to a battery of antigens and the antibody response to tetanus toxoid and influenza virus vaccination will be assessed before, during and after the intervention. We hypothesize that exercise training will result in improved immune responses including higher peak antibody titers and DTH responses, and sustained levels of protective antibodies. State-of-the-art analytical methods using multiple imputation and latent growth curve analyses will allow us to determine the growth and form of immune function parameters over the study period and the relative role played by physiological, behavioral, and psychosocial variables in this growth. Findings from the proposed study will help determine the role played by exercise training in immune functioning in the elderly thereby providing important empirical evidence to substantiate the prescription of exercise to combat disease and dysfunction. The public health yield of such information is likely to be substantial. In addition, the biobehavioral approach inherent in our aims will allow us to determine the complexity of the relationship between exercise and immune function.