Abstract Research from animal studies to population based studies supports the importance of immune cellular aging, the telomere/telomerase maintenance system, in human health and longevity. Telomeres, the caps protecting the ends of chromosomes, are important predictors of cardiovascular disease and early mortality. Telomerase is the enzyme that lengthens telomeres and promotes cellular and cardiovascular health. Mouse studies have shown that increasing exercise levels are associated with increased telomerase activity. Given the importance of examining experimentally whether human exercise training can slow cellular aging, we propose an ancillary study to the funded grant "Exercise and Inflammation: Autonomic, Affective &Cellular Mechanisms" (P.I. Richard Sloan) by adding measures of telomerase activity. The parent study is a controlled clinical trial of sedentary, unfit yet healthy young men and women, enrolled in 12 weeks of aerobic exercise training compared to a wait list control condition, to test its impact on inflammation and autonomic activity. Subjects are studied before and after 12 weeks of training, and after 4 weeks of sedentary deconditioning. We aim to test whether increasing aerobic exercise, and in turn fitness levels, of sedentary individuals over a 12-week period will increase in vivo telomerase activity compared to telomerase levels from a wait list control group. We will also examine if telomerase decreases after the 4 weeks of deconditioning. To carry this out, we will compare changes in telomerase activity in 154 participants randomized to the aerobic training intervention or the wait list control group, between baseline and post-intervention (12 weeks), and between post-intervention and deconditioning (4 weeks). As a secondary aim, we will also assess whether these changes are mediated through changes in inflammation, oxidative stress, and insulin resistance. Lastly, this funding would allow us to save cells to test exploratory questions about cell aging. Specifically, if telomerase activity changes as expected, we can examine telomere length, and telomere breakages, in these archived samples. These assays would not be supported by the current mechanism, but would be depend on additional private funding. To carry out these aims, this ancillary study adds the labor-intensive cell collections on 154 subjects remaining to be randomized, and assays of telomerase, oxidative stress, and insulin resistance. Inflammatory cytokines will already be measured as part of the parent study. The necessity of collecting and saving viable cells as subjects are enrolled into the ongoing parent study make this study extremely time sensitive and ideal for this ancillary study funding mechanism. This will be the first randomized controlled exercise intervention with the outcome of telomerase in humans. The proposed study could provide a unique window into how aerobic activity affects fundamental aspects of cell function by testing whether cell aging processes are slowed or reversed through increased aerobic fitness. PUBLIC HEALTH RELEVANCE: Immune cell aging is an important pathway to disease, and Animal studies suggest that exercise can retard cell aging. This will be one of the first intervention studies in humans to test effects of exercise on cell aging. It will provide further insight into mechanisms of cell aging, and whether telomerase can be used as a barometric indicator of health that is partly under people's control. (End of Abstract)