Tinna Traustadottir, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Aging is associated with reduced stress resilience due to diminished ability to manage or recover from acute changes in homeostasis. Even apparently healthy, older adults suffer dramatically poorer outcomes compared to young adults when exposed to acute stressors such as illness, injury, or exertion. However, the response in older individuals is highly heterogeneous, suggesting that age alone is not a good predictor of outcome. One factor that inversely correlates with morbidity and mortality in older adults is physical fitness. This study will investigate the effects of physical fitness on stress resilience in two areas related to aging: oxidative stress and neuroendocrine stress reactivity. Oxidative stress is believed to be a key mechanism in the aging process, and is implicated in many pathological processes. Similarly, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to play a role in aging and is linked to the increased risk for age-related disease. The hormesis theory suggests that a certain amount of stress can lead to better survival and reduced tissue damage following subsequent stress. While acute exercise is a stressor, regular exercise training results in adaptive responses that increase the tolerance for successive exercise stress. It is hypothesized that age-related differences in the response to acute stressors arise from a gradually diminished ability to up-regulate stress defenses, and that the mild stress associated with moderate physical activity leads to systemic adaptations that prevent or attenuate this decrease in stress resilience with aging. To test whether physical fitness provides older individuals with increased ability to resist disparate types of acute stressors, we will measure the response of fit and unfit older men and women to two acute stressors; forearm ischemia/reperfusion (oxidative stress), and a psychosocial laboratory stressor (neuroendocrine stress). Fitness will be determined by aerobic capacity (VO2 max) and peak leg power. The overall aim of this study is to provide enhanced understanding of the mechanisms by which physical fitness modifies stress resilience in older men and women. The results from this study can increase our understanding of how regular exercise confers its benefits on the aging process and serve as pilot data for follow-up mechanistic-oriented studies, exercise intervention studies, and studies to reliably evaluate dietary, lifestyle, and other therapeutic approaches to increase stress resistance capacity in individuals at increased risk. Public Health Relevance: Increased oxidative damage to cells and tissues and dysregulation of stress hormones have been linked to age-associated chronic diseases including atherosclerosis, cancer, cardiovascular disease and Alzheimer's disease. Interventions to improve the body's resistance to stress, resulting in lower oxidative stress and better regulation of the stress hormones, may prevent or delay the onset of age-related diseases and improve quality of life. The well-known benefits of regular exercise training in reducing the risk for chronic diseases may partly occur through modulation of oxidative stress pathways and better stress resilience. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY: Advanced age substantially increases the risk for a host of diseases including cardiovascular disease, type 2 diabetes, Alzheimer?s disease, and cancer. A major factor that appears to underlie this increased risk with age is reduced capacity to resist oxidative injury or oxidative stress. Therefore, maintaining or increasing the capacity to resist oxidative stress appears critical to the prevention of age-related disease and promotion of successful aging. One potential reason for the lower resistance to oxidative stress with age is a gradual shift in the redox state toward a more oxidized cellular environment potentially disrupting cell-signaling. Nuclear erythroid-2-p45-related factor-2 (Nrf2) is the master regulator of antioxidant defenses. Nrf2 drives expression of a host of genes involved in cellular detoxification and antioxidant defenses. There is strong evidence from animal studies that Nrf2 signaling is reduced with aging and can be at least partially restored with moderate exercise training, however the gap in current knowledge is whether these data do in fact translate to humans. This study will test the following hypotheses in young and older men and women: i) aging is associated with impaired Nrf2 signaling in response to acute exercise and ii) moderate exercise training will improve Nrf2 signaling in older, inactive individuals, and this will increase their resistance to oxidative stress. These hypotheses will be tested by comparing 25 young (18-28y) and 25 older (?60y) inactive individuals before and after an 8-week exercise intervention (n=15 per age group) and in comparison to non-exercising age-matched control groups (n=10 per age group). Nrf2 signaling will be measured in peripheral blood mononuclear cells (PBMCs) in response to acute exercise and will include gene expression (NRF2, NQO1, HO1, GCLC), protein abundance (NRF2, KEAP1, NQO1, HO1, GCLC) and Nrf2-ARE binding capacity. Resistance to oxidative stress will be measured by plasma F2-isoprostane response to forearm ischemia/reperfusion. The results will increase understanding of the mechanisms of diminished stress resilience with aging and the plasticity of these pathways. This will determine whether targeting Nrf2 signaling will be effective for prevention or treatment of these age-related changes which has an enormous public health impact due to the potential of lowering disease risk and medical costs. An additional significance of this project is creating opportunity for undergraduate and graduate students to become involved in research, an important purpose of the Academic Research Enhancement Award (AREA) program and a mission of Northern Arizona University.