Aging Fitness & Failure: Mechanisms of Diastolic Dysfunction

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DESCRIPTION (provided by applicant): Chronic physical inactivity carries with it substantial mobidity, mortality and cost for our aging population. The key finding of the previous funding period for this competitive renewal was that sedentary aging leads to marked atrophy and stiffening of the heart. In contrast, Masters athletes had cardiac compliance that was indistinguishable from young controls. Thus life long exercise training prevented the stiffening of the heart that previously had been considered to be an inevitable consequence of aging. Yet even prolonged and intense exercise training (up to 4-6 hours/week at the end of a year) failed to restore cardiac compliance in these healthy seniors. The global objective of this program is to determine the mechanism(s) of cardiac stiffening with sedentary aging, ascertain when in the aging process it occurs, and identify the minimal dose of sustained exercise training that preserves cardiac compliance over time. Our hypotheses are: Hypothesis 1a: A sedentary lifestyle leads to progressive atrophy and stiffening of the heart over a lifetime. Specific Aim 1a: To examine a cross-section of sedentary individuals over 5 decades from age 25 to 75 with comprehensive invasive and non-invasive measures of cardiac mechanics, relaxation, morphology and structural composition (lipid content and fibrosis). Hypothesis 1b: A sufficient amount of exercise exists that will prevent this stiffening process, if started early enough, and sustained over time; this amount is below that required to be a competitive Masters athlete. Specific Aim 1b: To identify healthy individuals who have consistently trained at 2 different doses: 30 min, 5 or more x/wk; or 30 min, 2-3 x/wk for at least 25 yrs. The same structural and functional assessment will be performed as in aim 1. Hypothesis 2: Chronic plasticity of myocardial compliance in response to aging is dependent on long term changes in metabolism, leading to accumulation of myocardial triglyceride and/or advanced glycation end products (AGEs). Specific Aim 2: to: a) measure myocardial triglyceride deposition using MRS in all the subjects from aim #1a and 1b encompassing a broad range of sedentary aging, and lifelong fitness levels; b) measure hemoglobin A1C as an index of protein glycation; c) perform delayed enhancement contrast MRI, and measure plasma markers of fibrosis. Hypothesis 3: AGE crosslinks must be broken before an improvement in cardiac compliance can occur with exercise training in previously sedentary seniors. The combination of an AGE crosslink breaker with exercise training will be superior to either intervention alone in reducing the cardiac stiffness associated with sedentary aging when initiated later in life. Specific Aim 3: To examine a novel intervention using ALT- 711 a specific breaker of the crosslinks of AGEs in parallel animal and human studies both alone and in combination with exercise training. Lay summary - these experiments will provide new and important information regarding how the heart stiffens with age, and whether regular physical activity can prevent it