RO1 National Institutes on Aging 2006-2011

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. After completion of these experiments, we will have obtained novel and clinically important information regarding the nature of the cardiac atrophy and stiffening associated with sedentary aging, including its age at onset and rate of change over the life span, as well as how much exercise is needed to prevent this process from occurring.  Mechanistic studies in both animals and humans will identify the unique mechanisms responsible for this process, focusing on the long term metabolic consequences of a sedentary lifestyle.  Finally, a novel intervention combining moderate (and sustainable) exercise training with a drug to break AGE crosslinks will be tested that may offer new hope for elderly patients who are suffering the clinical consequences of diastolic dysfunction.

"Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance and Risk of Cardiac Arrhythmias"

NASA - HEDS  1/10/2004 - 9/30/2012

Cardiac atrophy appears to develop during spaceflight or its ground based analogues, leading to diastolic dysfunction and orthostatic hypotension.  Such atrophy also may be a potential mechanism for the cardiac arrhythmias recently identified in some crew members after long duration exposure to microgravity aboard the Mir space station.  Recent work by the PI has suggested that cardiac atrophy may be progressive, without a clear plateau over at least 12 weeks of bed rest, and thus may be a significant limiting factor for extended duration space missions. The global objective of this proposal is to quantify the extent and time course of cardiac atrophy and identify its mechanisms. The functional consequences of this atrophy also will be determined for cardiac filling dynamics, orthostatic tolerance, and arrhythmia susceptibility both in space on the International Space Station, and following return to earth. Three specific aims will be addressed: 1) To determine the magnitude of cardiac atrophy associated with long duration spaceflight, and to relate this atrophy to measures of physical activity and cardiac work in flight.  Magnetic resonance imaging will be performed pre-and post-flight as the most accurate means of  measuring cardiac mass, and cardiac ultrasound will be performed in-flight to determine the time course and pattern of progression of atrophy in space; 2) To determine the functional importance of this atrophy for orthostatic tolerance and the regulation of stroke volume by using a combination of classical, invasive cardiovascular physiology to measure the static component of diastole, in conjunction with novel, non-invasive imaging techniques to measure the dynamic component of diastole; 3)  To identify changes in ventricular conduction and repolarization during and after long duration spaceflight, and relate these to changes in cardiac mass.  After completion of this study, the clinical manifestations of cardiac atrophy during long duration space flight will be defined clearly, and its significance for diastolic function and orthostatic tolerance will be elucidated, thus supporting the application of specific countermeasures currently being developed by the PI in parallel ground based experiments. Information will be obtained regarding ventricular conduction and repolarization that may provide insight into the risk for cardiac arrhythmias.  The information obtained from these spaceflight experiments also will be relevant for patients after prolonged confinement to bed rest, as well as conditions that alter cardiac stiffness such as congestive heart failure, ischemic heart disease, and normal aging.

“The Multisystem Effect of Exercise Training/Nutritional Support During Prolonged Bed Rest Deconditioning:  An Integrative Approach to Countermeasure Development for the Heart, Lungs, Muscles and Bones”

NASA-NSBRI  6/1/2005 – 8/30/2009

Sustained exposure to microgravity leads to adaptive changes in the cardiovascular and musculoskeletal systems that may result in substantial morbidity. For example cardiovascular atrophy, hypovolemia, and altered reflex responsiveness may lead to orthostatic hypotension and syncope. Disuse atrophy of skeletal muscle will diminish work capacity and may lead to muscle injury. Bone demineralization increases the risk of kidney stone formation, and may reduce bone strength, increasing the risk of fracture. Changes observed previously in short duration missions may be exacerbated during long duration missions, such as those required to sustain humans in space aboard the International Space Station (ISS) or a mission to Mars. Previous work has focused on one organ system at a time, ignoring the interaction among systems, and preventing the development of a specific countermeasure for an individual astronaut that might be effective for the heart, muscles and bones. The global objective of this proposal is to test an integrated countermeasure that will be effective against cardiovascular deconditioning, skeletal muscle atrophy, and bone demineralization, and that can be applied practically aboard the ISS or a mission to Mars. We propose to accomplish the following specific aims: Aim 1: To perform an exercise countermeasure using rowing ergometry combined with resistance training to obtain the most intensive stimulus to cardiac hypertrophy in the shortest period of time. The functional importance of cardiac atrophy after prolonged bed rest will be determined with a novel combination of invasive and non-invasive techniques to measure both the static and dynamic component of diastole; Aim 2: To assess the effect of exercise combined with potassium-magnesium-citrate supplementation in preventing microgravity-induced increases in bone resorption, urinary calcium excretion, and risk of stone formation. These aims will be accomplished by precise metabolic control and evaluation, and non-invasive (ultrasound) assessment of bone structure and function; Aim  3: To use dynamic and resistance exercise training to attenuate the loss of structure and functional capacity of skeletal muscle during prolonged bed rest. Methods will include measures of whole muscle size (magnetic resonance imaging), exercise capacity (strength and endurance), biochemistry (enzyme activities, ubiquitin-proteasome pathway induction), and histology (fiber type, morphometry, & capillary density).

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