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Role of IGF-1 In Diastolic Dysfunction of Aging

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14. Functional Senescence: Genetic, physiological, cellular and biochemical mechanisms that underlie age-related changes leading to dysfunction in tissues, systems, or organs. Aging is associated with diminished cardiac performance characterized by a prolonged relaxation phase. This impairment in relaxation, diastolic dysfunction, contributes to the increased incidence of congestive heart failure in people older than 65. Although one proposed mechanism underlying diastolic dysfunction of aging is an alteration in intracellular cardiac calcium handling, recent evidence suggests that an age-related decline in the pulsatility of growth hormone (GH) secretion or Insulin-Like Growth Factor-1 (IGF-1), the mediator of GH, may also be involved. To evaluate the role of GH and IGF- 1 senescence on diastolic function, an age-simulated GH deficient rat model will be used. Dwarf rats treated and subsequently withdrawn from GH will be compared to dwarfs continuously repleted with GH and to heterozygous, saline-treated dwarfs in order to assess diastolic function in the intact heart (echocardiography), cardiomyocyte (mechanics and Ca 2+ transients), and at the calcium regulatory protein level (i.e., SERCA2, phospholamban). We hypothesize that age-mediated reductions in the phasic secretion of GH (or IGF-1) alter the calcium regulatory proteins involved in myocardial relaxation and that this underlies diastolic dysfunction of aging. This study will provide the groundwork for future studies examining how IGF-1 signaling may modulate the programming and gene expression of the senescent myocardium.
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