Young at Heart.

Abstract

Theagingprocesshasa significant effecton the structure and function of the cardiovascular system. Also, an age-dependent increase in the prevalence of cardiovascular disease, hypertension, and heart failure is clinically observed. Experimentally, a plethora of cellular adaptations in the cardiovascular system are associated with aging. These changes broadly include increased sympathetic nerve activity (in part due to increased circulating catecholamines), increased cardiac responsiveness to the renin-angiotensin system, increased extracellular remodeling with increased cardiac fibrosis, increased reactive oxygen substrate production, and decreased functioning of autophagy (1). Over time, these cellular changes lead to arrest of normal cell cycle progression, loss of cardiomyocytes, cardiac hypertrophy, and altered diastolic functioning with impaired myocardial perfusion, a process broadly referred to as cardiac senescence. The GH/IGF-1 axis is a principal mediator of growth and metabolism with an established role in aging. In humans, after 60 years of age, there is a significant decline in circulating levels of both GH and IGF-1. Recognition of this phenomenon, known as “somatopause,” led to the proposal that replacement of GH and IGF-1 may mitigate the effects of aging (2). Indeed, this has spurred to the production of several dubious “supplements,” from deer antler preparations to amino acid mixtures, that tout antiaging effects and superficially appear to be related to GH and IGF-1. However, animal studies have demonstrated quite opposite results. Studies in Drosophila, worms, and rodents have established increased longevity with disruption of the GH/IGF-1 axis. For example, mice with diminished GH levels or with a GH receptor gene disruption (GHRKO) have increased longevity (3). Indeed, GHRKO mice are currently the longest lived mouse line with a mouse reaching a lifespan of almost 5 years (http://www. methuselahfoundation.org/). The relationship with IGF-1 and aging is more nuanced. Mice with a complete deletion of IGF-1 receptor (IGF-1R) exhibit a high degree of mortality (4), whereas female mice heterozygous for a mutated IGF-1R allele have an increased lifespan (5). Likewise, decreasing bioavailability of IGF-1 through deletion of the metalloproteinase PAPP-A (responsible for cleaving IGF-1 from IGF-binding protein 4) also increases lifespan (6). The role of IGF-1 in the myocardium is equally layered. Overexpression of skeletal muscle IGF-1 in mice using the -actin promoter/enhancer results in high levels of IGF-1 in muscle and heart without a concomitant increase in circulating IGF-1. These mice develop concentric ventricular hypertrophy before 10 weeks of age with no decline in cardiac function. After 10 weeks, however, the chronic effects of high IGF-1 manifest as ventricular stiffening, loss of ventricular compliance, decreased cardiac function, and cardiac fibrosis (7). Cardiac-specific deletion of IGF-1R (CIGF1RKO) has been reported to result in normal cardiac development but an attenuated response to exercise induced hypertrophy in 13to 15-week-old mice (8). This may be due, in part, to an up-regulation of AMP kinase action and subsequent antagonism of mammalian target of rapamycin/S6 kinase mediated hypertrophy (8). Inducible, cardiac-specific IGF-1R gene disrupted mice demonstrate varying results depending on the age of disruption. IGF-1R disruption in 3-month-old mice does not lead to any functional changes measured by in vivo pressure measurement or magnetic resonance imaging (9). Disruption at 11 months of age, however, is associated with an approximate 25% decrease in ventricular developed