Cardiovascular (CV) aging, featuring large artery stiffening, endothelial dysfunction, and impaired left ventricular (LV) diastolic function, is a maor risk factor for the development of cardiovascular diseases (CVD). Male aging is associated with a gradual and variable decline in serum testosterone (T) and low T is associated with accelerated CV aging. The purpose of this R01 proposal is to determine the key functional mechanisms underlying accelerated CV aging in older men with low T. The overall hypothesis is that mitochondrial dysfunction and oxidative stress are mechanisms underlying the apparent accelerated CV aging in older men with low T. To test this hypothesis Aim 1 will use cross-sectional comparisons of young and older men with normal T (?400 ng/dl), and older men with chronically low T (<300 ng/dl). Carotid artery stiffness, conduit and microvascular endothelial function (brachial artery flow-mediated dilation, hyperemic peak velocity time integral, and peripheral arterial tonometry) and indices of LV diastolic function will be measured during saline (control) and during systemic ascorbic acid infusion, an experimental model to acutely reduce reactive oxygen species (ROS). Additionally, oxidative stress burden and mitochondrial function (biogenesis, networks, respiration, dynamics, ROS) will be measured in harvested brachial artery and peripheral venous endothelial cells, and peripheral blood mononuclear cells. To better isolate the effects of low T from factors that change with aging and chronic low T, Aim 2 will expand on the cross-sectional comparisons by assessing measures of CV function, oxidative stress burden and mitochondrial function in older men with normal T before and after randomization to short-term (28 d) gonadal suppression (gonadotropin releasing hormone antagonist, GnRHant) + placebo (PL), GnRHant+T alone, or GnRHant+T+aromatase inhibitor (AI). AI will control for the effects of aromatization of T to estradiol (E2), and thereby isolate effects while suppressing E2, a potent modulator of CV function. In an exploratory aim, gluteal subcutaneous adipose tissue arterioles will be isolated and assessed for endothelial vasodilation in response to acetylcholine and agents that target ROS and mitochondrial function (e.g., the antioxidants Mito-TEMPOL and MitoQ). The results from this research should provide new mechanistic insight into the processes that mediate the impairment in CV function at the cellular and systemic level in older men with low T. These studies will lead to a better understanding of the independent role of T in age-related changes in CV function and the mechanisms of action, which will help guide future sex-specific therapies for the prevention of CVD.
The findings from this research should provide new information into whether declines in testosterone cause blood vessels and the heart in middle-aged and older men to become unhealthy. Moreover, determining the possible causes by which cardiovascular health changes in relation to declines in testosterone may lead to the development of preventative and therapeutic strategies that could favorably modify these factors, and thus, prevent or slow changes in vascular and cardiac health and decrease cardiovascular disease risk.
|Brown, David A; Perry, Justin B; Allen, Mitchell E et al. (2017) Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol 14:238-250|