Reduced serum testosterone (T), or hypogonadism, is estimated to affect about 5 million American men and to be associated with reductions in lean body mass, bone mineral density, muscle mass and libido. In studies supported by the Merit Award that this revised R01 application seeks to renew, we found that decline in serum T levels in aging Brown Norway rats, as in many aging men, results largely from the reduced ability of Leydig cells to produce testosterone in response to luteinizing hormone (LH). In Brown Norway rats, reduced T is associated with reductions in Leydig cell production of cAMP, cholesterol transport from intracellular sources into the mitochondria (the rate-determining step in T formation), steroidogenic acute regulatory protein (STAR), translocator protein (18-kDa; TSPO), and downstream steroidogenic enzymes. Decreases in the antioxidant molecules superoxide dismutase-1 and -2, glutathione peroxidase and glutathione (GSH), and increases in superoxide production, also are seen. We hypothesize that, over time, changes in the Leydig cell oxidant/anti-oxidant environment cause altered LH signal transduction, reduced cholesterol transport into the mitochondria, and ultimately decreased T production. We further hypothesize that maintaining a ?young? redox environment in aged Leydig cells, using biological and/or pharmacological means, will block such changes in steroidogenesis. To address these hypotheses, we will determine the intracellular deficits and molecular mechanisms that cause age-related reductions in T formation, focusing on the molecular consequences of imbalance in the intracellular redox environment that result from steroidogenesis itself or from pharmacologic or genetic manipulation. We will determine whether age-related reductions in Leydig cell T production can be delayed, prevented or reversed. We will compare the changes in Leydig cells of aging rodents to those of aging men by analysis of testicular biopsies, and through the use of testis xenografts. Finally, we will test the hypothesis that Leydig cell T production can be restored to higher (?young?) levels by pharmacological means that by-pass LH signal transduction. The potential impact of this latter approach to T elevation could be paradigm shifting for the clinical treatment of primary hypogonadism in aging (and young) men.
Reduced serum testosterone occurs commonly in aging men, and often is associated with altered mood, fatigue, and decreased lean body mass, bone mineral density and libido. The overarching hypothesis of this proposal is that changes in the balance between reactive oxygen accumulation and the antioxidant defense system cause reduced cAMP production by aged cells, and that this leads to reduced cholesterol transport into the mitochondria and ultimately to reduced testosterone production. We will compare the changes and mechanisms in Leydig cells of aging rodents to those in aging men with the ultimate goal to develop therapeutic approaches to delay, prevent or reverse age-related androgen deficiency.
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