Serum levels of testosterone decline as men age. Although the consequences of the decline are not fully understood, it is clear that there are related, life-altering effects of reduced testosterone on osteoporosis, cognition, and libido. Little is known about the molecular mechanisms by which testosterone decline occurs. We have established the Brown Norway rat as an appropriate model with which to study the molecular mechanisms underlying reproductive aging in humans, and have shown that the age-related reductions in serum testosterone are associated with deficits in Leydig cell steroidogenic function. Importantly, we found that exposure of old Leydig cells to LH, whether in vivo or in vitro, will not restore the ability of these cells to produce testosterone at high (""""""""young"""""""") levels, but that incubating the cells with the cAMP analog dbcAMP will do so. Thus, in effect, dbcAMP will reverse Leydig cell aging! These studies highlighted defects in signal transduction of central importance in age-related reduced steroidogenesis. The studies proposed in this application are designed to address the underlying molecular mechanisms by which Leydig cells undergo age-related functional changes that lead to reduced androgen formation. It is our overarching hypothesis that changes in the signal transduction cascade of aging Leydig cells result in the decreased ability of the aged cells to respond to LH and thus in reduced cAMP; that reduced cAMP is responsible for reductions in cholesterol transport into the mitochondria and in steroidogenic enzyme activities; and that reactive oxygen-mediated damage is responsible for changes in the LH signal transduction cascade that ultimately result in the reduced testosterone production that characterizes aging Leydig cells. We will examine critical components of this hypothesis in this revised competing renewal application, which has the following specific aims: 1. Determine the molecular basis for reduced cAMP production in response to LH stimulation. 2. Determine the mechanism by which cAMP restores """"""""young"""""""" levels of testosterone production to aged Leydig cells. 3. Determine whether reactive oxygen-mediated damage to specific components of the signal transduction cascade in old cells is the basis of the molecular changes that lead to reduced testosterone production by aged Leydig cells. ? ? ? ?
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