The maximal capacity of the testes of otherwise healthy Brown Norway rats to produce testosterone declines significantly with age. The long-term objectives of this project are to understand the intracellular and extracellular mechanisms that underlie this decline, and its consequences. In Part I, we will determine the effect of age on the intracellular transport of cholesterol to and into the mitochondria, and on its conversion to pregnenolone. The similarity of aged Leydig cells to LH-deprived adult cells suggests the possibility of age-related restricted access of LH. In Part II, we will compare LH levels in the interstitial compartment of young and old rat testes, and the ability of exogenously administered LH to enter the interstitial compartment. We will determine whether LH will stimulate steroidogenesis by old Leydig cells in vivo and vitro. Using reciprocal testicular transplants, we also will determine whether the steroidogenic abilities of Leydig cells from old rats can be restored when transplanted into young rats. In Part III, we will test the hypothesis that after the removal of old Leydig cells with EDS, ~new~ Leydig cells repopulate the old tests. We will compare the cells that repopulate young and old testes post-EDS with respect to cell structure, LH responsiveness, cholesterol transport proteins, and steroidogenic enzymes. We will determine when after their appearance the new Leydig cells become steroidogenically hypofunctional in order to understand whether extrinsic factors produced by aged animals cause Leydig cells to become steroidogenically hypofunctional, versus the possibility that this occurs independently of such factors. In Part IV, we will test the hypothesis that chronically active steroidogenesis in some way cause age-related reduced steroidogenesis, perhaps by producing oxygen free radicals. We will determine whether the chronic suppression of Leydig cells steroidogenesis will prevent reduced steroidogenesis. In the same experiments, we will determine whether the suppression of endogenous steroidogenesis will suppress age-related germ cell loss.
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