Aging in men results in progressive impoverishment of systemic androgen availability. Epidemiological data establish a close association between hypoandrogenemia and sarcopenia, osteopenia, visceral adiposity, insulin resistance, dyslipidemia, reduced quality of life and institutionalization. However, the precise mechanistic bases of reduced testosterone production in the older male are not known. The present proposal is predicated on the thesis that the male gonadal axis is regulated via reciprocal interactions among all three of GnRH, LH and testosterone. Interpreted from this vantage and compelling preliminary data, we postulate that the primary mechanisms of aging-related testosterone depletion include the following: HYPOTHESIS I: Restricted hypothalamic GnRH drive, which reduces the mass of LH contained in pulses. HYPOTHESIS II: Impaired Leydig-cell steroidogenesis, which enforces systemic hypoandrogenemia. HYPOTHESIS III: Reduced negative feedback by testosterone, which unleashes high-frequency, low- amplitude and irregular LH release. The immediate objective is to elucidate the relative timing, importance and prevalence of the foregoing putative regulatory deficits in the same 40 individuals as a function of age within the continuum 18-80 yr. These data will drive formulation of an R01 to investigate age-related adaptations in the gonadal axis longitudinally. The long-term goal is to stimulate novel insights into mechanistically selective preventive strategies to preserve anabolic support and enhance quality of life, physical and cognitive function and capable independent activities of older citizens. PUBLIC PRECIS. Studies focus on what causes low sex-hormone levels in older men. Low testosterone is important, because it predicts relative physical frailty (thin bones, reduced muscle strength and stamina), less life satisfaction, greater abdominal fat gain and increased cardiovascular risk. Knowing why testosterone falls should help foster new and safer ways to prevent the problem. ? ? ?
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