Aging depletes the primary trophic hormones, growth hormone (GH), insulin-like growth factor type I (IGF- I) and testosterone (Te). Inferred sequelae include diminished anabolic drive to muscle, bone, brain and sexual organs and accentuated visceral adiposity, insulin resistance, dyslipidemia and cardiovascular risk. A major unmet need is to understand the fundamental mechanisms that enforce GH/IGF-I deprivation in older individuals with aging-related relative Te deficiency. Compelling data obtained during the initial tenure of the MERIT award frame the thesis that aging and Te availability govern an ensemble of interlinked peptides that direct GH secretion. The minimal ensemble comprises GH-releasing hormone (GHRH), somatostatin (SS), GH-releasing peptide (ghrelin, CHRP), and GH and IGF-I. From this vantage, we pose the following mechanistic hypotheses: Hypothesis I: Aging and relative Te deficiency reduce feedforward synergism by GHRH and ghrelin. Hypothesis II: Aging and associated Te depletion suppress GH secretory-burst mass in part by: (i) elevating somatostatin (SS) outflow under high (nighttime) GH feedback; and (ii) augmenting SSergic restraint under low (daytime) GH feedback. Hypothesis III: Aging and concomitant Te withdrawal impair the expected capabilities of ghrelin to amplify GHRH feedforward and SS rebound-induced GH secretion. Hypothesis IV: Aging and Te deprivation potentiate negative feedback by circulating free (protein- unbound) IGF-I, which restricts GHRH's stimulation and accentuates SS's inhibition of GH outflow. Because no single peptidyl signal controls GH output, unique analytical tools and experimental strategies will be applied to aid interpretation. The expectation is to clarify how Te deficiency in older individuals including those receiving androgen-withdrawal therapies for urological neoplasms exacerbates aging- associated GH and IGF-I depletion. The outcomes should provide a fundamental rational basis for constructing novel interventions to forestall frailty-related disability, morbidity and mortality in older men. Public Precis The scientific objective is to elucidate why aging decreases the secretion of pituitary hormones, which otherwise maintain physical strength, normal body-fat content, skeletal calcium, muscle mass, cognition, sexual function and well being. The long-term goal is to develop new, safe and effective ways to prevent physical frailty and disability in older citizens, including in men who require treatments (e.g., for urological cancers) that markedly reduce male hormone concentrations.
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