Summary of work: Normal aging is associated with loss of lean body and muscle mass and strength. There are also increases in body fat, deterioration in lipid profiles and glucose intolerance (risk factors for heart diseasse) and reductions in cardiac function and fitness, immune function, and skin thickness. Reductions in sex steroid hormones, testosterone (T) in men and estradiol (E2) in women as well as growth hormone (GH) and its primary messenger, insulin like growth factor I (IGF-I), with age may contribute to these changes in body composition. Prior studies have shown partial reversal of age-related changes when rhGH was given to older persons. Work in our laboratory has demonstrated improved muscle strength, lipoprotein patterns, blood pressure, and glucose tolerance in men over 65 years of age treated with GH releasing hormone. Current studies examine the effects of GH and sex steroid hormone replacement, alone and combined, on body composition, skeletal muscle (strength, biochemistry, molecular biology), bone biochemistry, endocrine physiology (including plasma leptin, a hormone secreted by fat cells which influences satiety and energy metabolism), glucose and lipid metabolism, measures of gonadal, immune, renal, cardiac and arterial function, quality of life and psychological and sexual variables in healthy men and women over 65 years of age over a 6 month period. As of 9/1/98, 128 subjects have entered the study, 110 have completed, 6 have dropped out and 12 remain active. Because treatment groups are masked, analyses to date are limited to variables measured at baseline. Recently we assessed 60 men for the inter-relationships among nocturnal GH secretion, plasma IGF-I; serum T; body weight, total fat mass, lean body mass, bone mineral density at various sites by dual energy X-ray analysis (DEXA) and chemical measures related to bone turnover including serum osteocalcin, serum procollagen peptide-I, and 24 hr urine of deoxypyridinoline cross links (DPD) and calcium/creatinine ratios (UCa/Cr). We found GH secretion and IGF-I, but not T, to be directly related to hip density. In contrast, T, but not GH or IGF-I, was related to osteocalcin and procollagen peptide-I. Trochanteric BMD was also related to body fat mass, whereas GH was inversely related to fat. Both weight and fat mass were directly related to hip and spine density. Multivariate analyses revealed that weight or fat mass, but not GH, IGF-I or T are independently associated with hip but not spine density. T, but not other measures, is independently and positively related to procollagen peptide-I and osteocalcin. Our findings suggest that in healthy aged men, body weight and fatness are strong positive determinants of hip density, and that T stimulates bone forming (osteoblasts) and inhibits bone destroying (osteoclasts) cells. We have also demonstrated decreases with both age and time in serum T in men in the Baltimore Longitudinal Study on Aging, suggesting that a trend from 1970 to 1995 for lower T in the population as a whole is contributing to the profound reduction of T observed in some older men. Another study has confirmed an association of high IGF-I levels with risk of prostate cancer, suggested a possible protective role for IGF-II, and shown that neither of these measures improves risk estimates obtained from measuring PSA. These studies are aimed at understanding (a) the potential clinical utility of interventions with GH and/or sex steroid hormones and (b) the cellular, biochemical, and molecular events responsible for, and resulting from, altered secretion of these hormones with age. Such investigations may lead to novel therapies to delay or ameliorate the deleterious effects of aging on the musculoskeletal system and other systems which contribute to frailty and loss of mobility in the elderly. Data from the GH/sex steroid intervention study will be analyzed in early to mid-FY '99. New studies are being planned, investigating the effects of an oral GH stimulating agent (GHRP analogue) on bone in osteoporotic women and men and on cardiovascular risk factors and cardiovascular function in older men and women with and without heart disease.