Human aging is generally accompanied by a gradual decline in various physiological functions, which in some people results in physical impairments, and ultimately may cause disabilities which worsen the quality of life and limit the independence of the individual. It now appears that age-related disturbances in muscle strength, gait, and balance are at least partly reversible. Three well-documented accompaniments of the aging process are: (a) decreased circulating growth hormone (GH) and insulin-like growth factor-I (IGF-I), (b) reduced plasma sex steroid hormone levels; and (c) altered body composition, with decreased muscle mass and increased body fat. Recent evidence suggests that treatment with either recombinant human GH (rhGH) or sex steroids can improve body composition in some older persons, but the effects of such hormonal treatment (singly or in combination) on various physiological functions are unknown. We hypothesize that: (a) the decreases in GH, IGF-I and sex steroids that occur with aging, separately and interactively contribute to diminished skeletal muscle mass and strength, increased body fat, and reduced aerobic capacity in older women and men; and that (b) restitution of normal GH, IGF-I and sex steroid status by combined hormone therapy will exert additive or synergistic effects to increase muscle mass, strength, and aerobic capacity, and decrease body fat. We therefore propose to demonstrate, in a population of ambulatory, community-dwelling, sedentary women and men beyond the age of 65, with low IGF-I and sex steroid levels, and reduced mobility, that 6-months of hormonal treatment with rhGH, sex steroid hormones (estrogen/progestin in women and testosterone in men), or combined rhGH plus sex steroids will, singly or together, result in improvements in certain physiological variables such as skeletal muscle mass and strength, total body protein synthesis, aerobic capacity and myocardial function. Additionally, we propose to examine (1) molecular mechanisms by which the hormonal interventions may exert their effects, using the quantitative RNA template-specific polymerase chain reaction technique to quantify mRNAs for IGF-I, IGF-I receptors and IGF-I binding proteins in skeletal muscle biopsy specimens; and (2) the relationships between the latter molecular events and the physiological outcome variables. Should the proposed study reveal beneficial effects of hormone replacement, then longer-term investigations will be warranted to examine the interactions of hormone treatment with other interventions (e.g. exercise conditioning), and their effects on functional status measurements, in additional populations of older people.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Biological and Clinical Aging Review Committee (BCA)
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Marcell, T J; Harman, S M; Urban, R J et al. (2001) Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men. Am J Physiol Endocrinol Metab 281:E1159-64