A large body of scientific evidence has accumulated to support the concept that decreases in anabolic hormones that occur with aging contribute to the aging-related decline in tissue function and the aging phenotype. Growth hormone and insulin-like growth factor-1 (IGF-1) are two potent anabolic hormones, and decreases in these hormones have been hypothesized to contribute to the loss of muscle and bone mass, as well as cognitive and immune function, in older adults. In young adults, growth hormone is released in pulsatile bursts from the pituitary gland, with the majority of secretion occurring at night in association with slow-wave sleep. Similar pulses are observed in rodents, except that secretory pulses occur every 3.5 hours in males and hourly in females. The regulation of these pulses involve at least two hormones released by the hypothalamus: first, a growth-hormone-releasing hormone (GHRH), which increases growth-hormone release; and second, somatostatin, which inhibits its release. The dynamic interactions between these hypothalamic hormones regulate high amplitude, pulsatile, growth-hormone secretion. Activation of the hepatic growth-hormone receptor by growth hormone stimulates the synthesis and secretion of IGF-1 into plasma, which, in turn, stimulates DNA, RNA, and protein synthesis and is a potent mitogen for many tissues. Growth hormone and IGF-1 circulating in the blood suppress growth-hormone release from the pituitary in a typical feedback relationship—either directly at the level of the pituitary, or by stimulating somatostatin and/or inhibiting GHRH release from the hypothalamus.
Studies in humans have indicated a substantial decline in the ability of older individuals to secrete growth hormone, and it is now evident that the decline in high-amplitude growth-hormone secretion and plasma IGF-1 concentrations are one of the most robust and well-characterized events that occur with age. Similar to humans, decreases in the amplitude of growth-hormone pulses are observed in rodent models of aging, and these changes, as expected, are closely associated with a decline in plasma IGF-1. Although the specific etiology for the decline in growth-hormone pulse amplitude has not been fully detailed, studies in both humans and animals have documented that, rather than a decline in pituitary response to these hypothalamic peptides, alterations in the secretion of both hypothalamic release and inhibiting hormones appear to be the key factors in the decline in growth-hormone pulse amplitude with age. Since these hypothalamic hormones are controlled by brain neurotransmitters, the concept has evolved that alterations in the regulation of neurotransmitters within the brain are part of the mechanism for the decrease in growth hormone.
Although an attenuation of growth-hormone pulse amplitude is an important contributing factor in the decline in plasma IGF-1, studies have also demonstrated that, in response to growth-hormone administration, the ability to increase IGF-1 secretion is diminished in elderly individuals. These results indicate that not only a decline in growth-hormone pulse amplitude, but also tissue resistance to growth-hormone action, is responsible for the reduced plasma IGF-1 concentrations. In rodents, a two-fold increase in hepatic growth-hormone receptors has been reported with age, but this increase is unable to compensate for the reduced levels of growth hormone. Thus, there appears to be a failure of circulating growth hormone to activate intracellular signaling pathways that, in addition to the decrease in growth hormone, contribute to a decline in blood levels of IGF-1 in both animals and humans.
Even though a decreased response to growth hormone is an important component of the age-related decline in plasma IGF-1, this deficit can be partially overcome by administration of exogenous growth hormone. Studies in rodents have revealed that the administration of growth hormone increases IGF-1 and restores cellular protein synthesis in the muscle of old animals, indicating that the age-related decline in tissue function results, at least in part, from hormone deficiency. Other reports have been published demonstrating that either growth hormone or IGF-1 could partially reverse the decline in immune function, increase blood vessel elasticity, and increase life span in rodents. These studies were the first indications that the decrease in the concentration of growth hormone has clinical significance and may be responsible for the generalized catabolic state that accompanies normal aging. In the elderly, it has generally been reported that growth-hormone administration increases IGF-1, lean body mass, muscle mass, and skin thickness, and also reduces total body-fat content. In addition, there are reports of elevations in serum osteocalcin (a marker of bone formation) and nitrogen retention, raising the possibility that growth-hormone treatment may delay osteoporosis.
In addition to its role in regulating tissue growth, more recent studies indicate that administration of growth hormone reverses the age-related loss of blood vessels. These and related studies indicating that IGF-1 is produced in microvessels have led to the concept that a reduction in growth hormone and the subsequent decrease in plasma and microvascular-derived IGF-1 lead to a decline in tissue function and/or reduce the capacity of tissues to respond to appropriate stimuli. In fact, raising levels of IGF-1 in old animals has been shown to improve the function of several neurotransmitter systems, glucose utilization and cognition, and also to improve contractility in the heart.
Although there are many potential beneficial effects of growth-hormone therapy in aged animals and humans, the adverse effects of therapy include sodium retention, carpal tunnel syndrome, potential glucose resistance, and hyperinsulinemia. Epidemiological studies also indicate a significant correlation between levels of IGF-1 and prostate, breast, and lung cancer, raising the concern that administration of these mitogenic hormones may initiate and/or accelerate pathological changes in the elderly. These issues have not been directly tested to date, but studies indicate that moderate caloric restriction (60 percent of ad libitum food intake), which is capable of decreasing age-related pathology, also lowers plasma IGF-1 levels. Subsequent administration of IGF-1 to these animals removes the protective effects of moderate caloric restriction from specific carcinogens, providing support for the concept that the beneficial effects of moderate caloric restriction are mediated, in part, by decreasing levels of IGF-1. The association between IGF-1 and age-associated pathogenesis remains to be established. Thus, the available evidence suggests that a decline in growth hormone and IGF-1 contribute to the functional decline in tissues with age, but that raising the levels of these hormones may increase the risk of age-related pathology.
WILLIAM E. SONNTAG
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RUDMAN, D.; FELLER, A. G.; NAGRAJ, H. S.; GERGANS, G. A.; LALITHA, P. Y.; GOLDBERG, A. F.; SCHLENKER, R. A.; COHN, L.; RUDMAN, I. W.; and MATTSON, D. E. "Effects of Human Growth Hormone in Men over 60 Years Old." New England Journal of Medicine 323 (1990): 1–6.
SONNTAG, W. E.; LYNCH, C. D.; CEFALU, W. T.; INGRAM, R. L.; BENNETT, S. A.; THORNTON, P. L.; and KHAN, A. S. "Pleiotropic Effects of Growth Hormone and Insulin-Like Growth Factor (IGF)-1 on Biological Aging: Inferences from Moderate Caloric-Restricted Animals." Journal of Gerontology; Biological Sciences 54A (1999): 521–538.
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