A substantial volume of scientific evidence has been accumulated demonstrating that biological aging is associated with functional deficits at the cellular, tissue, organ, and system levels. Although several theories have been proposed to explain these changes, as well as the increased risk of disease with age, no single explanation has adequately accounted for the diversity of physiological changes associated with age. The concept that deficiencies in the neuroendocrine system contribute to aging evolved from studies indicating that (1) the endocrine system has an important role in developmental processes, (2) hormones have an important trophic and integrative role in maintaining tissue function, and (3) hormone deficiency results in deterioration of tissue function.
The neuroendocrine system is composed of the hypothalamus and pituitary gland and is under the influence of neurotransmitters and neuropeptides that regulate hypothalamic releasing and hypothalamic release inhibiting hormones secreted into the blood vessels that connect the hypothalamus and pituitary gland. The release of these hypothalamic hormones influences the secretion of anterior pituitary hormones that subsequently regulate tissue function. The hypothalamus and pituitary gland have the capacity to detect humoral secretions (hormones secreted) from target tissues and adjust hormone production to maintain an optimal internal "milieu" appropriate for normal function. It is well-established that the neuroendocrine system has a critical role in integrating biological responses and influencing: (1) cellular protein synthesis and general metabolism through the release of growth hormone and thyroid-stimulating hormone (TSH), respectively, (2) reproductive function through the release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, and oxytocin, and (3) plasma electrolytes and responses to stress through regulation of the hormones vasopressin (antidiuretic hormone, or ADH) and adrenocorticotropin (ACTH). In addition, the hypothalamus also has an important role in the integration of parasympathetic and sympathetic nervous system activity, and can thereby influence a wide variety of functions, including heart rate, blood pressure, vascular responses, and glucose metabolism. The hypothalamus has been implicated in the regulation of biological rhythms by its interactions with hypothalamic nuclei. More recently, the regulation of fat metabolism and food intake has been shown to be regulated through the hypothalamus by its response to the protein, leptin, and its synthesis of neuropeptide Y. It should be noted that the classification of hormones and their primary function presented here is an overly simplistic view of the neuroendocrine system, since critical interactions occur among these hormones that contribute to the coordinated regulation of cellular and tissue function.
Although the specific etiology of age-related changes in the neuroendocrine system is unknown, it has been proposed that cellular and molecular alterations in specific subpopulations of neurons within the hypothalamus and pituitary, and/or supporting structures within the brain, contribute to the decrease in tissue function. Some of the alterations may be related to loss of neurons or synapses, genetic errors, and/ or the production of free radicals, all of which lead to progressive aberrations in neurons and contribute to neuroendocrine aging. As a result, the neuroendocrine theory of aging is unique when compared to other theories of aging in that the neuroendocrine alterations are, in many cases, not considered the primary causative factors of biological aging, but rather are considered to be mediators of aging that are initiated by cellular changes in specific subpopulations of neurons or systems that closely interact with hypothalamic neurons.
Three classic examples of age-associated changes in neuroendocrine regulation, and the resulting consequences for tissue function, help emphasize the importance of this system in the development of the aging phenotype. First, with increasing age there is a decline in growth-hormone secretion that results in a decrease in insulin-like growth factor-1 (IGF-1) production in the liver and other tissues. The loss of these anabolic hormones contributes to the general decline in cellular protein synthesis, skeletal muscle mass, immune function, and cognitive ability in rodents, nonhuman primates, and humans. The decrease in growth-hormone release from the pituitary gland results from impaired release of growth-hormone-releasing hormone and increased release of somatostatin (an inhibitor of growth hormone) from hypothalamic neurons. Second, decreased secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons results in a decline in luteinizing hormone. This is the primary factor in the loss of reproductive cycles in the female rodent, and, in conjunction with the loss of ovarian follicles, contributes to the decline in estrogen levels in women. These latter changes result in atrophy of secondary reproductive tissues and have been implicated in the post-menopausal loss of bone and cognitive function. Decreased GnRH secretion in the male also contributes to a decrease in LH and androgen levels and to the corresponding loss of skeletal muscle mass and reproductive function. Finally, increased secretion of ACTH and the adrenal hormone, cortisol, in response to stress have been reported to contribute to atrophy and/or loss of neurons, as well as age-related decline in cognitive function. These latter findings have contributed to the hypothesis that increased levels of glucocorticoids contribute to brain aging.
Although other mechanisms are possible, the alterations in the secretion of hypothalamic hormones with age have been traced to deficiencies in the secretion of brain neurotransmitters. For example, the activity of dopamine and norepinephrine decreases with age, and both acute and chronic procedures used to increase levels of these neurotransmitters in aged animals have been shown to restore some aspects of neuroendocrine function. Studies have shown an increase in growth hormone release and a restoration of some aspects of reproductive function in older animals in response to the L-Dopa, dopamine and norepinephrine precursor. These findings have led investigators to conclude that a decline in neurotransmitter activity is a contributing factor in the neuroendocrine decline that accompanies aging. Nevertheless, the possibility that interactions with other hypothalamic peptides, the loss of neurons, or intracellular changes within hypothalamic neurons contribute to the loss of function cannot be excluded. In fact, the inability of hypothalamic neurons to compensate for the age-related alterations in circulating levels of hormones supports the concept that the normal feedback mechanisms that occur within the hypothalamus are impaired in aged animals. Whether these altered feedback mechanisms are related to the deficiencies in neurotransmitters or result from other aberrations within the aging neuroendocrine system remain to be established. Nevertheless, deficits in the regulation of these critical hormonal systems contribute to deterioration of tissue function and undoubtedly are an important factor in age-related disease and disability.
WILLIAM E. SONNTAG
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