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Neuroendocrinology and Aging
Posted on: April 22, 2005

Brown Sequard, the "father of endocrinology," was probably the first experimental gerontologist. He believed that testicular hormone secretion declined with age in men (as demonstrated many years later) and this led to a general decrease in body functions. In 1889 at the age of 72 years, feeling that he was failing in physical and mental vigor, he injected himself with crushed dog and guinea pig testes to which a little water was added and passed through a Pasteur filter. He announced that this treatment reinvigorated him and that he could now work in his laboratory all day and after dinner in the evening, could write and follow other mental pursuits. This aroused considerable skepticism among some but also led to many attempts to improve declining body functions by endocrine and other means that continue to the present day.

Early studies on hormone-aging relationships included measurements of changes in size and weight of endocrine glands and target organs, examination of alterations in their gross and microscopic appearance, bioassays of hormones in endocrine glands, blood, and urine, and clinical observations of endocrine related disorders in elderly individuals. The unavailability of RIAs for accurate measurement of hormone levels in the blood, and lack of knowledge of the commanding role of the hypothalamus in regulating pituitary and indirectly, target gland hormone secretion, greatly limited the scope of the early investigations, and little definitive information was forthcoming. This led several leading gerontological investigators (Korenchevsky, Verzar, and others) to conclude that hormones have only a minor role in aging processes. In light of present knowledge of the important involvement of the neuroendocrine system in aging processes, it can be stated that these conclusions were premature.

Studies on the relation of the neuroendocrine system to aging began in the 1960s and early 1970s. The first reports by Aschheim in France, Peng in Taiwan, and Meites in USA dealt with the relation of the hypothalamus to the reproductive decline in rats. Aschheim showed that when ovaries from young rats were transplanted to old noncycling rats after ovariectomy, the old rats failed to exhibit estrous cycles. On the other hand, when ovaries from old noncycling female rats were transplanted to young ovariectomized rats, estrous cycles ensued in many of the young rats. Peng confirmed these results, and also demonstrated that when the pituitary of old noncycling rats was removed and implanted underneath the median eminence of hypophysectomized young rats, many of the young rats resumed cycling. These important observations demonstrated that neither the ovaries nor the pituitary were mainly responsible for loss of cycling in aging rats, and suggested that cessation of cycling was probably due to faults that developed in the hypothalamus.

The first study to demonstrate direct hypo thalamic involvement in loss of reproductive cycles in rats was Meites report in 1969 showing that electrical stimulation of the preoptic area induced ovulation in old constant estrous rats. Injections of epinephrine-in-oil or progesterone also resulted in ovulation. The observation that electrical stimulation of the preoptic area was effective suggested that sufficient LHRH was present in the hypothalamus to elicit LH release, but the stimulus for its release was lacking. The finding that epinephrine also was effective in evoking ovulation suggested that the missing stimulus might be a catecholamine (CA). Subsequently Meites found that both dopamine and norepinephrine were significantly reduced in the hypothalamus of old as compared to the amounts present in the hypothalamus of young rats.

Administration of drugs that raised hypothalamic CAs, such as L-dopa, the precursor of CAs, or iproniazid, a monoamine oxidase inhibitor that depressed CA catabolism, induced resumption of estrous cycles in the old rats. The decrease in hypothalamic dopamine activity in old rats and mice was found to be mainly responsible for the rise in PRL secretion and development of numerous mammary and PRL-secreting pituitary tumors.

Administration of L-dopa or the longer acting ergot drugs that inhibit PRL secretion resulted in inhibition of PRL secretion and regression of mammary and pituitary tumors. The reduction in hypothalamic CAs was also found to be responsible for the decline in GH and somatomedin-C secretion in old male and female rats. Injections of L-dopa were shown to return pulsatile GH secretion in old male rats to the same levels as in young male rats. In elderly man, a similar decline in GH and somatomedin-C secretion was observed, and this too may be related to the reduction found in hypothalamic CAs.

Administration of drugs that elevated hypothalamic CAs were reported by four different laboratories to significantly lengthen the average lifespan in rats or mice, decrease the incidence of disease and tumors, promote sexual vigor and fertility, and improve memory. These effects were not usually associated with reduced food intake or loss of body weight. Other changes reported in the hypothalamus with age include loss of neurons in specific nuclei, a decrease in hormone receptors, an increase in hydrogen peroxide and hydroxyl radicals resulting from catabolism of CAs, a reduction in tyrosine hydroxylase, the rate-limiting enzyme for synthesis of CAs, and an increase in monoamine oxidase, the major enzyme responsible for catabolism of monoamines. These changes may largely account for the decline in hypothalamic CAs with age.

In addition to the dysfunctions that develop in the hypothalamus with age, there is evidence that other components of the neuroendocrine system develop faults. The pituitary of old rats has been reported to be less responsive to stimulation by GnRH, GHRH, TRH, and CRF than the pituitary of young rats. Similarly the pituitary of elderly human subjects was observed to be less responsive to stimulation by GnRH and GHRH than the pituitary of young individuals. There also is some evidence that target gland responses to pituitary hormones, and body tissue responses to target gland hormones may decrease with age. Some of these have been found to be associated with a decrease in receptors or to postreceptor changes in cells. These decreases in response of endocrine and nonendocrine tissues to hormones are believed to be of secondary importance to the faults that develop in the hypothalamus with age.

Significant declines also occur in the immune system with age. Since the neuroendocrine and immune systems function coordinately as a bidirectional network, and both systems exhibit a functional decline with age, it is important to determine the relation of each system to the decline of the other. There is evidence that the reduction in immune function with age is at least partly attributable to the decrease in GH and thyroid hormone secretion.

Administration of GH to old rats was reported to return size and function of the thymus gland, the chief component of the immune system, to the same levels as in young rats.

Administration of T4 similarly elevated thymic function in old mice. The effects of the immune system on neuroendocrine function with age are presently unknown, but there is substantial evidence that thymic peptides can alter hypothalamic, pituitary, and target gland hormone secretion.

Most gerontological investigators agree that the genome is of primary importance in regulating length of life, which is related to aging, and that environmental factors are involved. Other opinions are that the genome and environment exert their effects on aging processes mainly via the neuroendocrine and immune systems, the two systems of the body which are most important for integrating body functions and maintaining homeostasis. Other theories have emphasized changes in transfer of information from DNA via mRNA resulting in errors in protein synthesis, an increase in "free radicals" with resulting damage to many body cells, a failure of cells to divide or function due to loss of a genetic program, etc.

It is doubtful that any single theory of the causes of aging can explain all aspects of the aging phenomenon. It is clear however, that the neuroendocrine approach, although relatively recent in origin, has already provided some valuable knowledge and insights into the causes of the aging declines in body functions, and suggested methods of intervention that may inhibit or reverse aging processes and perhaps lengthen the lifespan.

Source: Joseph Meites; Remembrance: Neuroendocrinology and Aging. A Perspective; Endocrinology; 1992 by the Endocrine Society Vol. 130, No. 6
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