Aging Clin. Exp. Res. 9 (Suppl. to No. 4): 21-22, 1997

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During aging, the CNS undergoes several mor-phological and biochemical modifications, such as a progressive reduction in the number of neurons and in the density of dendrites and synapses and changes of neurotransmitters.

The neuronal loss and the compensatory gliosis are particularly marked in some brain areas, namely the hypothalamus, the hippocampus and the limbic system. Furthermore, the prevalent impairment of some neurotransmitters (e.g., catecholaminergic) and the relative resistance of others (e.g., cholinergic and serotoninergic), are responsible for an unbalance among the different neurotransmitters and neuro-modulators in the aged brain.

The neurotransmitter’s rhythmicity is also more or less impaired in aging; for instance the circadian rhythm of central serotonin becomes undetectable in aged animals, and this may affect other biological rhythms, due to the modulatory role played by sero-tonin on different bioperiodic functions.

The neuroendocrine changes occurring in aging may arise either from the structural changes of the hypothalamus, the hippocampus and the limbic sys-tem, or from the alterations of the central neuro-transmitter pattern. On the whole, the neuroendo-crine features of elderly people seem to be related more to disorders of the relationships between neural and endocrine signals than to specific alterations of the different endocrine structures.

The suprachiasmatic nuclei of the hypothalamus have also in humans an important role in the modu-lation of most circadian rhythms. The occurrence in aging of SCN structural and neurochemical altera-tions may affect several circadian rhythms which become dampened in old age. Another possible fac-tor responsible for the changes of circadian rhyth-micities in elderly people may be the reduction of the effects of external synchronizers, namely the rest-activity cycle and the social routine, because of the age-related changes of life habits.

The influences of ageing on biological rhythms are not uniform, since not all the rhythms undergo the

same modifications. Indeed, a progressive impair-ment of the rhythms with short period (i.e., < 24 h, or ultradian rhythms) occours, whereas the circadian rhythms (i.e., with a period of about 24 h) are gener-ally maintained although with some changes of their parameters, like the reduction of the amplitude or the shifts of the crest time. Due to the varying chang-es of the acrophase of the different rhyhtms, differ-ences in phase relationships among several biological rhythms show up with aging and therefore a more or less severe internal desynchronization becomes evi-dent in elderly people.

The chronobiological approach to the study of neuroendocrine functions in elderly people may af-ford insights on the age-related changes of the CNS and particularly of the limbic-hypothalamic system. In particular, the evaluation of the circadian rhythmic-ity of hormonal secretions may give information about the pathophysiology of neuroendocrine func-tions better than the dynamic tests, which in fact sometimes do not reflect the spontaneous hormonal release.

Many circadian rhythms are adaptive in nature, allowing the organism to adapt in phase to the peri-odic environmental changes, and therefore they represent an essential component of the organism plasticity. On the other hand, it is well-known that aged organisms are characterized by the impairment or even the loss of the adaptation capacity to chang-es of the external milieu as well as to stressful condi-tions.

In this context, the study of the circadian rhythm of melatonin, ACTH and cortisol secretion is very interesting in elderly people, due to their role in the adaptive responsens of the organism.

In particular the circadian periodicity of melatonin secretion may be considered as a marker of the cen-tral noradrenergic activity and as an endogenous synchronizer for several biological rhythms. It has also been suggested that the maintenance of mela-tonin circadian rhythm could even prolong the life span because of the possible anti-aging properties of

Neuroendocrine circadian rhythms in agingE. Ferrari, M. Locatelli, F. Magri, E. Robino, N. Pezza, T. Nescis, E. Germani, M. Mauri,and S.B. SolerteDept. of Internal Medicine and Medical Theraphy, Chair of Geriatrics, University of Pavia, Italy

Correspondence: Prof. E. Ferrari, Dep. Intern. Med. and Med. Therapy, Chair of Geriatrics, p.za Borromeo, 2 - 27100 Pavia, Italy.

melatonin itself.Our experience concerns the simultaneous evalua-

tion of several neuroendocrine rhythms in a large number of healthy aged subjects, without cognitive or affective disorders. The main results of our studies concern the age-related decrease of the amplitude of the circadian fluctuations of both hormonal parame-ters and body temperature, and the selective impair-ment of nocturnal melatonin, GH and PRL secre-tions.

Furthermore it becomes evident with aging a dis-sociation of the adrenocortical secretory pattern, characterized by the maintenance of normal cortisol levels at day-time and significantly higher levels at evening- and night-time by comparison to young controls, and by a marked decrease of serum DHEA-S at every time of the circadian cycle. The coexist-ence of relatively higher ACTH and cortisol levels during the night, namely at the moment of the maximal sensitivity of the HPA axis toward the ster-

oid feedback, suggests an impairment of this sensitiv-ity in physiological aging. Our results concerning the Dexamethasone suppression test agree with this hypothesis.

In conclusion, the age-related changes of the neu-roendocrine rhythms may be responsible for the impaired adaptive responses to stressful conditions and to environmental changes as well as for the metabolic and immunologic disorders occurring in elderly people.

REFERENCES 1 Ferrari E., Magri F., Dori D., Migliorati G., Nescis T., Molla G.,

Fioravanti M., Solerte S.B.: Neuroendocrine correlates of the aging brain in humans. Neuroendocrinology 61: 464-470, 1995.

2 Ferrari E., Magri F., Locatelli M., Balza G., Nescis T., Bat-tegazzore C., Cuzzoni G., Fioravanti M., Solerte S.B.: Chro-no-neuroendocrine markers of the aging brain. Aging Clin. Exp. Res.: 8: 320-327, 1996.

3 Magri F., Locatelli M., Balza G., Molla G., Cuzzoni G., Fio-ravanti M., Solerte S.B., Ferrari E.: Changes in endocrine circadian rhythms as markers of physiological and patho-logical brain aging. Chronobiol. Int. 1997, (in press).

E. Ferrari, M. Locatelli, F. Magri, et al.

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