Aging 3: 103-116, 1991

REVIEW ARTICLE

Pineal gland and aging G.P. Trentini, C. De Gaetani, and M. Criscuolo ... Institute of Pathological Anatomy, University of Modena, Pohchmco, Modena, Italy

INTRODUCTION Advancing age is characterized by a progressive impairment of virtually all cognitive a.nd behavioral functions, and several degenerative changes, such as neuron loss, myelin degeneration, gliosis and neurotransmitter system ?ecline, are considered the hallmarks of the agmg brain. In accord with many studies, the steady decline in the weight of fixed brain appears as a function of age between 20 and 100 years, and neurotransmitter system changes widely involve the central nervous system (CNS), including cholinergic, aminergic and peptidergic ne.urons (1-3). In particular, a marked decrease m volume total cell number and number of vasopres~inergic cells was observed in suprachiasmatic nuclei (SCN) in subjects aged 80-100 years (3).

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The notion that SCN are the major CIrcadian pacemaker of the mammalian brain, coordinating hormonal and behavioral circadian rhythms, has gained much support over the last decades (4). Circadian rhythms are a fundamental. feature of all living organisms, whose functional integrity not only depends on the maintenance of a constant internal milieu, but also on the maintenance of complex temporal relations between various oscillating variables at a cellular as well as an organic and organ-system level. The frequent occurrence of depression, the loss of reproductive capacity, as well as the decreased thermoregulatory ability, and, par-

ticularly, the fragmentation of sleep~V:'ak~ p~t­ terns suggest that circadian rhythmlclt.y IS ?ISrupted with aging at various levels of blol
Ke words: Aging, circadian rhythms, immune system, pineal gland, reproductive sy~tem: . . . . Co~respondence: Prof. Gian Paolo Trentini, Institute of Pathological Anatomy, Umverslty of Modena, Pohchmco, Via del Pozzo 71, 41100 Modena, Italy. Received and accepted March 7, 1991.

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ical and ultrastructural investigations into agerelated changes in the pineal gland of older animals, no definitive evidence for pineal degeneration in old age has emerged thus far (13-16). Increased lobulation of the parenchyma, fibrosis and gliosis are most commonly reported, but a slight decrease in the degree of cellularity was found only in males after the age of 44 (13, 14). Even the process of pineal calcification, today regarded as a parenchymal degenerative phenomenon correlated with past secretory activity (17, 18), did not appear to increase proportionally with advancing age (19, 20). However, the amount of calcareous concretions appears significantly higher in males than in females, and it presents a higher standard deviation, suggesting that the male pineal gland undergoes greater individual variation in the degree of calcification. Accordingly, this great inter-individual variability might be responsible for the lack of a linear correlation between aging and the amount of calcium deposition, which should, however, be progressive along the life, in that it represents a physiological process (19). In any case, the rodent species that characteristically develop heavy pineal gland calcification also present important reductions in pineal aMT (21), and aged men have significantly lower levels of serum aMT than elderly women (22). Accordingly, in a variety of species, including humans, serum aMT levels are significantly reduced in senescence, and the characteristic nocturnal peak is attenuated (21-32). A similar decrease in the amount of aMT was described in cerebrospinal fluid (33). Furthermore, the aMT decrease seems accentuated in patients with Alzheimer's disease (32). aMT reduction in aging does not appear to reflect a shift in the time of peak aMT synthesis and release, as it can be observed at several time points throughout the dark period (21, 25, 26), and has even been reported for serum aMT in daytime samples (28). The age-related decline in secreted aMT appears due to a reduction in synthesis rather than to changes in metabolism and clearance, as supported by the reduced urinary excretion of 6-hydroxymelatonin (aMT.6H) in both aged men and women (34). The excretion of aMT.6H is, in fact, considered a reliable index of aMT

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production, as it parallels aMT circadian variation and the marked plasma concentration decline that follows light exposure or pinealectomy (35-37). The age-related decrese in aMT synthesis is further supported by the observation that pineal aMT itself is significantly reduced in aging (21, 25, 27, 28, 30, 31), and that aMT plasma content in the confluens sinuum is significantly lowered in the senile rat (38). Several studies have addressed the genesis of pineal function decline in senescence, but the results are still controversial. A previous attempt to associate changes in pineal aMT and N-acetyltransferase, the rate limiting enzyme in aMT synthesis, with age in Wistar rats showed a poor correlation, although a small reduction in enzymatic activity was observed in the oldest group (23). Recently, no significant changes in N-acetyltransferase were noted in old rats from the same colony, but a significant decrease in HIOMT activity, the aMT forming enzyme, was found in the same animals over 12 months of age (39). The change in HIOMT activity could not be regarded as part of a general reduction in protein synthesis, as the enzyme level fell even though cytosolic protein content increased with age. In contrast to these results, no changes in HIOMT activity in postmortem human pineal tissue were previously found (40). The detection of reduced N-acetylserotonin lev. els during the night in old hamsters (27) and rats (31) suggests a possible decrease in Nacetyltransferase activity with aging; moreover, no changes in serotonin levels or in the lightdark ratios for serotonin and 5-hydroxyindoleacetic acid were detected in the pineal gland of the same animals (29, 31). On the other hand, a reduced metabolic rate in the mammalian aged pineal gland is supported by the demonstration that the rate of oxygen consumption and of glucose conversion into lactic and amino acids by pineal tissue is decreased with age (41, 42). Moreover, in comparison to the young adult pineal gland, the old gland reveals a distinct decrease in overall electrical activity, demonstrated either by the lower average number of successfully recorded units per gland, or the significant shift to lower frequencies of the nighttime discharges (30). A similar age-related decrease in spontaneous

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electrical activity was also described in locus coeruleus neurons (43), a structure responsible for most of the noradrenergic innervation of the brain. Noradrenergic neurotransmission, in general, was reported to decrease with age (3), and changes in the number of adrenergic receptors were detected in various parts of the brain (31, 44), including the pineal gland (45). In contrast to these results, a recent report failed to demonstrate changes in the density and affinity of pineal 0'1 and ~-adrenergic receptors after 3 months of age, even in the oldest animals (39), thus contending the possibility that a reduction in noradrenergic stimulation of aMT synthesis might be responsible for the age-related decline in pineal function. Similar contradictory results concern the diurnal rhythm in norepinephrine pineal content in old rats and hamsters (25, 29). On the other hand, age-related visual function impairments, e.g., changed sensory capacities or altered sensitivity to subtle environmental changes, may contribute to the reduced lightdark ratio in the aMT circadian rhythm. Accordingly, the circadian rhythm of retinal Nacetylserotonin and aMT appeared lost in old rats (46), a fact that should weaken its putative role in several important aspects of eye physiology as well as in the synchronization of biological rhythms to light by modulating the retinohypothalamic-pineal axis (46-49). Despite the fact that it is presently impossible to establish whether the decline in pin~al biosynthetic activity is due to a change in pineal regulatory mechanisms or to' a decrease in pinealocyte activity itself, all these data demonstrate a distinct decrease in pineal function with senescence, which may contribute to the agedependent decline in neuroendocrine capacity, particularly in deciphering the day/night cues. In keeping with this possibility, a dramatic agerelated reduction was demonstrated in the density and circadian rhythmicity of aMT binding sites in the hypothalamus and hippocampus, which directly correlated with the decrease in the diurnal levels of circulating aMT (50, 51). In conclusion, it is conceivable that the agerelated impairment of pineal function may represent the altered coupling between the central pacemaker(s) and the numerous effector mech-

anisms, which results in the overall tendency for dampened circadian rhythmicity that accompames agmg.

PINEAL GLAND AND AGING OF REPRODUCTIVE SYSTEM With aging, animals of both sexes including humans undergo a progressive reduction in reproductive capacity. This decline is much more gradual in males than in females, and spermatogenesis and testosterone secretion may continue to the end of life. On the other hand, the cessation of estrous/menstrual cycles in females represents a dramatic example of age-dependent neuroendocrine change, that is preceded by an increasing irregularity in reproductive cyclicity, and described in women as the perimenopausal period. Analogously, most female rats show a progressive increase in the occurrence of vaginal cornification, which results in a constant estrous/anovulatory (CEA) syndrome with polyfollicular ovaries and lack of ovulation by 15 to 24 months of age. During this period, some animals show long recurrent pseudopregnancies of up to 30 days duration or longer, and numerous corpora lutea secreting progesterone. Subsequently, the oldest rats, 2 to 3 years of age, exhibit an anestrous state with atrophic ovaries and an infantile-appearing uterus. What factors trigger the onset of acyclicity, and are therefore responsible for the gradual reduction in reproductive capacity observed during the transition period from regular cyclicity to constant estrous (CE), is still an open question. A number of studies appear to demonstrate that neither ovaries (52) nor pituitary (53) are primarily responsible for the reproductive decline in rats, and the primary lesion probably occurs at the level of the hypothalamus, where it involves the neurotransmitter mechanisms modulating the release of LHRH (54, 55). On the other hand, in mice and women, ovarian quiescence seems to be the major factor implicated in the loss of estrous cycles (56), though a role for hypothalamic dysfunction is supported by the apparent origin of hot flushes in the hypothalamus (57). An important feature of age-related decline in reproductive function of rats and mice is that it

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can be delayed, or even reversed, by correcting the faults that develop in neuroendocrine function. Moreover, a similar decline can also be hastened in young rats and mice by experimental interventions on the neuroendocrine system. In previous experiments, it was shown that pinealectomy in young rats led to the prolongation of the estrous cycle (58), and that exposure to continuous light, a condition that suppresses the circadian rhythm of aMT production, provoked a CEA state similar to that of old rats (59). We also showed that the daily administration of aMT is able to reinstate the reproductive cyclicity and ovulation blocked by exposure to continuous light, an effect which is suppressed either by the administration of Methiothepin, a serotonin-receptor antagonist, or by feeding rats a tryptophan-poor diet (59). Presently, an increasing amount of evidence suggests that by means of aMT the pineal gland modulates the timing and activity of the central neuro-transmitter mechanisms, particularly the serotonergic system, and thus regulates reproductive function (60-63). In senescence, the decline in pineal function is associated with a significant increase in serotonin dominance in all brain areas except the pons-medulla (64). The reduction in hypothalamic catecholamine content and turnover, and the increase in serotonin turnover is believed to represent the primary cause for the low gonadotropin secretion in aging male (65) and female (66) rats. In keeping with this view, the CEA syndrome of old rats can be reversed by treatment with drugs that modify the activity of catecholaminergic and serotonergic neurons (54, 67-69), or by the nightly administration of physiological amounts of aMT, at least in a certain number of aged rats (70). Furthermore, aMT administered at night via drinking water (0.4 JLg/mL) to female rats during the period from 14 to 25 months of age leads to a significant delay in the onset of the CEA syndrome, as demonstrated by the higher number of ovulating rats, and the reduced trend towards the estrous phase in treated rats, compared to untreated controls. Another important finding is that the naloxone-induced release of LH, still detectable in 16-month-old female rats, is lost in untreated

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rats at the age of 18 and 20 months, while it is preserved by chronic aMT administration at the same age. No differences instead are detected in pituitary responsiveness to GnRH under the same experimental conditions (T rentini et ai., in preparation). A similar decrease in LH and testosterone response to naloxone was previously reported in old (18-20 months) male rats (71), and humans (72). In elderly men, naloxone was unable to modify either LH or FSH levels, suggesting that age induces a selective impairment in the endogenous opioid peptides controlling gonadotropin secretion (72). In analogy with previous data (56, 73), these results confirm that the hypothalamo-pituitary unit of rats, per se, is not intrinsically impaired by the process of aging, but the neural signals impinging on the LHRH pulse generator are altered. Thus, the age-related loss of sensitivity to naloxone, a prototypic opiate receptor antagonist widely used to assess the amount of tonic inhibition by endogenous opioids, suggests that endogenous opioid peptides may represent one of the signals altered by aging. In keeping with this view, aged animals showed a general and significant decrease in enkephalin and betaendorphin (,B-EP) immunoreactivity, and in delta and mu opiate receptors in the CNS, particularly in the medial basal hypothalamus (MBH) (74). Furthermore, naloxone is known to possess a higher affinity for the mu class of opiate receptors than for other types (75), and ,B-EP demonstrates a high selectivity for the mu receptor in brain tissue (76). These lines of evidence on the whole support a role for ,B-EP in the reproductive decline with aging, possibly also operative in humans, as suggested by the significant decrease in the number of hot flushes induced by naloxone infusion in menopausal women with symptomatic vasomotor instability (57). Analogously, the elevated prolactin and depressed LH levels that occur in old rats appear set against a background of hypothalamic opioid alteration, since hypothalamic ,B-EP is known to stimulate prolactin and to inhibit LH and FSH secretion (7779), by suppressing the release of dopamine (80, 81) and GnRH (82, 83) into hypophysial portal blood. Although the evidence points to a link be-

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tween serotonergic and endorphinergic neurons, with serotonin supposedly regulating opioid activity in the hypothalamus (84, 85), a transsynaptic, perhaps serotonergic mechanism may represent the final common pathway for all these modifications in view of the significant increase in serotonin dominance previously said to occur in aging brain. Several experimental findings suggest that pineal gland and aMT exert significant effects on opioid functions (86, 87). ~-EP content in MBH demonstrated a daily rhythm with a nocturnal peak (88-90), whose circadian nature and photo-synchronization were proven by its persistence in constant darkness (Trentini et aI., in preparation), and by the changes that followed experimental modifications in the lighting regimen (88-91). The pineal gland appeared to be involved in the photo-synchronization of the ~-EP circadian rhythm, as pinealectomy or superior cervical ganglionectomy modified the timing of ~-EP rhythm (91). Accordingly, most of the behavioral functions which are regulated by the central opioid system demonstrate a c1earcut day-night rhythm (85, 92, 93), and pinealectomy eliminated the daily rhythm of pain sensitivity, while naloxone reversed the analgesic response induced by the administration of aMT (86). In aging mice, significant declines were observed both in the absolute levels and the diel rhythms of morphine analgesia, with the most pronounced changes occurring at night. The administration of aMT reversed the agerelated decline in nocturnal morphine analgesia, suggesting that pineal gland and aMT exerted an influential role on the age-related changes in opioid responses (94). Similar conclusions can be drawn from the above-mentioned studies on the age-related decline in reproductive function. Besides delaying the onset of postreproductive CEA syndrome, the chronic nocturnal administration of aMT maintained the plasma LH response to naloxone stimulation, showing that the nocturnal increase in the level of circulating aMT has a protective effect on the opiatergic pathway controlling LH (GnRH) secretion. On the other hand, a causative role for the altered opioid activity might be ascribed to the derangement in the secretion of sex steroid hormones, rather than

to pineal gland, as estrogens were reported to be essential for the expression of the ~-EP circadian rhythm (95). However, the protective effect aMT exerts on the opioid system does not appear to depend on changes in circulating steroids, since aMT treatment in aged rats with CEA state did not bring about significant changes in plasma levels of estrogens (and of prolactin), except in rats ovulating in response to aMT (70). This seems to confirm the central site of action of aMT, which probably affects the hypothalamic opiatergic neurons either directly or through the serotonergic system. Therefore, the age-related decline in pineal function, and, particularly, the decrease in its nocturnal secretory activity may disrupt the circadian organization of the hypothalamic opioid system, and thus lead to a progressive deterioration of the mechanisms that control reproductive behavior. However, the demonstration of an age-related decay in the hypothalamic ~-EP circadian rhythm will be needed to verify this hypothesis.

PINEAL GLAND AND GENERAL AGING OF THE ORGANISM Although genetically programmed (96), circadian rhythmicity requires a functional pineal gland to be entrained to the environment right from early development. aMT is, in fact, a component in the mechanism for communicating photoperiodic information from the mother to the fetus during gestation, to synchronize offspring maturation to the seasonal environment (97, 98). In the functional absence of the maternal pineal, the fetus does not receive photoperiodic information from the mother's SCN region, where aMT exerts its action (99). The same mechanism operates in adult life; by transducing changing photoperiod information into an aMT signal, the pineal gland provides a daily and seasonal cue that plays· an important role in the resynchronization of the circadian system in animals and humans (100-102), including the rhythm of its own secretory activity (103). This effect seems due to the direct action of aMT on the circadian pacemaker in the SCN (104), which thus coordinates a variety of neurophysiological and neuroendocrine activities (60-63),

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apparently through the mediation of the serotonergic and opiatergic systems. Therefore, the pineal gland appears to represent an integral part of a highly integrated and finely tuned mechanism, delegated to control the normal operations of the different components of the neuroendocrine system. It is easily understandable that any change that develops in this mechanism can derange the regular functioning of the neuroendocrine system, and result in many changes in body functions. The fact that both pineal function and the expression of various circadian rhythms, as well as their internal synchronization, are altered in senescence points to the circadian rhythm generating system, and to the pineal gland, as the site of origin of age-related changes in overt rhythms. However, at present, there are no direct indications of age-related structural or functional changes in the SCN of experimental animals (105, 106), while the alterations observed in SCN in humans were reported to occur at a later age than changes in circadian rhythmicity (3, 6, 9). Thus, hypothalamic structural modifications may only be a late correlate of functional alterations that occur much earlier, with the agerelated decay in pineal function appearing as a good candidate for the derangement of circadian rhythmicity. As previously shown, the administration of aMT may in fact contribute in prolonging the temporal patterning of the function of various systems, which appear to be changed in senescence. As a consequence, the age-related decay in circadian organization and the relative loss of co-ordination among the many interdependent oscillating physiological activities should result in a stressful condition, a sort of "neurohumoral hysteresis" (107), which may lead to the progressive damage of the regulatory neurons by the very substances, e.g., neurotransmitters, hormones, metabolites, that these neurons control. Thus, aging of the pineal gland with the subsequent "melatonin deficiency syndrome" (108) may represent the initiating event of a chain of neuroendocrine and peripheral alterations which promote the involutional process of aging. Of particular significance among the peripheral changes that accompany the process of aging

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is the decline in normal immune functions that occurs in animals and humans. Age-related immune dysfunction, particularly of the T-cell arm, is generally associated with an increased frequency of autoimmune disorders, viral and fungal infections, and cancer. Although the inception of neuroimmunoendocrinology was met with a certain amount of skepticism particularly on the part of the immunologist, the immunomodulatory role of the neuroendocrine system is generally accepted at present (109, 110). It was demonstrated, moreover, that a variety of neurohormones, such as ACTH, endorphins, enkephalins, AVP, thyrotropin, VIP, substance P, somatostatin, GH and prolactin, modulate in vivo and in vitro immune responses in a facilitating or inhibitory manner (111, 112). In addition, significant circadian and circannual rhythms of lymphocyte subpopulations were demonstrated in peripheral blood, with lowest levels of all circulating subsets between noon and 4 p.m., and highest values at around midnight (113-116). The largest fluctuations were described for the total T-cell population (116). The pineal gland was shown to exert profound influences on the regulation of defense mechanisms, according to a precise circadian rhythm. Functional or pharmacological pinealectomy, induced by permanent lighting or propanoiol treatment, was associated with reduced antibody production and atrophy of thymolymphatic tissues (117, 118), while surgical pinealectomy brought about a significant decrease in the release of interleukin-2 from activated Thelper cells (119). This immune impairment was reversed by late-afternoon administration of aMT (118, 119), which demonstrated a significant ability to specifically enhance the T-cellmediated immune response in normal mice, and appeared to potentiate the secondary response when only administered during primary immunization (118). Furthermore, evening administration of aMT was able to reverse the immunosuppressive effects that acute stress exerts on the T-cell component of the thymic medulla, and on the antibody response to protein antigens, such as sheep red blood cells (SRBC). It also fully protected stressed mice against a lethal injection of encephalomyocarditis virus (118, 120). The im-

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mune enhancing effect of exogenous aMT, even in stress models, was completely abolished by treatment with the opioid receptor antagonist naltrexone, suggesting that the immunoregulatory action of aMT is indirect, and probably mediated via the endogenous opioid system. Accordingly, aMT did not express immunologic activity in in vitro systems, and in vitro lymphohemopoietic cells appeared to lack specific binding sites for 3H-aMT (120). On the contrary, endorphin receptors, similar to those in the brain, were demonstrated on lymphocytes by using radiolabeled opiates (121) or I3-EP (122), or by blocking their immunoregulatory signals with naloxone (112, 123; 124). Opiate peptides, and particularly I3-EP, were shown to participate in the regulation of the Tcell immune response, as they shared most of the immunoregulatory effects exerted by the pineal gland. Among others, I3-EP appeared to stimulate T-cell proliferation (123), reverse a-EP suppression of anti-SRBC antibody production (112), and mediate some forms of stressinduced suppression of the immune response (125). Classical opiate receptors also enhanced the natural cytotoxicity of lymphocytes and macrophages toward tumor cells upon binding I3-EP (126, 127). A similar effect may be presumed for the pineal gland, since pinealectomy was found to significantly inhibit NK cell activity (119), while aMT administration was reported to significantly enhance the number of NK cells in peripheral blood (128). Moreover, significant circadian rhythms were observed in the number of circulating NK cells, as well as in their cytolytic activity in vitro and in the response to interferon stimulation or glucocorticoid inhibition (128). On the other hand, several findings indicate that even the serotonergic system is involved in neuroimmunomodulation, mainly by exerting an inhibitory action on the immune response (129, 130). Without entering the very complex and still controversial matter of interactions between the immune and neuroendocrine systems, these findings are consistent with the idea that the pineal gland exerts immunomodulatory effects via opioid peptides and, possibly, the serotonergic system. On the one hand, they provide a mo-

lecular basis, in the form of rhythmic aMT secretion, for the entrainment of circadian rhythms of immunity with the general rhythmicity of the neuroendocrine system. On the other, they lead to the thought that the early events of immune dysfunction which accompanies aging may be part of the general disarray in neuroendocrine circadian organization, in which pineal function decline appears to represent an integral component. At present, however, data on possible changes in the circadian organization of immune function in senescence are not available. Further studies directed at possible correlations between circadian synchrony on one hand, and immune cell proliferation, antibody production,or immune responses to facilitating and inhibitory stimuli on the other, may reveal functional correlates of circadian rhythm alterations in senescence. In keeping with the decline of immune function, the cumulative cancer risk calculated to increase with approximately the fourth power of age in both short and long lifespan species (131) lends further support to pineal involvement in events that mark the course of aging. In a variety of experimental models, in fact, the pineal gland and aMT were reported to exert such important oncostatic and antiproliferative activities that the terms oncostatic gland (132) and anticancer hormone (133) were advanced. In particular, the experimental models used to investigate pineal effects on tumorigenesis showed that the most consistent response of nearly all the tumor types studied thus far was their increased growth and metastatic spread following pinealectomy. Coherently, aMT appeared to exert an inhibitory effect on tumor growth in vivo, at times only compromising the growth-promoting effects of pinealectomy, at times inhibiting tumor growth when administered at a particular time of day, mainly in the late afternoon (132). However, tumor growth was completely unaffected when aMT was only administered during tumor initiation (132), indicating that its oncostatic mechanisms probably impinge upon the phase of tumor promotion/ progression. On the other hand, in in vitro studies, physiological concentrations of aMT or of purified pineal extracts (134) significantly inhibited the

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proliferative activity of a number of established human cancer cell lines, e.g., breast cancer cells (133, 135, 136), ovarian carcinoma SW-626 (our unpublished results), erythroleukemia, melanoma, and larynx carcinoma (134). At least for breast cancer cells, the antimitogenic effect of aMT seems to occur via an interaction with estrogen receptors, since aMT did not modify the growth of estrogen receptor negative tumor cells (136, 137), and appears similar to that of the antiestrogen, tamoxifen, which delays cell transit from G1 to S phase of the cell cycle (138). Furthermore, recent data suggest that aMT may interact with the release and/or the action of either inhibitory or stimulatory autocrine growth factors (139, 140), and in this way inhibit tumor growth. It therefore appears from our current understanding that the pineal gland may transmit its oncostatic messages to neoplastic cells through several mechanisms, including either the direct antiproliferative action of aMT or the regulatory effects it exerts on neuroendocrine functions and immune surveillance. Accordingly, significant correlations between central opioid (141, 142) and aminergic system (143-145) and tumor growth and metastatic spread were reported. Hence, it seems correct to hypothesize that the decline in aMT secretion, with the parallel impairment in neuroendocrine and immune functions which occurs in senescence, may playa key role in increasing the age-specific cancer rate that limits lifespan. The observation that daily administration of bovine pineal extract to rats from 3.5 to 25-30 months of age significantly reduced tumor incidence in comparison with untreated animals (146) supports this hypotheSIS.

CONCLUSIONS Once considered a gland, the pineal is now definitely recognized as a neuroendocrine transducer, whose chief function is that of synchronizing endogenous circadian rhythms with the nycterohemeral cycle, via the translation of neural impulses to aMT release. The target of this function is the central neurotransmitter system, mainly its serotonergic and opiatergic compo-

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nents, which is sensitized to photoperiodic information driven by aMT since fetal life. However, a direct effect of aMT at the level of peripheral organs and organ-systems is also increasingly recognized. Advancing age is characterized by 'the alteration of the temporal organization of the circadian rhythms of several endocrine and biochemical processes. This results in the loss of coordination among the many inter-dependent oscillating functions, with possible deleterious functional and anatomical changes that may limit lifespan. This circadian disorganization leads to the theory that some central parts of the circadian timekeeping system were changed with advancing age, since it does not appear very likely that all circadian changes occurring in different effector pathways may be completely independent. To date, the pineal gland is the only component of the circadian timekeeping system consistently known to undergo an age-dependent functional decline, with reduced levels of circulating aMT, particularly in its cyclic nocturnal peak. Furthermore, the daily administration of aMT along the course of aging tends to delay the decline in reproductive function; this effect is apparently mediated through the neuroendocrine system, where aMT seems to protect endogenous opioid peptides from the selective impairment repeatedly reported to occur in senescence. A similar protective effect was described in mice; aMT treatment reversed or delayed the symptoms of age-related debility, disease and cosmetic decline in a dramatic fashion, and prolonged life by circa 20 percent (120). aMT replacement in the elderly, therefore, may achieve a more youthful endocrine balance and homeostasis, and consequently a possible protection of the body oS a whole. While these data are still fragmentary and additional experimental evidence is needed to confirm the positive effect of aMT on various involutional processes, they are supportive of a key role for the pineal gland in the timetable of age-related changes in the neuroendocrine system, and general physiology. At the moment, however, the etiopathogenetic mechanisms of the pineal functional decay in old age remain to be determined.

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ACKNOWLEDGEMENTS We wish to thank Mrs. Gabriella Carpi for carefully typing the manuscript. The work was supported by MPI (Ministero Pubblica Istruzione) (40% and 60%).

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