Melatonin or a melatonin agonist corrects age-related changes in circadian response to environmental stimulus

Olivier Van Reeth, Laurence Weibel, Elisabeth Olivares, Sonia Maccari, Elisabeth Mocaer, Fred William Turek
2001 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  
Melatonin or a melatonin agonist corrects agerelated changes in circadian response to environmental stimulus. Am J Physiol Regulatory Integrative Comp Physiol 280: R1582-R1591, 2001.-The effects of a melatonin agonist, S-20098, included in the diet were tested on a specific effect of aging in hamsters: the marked decline in the phase shifting effects of a 6-h pulse of darkness on a background of constant light. In contrast to young hamsters, old hamsters fed with the control diet showed little
more » ... diet showed little or no phase shifts in response to a dark pulse presented in the middle of their inactive or active period. Old hamsters fed with S-20098 showed phase shifts that were ϳ70% of the ones in young animals and significantly greater than those in old controls. The phase advancing response to a dark pulse presented during the inactive period was dose dependent and reversed after S-20098 discontinuation. Melatonin included in the diet showed comparable restorative effects on the phase shifting response to a dark pulse in old hamsters. Replacement therapy with melatonin or melatonin-related compounds could prove useful in treating, preventing, or delaying disturbances of circadian rhythmicity and/or sleep in older people. aging; circadian rhythm; sleep AGING HAS PRONOUNCED EFFECTS on the expression of endocrine, metabolic, and behavioral circadian rhythms in a variety of mammalian species, including humans (19, 31, 38, 39) . At least some of those agerelated changes may be due to alteration in the functional activity of the master circadian pacemaker, the hypothalamic suprachiasmatic nuclei (SCN): aged rodents exhibit alterations in SCN glucose use (45), ␣ 1adrenergic receptor levels (43), number, or size of vasoactive intestinal peptide and vasopressin cells (26, 32) and a decreased density of melatonin receptors associated with its blunted diurnal rhythms (44). In addition, advanced age has been associated with a decrease in the responsiveness of the circadian clock to the phase-shifting effects of a variety of pharmacological or nonpharmacological synchronizers (21, 38, 39, 48) , and light-induced gene expression is also reduced in old rats and hamsters (28 , 49). Taken together, these results indicate that the aging circadian system is less sensitive to the synchronizing effects of stimuli that are normally involved in entraining the circadian clock to the 24-h changes in the external environment. Although the use of hormonal replacement therapy to reverse or attenuate the negative effects of aging on a variety of physiological and metabolic systems is an intensely active area of scientific and medical interest (16), such an approach has not previously been shown to prevent or reverse agerelated changes in the circadian clock system. The pineal hormone melatonin is a particularly attractive candidate for such studies for a number of reasons, including 1) the robust 24-h rhythm in melatonin production (1) provides a reliable chemical equivalent of the temporal position of light and dark throughout the 24-h day, 2) the age-related decline in circulating melatonin levels is associated with aging of the circadian clock and other physiological systems in mammals (13, 25) , 3) melatonin receptors have been localized to the mammalian SCN (42), 4) in vitro application of melatonin or melatonin agonists to SCN cells can induce changes in neuronal activity and circadian phase (47), and 5) their in vivo administration can phase shift and/or entrain circadian rhythms in rodents (9, 24, 34, 35) . Furthermore, the observation that daily melatonin injections can enhance the organization of disrupted circadian rhythms (41) and that pinealectomy facilitates the loss of circadian rhythmicity in rodents kept in constant light (8) supports the hypothesis that the pineal gland and melatonin contribute to the integrity of circadian rhythmicity in mammals; this integrity is often observed to break down with advancing age. In the present study we tested the effects of a melatonin agonist, S-20098 (3), or melatonin on a specific and easily quantifiable effect of advanced age in golden hamsters: the marked decline in the phase shifting effects of a single 6-h pulse of darkness (36) in animals free-running in constant light (38). The results demon-Address for reprint requests and other correspondence: O. Van
doi:10.1152/ajpregu.2001.280.5.r1582 pmid:11294784 fatcat:ieqanobqkjhxleh26ocnxwic4a