Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Abstract

The pineal hormone melatonin is secreted in all mammals during the dark phase of the circadian cycle (1), but, even more importantly, there are indications that it is a key regulator of aging and senescence (2, 3). The role of melatonin in controlling sexual maturity, sexual cycling, cancer, stress, and the immune response makes it likely that the pineal may be a factor in the syndrome of aging (4)(5)(6). With this in mind, we have administered exogenous melatonin in the drinking water of mice during a fixed circadian dark cycle-i.e., when melatonin is normally produced-in order to ascertain its influence on patterns of survival. In addition, as the pineal gland is the prime source of melatonin, we transplanted the pineal gland from young to syngeneic histocompatible older recipients. We have utilized the thymus as the graft recipient site inasmuch as the thymus and the pineal gland share a common adrenergic innervation via the superior cervical ganglion (7,8). This common innervation is of importance as melatonin synthesis is inhibited by pharmacologic sympathetic blockade, which also modulates the immune response (9). Moreover, the pineal morphologically contains lymphocytes and it has been likened in its embryologic developmental origin to the thymus (10).In our studies, exogenous nocturnal circadian administration of melatonin or engraftment of young homologous (3-4 months) pineals to old (18-22 months) syngeneic mice adjacent to the thymus, leaving the recipient's pineal in situ, resulted in a significant enhancement of survival independent of significant weight loss. These results suggest that the pineal may act as an endogenous clock governing aging.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. MATERIALS AND METHODSMelatonin Administration. Mice were fed ad libitum using NAFAG pellets (Gossau, Switzerland) and housed 4-10 to a cage in air-conditioned quarters at 22°C. Light exposure was controlled by a fixed timer that governs a standard fluorescent fixture (Philips TLD 36W/84). Melatonin, solubilized in ethanol, was given in the drinking water during a fixed darkness cycle from 6 p.m. to 8:30 a.m. (10 pg/ml of tap water, 0.01% ethanol). The control (only ethanol) and melatonin-containing water bottles were removed from 8:30 a.m. to 6 p.m. No drinking water was given during that period. The mice were individually weighed at intervals to determine whether the effects seen were related to dietary intake.Pineal Grafting. In young-to-old, pineal-to-thymus grafting, the "young" pineals were obtained from 3-to 4-monthold, postpubertal mice. Syngeneic recipients were groups of "aging" mice. The recipient mice were uniform as to sex and age, housed 3-7 per cage. They were prepared for surgery and studied in groups, as indicated in Tables 1 and 2. Weight changes of control and pineal-transplanted animals were recorded monthly. Donor mice were killed by ...

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