The pineal gland and melatonin in relation to aging: a summary of the theories and of the data.

Abstract Within recent years, many investigators have implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. These theories stem from the importance of melatonin in a number of biological functions and the fact that melatonin production in the organism is gradually lost throughout life, such that in very old individuals of any species the circadian melatonin rhythm is bearly discernible. In most species, from algae to humans, where it has been investigated, melatonin has been shown to exhibit a strong circadian rhythm in production and secretion, with high levels of the indole always being associated with the dark period of the light:dark cycle. One theory states that when the melatonin rhythm deteriorates during aging, other circadian rhythms are likewise weakened and rhythms become dysynchronized. This dysynchronization is believed to contribute significantly to aging and to render animals more susceptible to age-related diseases. Another theory assumes that the waning melatonin cycle provides an important switch for genetically programmed aging at the cellular level; furthermore, because all cells in the organism are exposed to the same gradually dampening melatonin signal throughout life, all cells age more or less at the same rate. In this theory, it is presumed to be the duration of the nocturnally elevated melatonin (which, like the amplitude, is reduced during aging), which, when coupled to a time-gating signal, is consequential in determining the rate of aging. Another compelling argument that the reduction in melatonin with age may be contributory to aging and the onset of age-related diseases is based on the recent observations that melatonin is the most potent hydroxyl radical scavenger thus far discovered. A prominent theory of aging attributes the rate of aging to accumulated free radical damage. Inasmuch as melatonin can markedly protect macromolecules, especially DNA, against free radical attack, it could, indeed, be a major factor in determining the rate at which organisms age. Besides its ability to directly scavenge the highly toxic hydroxyl radical, melatonin also promotes the activity of the antioxidative enzyme glutathione peroxidase, thereby further reducing oxidative damage. These actions may be manifested more obviously in the central nervous system, which is highly susceptible to damage by oxygen-based radicals and, because of its inability to regenerate and its high vulnerability to oxidative attack, its deterioration may be especially important in aging. Thus, if melatonin preferentially affords antioxidant protection to the brain, it could be a major player in delaying aging and age-related diseases. In the few studies where animals have been supplemented with exogenous melatonin throughout life, life span has been increased up to 25%. Besides its protection of the brain, melatonin has been shown to prevent damage by oxidants to DNA in other organs. Again, protecting DNA is particularly important because there are only two copies in each diploid cell, and structurally impaired DNA would not properly transcribe, leading to metabolic inefficiency and possibility to death of the cell. Thus, for a number of reasons, maintaining a robust melatonin rhythm by exogenously administering the indole may prove to have a variety of beneficial effects, which collectively could serve to prolong life, postpone aging, and reduce the chances of age-related diseases.