The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.
