Review
Melatonin and the aging brain

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Abstract

The events associated with brain aging are enumerated with emphasis on increased oxidative and inflammatory processes and on mitochondrial dysfunction. Several of these factors are further increased in a wide range of overt age-related neurological diseases. This generality has given impetus to concepts concerning similar therapeutic approaches common to a series of neurodegenerative disorders. Animal and cell culture models of several such disorders have benefited from the application of melatonin. The mechanisms underlying the neuroprotective properties of melatonin are likely to involve activation of specific melatonin receptors. This can lead to modulation of transcription factors and consequent altered gene expression, resulting in enhancement of antioxidant enzymes and downregulation of basal levels of inflammation. Melatonin has potential utility both in slowing normal brain aging and in treatment of neurodegenerative conditions. This is reinforced by the low cost of melatonin and its very low toxic hazard.

Section snippets

The aging brain is associated with oxidative stress, excess inflammation and mitochondrial dysfunction

Aging involves a very complex series of changes both at the genetic and the phenotypic level. Among the more universal mechanisms, are selective deletions of portions of mitochondrial DNA (Melov et al., 1999, Wei and Lee, 2002), changes in immune function, and the presence of an imbalance between pro-oxidant and antioxidant factors. Alterations in these parameters have been repeatedly shown to occur with cerebral aging (LeBel and Bondy, 1992, Ames et al., 1993, Lass et al., 1998, Calabrese et

The treatment of age-related neurological disease

Recent therapeutic approaches to the most common disease associated with human brain aging, Alzheimer's disease (AD), have included both anti-oxidant and anti-inflammatory drugs. These directions are validated by epidemiological studies suggesting that the extended use of anti-inflammatory agents (for example by patients with arthritis) reduces the risk of AD (McGeer and McGeer, in press). Other epidemiological data have implicated the utility of antioxidants in lowering the incidence of AD (

Melatonin as an anti-oxidant

Melatonin is present in bacteria, plants, eukaryotes, and fungi as well as all phyla of multicellular animals and it may be that its original evolutionary role was as an anti-oxidant (Hardeland and Poeggeler, 2003). Melatonin has been shown to possess antioxidant properties in both tissue culture and in intact animals. A much discussed issue is whether it acts in this manner directly or by way of activating critical pathways involved in the disposition of free radicals (Srinivasan et al., 2006

Conclusion

The median age of the United States population is rapidly increasing and this will lead to a corresponding increase in the incidence of many age-related syndromes. Aging is often associated with both memory and motor deficits including impaired locomotor, postural and balancing skills. The potential for major increases in incidence of neurodegenerative disorders will be especially pronounced in view of the declining cardiovascular death rate. Retardation of the appearance of changes found with

Acknowledgment

This work was supported in part by grants from the National Institutes of Health (ES 7992 and AG 16794).

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