Aging and the brain: a new frontier.

With aging, both "normal" senescent age-related changes (ARCs) and late-onset diseases affect the brain, producing declines in performance. The brain as a postmitotic structure is particularly vulnerable to ARCs, and senescence is by far the most powerful risk factor for neurological diseases of the elderly such as sporadic Alzheimer's disease. The concept of senescence as an immutable result of the passage of time is yielding to understanding of the biology of ARCs. Both individual and species differences in longevity illustrate the variable effects of time. Whereas human life expectancy has been extended by prevention and treatment of specific diseases, life span can be altered by modifying the processes producing ARCs. Models of prolonged life span (eg, modifications of Caenorhabditis elegans longevity genes, restricted caloric intake) demonstrate the feasibility of extending longevity throughout the phylogenetic spectrum. Both programmed and variable factors produce ARCs. Cell survival depends on a balance of opposing factors--oncogene and anti-oncogene products, cyclins, growth factors, and so on; apoptotic death results when the balance shifts. Variable factors, including accumulation of oxygen free radicals, protein conformational changes, decline in chaperone functions, and secondary loss of mitochondrial energy production, can also result in neuronal degeneration. To prevent the increased neuronal vulnerability of senescence, ARCs must be modified. The "new frontier" in neurology is the challenge of understanding the changes of aging, both to determine their impact on disease and to prevent their consequences.