Cellular and molecular biology of neural aging. Actual situation and perspectives.

This paper discusses the problem of aging with special emphasis on the caus es and course the process follows in the nervous system. Experiments showin g that both life-span and life expectancy can be lengthened by molecular ge netic techniques, as well as the evolutionary meaning of aging and death ar e discussed. Several timely questions are posed such as: What is and why do es aging occurs? Does aging and death have any meaning from the point of vi ew of natural selection? How does aging occur in the nervous system? The la tter question is important because in common parlance, and even in the medi cal environment, it is now customary to consider normal aging and neurodege nerative diseases, such as Alzheimer, as if they were synonyms. This paper challenges this erroneous view by establishing the objective differences be tween these entities. The paper also discusses the recent collapse of two established dogmas of n eurobiology: first that neurogenesis does not exist in the adult human brai n, and second, that normal aging results from loss of neurons. Loss of neur ons is thought to be irreversible in the adult human brain, because dying n eurons cannot be replaced. This inability to generate replacement cells is thought to be an important cause of neurological disease and aging of the b rain. This view is no longer tenable because of recent findings showing tha t new neurons are generated from dividing progenitor cells in the adult hum an brain. These findings are related to other investigations showing that, contrary to the commonly held notion that widespread cortical neuronal deat h is an inevitable concomitant of brain aging, neuron death is scarce and r estricted in normal aging and unlikely to account for age-related impairmen t of neocortical and hippocampal functions. The emerging view is that age-r elated memory impairment is likely to reflect more subtle structural altera tions and molecular changes in specific neurons and circuits that mediate s uch functions. Both behavioral and electrophysiological studies suggest tha t key hippocampal circuits are functionally compromised, and that these fun ctional declines do not reflect neuronal loss. In the final part of the paper, modern theories and facts about cellular ag ing are reviewed and discussed. Normal human cells undergo a finite number of cell divisions and ultimately enter a non-dividing state called replicat ive senescence. The latter is dependent upon cumulative cell divisions and not chronologic or metabolic time, indicating that a molecular "mitotic clo ck" limits proliferation. It has been proposed that shortening of telomeres (specialized structures at the ends of eukaryotic chromosomes involved in chromosome protection, positioning and replication), is the "molecular cloc k" that triggers senescence. Telomerase, the enzyme that synthesizes telome res is not expressed in normal somatic cells, with the exception of ovaries and testes. Telomerase is reactivated in cancer, where immortal cells are likely required to maintain tumor growth. Introduction of telomerase in nor mal somatic human cells produces extension of life-span of the transfected cells, confirming that telomere shortening regulates the timing of cellular senescence. Ectopic expression of human telomerase immortalizes cells with out malignant transformation. The availability of primary human Cells with greatly extended or immortal life-span in the absence of malignant transfor mation will serve as valuable research tools as well as provide therapeutic opportunities for diseases showing premature aging such as Down and Werner syndromes and other age-related conditions.