Many times, "aging" and "neurodegeneration" are mentioned in the same breath, as if they are two state-points along a continuum, leading from the normality of old age to the state of confusion of senile dementia. Indeed, Terry and Katzman made this explicit prediction: they started from the observation that dementia occurs when there is a loss of about 40% of neocortical synapses and combined this with their estimations of the rate of age-dependent synaptic loss, as assessed by their analyses in human postmortem samples, extrapolating the data to the current estimations of human lifespan . Apart from the anecdotal evidence of many centenarians that age successfully , including the Guinness Book of Records' oldest certified human being, Madame Calment, who died in 1997 at the age of over 122 years without showing any signs of clinical dementia, the set of data that underlies the provocative hypothesis mentioned above might have been corrupted, unknowingly, by the inclusion in the analysis of subclinical instances of neurodegenerative pathology. Indeed, a similar error crept in the early sets of data that led to the conclusion that normal aging is associated with significant neuronal loss in all regions of the brain, a conclusion that only recently has been disproved . Even the term "neurodegeneration" is problematic, despite the obvious etymology, because the term has been used in reference to a large group of neurological diseases, with heterogeneous clinical and pathological manifestations, affecting specific, but different regions of the nervous system . Another experimental observation that complicates the issues is that the pathological markers associated with various neurodegenerative diseases, such as Lewy bodies, neurofibrillary tangles (NFTs), senile plaques, or other protein depositions, can be detected in the brain of aged asymptomatic individuals . These observations obviously raise the question of whether such individuals were just aging normally or were sampled at a presymp-tomatic stage of a neurodegenerative disease — there are, as yet, no definite answers to these issues. The study of the relationship between normal aging and neurodegeneration can be significantly helped by studies on animal models, because none of the human neurodegenerative diseases appear naturally in the animals. Through genetic manipulations, various animal models have been constructed that mimic one or another of the neurodegenerative phenotypes . At the same time, behavioral studies allow a more and more detailed assessment of the cognitive status of the animals, leading to the generation of sophisticated models of learning and memory and the study of the effects of aging on such processes .
The animal studies also allowed a very detailed analysis of the metabolic changes associated with the process of normal aging, as reviewed in this chapter. What these studies indicate is that normal neuronal aging is a physiological process, characterized primarily by a decrease in the neuronal homeostatic reserve, where this homeo-static reserve is defined as the capacity of the cells to oppose the destabilizing effects of various metabolic stressors (Figure 14.4). A detailed discussion of the evidence was presented in earlier articles [122, 149]. Briefly, this hypothesis is based on the view that central to the changes in the cellular physiology of the aged neurons is a dysfunction of the metabolic triad: Ca2+ - mitochondria - ROS. It also states that the functional deficits of the aged neurons become evident only in a use-dependent manner, when the metabolic demands become excessive. This view accounts also for the lack of significant levels of neuronal loss with aging. On this weakened homeostatic reserve, any significant pathological instance that requires a strong metabolic response, be it trauma, stroke, or any idiopathic neurodegenerative process, would result in a significant level of neuronal death. In this model, it is the decreased homeostatic reserve that explains the increased neuronal vulnerability with age, an increased vulnerability that manifests itself in a variety of pathological scenarios.
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