Free radical theory of aging: A hypothesis on pathogenesis of senile dementia of the Alzheimer’s type
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Senile dementia of the Alzheimer’s type (SDAT) is the major cause of dementia. It is a spontaneous, i.e. sporadic, systemic disorder whose major manifestations are in the brain. It is hypothesized that SDAT may be the result of one of a number of potential mutations in a mitochondrial DNA molecule, early in development and after germ cell segregation, that impairs oxidative phosphorylation and increases production of \(O\mathop \cdot \limits_2^ -\) and H2O2. Replicative segregation distributes the mutated mtDNA to the cells of the developing organism in such a manner that with advancing age cellular dysfunction occurs first in areas of the brain associated with Alzheimer’s disease. Cell damage and death is attributed to random free radical damage secondary to falling ATP production and increasing formation of \(O\mathop \cdot \limits_2^ -\) and H2O2 due to aging of the normal and defective mitochondria. The increasing oxidative stress contributes to cell damage and eventual death in part by impairing cellular control of Ca2+ concentration; sustained increases in cellular Ca2+ disrupts the cytoskeleton and activates calcium dependent catabolic enzymes.
SDAT is essentially due to acceleration of normal neuronal aging. The amyloid associated with SDAT is apparently a consequence of normal neuronal metabolism and of the changes associated with normal neuronal death.
The incidence of SDAT may be decreased by efforts to prevent mutation of a mtDNA molecule early in development, for example, possibly by decreasing maternal deleterious free radical reactions by dietary modulation and/or antioxidant supplements. Similar efforts by the general population may also decrease the incidence by disproportionately slowing the rate of production of free radical damage in those individuals destined to develop Alzheimer’s disease owing to their higher rate of initiation of deleterious free radical reactions. The function of SDAT patients may be temporarily improved by “ rescuing” some impaired neurons, and the underlying mitochondrial decline slowed, by measures similar to those employed with other mitochondrial disorders.
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