NEURODEGENERATION AND MITOCHONDRIAL DYSFUNCTION IN AGING

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DESCRIPTION: (Verbatim from the Applicant's Abstract) neurodegenerative diseases involve promotion of a pathological process by events associated with normal aging. Senescence is generally an essential concomitant of the progression of neurological disease and if this were retarded, the incidence of many such disorders would be significantly reduced. Prevention of deficits is more readily accomplished than attempts to compensate for impaired neurological function. This application posits that the cerebral mitochondrion is a susceptible target of age-related pro-oxidant events within the CSN, that the administration of exogenous factors may modify the velocity of these events and that this can influence other biological and behavioral consequences of aging. Maturational changes in mitochondrial function, structural integrity and mtDNA characteristics will be studied throughout the lifespan of C57BL/6 mice. Attempts to retard the onset of changes in mitochondrial parameters including gene deletions, membrane stability and levels of key enzymes, will be made by dietary supplementation with antioxidants, specifically targeted toward protection against free radicals produced by the reduced efficiency of the respiratory chain encountered with advancing age. Results will be substantiated with those obtained from mitochondria derived from neural cell lines exposed to low oxidant conditions for several generations. The role of both active oxygen and nitrogen species as contributory factors in these events and their potential modulation by antioxidants will be taken into account. The protective potential of antioxidants in combination, targeted toward several sources of oxidative events, will be evaluated. While the onset of neurological disease generally does not represent merely an acceleration of normal aging, there may be biological loci common to both. The identification and protection of such common targets will help in the development of agents that can reduce the incidence of neurodegenerative disorders.