We propose an interdisciplinary study of aging processes occurring in human and animal brain, complemented by tissue culture studies. Our objectives are to determine age-related changes in the nervous system as reflected in: 1) the activity of the enzymes associated with the formation and degradation of putative neurotransmitters; 2) enzyme synthesis and degradation capability in brain; 3) polyamine metabolism, as another indicator of cellular synthetic activity; 4) biochemical and morphological studies of human cells (i.e., fibroblasts) in culture. The enzymes which are related to putative neurotransmitters to be studied in selected areas of human brain obtained at autopsy include: tyrosine hydroxylase, DOPA decarboxylase, dopamine-Beta hydroxylase, monoamine oxidase, glutamic acid decarboxylase, choline acetyltransferase, acetylcholinesterase. The study of these enzymes, their substrates (i.e., amino acids) and products (i.e., dopamine, norepinephrine, GABA, and others) will require the use of chromatographic, fluorometric, spectrophotometric, radiochemical, and immunoassay techniques. When indicated, the biochemical data will be correlated with the histological findings. As an index of de novo enzyme synthesis, studies in animals as a function of age will be conducted in which specific, irreversible inhibitors of enzymes (i.e., monoamine oxidase and acetylcholinesterase) will be given and the return of enzymic activity measured. Enzyme activity (i.e., glutamic acid decarboxylase) will be compared with the number of molecules of that enzyme measured by immunoassay, to assess the catalytic efficiency as a function of age in discrete regions of animal and human brain. Human cell culture studies will be done in which the morphology, motility, rate of protein synthesis and degradation, and the metabolism of polyamines will be investigated as related to the age of the cultures. We expect that age-related changes can be altered by regulating key metabolic processes.
NIH ExPorter
NIH ExPorter