Biochemical studies on the mechanism of Generation and accumulation of altered enzymes with age

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(1) We performed model experiments where partially purified aminoacyl tRNA synthetases are incubated with active oxygen producing systems. A part of the enzymes was rendered heat-labile, thus mimicking "old" enzymes in terms of heat-inactivation profiles. It is therefore suggested that active oxygens might be involved in the generation of altered proteins.(2) We demonstrated that half-lives of proteins microinjected into mouse hepatocytes in primary culture as well as intracellularly labeled proteins are extended by 50 to 60% in the cells from old animals. It is therefore suggested that accumulation of altered proteins in senescent animals is partly due to decrease in the turnover of proteins.(3) Twenty third month-old mice were subjected to dietary restriction for 2 months, and then proportion of heat-labile enzymes and half-life of proteins were examined. Proportion of heat-labile enzymes was decreased to a level of young animals and so are the half-lives of proteins.Thus it is suggested that anti-aging effect of dietary restriction is at least partly to "rejuvenate" decreased protein metabolism that occur with age.(4) Using anti-ubiquitin antibody we measured amounts of free and conjugated ubiquitin in the brain, liver and kidney of young and old mice. The amount of free ubiquitin in the brain was decreased by about 40% in the old animals but not in the other tissues. Conjugated forms of ubiquitin was increased significantly in the old brains but not in other tissues. The turnover of altered proteins is thus suggested to decrease in the brain of old animals.