Enzyme adaptation as a biochemical probe of development and aging

Abstract

The time required to initiate certain hepatic enzyme adaptations is directly proportional to chronological age of the rat, from 2 months to 2 years, and recently was proposed as a biochemical parameter of aging. Marked alterations in temporal expression of tyrosine aminotransferase adaptations occur also during development from the 21-day fetus to 2 months of age. Similar evidence exists for the induction of glucokinase during the first few weeks of postnatal life. The apparent relationship to the previously reported manifestations of senescence provides support for the view that senescence is a consequence of normal growth and development. Delayed initiation of increased NADPH:cytochrome c reductase activity following administration of phenobarbital is attributable entirely to delayed initiation of an increase in the rate of enzyme synthesis. Data were obtained by determining specific radioactivity of homogeneous preparations of enzyme previously labelled with leucine- 3H from young and old rats, either untreated or injected with phenobarbital. That time course and capacity for hepatic gene-mediated response does not deteriorate in old age is indicated by the following observations: (1) the increase in specific radioactivity of purified NADPH:cytochrome c reductase occurs to the same extent in young and old rats, although older animals require more time; (2) following administration of those hormones which mediate directly the stimulation of enzyme synthesis, cortisol, insulin and glucagon for tyrosine aminotransferase and insulin for glucokinase, neither time course nor degree of response varies from 2 months to 2 years of age. It was concluded that hepatic protein synthesis is not impaired in aged rats, and that the immediate cause of the delayed enzyme adaptations is probably an altered availability of the appropriate hormonal effectors. Adaptive responsiveness of glucokinase to glucose feeding and of tyrosine aminotransferase to exposure to certain conditions of stress require, at least, the integrity of adrenal function and, probably, the presence of insulin. In both cases these complex hormonal interactions are susceptible to pituitary control. Modified temporal expression of hepatic enzyme adaptation may represent a general reflection of hormonal fluctuations which accompany development and aging, and may provide a unique opportunity to investigate the nature of biochemical changes which accompany and/or cause senescence in vivo. The extent to which the age-dependent modifications in enzyme adaptation are attributable to altered availability of pituitary hormones, impaired responsiveness of endocrine cells to pituitary control mechanisms or additional unknown factors remains to be determined.