SENESCENT CHANGES IN METABOLISM

衰老过程会导致生物体敏感性的改变

The aging process can result in altered sensitivity of an organism to the effects of environmental toxins. We are interested in examining the alterations that occur with advancing age in the processes of absorption, distribution, metabolism, and excretion of toxicants and how such changes may affect the toxicity of such chemicals. Our model system is the aging male Fischer rat, a colony of which is being maintained with ages from 1-36 months. We have studied gastrointestinal absorption and observed that while active transport declines with age, passive diffusion does not appear to change. Body composition, which can play a major role in the distribution of compounds changes with age, with a decrease in the lean body mass being accompanied by an increase in adipose tissue. For lipophilic compounds, this results in an increased depot volume and thus enhanced retention. A decrease in renal elimination has been reported for many drugs. However, we have also observed a decline in the rate of bile flow, resulting in a decreased rate of excretion in feces as animals age. Previous work has shown that the phase I reactions, especially oxidations, may increase, decrease, or remain unchanged with age. We are conducting a systematic examination of age-related changes in the phase II (conjugation) reactions. We have observed that glutathione conjugation does not change with age. However, glucuronidation by the enzyme that metabolizes chloramphenicol and bilirubin undergoes an age-related decline. This results in higher levels of the unconjugated chemical in the body. However, we did not observe any enhanced toxicity in the aging rat. Examination of other conjugation pathways as a function of age are currently in progress, as are correlations of altered metabolism with toxic effects. We are also planning to conduct studies on the effects of age on dermal absorption and metabolism.