SENESCENT CHANGES IN METABOLISM

新陈代谢的衰老变化

• 批准号: 3941461
• 负责人: L S BIRNBAUM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3941461
• 关键词: active transport; aging; brain metabolism; environmental toxicology; gastrointestinal toxin absorption; kidney function; kidney metabolism; liver metabolism; lung; passive transport; small intestines; stress; toxin metabolism

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.

衰老过程会导致生物体的敏感性改变 环境毒素的影响。 我们有兴趣 研究随着年龄的增长而发生的变化 吸收、分布、代谢和排泄过程 以及这些变化如何影响这些有毒物质的毒性 化学品 我们的模型系统是衰老的雄性Fischer大鼠， 其群体维持在1-36个月龄。 我们研究了胃肠道吸收，并观察到， 主动转运随年龄增长而下降，被动扩散则随年龄增长而下降。 似乎没有改变。 身体成分，这可以发挥重大作用 在化合物分布中的作用随年龄而变化， 瘦体重的减少伴随着增加 在脂肪组织中。 对于亲脂性化合物，这导致 增加了储库容量，从而提高了保留率。 减少 据报道，许多药物的肾脏消除。 然而，在这方面， 我们还观察到胆汁流速下降， 随着动物年龄的增长，粪便中的排泄率下降。 以前的工作表明，I相反应，特别是 氧化，可能会增加，减少，或保持不变， 年龄 我们正在进行一项系统的检查， 第二阶段（共轭）反应的变化。 我们观察到 谷胱甘肽结合不随年龄变化 然而，在这方面， 氯霉素代谢酶的葡萄糖醛酸化 胆红素会随着年龄的增长而下降 这导致 体内未结合的化学物质的水平更高。 然而，在这方面， 我们在衰老大鼠中没有观察到任何增强的毒性。 检查作为年龄函数的其他结合途径 目前正在进行中，因为是相关的改变 具有毒性作用的新陈代谢。 我们还计划进行 研究年龄对皮肤吸收的影响， 新陈代谢.