Effects of phentermine and phenformin on biomarkers of aging in rats
Effects of phentermine and phenformin on biomarkers of aging in rats
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DOI：
10.1159/000081430
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发表时间：
2005-01-01
期刊：
影响因子：
3.5
通讯作者：
Roth, GS
中科院分区：
文献类型：
--
作者：
Anisimova, VN;Ukraintseva, SV;Roth, GS
背景：热量限制（CR）是唯一已知的能显著延长实验动物平均和最长寿命的治疗方法。模拟CR某些作用的干预措施可能是人类潜在的抗衰老治疗方法。降低食欲的药物（食欲抑制剂）代表一类候选治疗。降低生物体葡萄糖利用的试剂也可以代表另一类候选CR模拟物。目的：在我们的研究中，我们解决了以下问题：（1）与CR相比，用抗抑郁药治疗是否能减少实验动物的热量摄入和体重？(2)抗糖尿病药物治疗是否影响热量摄入和体重？（3）用这些药物中的任何一种治疗是否以与CR观察到的相似的方式影响生物体的代谢参数？研究方法：将120只6月龄雌性Wistar LIO大鼠随机分为4组，分别给予：（1）安慰剂组（2）抗糖尿病药物非那普利（2 mg/kg）;（3）厌食药物芬特明（1 mg/kg），和（4）与前一周食物摄入量最少的组（成对喂养的对照组）相同的食物量。在16周期间每周测量食物和水摄入量、体重和直肠温度。在实验第16周结束时，估计了血糖、总β-脂蛋白和前β-脂蛋白组分、胆固醇、甘油三酯、胰岛素、总三碘甲状腺原氨酸和游离甲状腺素的血清水平。二烯共轭物和席夫碱的含量，总抗氧化活性，铜/锌超氧化物歧化酶，谷胱甘肽S-转移酶，谷胱甘肽过氧化物酶的活性，以及活性氧（ROS）的产生在脑和肝匀浆和血清中进行了研究。结果如下：与自由采食对照组相比，暴露于配对饲喂的对照组的摄食量显著降低（约20%），因此表现出中度CR。与自由进食的对照组相比，用芬特明治疗使热量摄入减少约12%。与对照组相比，该组的体重和水摄入量仅略有下降（分别约为2%和5%）。芬特明组的平均直肠温度（38 ℃）显著高于自由进食组（37.8 ℃）和成对进食组（37.6 ℃）。用芬特明治疗也导致研究的所有组织中ROS水平显著降低，而在自由采食（血清）和成对饲喂（脑）对照中发现最高的ROS产生。与自由进食对照组相比，用苯丙氨酸治疗对摄食量和饮水量、体重和体温没有显著影响。用这种抗糖尿病药物治疗的大鼠显示出ROS产生的中间值。各组间总抗氧化活性差异不明显。结论：芬特明治疗减少热量摄入略低于CR研究中常见的情况。由于强制减少进食引起的CR和由于物质抑制食欲引起的CR似乎通过不同的代谢机制起作用，因此可能以不同的方式影响衰老和寿命。版权所有（C）2005 S. Karger AG，巴塞尔。
Background: Caloric restriction (CR) is the only treatment known to substantially prolong both average and maximal life span in experimental animals. Interventions that mimic certain effects of CR could be potential anti-aging treatments in humans. Drugs which reduce appetite (anorexiants) represent one class of candidate treatments. Agents that reduce the glucose utilization by the organism could also represent another class of candidate CR mimetics. Objective: In our study, we addressed the following questions: ( 1) Does treatment with an anorexiant reduce caloric intake and body weight of experimental animals comparable to that caused by CR? (2) Does treatment with an antidiabetic agent influence caloric intake and body weight? ( 3) Does treatment with any of these drugs affect metabolic parameters of an organism in the way similar to that observed with CR? Methods: One hundred and twenty 6-month-old female Wistar-derived LIO rats were randomly subdivided into four groups and exposed to: ( 1) ad libitum feeding with placebo ( controls); (2) the antidiabetic drug phenformin (2 mg/kg); (3) the anorectic drug phentermine (1 mg/kg), and (4) the same amount of food as the group with the least food intake during the previous week (pair-fed controls). Food and water intake, body weight, and rectal temperature were measured weekly during 16 weeks. At the end of the 16th week of the experiment, serum levels of glucose, total beta-lipoprotein and pre-beta-lipoprotein fractions, cholesterol, triglycerides, insulin, total triiodothyronine, and free thyroxine were estimated. The contents of diene conjugates and Schiff's bases, total antioxidant activity, the activities of Cu/Zn superoxide dismutase, glutathione S-transferase, and glutathione peroxidase, and the generation of reactive oxygen species (ROS) were studied in brain and liver homogenates and in the serum. Results: The controls exposed to pair feeding had a significantly reduced food consumption (about 20%) as compared with the ad libitum fed controls and thus exhibited a moderate CR. Treatment with phentermine reduced the caloric intake by about 12% as compared with the ad libitum fed controls. Body weight and water intake in this group were only slightly decreased ( by about 2 and 5%, respectively) as compared with the controls. The mean rectal temperature in the phentermine group (38degreesC) was significantly higher than in the ad libitum fed (37.8degreesC) and pair-fed (37.6degreesC) controls. Treatment with phentermine also resulted in significantly reduced ROS levels in all tissues studied, while the highest ROS production was found in ad libitum (blood serum) and pair-fed ( brain) controls. Treatment with phenformin did not significantly influence food and water consumption, body weight, and temperature when compared with the ad libitum fed controls. Rats treated with this antidiabetic drug showed intermediate values of ROS generation. Differences among the groups in total antioxidant activity were not obvious. Conclusions: Treatment with phentermine reduces caloric intake slightly less than is commonly observed in CR studies. CR due to forcibly reduced feeding and CR due to substance-suppressed appetite appear to act through different metabolic mechanisms and thus may affect aging and longevity in different ways. Copyright (C) 2005 S. Karger AG, Basel.