Duration of rapamycin treatment has differential effects on metabolism in mice.
Duration of rapamycin treatment has differential effects on metabolism in mice.
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DOI：
10.1016/j.cmet.2013.02.008
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发表时间：
2013-03-05
期刊：
影响因子：
29
通讯作者：
Bartke A
中科院分区：
文献类型：
--
作者：
Fang Y;Westbrook R;Hill C;Boparai RK;Arum O;Spong A;Wang F;Javors MA;Chen J;Sun LY;Bartke A
雷帕霉素 (TOR) 信号传导的进化保守靶标控制着生长、代谢和衰老。首次有力地证实了药理诱导哺乳动物寿命延长的结果，用雷帕霉素（一种机械 TOR (mTOR) 抑制剂）治疗的小鼠寿命得到延长。然而，也有报道称雷帕霉素治疗对代谢产生不利影响，尽管代谢受损，但生存率却提高了。雷帕霉素如何延长小鼠的寿命并产生如此矛盾的效果尚不清楚。在这里，我们表明，雷帕霉素治疗的有害影响仅在治疗的早期阶段观察到。当治疗持续 20 周后，这些效应被逆转或减弱。小鼠的代谢状况更好，耗氧量和生酮作用增加，胰岛素敏感性显着增强。因此，延长雷帕霉素治疗导致有益的代谢改变，与之前观察到的寿命延长一致。我们的研究结果为“雷帕霉素悖论”提供了可能的解释，并支持这些代谢改变对长寿的潜在因果重要性。
The evolutionarily conserved target of rapamycin (TOR) signaling controls growth, metabolism and aging. In the first robust demonstration of pharmacologically-induced life extension in a mammal, longevity was extended in mice treated with rapamycin, an inhibitor of mechanistic TOR (mTOR). However, detrimental metabolic effects of rapamycin treatment were also reported, presenting a paradox of improved survival despite metabolic impairment. How rapamycin extended lifespan in mice with such paradoxical effects was unclear. Here we show that detrimental effects of rapamycin treatment were only observed during the early stages of treatment. As the treatment continued for 20 weeks, these effects were reversed or diminished; the mice had better metabolic profiles, increased oxygen consumption and ketogenesis, and markedly enhanced insulin sensitivity. Thus, prolonged rapamycin treatment led to beneficial metabolic alterations, consistent with life extension previously observed. Our findings provide a likely explanation of the “rapamycin paradox” and support the potential causal importance of these metabolic alterations in longevity.
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生长激素受体的破坏可防止卡路里的限制改善胰岛素作用和寿命。
影响因子：
3.7
作者：
Bonkowski MS;Dominici FP;Arum O;Rocha JS;Al Regaiey KA;Westbrook R;Spong A;Panici J;Masternak MM;Kopchick JJ;Bartke A
通讯作者：
Bartke A
影响因子：
7.7
作者：
Houde VP;Brûlé S;Festuccia WT;Blanchard PG;Bellmann K;Deshaies Y;Marette A
通讯作者：
Marette A
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
8.8
作者：
Blum, CB
通讯作者：
Blum, CB