Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, WC1E 6BT London, United Kingdom.
Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):20817-20819. doi: 10.1073/pnas.1913212116. Epub 2019 Sep 30.
Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter's effects on lipid metabolism. In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.
预期寿命的延长导致与年龄相关的疾病患病率上升，因此迫切需要新的策略来改善老年人的健康状况。在不同的生物体中，降低胰岛素/胰岛素样生长因子信号（IIS）和雷帕霉素靶蛋白（mTOR）营养感应信号网络的活性可以延长寿命并改善衰老过程中的健康状况。然而，该网络中的广泛反馈和抑制的不良反应表明，同时针对网络中的特定效应物可能是最有效地对抗衰老影响的方法。我们表明，丝裂原活化蛋白激酶激酶（MEK）抑制剂曲美替尼、mTOR 复合物 1（mTORC1）抑制剂雷帕霉素和糖原合酶激酶-3（GSK-3）抑制剂锂联合使用可显著增加寿命。值得注意的是，三药联合可使寿命延长 48%。此外，锂与雷帕霉素的联合使用消除了后者对脂质代谢的影响。总之，结合已确立的、延长寿命的药物抑制剂来针对特定节点的多药理学方法可能是靶向营养感应网络以改善晚年健康的最有效方法。
