Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Biometrics Matters Limited, Hamilton 3216, New Zealand.
Sci Transl Med. 2018 Jul 11;10(449). doi: 10.1126/scitranslmed.aaq1564.
Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.
雷帕霉素靶蛋白（mTOR）激酶的抑制作用可延长寿命并改善与衰老相关的病理，包括模型生物中免疫功能下降。本 2a 期随机、安慰剂对照临床试验的目的是确定在 264 名老年受试者中给予研究药物 6 周后，低剂量 mTOR 抑制剂治疗是否能增强免疫功能并降低感染率。一种雷帕霉素靶蛋白（mTOR）的催化（BEZ235）和变构（RAD001）抑制剂的低剂量组合，选择性抑制 mTOR 下游的雷帕霉素复合物 1（TORC1），该组合安全，并且与研究药物开始后一年老年受试者报告的感染率显著降低（= 0.001）相关。此外，我们观察到该治疗组的抗病毒基因表达上调和流感疫苗接种反应改善。因此，选择性 TORC1 抑制有可能改善老年人的免疫功能并降低感染率。
