TORC1 inhibition enhances immune function and reduces infections in the elderly
TORC1 inhibition enhances immune function and reduces infections in the elderly
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DOI：
10.1126/scitranslmed.aaq1564
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发表时间：
2018-07-11
影响因子：
17.1
通讯作者：
Klickstein, Lloyd B.
中科院分区：
文献类型：
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作者：
Mannick, Joan B.;Morris, Melody;Klickstein, Lloyd B.
抑制雷帕霉素（mTOR）蛋白激酶的机制靶点可延长寿命并改善衰老相关的病理学，包括模型生物体中免疫功能下降。这项2a期随机、安慰剂对照临床试验的目的是确定低剂量mTOR抑制剂治疗是否增强了264名接受研究药物6周的老年受试者的免疫功能并降低了感染率。选择性抑制mTOR下游雷帕霉素复合物1（TORC 1）靶点的催化（BEZ 235）加变构（RAD 001）mTOR抑制剂的低剂量组合是安全的，并且与研究药物开始后一年内老年受试者报告的感染率显著降低（P = 0. 001）相关。此外，我们观察到抗病毒基因表达的上调和对流感疫苗接种的反应的改善。因此，选择性TORC 1抑制有可能改善老年人的免疫功能并减少感染。
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 (P = 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.