Background

The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process.

Methods

Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar.

Results

The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling.

Conclusions

Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process.

中文翻译：

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胰岛素/IGF-1 信号通过 STAT3 通路促进免疫抑制：对衰老过程和年龄相关疾病的影响

背景

胰岛素/IGF-1 信号通路在秀丽隐杆线虫和哺乳动物物种的寿命调节中具有重要作用，即该通路活性降低可延长寿命，而活性增加则加速衰老过程。胰岛素/IGF-1 通路控制蛋白质和能量代谢以及胰岛素/IGF-1 反应细胞的增殖和分化。胰岛素/IGF-1 信号还调节先天性和适应性免疫系统的功能。本综述的目的是阐明胰岛素/IGF-1 信号传导是否与已知会促进衰老过程的免疫抑制 STAT3 信号传导有关。

方法

从 Pubmed、Scopus 和 Google Scholar 等主要数据库中检查了包含胰岛素/IGF-1 和 STAT3 信号之间联系的原创文章和评论文章。

结果

胰岛素/IGF-1 受体的激活通过 JAK 和 AKT 驱动的信号通路刺激 STAT3 信号传导。STAT3 信号传导是免疫抑制细胞的主要激活剂，能够抵消与衰老过程相关的慢性低度炎症。然而，STAT3 信号的激活通过诱导 SOCS 因子刺激负反馈反应，这些因子不仅抑制胰岛素/IGF-1 受体的活性，还抑制许多细胞因子受体的活性。胰岛素/IGF-1 信号传导的抑制会引起胰岛素抵抗，这种情况会随着年龄的增长而增加。STAT3 信号还触发非免疫细胞和免疫细胞的衰老，尤其是通过激活 p53 信号。

结论

鉴于细胞衰老、炎症和抵抗免疫抑制会随着衰老而增加，这可能解释了为什么过量的胰岛素/IGF-1 信号会促进衰老过程。