Abstract

This review discusses genetic and molecular pathways that link circadian timing with metabolism, resulting in the emergence of positive and negative regulatory feedback loops. The Nrf2 pathway is believed to be a component of the anti-aging program responsible for the healthspan and longevity. Nrf2 enables stress adaptation by activating cell antioxidant defense and other metabolic processes via control of expression of over 200 target genes in response to various types of stress. The GSK3 system represents a “regulating valve” that controls fine oscillations in the Nrf2 level, unlike Keap1, which prevents significant changes in the Nrf2 content in the absence of oxidative stress and which is inactivated by the oxidative stress. Furthermore, GSK3 modifies core circadian clock proteins (Bmal1, Clock, Per, Cry, and Rev-erbα). Phosphorylation by GSK3 leads to the inactivation and degradation of circadian rhythm-activating proteins (Bmal1 and Clock) and vice versa to the activation and nuclear translocation of proteins suppressing circadian rhythms (Per and Rev-erbα) with the exception of Cry protein, which is likely to be implicated in the fine tuning of biological clock. Functionally, GSK3 appears to be one of the hubs in the cross-regulation of circadian rhythms and antioxidant defense. Here, we present the data on the crosstalk between the most powerful cell antioxidant mechanism, the Nrf2 system, and the biorhythm-regulating system in mammals, including the impact of GSK3 overexpression and knockout on the Nrf2 signaling. Understanding the interactions between the regulatory cascades linking homeostasis maintenance and cell response to oxidative stress will help in elucidating molecular mechanisms that underlie aging and longevity.

中文翻译：

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Biorhythms和长寿守门人之间的串扰：糖原合酶激酶3的双重作用。

摘要

这篇综述讨论了将昼夜节律与代谢联系在一起的遗传和分子途径，从而导致正向和负向调节反馈回路的出现。Nrf2途径被认为是抗衰老计划的组成部分，负责健康和长寿。Nrf2通过控制200多种靶基因的表达来响应各种类型的应激，从而通过激活细胞抗氧化剂防御和其他代谢过程来实现应激适应。与Keap1不同，GSK3系统代表一个控制Nrf2水平的精细振荡的“调节阀”，Keap1可在没有氧化应激的情况下防止Nrf2含量的显着变化，并通过氧化应激使其失活。此外，GSK3修饰核心生物钟蛋白（Bmal1，Clock，Per，Cry和Rev-erbα）。反之亦然，除了Cry蛋白外，抑制昼夜节律的蛋白（Per和Rev-erbα）的激活和核转位可能与生物钟的微调有关。在功能上，GSK3似乎是昼夜节律和抗氧化剂防御的交叉调节中枢之一。在这里，我们介绍了哺乳动物中最强大的细胞抗氧化剂机制，Nrf2系统和生物节律调节系统之间的串扰数据，包括GSK3过表达和敲除对Nrf2信号的影响。理解调节稳态之间的相互作用以及维持稳态和细胞对氧化应激的反应之间的相互作用，将有助于阐明衰老和长寿的分子机制。