A multi-system approach to ameliorate the age-dependent loss of the Nrf2-mediated cellular stress response: implications on stress adaptation and longevity.

项目摘要 衰老和年龄相关疾病的一个主要标志是无法激活细胞质量 暴露于内源性和外源性氧化损伤后的控制机制，如果不去除， 会严重破坏细胞DNA脂质和蛋白质细胞损伤的累积会加速 衰老表型因此，适应性应激的调控机制的表征 反应（ASR）仍然是衰老研究的重要目标。 细胞依赖于ASR对轻度氧化应激的短暂和可逆的反应（导致 从代谢和环境条件）激活应激反应基因，从而使细胞和 生物体，以科普各种各样的细胞毒性条件。ASR由两个部分组成： 立即激活应激反应基因以去除损伤，然后延迟失活 当不再需要时，一个主要的转录调节因子是Nrf 2，它在氧化后 应激转录激活保护途径和酶以对抗细胞毒性条件。BACH1 作为Nrf 2信号传导的时间延迟转录抑制因子抑制ASR。但随着 随着年龄的增长，Nrf 2靶基因表达下降，导致细胞功能障碍、损伤和 衰老 从历史上看，减少年龄依赖性Nrf 2下降的主要方法集中在Nrf 2 过表达或抑制其胞质抑制剂Keap 1。不幸的是，这些方法都失败了 以恢复ASR，并且在某些情况下，被证明是有害的。相反，Bach 1可能在以下方面发挥关键作用： 恢复ASR，如其年龄依赖性增加所支持的。我假设减少/去除 Bach 1信号在以后的生活中将允许Nrf 2信号放大和Nrf 2的恢复。 介导的适应性应激反应。我建议研究Nrf 2/Bach 1的年龄依赖性变化， 在3种模型系统（人原代细胞，D.黑腹动物和小鼠）（目的1- 3）。此外，我将试图通过抑制Bach 1来恢复Nrf 2介导的ASR的年龄依赖性下降 （直接）和热量限制（间接），因为以前曾报道热量限制可以降低年龄- 相关的氧化应激增加（目的2和3）。总之，这种探索将提供一种替代方案， 一种随着年龄增长而恢复ASR的方法，具有减缓衰老过程和/或疾病的潜力 进展

Project Summary One major hallmark of aging and age-associated diseases is the inability to activate cellular quality control mechanisms after exposure to endogenous and exogenous oxidative damage, which if not removed, can wreak havoc upon cellular DNA, lipids, and proteins. The accumulation of cellular damage can accelerate the aging phenotype. Therefore, the characterization of regulatory mechanisms of the adaptive stress response (ASR) remains an important goal of aging research. Cells rely upon the ASR for the transient and reversible response to mild oxidative stress (resulting from metabolic and environmental conditions) to activate stress responsive genes, thereby enabling cells and organisms to cope with a wide array of cytotoxic conditions. The ASR consists of two components: the immediate activation of stress responsive genes for damage removal, followed by the time-delayed inactivation of the response, when no longer necessary. A master transcriptional regulator is Nrf2, which upon oxidative stress transcriptionally activates protective pathways and enzymes to counteract cytotoxic conditions. Bach1 acts as a time-delayed transcriptional suppressor of Nrf2 signaling to inactivate the ASR. However, with increasing age Nrf2-target gene expression declines, contributing to cellular dysfunction, damage and senescence. Historically, the primary approach to reduce the age-dependent Nrf2 decline was focused on Nrf2 overexpression or the suppression of its cytosolic inhibitor Keap1. Unfortunately, these approaches have failed to restore the ASR and, in some instances, proven detrimental. Instead, Bach1 may play a crucial role in restoring the ASR, as supported by its age-dependent increase. I hypothesize that reducing/removal of Bach1 signaling in later life will allow for Nrf2 signal amplification and the restoration of the Nrf2- mediated adaptive stress response. I propose to investigate the age-dependent change in Nrf2/Bach1 signaling upon oxidative stress in 3 model systems (human primary cells, D. melanogaster, and mice) (Aims 1- 3). Additionally, I will seek to restore the age-dependent decline in the Nrf2-mediated ASR by Bach1 inhibition (direct) and caloric restriction (indirect), as caloric restriction has been previously reported to reduce the age- associated increase in oxidative stress (Aims 2 & 3). Together, this exploration will offer an alternative approach for restoration of the ASR with age, with the potential for slowing the aging process and/or disease progression.