Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan.
J Biochem. 2022 May 11;171(5):579-589. doi: 10.1093/jb/mvac014.
Oxidative stress is one of the major causes of the age-related functional decline in cells and tissues. The KEAP1-NRF2 system plays a central role in the regulation of redox balance, and NRF2 activation exerts antiageing effects by controlling oxidative stress in aged tissues. α-Klotho was identified as an ageing suppressor protein based on the premature ageing phenotypes of its mutant mice, and its expression is known to gradually decrease during ageing. Because α-klotho has been shown to possess antioxidant function, ageing-related phenotypes of α-klotho mutant mice seem to be attributable to increased oxidative stress at least in part. To examine whether NRF2 activation antagonizes ageing-related phenotypes caused by α-klotho deficiency, we crossed α-klotho-deficient (Kl-/-) mice with a Keap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation in Kl-/- mice extended the lifespan and dramatically improved ageing-related renal phenotypes. With elevated expression of antioxidant genes accompanied by an oxidative stress decrease, the antioxidant effects of NRF2 seem to make a major contribution to the attenuation of ageing-related renal phenotypes of Kl-/- mice. Thus, NRF2 is expected to exert an antiageing function by partly compensating for the functional decline of α-Klotho during physiological ageing.
氧化应激是导致细胞和组织与年龄相关的功能下降的主要原因之一。KEAP1-NRF2 系统在调节氧化还原平衡中起着核心作用，NRF2 的激活通过控制衰老组织中的氧化应激来发挥抗衰老作用。α-Klotho 是一种衰老抑制蛋白，其突变小鼠表现出早衰表型，其表达水平随着年龄的增长而逐渐降低。由于 α-Klotho 具有抗氧化功能，因此 α-Klotho 突变小鼠的衰老相关表型至少部分归因于氧化应激的增加。为了研究 NRF2 激活是否拮抗 α-Klotho 缺乏引起的与衰老相关的表型，我们将 α-Klotho 缺陷（Kl-/-）小鼠与 Keap1 敲低背景（整个身体中 NRF2 途径持续激活）杂交。Kl-/- 小鼠中 NRF2 途径的激活延长了寿命，并显著改善了与衰老相关的肾脏表型。随着抗氧化基因的表达升高和氧化应激的降低，NRF2 的抗氧化作用似乎对减轻 Kl-/- 小鼠与衰老相关的肾脏表型有重要贡献。因此，NRF2 有望通过部分补偿生理衰老过程中 α-Klotho 的功能下降来发挥抗衰老作用。
