Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave GER306A, Los Angeles, CA 90089-0191, USA.
Andrus Gerontology Center of the Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave GER306A, Los Angeles, CA 90089-0191, USA; Division of Molecular & Computational Biology, Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90089-0191, USA.
Redox Biol. 2018 Apr;14:35-40. doi: 10.1016/j.redox.2017.08.014. Epub 2017 Aug 24.
Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21-29 years) and older (60-69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE-driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells.
动物研究表明，应激诱导的 Nrf2 调节的抗氧化基因表达增加，这是细胞保护的关键机制，随着衰老而下降。本研究旨在探讨这是否也发生在人类身上。我们测量了来自年轻成人（21-29 岁）和老年（60-69 岁）非吸烟者的人支气管上皮（HBE）细胞中 Nrf2 调节的抗氧化基因的基础和诱导水平，并探讨了影响表达的因素。与年轻成人供体的细胞相比，老年供体的细胞中三种代表性的 Nrf2 调节基因，即谷氨酸半胱氨酸连接酶的催化和调节亚基（GCLC 和 GCLM）和 NAD（P）H 醌氧化还原酶 1（NQO1）的基础表达更高。暴露于 Nrf2 激活剂，萝卜硫素（SF）后，这些抗氧化基因在年轻成人和老年供体的细胞中表达均增加；然而，SF 对老年供体细胞的诱导作用明显低于年轻成人细胞。此外，SF 对 EpRE 驱动的报告基因的激活作用在老年供体细胞中低于年轻成人细胞。老年供体细胞中 Nrf2 蛋白的基础表达也低于年轻成人细胞。此外，我们发现，与年轻成人供体相比，老年供体的细胞中 Bach1 和 c-Myc 两种 Nrf2 抑制物的基础表达更高。总之，我们的数据表明，与其他物种一样，Nrf2 调节基因的基础表达随着年龄的增长而增加，而诱导能力随着年龄的增长而下降。Nrf2 抑制物如 Bach1 和 c-Myc 的表达增加可能导致人支气管上皮细胞中 Nrf2 调节的抗氧化基因的诱导能力随着年龄的增长而受损。
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