Nicotinamide phosphoribosyltransferase delays cellular senescence by upregulating SIRT1 activity and antioxidant gene expression in mouse cells
Nicotinamide phosphoribosyltransferase delays cellular senescence by upregulating SIRT1 activity and antioxidant gene expression in mouse cells
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DOI：
10.1111/gtc.12542
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发表时间：
2017-12-01
期刊：
影响因子：
2.1
通讯作者：
Bessho, Yasumasa
中科院分区：
文献类型：
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作者：
Khaidizar, Fiqri D.;Nakahata, Yasukazu;Bessho, Yasumasa
衰老细胞在老年动物的组织中积累，使组织功能恶化。从老年小鼠中消除衰老细胞不仅可以减缓已经建立的年龄相关疾病的进展，而且还可以延长中位寿命。烟酰胺磷酸核糖基转移酶（NAMPT）是哺乳动物NAD（+）修复通路中的限速酶，对人类原代细胞衰老具有保护作用。然而，目前尚不清楚NAMPT如何在体外和体内对衰老产生保护作用。在本研究中，我们发现小鼠胚胎成纤维细胞（MEF）在连续传代过程中，NAMPT和NAD（+）含量逐渐下降，直至衰老。此外，我们发现组成型Nampt过表达增加了体外MEF细胞NAD（+）含量，延缓了细胞衰老。我们进一步发现，组成型Nampt过表达可增加SIRT1活性，增加抗氧化基因、超氧化物歧化酶2和过氧化氢酶的表达，促进抗氧化应激。这些发现表明，MEF细胞中Nampt的过表达通过SIRT1激活超氧化物歧化酶2和过氧化氢酶基因表达的上调来减缓氧化应激，从而延缓细胞衰老。
Senescent cells accumulate in tissues of aged animals and deteriorate tissue functions. The elimination of senescent cells from aged mice not only attenuates progression of already established age-related disorders, but also extends median lifespan. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD(+) salvage pathway, has shown a protective effect on cellular senescence of human primary cells. However, it still remains unclear how NAMPT has a protective impact on aging in vitro and in vivo. In this study, we found that primary mouse embryonic fibroblast (MEF) cells undergo progressive decline of NAMPT and NAD(+) contents during serial passaging before becoming senescent. Furthermore, we showed that constitutive Nampt over-expression increases cellular NAD(+) content and delays cellular senescence of MEF cells in vitro. We further found that constitutive Nampt over-expression increases SIRT1 activity, increases the expression of antioxidant genes, superoxide dismutase 2 and catalase and promotes resistance against oxidative stress. These findings suggest that Nampt over-expression in MEF cells delays cellular senescence by the mitigation of oxidative stress via the upregulation of superoxide dismutase 2 and catalase gene expressions by SIRT1 activation.