Engel Nicole, Mahlknecht Ulrich
Department of Hematology/Oncology, University of Heidelberg Medical Center, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Int J Mol Med. 2008 Feb;21(2):223-32.
The sirtuin 1 protein (SIRT1) is a member of the class III NAD+-dependent histone deacetylases, which are also referred to as the 'sirtuins'. The sirtuins and silent information regulator 1 (SIRT1) in particular, are known to play a role in the response to DNA damage, metabolism, longevity and carcinogenesis. SIRT1 regulates different cellular processes such as proliferation, differentiation and apoptosis through deacetylation of important regulatory proteins such as p53, FOXO3a and NFkappaB. A number of different modifiers of SIRT1 expression and activity have been discovered and even food and cosmetic additives (e.g. resveratrol and dihydrocoumarin) have been suggested to either activate or inhibit the activity of human SIRT1. We screened a panel of 18 different drugs which are frequently used in everyday clinical practice with regard to their influence on cell survival and SIRT1 expression in freshly isolated peripheral blood mononuclear cells (PBMCs) from young and healthy volunteers. In this context, we identified L-thyroxin, insulin and sodium nitroprusside to be potent activators of human SIRT1 expression. In addition, treatment of PBMCs with sodium nitroprusside was associated with a significant cellular lifespan extension, while L-thyroxin and insulin were unable to prolong lifespan, suggesting that isolated upregulation of SIRT1 is in fact insufficient to promote longevity. These findings have an important impact on the long-term use of a number of frequently used clinical agents in the treatment of chronic disease with respect to aging and carcinogenesis.
沉默信息调节因子1蛋白（SIRT1）是Ⅲ类烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性组蛋白脱乙酰酶家族的成员，这类酶也被称为“沉默信息调节因子”。沉默信息调节因子，尤其是沉默信息调节因子1（SIRT1），已知在DNA损伤反应、新陈代谢、寿命和致癌作用中发挥作用。SIRT1通过对重要调节蛋白（如p53、FOXO3a和核因子κB）进行去乙酰化来调节不同的细胞过程，如增殖、分化和凋亡。已经发现了许多不同的SIRT1表达和活性调节剂，甚至有研究表明食品和化妆品添加剂（如白藜芦醇和二氢香豆素）可以激活或抑制人SIRT1的活性。我们筛选了一组在日常临床实践中常用的18种不同药物，研究它们对来自年轻健康志愿者的新鲜分离外周血单个核细胞（PBMC）的细胞存活和SIRT1表达的影响。在此过程中，我们确定左旋甲状腺素、胰岛素和硝普钠是人类SIRT1表达的有效激活剂。此外，用硝普钠处理PBMC与显著延长细胞寿命有关，而左旋甲状腺素和胰岛素则无法延长细胞寿命，这表明单独上调SIRT1实际上不足以促进长寿。这些发现对于许多常用临床药物在治疗慢性疾病时关于衰老和致癌作用的长期使用具有重要影响。
