Tumor Suppression Group, Spanish National Cancer Research Center, 3 Melchor Fernandez Almagro Street, Madrid E-28029, Spain.
Nat Commun. 2010 Apr 12;1:3. doi: 10.1038/ncomms1001.
Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16(Ink4a), a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer.
基因过表达蛋白去乙酰化酶 Sir2 可延长多种低等生物的寿命，这促使人们关注其最接近的哺乳动物同源物 Sirt1 对衰老和癌症的影响。我们通过其自身调控元件（Sirt1-tg）生成了 Sirt1 中度过表达的转基因小鼠。老年 Sirt1-tg 小鼠的 DNA 损伤水平较低，衰老相关基因 p16(Ink4a)的表达降低，整体健康状况更好，自发性癌和肉瘤的数量减少。然而，这些效果还不够强大，无法延长寿命。为了进一步扩展这些观察结果，我们在野生型小鼠中建立了一种与代谢综合征相关的肝癌模型，该模型中会发生多种癌。Sirt1-tg 小鼠对肝癌的易感性降低，并且对来自 DNA 损伤和代谢损伤的肝保护作用增强。总之，这些结果为 Sirt1 在哺乳动物中的抗衰老活性及其在衰老和代谢综合征相关癌症中的肿瘤抑制活性提供了直接证据。
