Sasaki Tsutomu, Maier Bernhard, Bartke Andrzej, Scrable Heidi
Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Aging Cell. 2006 Oct;5(5):413-22. doi: 10.1111/j.1474-9726.2006.00235.x. Epub 2006 Aug 25.
Sir2 is an NAD+-dependent deacetylase that regulates lifespan in yeast, worms and flies. The mammalian orthologs of Sir2 include SIRT1 in humans and mice. In this study, we analyzed the level of SIRT1 in human lung fibroblasts (IMR90) and mouse embryonic fibroblasts (MEFs) from mice with normal, accelerated, and delayed aging. SIRT1 protein, but not mRNA, decreased significantly with serial cell passage in both human and murine cells. Mouse SIRT1 decreased rapidly in prematurely senescent (p44 Tg) MEFs, remained high in MEFs with delayed senescence (Igf-1r-/-), and was inversely correlated with senescence-activated beta-galactosidase (SA-betaGal) activity. Reacquisition of mitotic capability following spontaneous immortalization of serially passaged wild-type MEFs restored the level of SIRT1 to that of early passage, highly proliferative MEFs. In mouse and human fibroblasts, we found a significant positive correlation between the levels of SIRT1 and proliferating cell nuclear antigen (PCNA), a DNA processing factor expressed during S-phase. In the animal, we found that SIRT1 decreased with age in tissues in which mitotic activity also declines, such as the thymus and testis, but not in tissues such as the brain in which there is little change in mitotic activity throughout life. Again, the decreases in SIRT1 were highly correlated with decreases in PCNA. Finally, loss of SIRT1 with age was accelerated in mice with accelerated aging but was not observed in long-lived growth hormone-receptor knockout mice. Thus, as mitotic activity ceases in mouse and human cells in the normal environment of the animal or in the culture dish, there is a concomitant decline in the level of SIRT1.
Sir2是一种依赖烟酰胺腺嘌呤二核苷酸（NAD+）的脱乙酰酶，可调节酵母、线虫和果蝇的寿命。Sir2在哺乳动物中的同源物包括人类和小鼠中的SIRT1。在本研究中，我们分析了正常衰老、加速衰老和延缓衰老小鼠的人肺成纤维细胞（IMR90）和小鼠胚胎成纤维细胞（MEF）中SIRT1的水平。在人类和鼠类细胞中，随着细胞传代次数增加，SIRT1蛋白水平显著下降，但其mRNA水平未下降。在早衰（p44 Tg）的MEF中，小鼠SIRT1迅速下降；在延缓衰老的MEF（Igf-1r-/-）中，SIRT1水平保持较高，且与衰老激活的β-半乳糖苷酶（SA-βGal）活性呈负相关。连续传代的野生型MEF自发永生化后重新获得有丝分裂能力，使SIRT1水平恢复到早期传代的高增殖MEF的水平。在小鼠和人类成纤维细胞中，我们发现SIRT1水平与增殖细胞核抗原（PCNA）水平之间存在显著正相关，PCNA是一种在S期表达的DNA加工因子。在动物体内，我们发现SIRT1在有丝分裂活性也下降的组织（如胸腺和睾丸）中随年龄增长而下降，但在有丝分裂活性在整个生命过程中变化不大的组织（如大脑）中则不然。同样，SIRT1的下降与PCNA的下降高度相关。最后，在加速衰老的小鼠中，SIRT1随年龄的下降加速，但在长寿的生长激素受体基因敲除小鼠中未观察到这种现象。因此，在动物或培养皿的正常环境中，当小鼠和人类细胞的有丝分裂活性停止时，SIRT1水平会随之下降。
