Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
Cell Metab. 2012 Dec 5;16(6):738-50. doi: 10.1016/j.cmet.2012.11.007.
Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.
LMNA 基因的异常剪接或前层粘连蛋白 A 的异常加工导致早老综合征。在这里，我们表明 lamin A 与 SIRT1 相互作用并激活 SIRT1。在 progerin 或 prelamin A 的存在下，SIRT1 与核基质 (NM) 的结合减少，去乙酰化酶活性降低，导致 Zmpste24(-/-) 小鼠中的成体干细胞 (ASC) 迅速耗竭。白藜芦醇增强了 SIRT1 和 A 型层粘连蛋白之间的结合，增加了其去乙酰化酶活性。白藜芦醇治疗可挽救 ASC 下降，减缓体重减轻，改善小梁骨结构和矿物质密度，并显著延长 Zmpste24(-/-) 小鼠的寿命。我们的数据表明 lamin A 是 SIRT1 的激活剂，并为白藜芦醇激活 SIRT1 提供了一种机制解释。保守的 SIRT1 长寿途径与早老症之间的联系表明，早老症存在基于干细胞和 SIRT1 途径的治疗策略。
