Smith Jesse J, Kenney Renée Deehan, Gagne David J, Frushour Brian P, Ladd William, Galonek Heidi L, Israelian Kristine, Song Jeffrey, Razvadauskaite Giedre, Lynch Amy V, Carney David P, Johnson Robin J, Lavu Siva, Iffland Andre, Elliott Peter J, Lambert Philip D, Elliston Keith O, Jirousek Michael R, Milne Jill C, Boss Olivier
Sirtris, a GSK company, 200 Technology Square, Cambridge, MA 02139, USA.
BMC Syst Biol. 2009 Mar 10;3:31. doi: 10.1186/1752-0509-3-31.
Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.
Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.
CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.
热量限制（CR）能带来诸多健康益处，并改善诸如2型糖尿病等衰老相关疾病。CR下游通路的组成部分可能为开发治疗衰老相关疾病的疗法提供干预靶点。烟酰胺腺嘌呤二核苷酸（NAD +）依赖性蛋白脱乙酰酶SIRT1被认为是酵母、啮齿动物和人类中CR关键的下游调节因子之一。已鉴定出SIRT1的小分子激活剂，它们在通常与衰老相关的疾病动物模型（包括2型糖尿病）中显示出疗效。为了确定用两种结构不同的SIRT1激活剂SIRT501（配方白藜芦醇）和SRT1720处理三天的小鼠肝脏中诱导的分子过程，我们采用了系统生物学方法，并将因果网络建模（CNM）应用于基因表达数据，以阐明SIRT1激活的下游效应。
在此我们证明，SIRT1激活剂在体内重现了CR下游的许多分子事件，例如在高脂、高热量饮食喂养的小鼠中增强线粒体生物发生、改善代谢信号通路以及减弱促炎通路。
对用SRT501或SRT1720处理的小鼠的基因表达数据进行CNM，并结合支持性的体外和体内数据表明，SRT501和SRT1720产生的信号谱与CR相似，改善了葡萄糖和胰岛素稳态，并在体内通过激活SIRT1发挥作用。综合这些结果，使用SIRT1小分子激活剂对2型糖尿病进行治疗干预是令人鼓舞的，目前多项临床试验正在对此策略进行研究。
