Chen Danica, Bruno Joanne, Easlon Erin, Lin Su-Ju, Cheng Hwei-Ling, Alt Frederick W, Guarente Leonard
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Genes Dev. 2008 Jul 1;22(13):1753-7. doi: 10.1101/gad.1650608. Epub 2008 Jun 11.
Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.
据报道，热量限制（CR）可提高小鼠、大鼠和人类体内的SIRT1蛋白水平，而SIRT1直系同源物活性的提高可延长酵母、蠕虫和果蝇的寿命。在本研究中，我们对“CR在所有组织中诱导SIRT1活性”这一范式提出质疑，因为我们发现，实际上CR会降低肝脏中这种去乙酰化酶的活性，而高热量饮食则会激活它。我们通过检测SIRT1及其小分子调节剂NAD和NADH的水平，以及评估肝脏特异性SIRT1基因敲除小鼠在不同饮食条件下的表型，证明了这种变化。我们的研究结果表明，设计靶向SIRT1以提供统一全身益处的CR模拟物可能比目前想象的更为复杂。
