Krishnamurthy Janakiraman, Torrice Chad, Ramsey Matthew R, Kovalev Grigoriy I, Al-Regaiey Khalid, Su Lishan, Sharpless Norman E
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599-7295, USA.
J Clin Invest. 2004 Nov;114(9):1299-307. doi: 10.1172/JCI22475.
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
Ink4a/Arf基因座编码两种肿瘤抑制分子p16INK4a和Arf，它们是细胞衰老的主要调节因子。为了研究体内衰老与老化之间的联系，我们检测了衰老啮齿动物模型中Ink4a/Arf的表达。我们发现，随着年龄的增长，几乎所有啮齿动物组织中p16INK4a和Arf的表达都显著增加，而其他相关细胞周期抑制剂的表达几乎没有变化。表达的增加仅限于所研究的每个器官内明确界定的区域，并且发生在不同谱系的上皮细胞和基质细胞中。热量限制可使肾脏、卵巢和心脏中与年龄相关的p16INK4a和Arf表达增加减弱，这种减少与衰老体内标志物的表达降低以及这些器官的病理变化减少相关。最后，Ink4a/Arf表达与年龄相关的增加可独立归因于Ets-1（一种已知的p16INK4a转录激活因子）以及未知的Ink4a/Arf共调节分子的表达。这些数据表明，Ink4a/Arf肿瘤抑制基因座的表达是哺乳动物衰老的一个强大生物标志物和可能的效应因子。
