三个独立的研究同时证实,抑制肿瘤细胞生长的基因在细胞衰老过程中也起着重要的作用。研究发现,衰老细胞中p16INK4a基因的浓度和表达增加,与早期细胞相比,这些衰老细胞工作效率差,即使把这些细胞从年老的老鼠转入年幼的老鼠体内,仍然记得他们的“年老”。而没有转入p16INK4a基因的老鼠细胞随着年龄的增大滞缓现象比较小,继续行使着与年幼老鼠相似的功能。
??North Carolina大学,密西根州立大学和哈佛大学医学系的研究小组在胰脏的胰岛细胞,大脑和血液的干细胞观察到相似的结果。
??研究结果显示出不同类型细胞有着共同的衰老机制,表明象糖尿病类的衰老相关疾病是由于细胞生长衰竭而导致的。三个研究的合作者以及UNC医学院医学和遗传学副教授Dr. Norman E. Sharpless说,“随着年龄的增长,p16INK4a表达的增加,某些干细胞失去分化和替换他们自己的功能,” UNC癌症综合中心成员Sharpless说。
??三人一组的报告出版在9月6日的《Nature》杂志上。三个研究小组分别是UNC,Michigan大学和哈佛大学医学院。
??UNC主要集中于p16INK4a对胰脏胰岛细胞功能影响的研究。胰岛细胞是负责胰岛素的产生和分泌的。因为p16INK4a阻止癌细胞的分化,随着年龄的增长,表达也会增加,科学家推测,该基因在衰老中也起着相似的功能。研究者建立了老鼠种系,即缺失p16INK4a的(基因删除或基因敲除),或通过遗传学手段增加衰老过程中该蛋白的量。
??根据Sharpless的研究,缺失p16INK4a基因的老鼠随着年龄的增长,胰岛细胞继续增殖,“与年幼的动物很相似,在含有过量p16INK4a的老鼠中,胰岛细胞过早地衰老,很早就停止分化。”
??“这些结果暗示,如果我们以某种方式减弱人体中p16INK4a,那么可能导致成人体内胰岛的再生长,为糖尿病提供新的治疗方案。” Sharpless说。在大脑干细胞和血液干细胞的研究中也得到相似的结果。
??Dr. Sean Morrison领导的Michigan研究者调查了神经干细胞和祖细胞中p16INK4a的功能,祖细胞可以形成新的神经元和其他的脑细胞。研究表明,在衰老的细胞中,p16INK4a表达大大增加。而且,p16INK4a缺失的神经干细胞工作得较好,在某些程度上与正常对照相似不会衰老。Sharpless说。
??UNC研究的主要作者,Sharpless实验室的博士后Janakiraman Krishnamurthy是Michigan报告的合著者。哈佛小组领导的Dr. David Scadden在hematopoietic干细胞中研究p16INK4a的功能,hematopoietic干细胞在成人的一生中不断的增生产生大量新的血细胞。结果表明,p16INK4a是以前在血液干细胞中观察到的年老信号的分子基础。哈佛研究也证实,缺失p16INK4a年老鼠的血液干细胞的功能比对照组老鼠要好,这些表明,p16INK4a是引起那些细胞老化的原因。
??Sharpless注意到,基于p16INK4a研制的新的衰老治疗包括两个重要的条件,“第一,即使缺失p16INK4a的年老老鼠干细胞功能增加,但他们不会活得更长久。这是因为p16INK4a是一个重要的抑癌基因,与对照组相比,缺失p16INK4a的老鼠会产生更多的癌。第二,在以上三个研究中,p16INK4a缺失是和部分衰老紧密联系在一起的,这表明,除了p16INK4a基因外,还存在其他物质引起衰老的,但我们还不知道是些什么物质。”
??然而,该基因研究证明是衰老研究的一个生物标记,Sharpless说:“如果你每天继续限制自己摄入热量,喝绿茶或白藜芦醇来组织衰老的话,你为什么不想想:有益的事情不完全是良性循环?现在我们有了一个生物标记可以检测一些事情的效果。” Sharpless说。
英文原文:
General Mechanism Of Cellular Aging Found; Tumor Suppressor Gene May Be Key
Three separate studies confirm a gene that suppresses tumor cell growth also plays a key role in aging. The researchers found increasing concentration, or expression, of the gene p16INK4a in older cells; these aging cells worked poorly compared to young cells and remembered their "age" even when transferred from old mice to young mice. The cells of mice bred without the gene showed less sluggishness as the animals aged and continued to function in a manner more similar to cells from younger mice.
Teams from the medical schools at the University of North Carolina at Chapel Hill, University of Michigan and Harvard University observed similar results in pancreatic islet cells and brain and blood stem cells.
The results show disparate cell types share a common aging mechanism and suggest that aging-related diseases such as diabetes result from a failure of cell growth, said Dr. Norman E. Sharpless, co-author on the three studies and an assistant professor of medicine and genetics at the UNC School of Medicine. "The studies indicate that certain stem cells lose their ability to divide and replace themselves with age as the expression of p16INK4a increases," said Sharpless, a member of the UNC Lineberger Comprehensive Cancer Center.
The trio of reports are published online Sept. 6 in the journal Nature. The three research teams are from the medical schools at UNC, the University of Michigan and Harvard University.
The UNC study focused on p16INK4a effects on the function of pancreatic islet cells. Islet cells are responsible for insulin production and secretion. Because p16INK4a stops cancer cells from dividing and demonstrates increased expression with age, the scientists suspected the gene played a similar role in aging. The researchers developed strains of mice that were either deficient in p16INK4a (the gene was deleted, or 'knocked out") or genetically altered to have an excess of the protein to a degree seen in aging.
According to Sharpless, islet proliferation persisted in p16INK4a -deficient animals as they aged, "almost as if they were younger animals." In mice with an excess of p16INK4a, "islet cells aged prematurely; they stopped dividing early."
"This suggests that if we could attenuate p16INK4a expression in some way in humans, it could lead to enhanced islet re-growth in adults and a possible new treatment for diabetes," Sharpless said.
Similar results were found in the other studies, which focused on brain stem cells and blood stem cells.
The Michigan researchers, led by Dr. Sean Morrison, examined the role played by p16INK4a in neural stem cells, progenitor cells that can form new neurons and other brain cells. The team showed that p16INK4a increases markedly in those cells with aging. Moreover, p16INK4a -deficient neural stem cells work better and don't age to the same extent that wild-type (normal) stem cells do, Sharpless said.
Dr. Janakiraman Krishnamurthy, lead author of the UNC study and a postdoctoral scientist in the Sharpless lab, was a co-author of the Michigan report. The Harvard team, led by Dr. David Scadden, studied the role of p16INK4a in hematopoietic stem cells, which proliferate continuously during the adult lifespan and produce massive amounts of new blood cells on an hourly basis. Their results suggest that p16INK4a is the molecular basis for an old-age "signal" previously observed in blood stem cells. The Harvard study also showed that blood stem cells from old mice lacking p16INK4a functioned better than old cells from wild-type mice, suggesting p16INK4a causes aging of these cells as well.
Sharpless cautions that any promise of a potential new aging treatment based on p16INK4a should include two important caveats. "First, even though old mice lacking p16INK4a show enhanced stem cell function, they do not live longer. This is because p16INK4a is an important cancer-suppressor gene, and mice lacking p16INK4a develop more cancers than old, normal mice," he said.
"Secondly, in all three studies, p16INK4a loss was associated with an improvement in some but not all of the consequences of aging. There are clearly things in addition to p16INK4a that contribute to aging. We don't yet know what they are."
However, the gene may prove immediately useful as a biomarker for studies of aging, Sharpless said. "If you were going to calorically restrict yourself or take green tea or resveratrol every day for years in an effort to prevent aging, wouldn't you like some evidence that these not entirely benign things were having a beneficial effect? Now we have a biomarker that can directly test the effects of such things," he said.
UNC filed a patent on the use of p16INK4a as a biomarker of human aging in 2004. Co-inventors of the patent are Sharpless and Krishnamurthy. Other authors of the UNC study are UNC graduate student Matthew R. Ramsey; Dr. Keith L. Ligon, pathologist at Brigham and Women's Hospital and Harvard Medical School in Boston; Chad Torrice, technician in the Sharpless lab; Dr. Angela Koh, postdoctoral scientist at the Joslin Diabetes Center and Harvard Medical School; and Dr. Susan Bonner-Weir, also of the Joslin Diabetes Center and Harvard Medical School.
The UNC research was supported by grants from the Sidney Kimmel Cancer Foundation for Cancer Research, the Paul Beeson Physician Faculty Scholars in Aging Research Program, the Ellison Medical Foundation, and the National Institute of Aging, a component of the National Institutes of Health.