三個獨立的研究同時證實,，抑制腫瘤細胞生長的基因在細胞衰老過程中也起著重要的作用。研究發(fā)現(xiàn),，衰老細胞中p16INK4a基因的濃度和表達增加,，與早期細胞相比，這些衰老細胞工作效率差,，即使把這些細胞從年老的老鼠轉(zhuǎn)入年幼的老鼠體內(nèi)，仍然記得他們的“年老”,。而沒有轉(zhuǎn)入p16INK4a基因的老鼠細胞隨著年齡的增大滯緩現(xiàn)象比較小,，繼續(xù)行使著與年幼老鼠相似的功能。
??North Carolina大學,，密西根州立大學和哈佛大學醫(yī)學系的研究小組在胰臟的胰島細胞,，大腦和血液的干細胞觀察到相似的結(jié)果。
??研究結(jié)果顯示出不同類型細胞有著共同的衰老機制,，表明象糖尿病類的衰老相關疾病是由于細胞生長衰竭而導致的,。三個研究的合作者以及UNC醫(yī)學院醫(yī)學和遺傳學副教授Dr. Norman E. Sharpless說,“隨著年齡的增長，p16INK4a表達的增加,，某些干細胞失去分化和替換他們自己的功能,，” UNC癌癥綜合中心成員Sharpless說。
??三人一組的報告出版在9月6日的《Nature》雜志上,。三個研究小組分別是UNC,，Michigan大學和哈佛大學醫(yī)學院。
??UNC主要集中于p16INK4a對胰臟胰島細胞功能影響的研究,。胰島細胞是負責胰島素的產(chǎn)生和分泌的,。因為p16INK4a阻止癌細胞的分化，隨著年齡的增長,，表達也會增加,，科學家推測，該基因在衰老中也起著相似的功能,。研究者建立了老鼠種系,，即缺失p16INK4a的（基因刪除或基因敲除），或通過遺傳學手段增加衰老過程中該蛋白的量,。
??根據(jù)Sharpless的研究,，缺失p16INK4a基因的老鼠隨著年齡的增長,，胰島細胞繼續(xù)增殖，“與年幼的動物很相似,，在含有過量p16INK4a的老鼠中,，胰島細胞過早地衰老，很早就停止分化,。”
??“這些結(jié)果暗示,，如果我們以某種方式減弱人體中p16INK4a，那么可能導致成人體內(nèi)胰島的再生長,，為糖尿病提供新的治療方案,。” Sharpless說。在大腦干細胞和血液干細胞的研究中也得到相似的結(jié)果,。
??Dr. Sean Morrison領導的Michigan研究者調(diào)查了神經(jīng)干細胞和祖細胞中p16INK4a的功能,，祖細胞可以形成新的神經(jīng)元和其他的腦細胞。研究表明,，在衰老的細胞中,，p16INK4a表達大大增加。而且,，p16INK4a缺失的神經(jīng)干細胞工作得較好,，在某些程度上與正常對照相似不會衰老。Sharpless說,。
??UNC研究的主要作者,，Sharpless實驗室的博士后Janakiraman Krishnamurthy是Michigan報告的合著者。哈佛小組領導的Dr. David Scadden在hematopoietic干細胞中研究p16INK4a的功能,，hematopoietic干細胞在成人的一生中不斷的增生產(chǎn)生大量新的血細胞,。結(jié)果表明，p16INK4a是以前在血液干細胞中觀察到的年老信號的分子基礎,。哈佛研究也證實,，缺失p16INK4a年老鼠的血液干細胞的功能比對照組老鼠要好，這些表明,，p16INK4a是引起那些細胞老化的原因,。
??Sharpless注意到，基于p16INK4a研制的新的衰老治療包括兩個重要的條件,，“第一,，即使缺失p16INK4a的年老老鼠干細胞功能增加，但他們不會活得更長久,。這是因為p16INK4a是一個重要的抑癌基因,，與對照組相比，缺失p16INK4a的老鼠會產(chǎn)生更多的癌,。第二,，在以上三個研究中,，p16INK4a缺失是和部分衰老緊密聯(lián)系在一起的，這表明,，除了p16INK4a基因外,，還存在其他物質(zhì)引起衰老的，但我們還不知道是些什么物質(zhì),。”
??然而,，該基因研究證明是衰老研究的一個生物標記，Sharpless說：“如果你每天繼續(xù)限制自己攝入熱量,，喝綠茶或白藜蘆醇來組織衰老的話,，你為什么不想想：有益的事情不完全是良性循環(huán)？現(xiàn)在我們有了一個生物標記可以檢測一些事情的效果,。” Sharpless說,。
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.
