在本期Nature中，三个实验室分别报告了一种蛋白的发现。该蛋白专门在干细胞中调控衰老。 这个发现可帮助回答一个根本问题：为什么哺乳动物的祖先细胞随着年龄增长会逐渐失去其分裂和生成新细胞的能力？Norman Sharpless及其同事培育出一种剔出了肿瘤抑制因子p16 INK4a的小鼠，该因子是细胞周期控制中涉及的一种蛋白，已知会以一种依赖于年龄的方式表达。在对该蛋白在血液、胰腺和大脑的再生中所起作用进行的研究中，三个小组分别发现，p16 INK4a不仅是一种生物标记，而且是衰老过程的一个促成因子。通过比较p16 INK4a在小鼠体内表达增多或减少所产生的效应，他们发现，p16 INK4a阻止干细胞的增殖，但只是在比较老的小鼠体内。综合起来，该研究表明，p16 INK4a通过肿瘤抑制因子的行动减少癌症的发病，与此同时通过降低干细胞功能对衰老做出贡献。该研究还表明，2-型糖尿病也许与胰岛失去再生能力有关，阻断该蛋白在某些组织中的作用，也许能够抵抗衰老的某些效应。
原始出处
Anna V. Molofsky1,4, Shalom G. Slutsky1,4, Nancy M. Joseph1, Shenghui He1, Ricardo Pardal1,3, Janakiraman Krishnamurthy2, Norman E. Sharpless2 and Sean J. Morrison1. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448-452(28 September 2006) | doi:10.1038/nature05091; Received 10 April 2006; Accepted 25 July 2006; Published online 6 September 2006.
英文摘要
Mammalian ageing is associated with reduced regenerative capacity in tissues that contain stem cells1, 2. It has been proposed that this is at least partially caused by the senescence of progenitors with age3, 4; however, it has not yet been tested whether genes associated with senescence functionally contribute to physiological declines in progenitor activity. Here we show that progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb, as well as multipotent progenitor frequency and self-renewal potential, all decline with age in the mouse forebrain. These declines in progenitor frequency and function correlate with increased expression of p16INK4a, which encodes a cyclin-dependent kinase inhibitor linked to senescence5. Ageing p16INK4a-deficient mice showed a significantly smaller decline in subventricular zone proliferation, olfactory bulb neurogenesis, and the frequency and self-renewal potential of multipotent progenitors. p16INK4a deficiency did not detectably affect progenitor function in the dentate gyrus or enteric nervous system, indicating regional differences in the response of neural progenitors to increased p16INK4a expression during ageing. Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression.
