The evolution and molecular basis of adaptations to Telomere Biology in immortal worms.

我们都会变老。就像我们的身体在日常磨损后自我修复的能力会减慢一样。许多与衰老相关的急性和慢性疾病都是我们身体细胞无法自我更新的结果，这反过来又降低了我们各种组织和器官的效率，使其达到不健康的水平，总的来说，这些都是退行性疾病。另一组与衰老相关的疾病是我们的细胞周期失去控制并形成肿瘤。事实上，一种衰老理论认为，这实际上是一种权衡，一方面允许我们的细胞循环、替换和修复损伤，另一方面需要限制它们的复制能力，这样它们就不会循环失控。因此，我们正常的健康细胞可以分裂的次数是有限的，当这些分裂耗尽时，它们就会进入一种叫做“衰老”的状态。细胞分裂的次数通过复制DNA的机制与细胞衰老有关。每个细胞周期我们的DNA都必须被复制，这样才能给每个细胞一个拷贝。当这种情况发生时，我们细胞中的DNA链每个周期都会变短。我们的DNA链的末端有特殊的重复DNA序列，碱基序列TTAGGG的1000个副本，在末端被称为“端粒”。这些序列是由一种叫做“端粒酶”的酶添加的。端粒通常起着保护DNA链的作用，每次细胞分裂时，端粒序列都会变短。当这些重复序列达到极短的长度时，端粒发出的信号告诉细胞衰老。这是一个可能导致衰老的分子过程。值得注意的是，衰老的重要性可以通过以下事实来说明：大多数癌症是由逃避衰老的细胞形成的，它们不恰当地激活了端粒酶，从而在不应该保留的时候保留了DNA末端。有些动物似乎活得很长，而有些动物似乎根本不会变老。这些动物是怎么做到的？它们的细胞会像我们的一样衰老吗？如果不是，他们是怎么做到的？鉴于衰老过程在我们社会中的重要性，我们相信研究这些动物可能对理解衰老的关键遗传过程具有重要意义。出于这个原因，我们研究的是一种叫做涡虫或扁虫的“不朽”蠕虫。这些特殊的动物大多生活在淡水或潮湿的陆地栖息地，似乎有无限的再生能力。这意味着他们修复任何损伤或伤害，以重建功能齐全的动物。例如，被斩首的动物可以再生头部，包括大脑。支撑这种能力的是一群成体干细胞，它们遍布这些蠕虫的身体。这些细胞能够取代这些蠕虫体内的所有细胞类型，并且似乎可以无限地分裂。事实上，我们认为这些动物可能通过避免细胞衰老而有效地长生不老。我们已经初步研究了它们的端粒是否变短了。我们发现蠕虫能够在细胞分裂时阻止DNA的缩短，我们认为这可能是它们避免衰老的原因。它们通过激活端粒酶来应对损伤或损伤，从而诱导干细胞增殖。乍一看，这似乎是一个令人满意的答案，但实际上我们不知道这是如何控制的，也不知道这种情况是如何演变的。另一个重要的问题是，如果涡虫的细胞能够继续分裂，它们是否更容易患肿瘤？如果是这样，这些动物是如何应对这种风险的？在这项研究中，我们将研究这些神奇动物的端粒生物学，看看它们是如何避免衰老的。我们并不确切知道我们期望发现什么，但我们确信结果会令人兴奋。要了解更多关于涡虫和我们的工作，请访问www.aboobakerlab.com

We all get older. As we do our body's ability to repair itself after everyday wear and tear slows down. Many acute and chronic diseases associated with ageing are a result of our bodies cells failing to renew themselves and this in turn reduces the effectiveness of our various tissues and organs to levels that are unhealthy, collectively these are degenerative diseases. Another set of diseases associated with getting older are those where our cells cycle out of control and form tumours. In fact one theory of ageing suggests that it is in fact a trade off between allowing our cells to cycle and replace and repair damage and the need to limit their ability to replicate so that they don't cycle out of control. Thus our normal healthy cells are limited in the number of times they can divide, and when these divisions have been used up they enter a state called "senescence". The number of cell divisions is linked to cells becoming senescent through the mechanism that copies DNA. Every cell cycle our DNA must be copied so that one copy can be given to each cell. As this happens the strings of DNA in our cells get shorter each cycle. The ends of of our DNA strings have special repeated DNA sequences, 1000s of copies of the base sequence TTAGGG, at the ends called "telomeres". These sequences are added by a enzyme called "telomerase". Telomeres normally act as protective caps to our DNA strings, and its is the telomere sequences that get shorter every time a cell divides. When these repeat sequences reach a critically short length signals from the telomeres tell the cell to become senescent. This is one potential molecular process that leads to ageing. Significantly, the importance of senescence is illustrated by the fact that most cancers are formed by cells that have escaped senescence and inappropriately activated the enzyme telomerase so that DNA ends are maintained when they shouldn't be.Some animals seem to live for a very long time and others appear not to age at all. How do these animals do this? Do their cells age and senesce like ours do? If not how do they manage this? Given the significance of the ageing process in our society we believe that studying these animals may prove to be significant for understanding key genetic processes of ageing.For this reason we work with "immortal" worms called planarians or flatworms. These particular animals mostly live in freshwater or damp land habitats and appear to have an indefinite capacity to regenerate. This means that they repair any damage or injury to reconstitute fully functional animals. For example decapitated animals will regenerate the head including the brain. Underpinning this ability is a population of adult stem cells that are spread through the bodies of these worms. These cells are able to replace all cell types in the bodies of these worms and seem to keep dividing indefinitely. In fact we think that these animals may potentially be effectively IMMORTAL by avoiding cellular senescence. We have taken a preliminary look at whether their telomeres get shorter. We have found that worms are able to stop there DNA form shortening as cells divide, and we think this maybe how they avoid senescence. They do this by activating the enzyme telomerase in response to damage or injury that induces their stem cells to proliferate. At first glance this seem like a satisfying answer but actually we don't know how this is controlled or how this scenario evolved. Another important question is whether planarians are more susceptible to tumours if their cells can keep dividing? If so how do these animals deal with this risk? In this study we will investigate the telomere biology of these mazing animals to see how they seem to avoid both senescence (ageing). We don't really know exactly what we expect to find, but we are sure the results will be exciting. To learn more about planarians and our work please visit www.aboobakerlab.com