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

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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