Award details

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

Reference	BB/K007564/1
Principal Investigator / Supervisor	Professor Aziz Aboobaker
Co-Investigators / Co-Supervisors	Professor Edward Louis
Institution	University of Oxford
Department	Zoology
Funding type	Research
Value (£)	633,419
Status	Completed
Type	Research Grant
Start date	03/06/2013
End date	30/11/2016
Duration	42 months

Abstract

Current invertebrate systems for studying molecular and cellular processes of aging are mainly limited to C. elegans and D. melanogaster. These species are from the same major protostome branch of the animal tree (Ecdysozoa), are relatively short lived and are essentially post-mitotic as adults. These features might suggest they may not be useful as a model of aging in mammals. However, this could not be further from the truth as the genetic power and simplicity of these model organisms has been absolutely key in establishing key insights into conserved aspects of aging biology. This suggests that other invertebrates from alternative parts of the animal tree and with starkly contrasting life histories may also contribute to our fundamental understanding of the aging process. Animals that are relatively longer lived, utilize an adult stem cell system and are amenable to molecular genetic studies as adults might be particularly useful. Here we will investigate this proposal by studying telomere biology in planarians. Our preliminary work has ported existing tools for studying telomeres and telomere biology to the model planarian S. mediterranea and suggests planarians will be an excellent system for these studies. We can now measure telomere length, telomerase activity, assess karyotype instability and investigate the function of other components of the telomere protein complex. This work suggests that asexual planarians may potentially be immortal and avoid the aging process at the organismal level altogether. We will investigate the replicative capacity of planarian adult stem cells in relation to telomere biology and study how the regulation of telomere biology has evolved. Finally we will study telomere biology in planarians that have reduced regenerative capacity and a finite lifespan despite having a population of pluripotent stem cells. Together these studies will provide novel insights into telomere biology and aging in animal pluripotent stem cells.

Summary

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

Impact Summary

Away from immediate academic beneficiaries other model organism researchers and evolutionary biologists will benefit from our activity on this project, particularly those researchers broadly interested in telomere biology and aging research. The research proposed here is in a novel area that has not been previously pursued (accept in our group). Beyond other academics in the immediate area our findings will be directly relevant to large and growing part of the industrial biomedical sector that is becoming more focused on Ageing. Telomere biology is a large field with clear potential medical applications as evidenced by the number of commercial medical, biotech and biopharmaceutical studies that are actively researching telomere biology, compounds that effect telomere maintenance and even providing bespoke telomere length measurement services for individuals. We will contribute by describing telomere biology in an invertebrate system, that has life history traits suggesting special adaptations in telomere maintenance. More specifically we will be investigating a scenario where telomere maintenance in adult stem cells is potentially indefinite without apparently predisposing to tumors. We also believe that given the conservation of molecular mechanisms between phyla some planarian species may be excellent systems in which to assay potential drugs relevant to ageing and stem cell biology, our work will establish evidence as to whether this is a viable possibility. Our research is basic biomedical research and we realize the importance of explaining to the public why what may appear quite abstract (working with worms) is actually rather important for understanding of key processes that are relevant to healthy ageing and life long well being. For this reason the AAA lab engages in extensive public engagement and outreach through our website, through talks, visits to schools and societies and through YOUTUBE videos. For example AAA YOU TUBE views are well in access of150,000 views. This work provokes questioning, debate and awareness in society. Performing a Google search will demonstrate the plethora of media coverage and public interest our work has generated through our public engagement work. This effort shows one of the pathways to impact we take in addition to our research. We will continue to present our work at conferences, events and in the media to ensure the public knows what they are paying for. As opportunities arise we will also investigate whether our model system(s) can be used in industry, for example to screen compounds that block or promote telomerase activity. We will measure success of our pathways to impact by recording the feedback we get from society at large, and where appropriate answer questions or enter into wider debate about the impact of our work and of others in our general research area.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Ageing, Stem Cells
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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