Long non-coding RNA function during cellular ageing

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Ageing is the largest risk factor for most human diseases in developed countries, including progressive diseases such as Alzheimer's and Parkinson's, diseases like cancer that show variable rates of onset, and catastrophic system failures such as heart-attack and stroke. As we are getting older, these age-associated diseases are becoming an ever increasing burden for our society. While the study of specific disease processes has long been a major focus of biomedical research, there is a growing realisation of the importance to study the normal ageing process itself as an essential part of the problem, and to explore ways to slow or reverse its effects. Ageing is a complex process that can be seen as an inevitable feature of the ravages of time. Recent discoveries, however, demonstrate that ageing can be modified in dramatic ways by simple interventions. For example, genetic manipulations or drugs can delay ageing and improve health late in the life of laboratory animals. The processes involved in ageing are similar in different organisms, including humans. A central challenge of ageing research remains to understand biological factors regulating healthy lifespan. Biological processes such as ageing are influenced by the genetic information encoded in the genome. Genes coding for proteins have long been the main focus of research, while recent findings reveal that genomes also contain many genes that do not code for proteins but for so-called non-coding RNAs. The non-coding RNAs with known functions play critical roles in regulating other genes in different ways. But the roles of most non-coding RNAs are not yet known. Notably, several examples are emerging where non-coding RNAs are involved in ageing and associated diseases. However, how genome regulation and non-coding RNAs affect the healthy lifespan is largely unknown. It is therefore important to find out what roles ageing-associated non-coding RNAs play in the information flow from the genome to longevity. Using fission yeast as a simple and cost-effective model organism, we have recently discovered a fascinating non-coding RNA that becomes up-regulated during ageing and prolongs the lifespan of yeast cells. We now want to study the detailed function of this non-coding RNA in gene regulation and ageing. Remarkably, gene regulation and ageing are similar from yeast to human, but are much easier to study in the simple yeast. Yeast cells enter a dormant, non-dividing state under limiting nutrients. The transition to this dormant state provides a compelling cellular system to analyse our ageing-associated non-coding RNA and gene-regulatory processes affecting the lifespan in this state. We have created genetically manipulated mutant cells in which the non-coding RNA is either over-abundant, leading to long-lived cells, or completely absent, leading to short-lived cells. In order to study the role of our non-coding RNA during ageing, we will apply complementary genome-wide methods that can systematically determine different regulatory aspects for all genes. We will also combine cells that lack our non-coding RNA with cells that lack different proteins to study the effects of such double mutants on lifespan. This potent approach can point to biological processes that are important for non-coding RNA function. Moreover, we will use current methods to identify genes, other RNAs or proteins that interact with our non-coding RNA and thus may determine its function. Combining these complementary approaches will provide vital clues on biological functions, which we will then test with further detailed analyses to obtain rich information on how our non-coding RNA regulates genes and lifespan. We anticipate that this project will provide a valuable platform to better understand universal principles of non-coding RNA function for gene regulation during ageing, which could help to eventually develop interventions that extend healthy lifespan in humans.