Identification of genetic factors affecting cellular ageing in fission yeast

With age, we gradually accumulate both environmentally and intrinsically generated defects at different levels in our bodies: from errors in DNA (mutations), proteins (aggregates), organelles (mitochondrial dysfunction) to cells (cancer) and organs (heart failure). Ageing is the largest risk factor for the majority of human diseases in the Western world, including progressive diseases such as Alzheimer's and Parkinson's, diseases like cancer that show variable rates of onset, and catastrophic systems failures such as heart-attack and stroke. While the study of specific ageing-related disease processes has long been a major focus of biomedical and biological research, there is a growing realisation of the importance of analyzing the normal ageing process itself as an essential part of the problem, and of exploring ways to slow or reverse its effects. Ageing is a multi-factorial problem that can be seen as an inevitable feature of the ravages of time and the harmful environments in which organisms live. Recent discoveries, however, demonstrate that ageing can be modified in dramatic ways by relatively simple interventions. For example, single gene mutations and dietary restriction can delay ageing and provide a universal improvement in health late in the life of laboratory animals. Moreover, the pathways involved in ageing are conserved in evolution, and genetic variants in their components are associated with differences in lifespan in humans. A central challenge of ageing research, however, remains to tease out a comprehensive and unified picture of the genetic factors and mechanisms determining longevity. We plan to utilize fission yeast as a model organism to advance our understanding of complex processes with fundamental importance for ageing. Remarkably, many of these processes are now known to be similar from yeast to human. Yeast cells enter a quiescent, non-dividing state under limiting nutrients, and the lifespan in this state depends on both genetic and environmental factors. Such quiescent yeast cells provide a valuable system to analyze basic processes affecting ageing and longevity. We will analyze how the global regulation of genes and proteins is modified during ageing, and how any changes might affect longevity. We will also exploit a collection of all viable gene knock-out mutants to systematically identify those genes that lead to longer or shorter lifespan. We will further examine how lifespan varies among wild yeast strains from different geographical locations, and whether this variation goes with changes in gene expression. Finally, we will integrate these complementary global data sets and follow-up the most promising findings to uncover particular roles of specific genetic factors in cellular ageing and longevity. Importantly, this research will provide a valuable platform to understand the genetic factors involved in ageing in humans, to eventually develop interventions that slow ageing and thus prevent or delay the numerous age-associated diseases.

To identify genetic factors affecting cellular ageing in fission yeast, we will apply multiple genome-wide and genetic approaches, including state-of-the-art RNA sequencing and proteomics methods, high-throughput phenotyping of a deletion mutant library and of natural fission yeast isolates, as well as large-scale screening of genetic and regulatory interactions among ageing genes. Chronological lifespan in fission yeast, determined in quiescent cells under limiting nitrogen, will serve as a simple yet powerful system to unravel vital processes mediating cellular ageing and longevity. Integrated mining of the resulting genome-scale data sets will reveal global principles for longevity and will provide predictions for key genetic factors that directly impinge on ageing. We will pursue such promising factors by further targeted experiments. This research will provide 1) detailed insight into transcriptome and proteome modulation during ageing; 2) a systematic functional profiling of genes relating to ageing; 3) a survey of intra-species variation in lifespan and accompanying genome regulation; and 4) a basis for a systems-level understanding of genetic mechanisms underlying the ageing process. Integration of these complementary approaches into a research project will thus provide important insight into genotype-phenotype relationships underpinning cellular ageing and longevity.

Who will benefit from this research? This is basic research in nature, and the immediate impact from the proposed work relate to scientific and knowledge advancement and the development of skills, capacity and capability. In the longer term, this research has the potential to impact in areas of wealth and health. Beneficiaries beyond academia therefore are the commercial private sector and the wider public. How will they benefit from this research? The proposed research takes state-of-the-art approaches to address fundamental questions relating to genetic mechanisms involved in ageing. It will combine the latest genomics and proteomics technologies with high-throughput screening of genetically diverse strain libraries and associated computational approaches. The research will deliver increased capacity and capability in these strategically relevant areas through the provision of training and the further development of key methodologies and tools. Establishment of these technologies is significant as they have a wide range of applications that reach beyond basic science into fields relating directly to human health and the commercial (biotechnology) sector. The commercial sector might benefit by recruiting highly skilled and experienced scientists trained through this project. In the longer term, it might benefit by exploiting potential drug targets to reverse or slow the effects of ageing as a major risk factor for multiple diseases. Companies developing next-generation sequencers and mass spectrometers will also benefit from our forefront applications and feedback to optimize their procedures and performance of equipment. The ageing population is a major problem in our society, with huge cost implications due to an increase in associated diseases and diminished quality of life. It goes without saying that any measures that promote healthy ageing will provide substantial and broad ranging benefit to our society with respect to economy, quality of life, health and creative output. Ultimately, the general public may thus benefit from our fundamental contribution to the understanding of genetic mechanisms involved in ageing that will guide and empower research in more complex systems and help to develop prospective broad-spectrum, preventative interventions against age-related disease.