Harwell Ageing Screen
The Harwell Ageing Screen is a large-scale project to study the genetics of ageing and age-related diseases. Faced with an ageing population, there is a pressing need to improve our understanding of age-related diseases so that new treatments can be developed. We select and breed mice with characteristics of these conditions to investigate the underlying genetics.
The biggest problem currently facing UK healthcare is ageing. We have an ageing population and the incidence of the majority of diseases – cancer, heart disease, diabetes - goes up exponentially with age. We are using mice to determine the genes that specifically give rise to such age-related diseases, an enormous challenge and the first attempt of its kind. We investigate these conditions, and relevant traits, using a large-scale mutagenesis screen in ageing mice. This allows us to identify genes and pathways involved in these conditions and creates new models for further in-depth research.
Generation of mutants
The Harwell Aging Screen uses ENU-induced mutagenesis to create mice with a wide range of genetic mutations. These mice live for 18 months - relatively old for a mouse - and are closely observed throughout their lives.
ENU (N-ethyl-N-nitrosourea) is a powerful chemical mutagen that causes random point mutations throughout the genome of the mouse. The mice are given three weekly 100mg/kg doses by intraperitoneal injection from 10 weeks of age, and are bred over three generations (G1 to G3) to identify both dominant and recessive inherited mutations.
The random nature of these mutations means that we can identify entirely novel mutations, determine which gene they are located within, and identify the phenotype or condition they cause. This procedure therefore has the advantage that it makes no assumptions about the gene, so can identify previously unknown areas for research, revealing new insights into age-related conditions.
Phenotype-driven screens and analysis
The mice undergo a series of tests at various ages to detect any behavioural, cognitive or physiological abnormalities. More detail on these tests can be found in the Phenotyping section, as these screens are not only used by our own research programmes, but also provided as an external service for the scientific community.
Once a phenotype of interest has been identified, we use next generation sequencing (NGS) to locate the mutations' position in the genome. This allows us to identify the gene or non-coding region mutated and determine the effect of the mutation on the protein structure and function. From this, we can deduce the molecular pathways that the protein is involved in. This gives us a valuable insight into how the mutation could result in the phenotype and its possible role in human ageing and disease.
We preserve the DNA or sperm from the founder G1 male in our ENU DNA archive and FESA biobank for future use by our own researchers and use by external scientists. This means we can re-establish a line of particular interest in a relatively short time period at a later date in order to investigate it in more depth. All results from the screen are made available in our database MouseBook.
The Harwell Ageing Screen provides an important resource for researchers. Diseases of ageing pose an increasing financial and social burden for society, and animal models like those created by this screen are a vital part of tackling this. Our ultimate aim is to identify the underlying causes of age-related diseases to enable further investigation and the development of new treatments.