unlock:epi: unlocking the epigenome to understand, detect and modify age- related disease formation (360G-Wellcome-323357_Z_24_Z)

The epigenome is essential for establishing cell fate and function, and it changes throughout life due to external influences and ageing. While epigenetic features, particularly DNA methylation (DNAme), have been used to predict ageing or age-related disease, it remains unclear whether epigenetic changes can causally drive dysfunction. We also know little about how different tissues of individuals age, and whether epigenetic “footprints” in one tissue have the potential to reflect those in another, which could aid non-invasive detection and prediction of diseases. Across three work packages, I will investigate: 1\. DNAme patterns across multiple tissues from the same individuals, exploring cell-specific mechanisms underlying epigenetic ageing, organ-specific versus systemic epigenetic ageing, and how well tissues within an individual mirror each other; 2\. The potential of DNAme in non-invasive saliva samples to predict organ-specific age-related diseases or resilience, which could prove transformative for healthcare; and 3\. The causal role of epigenetic ageing, by testing whether targeted CRISPR DNAme editing elicits changes in cellular behaviour and “rejuvenates” cellular function. The proposed work will unlock significant insights into the causality of the ageing epigenome, helping us to understand, detect, and modify age-related diseases.