MRC Human Genetics Unit
Medical Research Council Human Genetics Unit

Which molecular mechanisms underlie age-dependent disease risk?

Advanced age is the most significant risk factor for neurodegenerative, cardiovascular and malignant diseases. Why age predisposes to disease risk and how is poorly understood. What are the molecular mechanisms underlying age-dependent disease risk, and can we delay them?

Recent models estimate that delaying ageing by targeting an underlying common process, could solve the problem of competing risks and have an economic value of $7.1 trillion over 50 years (1).

1.Goldman, D. The economic promise of delayed aging. Cold Spring Harb. Perspect. Med. 6, (2016).

Our research has three themes:

Altered nuclear biology in Cellular Ageing

Theme 1: How does cellular senescence contribute to human ageing and disease? 

Over the last decade, we have made important contributions to the mechanistic and molecular understanding of the complex changes leading to cellular senescence. These include the role of chromatin changes in cellular senescence and Progeria and the interaction of senescent cells with their environment. While we continue our pursuit in understanding the basic mechanisms behind cellular senescence, there is one question that hinders translation of this knowledge:

Dynamics of age-related clonal haematopoiesis

Theme 2: Somatic mosaicism in ageing and cancer (With Kirschner, Schumacher and Marioni labs. Supported by LBC, GS and UK Biobank) 

Age-related clonal haematopoiesis (ARCH) is apparent in the general population from age 60 with a steady increase to 18-20% over age 90 driven by somatic mutations in leukaemic driver genes, leading to reduced diversity of the blood pool. ARCH carries an increased risk for leukaemia, cardiovascular disease and ischemic heart failure. Through data generation and annotation of two existing unique cohorts of aged individuals, the Lothian birth cohorts (LBC) 1921 and 1936, we aim to establish a direct link between age-related morbidities in relation to ARCH. Our own work showed that ARCH mutations may contribute to premature ageing. We found an increase in epigenetic age – a measure of biological rather than chronological age – for 73 participants with ARCH from the LBCs.

Epigenetic age and epigenetic rejuvenation

Theme 3: Epigenetic age and epigenetic rejuvenation

The recent generation of predictors that accurately predict biological age has led to a new, quantitative era in molecular ageing research. Epigenetic ageing clocks predict chronological age based on the hyper-or hypomethylation of specific CpGs, which correlate strongly with age (Fig.1). Significant associations with known age-accelerating conditions, such as Werner syndrome, Down’s syndrome patients, HIV therapy and many others, have confirmed that epigenetic age is a quantitative measurement for biological age.