Title: Does epigenetic age acceleration predict future accelerated musculoskeletal ageing?
Funder: Dunhill Medical Trust

Abstract: Background The ability to predict those at risk of adverse musculoskeletal ageing is vital if therapeutic strategies are to be successful (Kern et al., 2005). Therefore, the identification of biomarkers that capture ‘biological’ age have the potential for significant clinical utility. Epigenetic changes, specifically those within the DNA methylome, enable precise age prediction (Teschendorff et al., 2010, Rakyan et al., 2010) and ‘epigenetic clocks’ have been formulated to capture ‘biological’ ageing (Horvath, 2013). The objectives of my fellowship are: Primary aim: • To describe the longitudinal associations between epigenetic age acceleration at baseline, and musculoskeletal outcomes 10 and 17 years later. Secondary aims: • To establish the association between baseline epigenetic age acceleration and the 10 and 17 year incidence of fractures and falls. • To identify novel epigenetic patterns and individuals marks which are associated with indices of bone and muscle ageing through Epigenome-Wide Association Study. Methods My fellowship will focus on the Hertfordshire Cohort Study (HCS); a group of community-dwelling, older adults. The musculoskeletal phenotyping of the cohort I completed in 2017 included questionnaires, short performance physical battery testing, dynamometry, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), High Resolution pQCT which provided longitudinal measures of phenotyping which was performed in 2011-12. These two time-points will be used to assess the relationship between epigenetic age at baseline (1998-2001) and musculoskeletal phenotype at approximately 10 years (2011-12) and approximately 17 years (2017). DNA samples derived from whole blood leukocytes at HCS baseline (1998-2001) will be assessed for genome-wide methylation profiles (Pidsley et al., 2016). I will use epigenetic clocks (Horvath, 2013, Hannum et al., 2013) to calculate epigenetic age and age acceleration. These will be compared with musculoskeletal outcomes. In additional, exploratory analyses, I will use an epigenome-wide approach to elucidate specifc CpGs, differentially-methylated regions of interest, and patterns of CpG methylation associated with musculoskeletal outcomes. Impact The findings from this study will contribute significantly to the understanding of the relationship between epigenetics and future musculoskeletal phenotype. This will pump-prime future, post-fellowship work to investigate whether our findings are replicated in other ageing cohorts and will ultimately lead to a novel tool which incorporates epigenetic and clinical parameters to predict those at risk of adverse musculoskeletal ageing. This tool has the potential to significantly improve the predictive value of currently available tools and thus enable health resources to be targeted to those older persons with the greatest need.

Lay abstract: The number of older people in the population is increasing rapidly and with ageing comes diseases of muscle and bones. These diseases weaken those structures leading to an increased risk of falling over and fracturing a bone. This is worrying because fractures, as well as causing pain and immobility, also increase the risk of other diseases and death. We know that our age in years is not necessarily the same as the age of our body or ‘biological age’. When we think of bone and muscles, some people aged 85 are running marathons whilst others are unable to walk. A new measure of biological age, called epigenetic age, looks at a particular pattern of genes being switched on or off and gives an age of the body which may be different to the conventional age (time from birth). Through our research we aim to answer the following questions: 1. Can a new measure of biological ageing look into the future to tell us: a. How healthy a person’s muscles and bones will be in 10-20 years? b. How likely a person is to fall over or have a fracture in the next 10-20 years? 2. If particular genes are switched on or off, do we see differences in a person’s muscles and bones in 10-20 year’s time? These questions will be answered using information we have collected over the last 20 years regarding the bone and muscle health of a group of older persons living in Hertfordshire. We have recorded their physical function, bones and muscles using specialist tests and scans. These results give us measures of how healthy their bones and muscles are. We will use blood samples taken between 1998 and2003 to measure their biological ageing at that time and see if it relates to how healthy their bones and muscles are (using the above tests and scans) 10-20 years later. If we discover an association between the new measure of biological age and the ageing of muscles and bones, this could be used by healthcare professionals in clinics to spot those at risk of diseases of musculoskeletal ageing. This would lead to earlier treatment and healthier ageing of those individuals, and a reduced burden from dependence, falls and fractures for society as a whole. The discovery of particular elements of genetic material associated with diseases of musculoskeletal ageing could translate into treatments to improve musculoskeletal ageing.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL