Does accelerated epigenetic ageing predict accelerated future musculoskeletal ageing?

Abstract

The ability to predict those at risk of more rapid musculoskeletal ageing is vital if therapeutic strategies are to be successful. Precise description of the ageing musculoskeletal phenotype combined with the mapping of epigenetic changes, specifically those within the DNA methylome, enable precise age prediction and ‘epigenetic clocks’ have been formulated to capture ‘biological’ ageing. With this in mind, the broad aims of my thesis are:
• To describe the longitudinal change in bone microarchitecture and muscle strength
• To investigate the association between baseline epigenetic age acceleration and musculoskeletal outcomes
• To identify novel epigenetic marks which are associated with key musculoskeletal indices of grip strength and bone mineral density through Epigenome-Wide Association Study
This thesis is focused on the Hertfordshire Cohort Study (HCS); a group of community-dwelling, older adults in which baseline blood samples are available for epigenetic analysis. In 2017 I led a musculoskeletal phenotyping pass of the cohort including grip dynamometry, dual-energy X-ray absorptiometry (DXA) and High Resolution peripheral quantitative computed tomography (HR-pQCT) to complement the same assessments which had previously been performed in 2011-12. Longitudinal change in HR-pQCT parameters, grip strength and hip bone mineral density was analysed and the determinants of HR-pQCT parameter change were examined. Using DNA from whole blood leukocytes at HCS baseline (1998-2004) DNA methylation was measured and epigenetic age acceleration calculated (HorvathAge, GrimAge and PhenoAge). The relationship between epigenetic age acceleration at baseline (1998-2004) and musculoskeletal phenotype was examined. In additional exploratory analyses an epigenome-wide approach was utilised to elucidate specific CpG sites associated with cross-sectional grip strength and total femoral neck bone mineral density.
Baseline values of HR-pQCT parameters and greater decline in trabecular Bone Mineral Density (BMD) were associated with fracture and change in trabecular BMD was associated with a single-nucleotide polymorphism (SNP) in the WNT16 gene (β= -0.28 (-0.50,-0.07), p=0.011). Greater epigenetic age acceleration, as calculated via the new iterations of the epigenetic clocks (in particular GrimAge), was associated with lower maximum grip strength (β= -1.25 (-2.24,-0.26), p<0.02) and gait speed (β= (-0.04 (-0.09,-0.00), p<0.05) at multiple time points in males. In epigenome-wide analyses, methylation of a CpG site proximal to ECE1 was associated with maximum grip strength (adjusted p<0.05) and biologically plausible pathways including those governing the regulation of the actin cytoskeleton were significantly associated with total femoral neck bone mineral density (p<0.05).
These findings are largely hypothesis building and require further investigation and replication. However, they do add to our current understanding of skeletal changes associated with ageing, the ability of epigenetic clocks to predict future musculoskeletal phenotypes and identify novel loci of methylation which are associated with musculoskeletal ageing.

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ORCID for Cyrus Cooper: orcid.org/0000-0003-3510-0709

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