Longitudinal multi-omic datasets to inform the role of alternative splicing dysregulation in ageing and age-related diseases

Abstract

Ageing is a complex biological process characterised by a progressive decline in physical, mental and cognitive function, increasing the risk of various chronic diseases and significantly influencing the quality of life in older age. Investigating molecular mechanisms of ageing is the focus of extensive research. Among the biological processes related to ageing is alternative splicing, a post-transcriptional regulation of gene expression. Altered splicing patterns with age have been increasingly recognised, underscoring the role of splicing regulation in ageing. However, ageing manifests differently across individuals, making chronological age an unreliable indicator of the ageing process. In addition, the role of alternative splicing in age-related diseases is less well understood.

In this thesis, the longitudinal MultiMuTHER twin study, a subset of 335 older female twins from the TwinsUK registry, was utilised to assess longitudinal changes in alternative splicing within participants and to examine the influence of metabolites and age-related diseases on splicing variation. Time-dependent alterations in different forms of splicing were identified, with intron retention, a type of mis-splicing, predominantly increasing over time. I observed an increase in the heritability of intron retention over time, suggesting that genetic control may become more influential than environmental factors as individuals age. Moreover, the depletion of splicing factors during ageing may contribute to the rise in intron retention. Finally, intron retention was positively associated with diabetes, hypertension, multimorbidity (the co-occurrence of multiple chronic conditions), and uremic toxin metabolism. Importantly, the longitudinal findings of this study suggested that mis-splicing is more likely a consequence of disease rather than a cause, providing an important complement to previous cross-sectional studies.

Altogether, this thesis highlights the significance of alternative splicing, especially mis-splicing, in normal ageing and age-related pathologies, representing a promising avenue for improving our understanding of ageing mechanisms and developing anti-ageing strategies.

Date of Award	1 Feb 2025
Original language	English
Awarding Institution	King's College London
Supervisor	Kerrin Small (Supervisor)