A comparison of the determinants of healthy ageing

: a Mendelian randomisation approach

Abstract

The ageing global population has prompted many nations to prioritise ageing research to mitigate the challenges and capitalise on the opportunities presented by this demographic shift. Central to this is the recognition that additional years of life must not be dominated by poor health. Research into healthy ageing seeks to extend healthspan, preserving functional capacity and minimising age-related decline and morbidity.
Despite numerous theories, the processes underlying ageing phenotypes remain poorly understood, with competing theoretical models offering contrasting perspectives. One model suggests fundamental ageing processes drive functional decline and increase disease risk, advocating for interventions targeting shared mechanisms to improve healthspan. An alternative model posits that age-related phenomena arise independently with distinct causes, suggesting the need for targeted strategies. This thesis explored whether functional aspects of healthy ageing share causal determinants. The literature was systematically reviewed for putative determinants of measures of cardiovascular, cognitive, and physical function, and used Mendelian randomisation to assess the causal effects of 55 putative determinants on grip strength, arterial stiffness, systolic blood pressure, pulse pressure, fluid intelligence and reaction time.
While several putative determinants showed robust causal effects, cross-functional effects on ageing-related phenotypes across three bodily systems were uncommon, with the exception of educational attainment. The findings offer limited support for theories of universal ageing mechanisms underlying systemic ageing phenotypes, but support education as a public health priority, highlighting its likely impact as a population-level tool to deliver broad benefits for healthy ageing. Furthermore, domain-specific causal effects suggest targeted interventions could also improve specific aspects of healthy ageing.
Future studies should explore the mechanisms linking education with healthy ageing and include non-European ancestry cohorts to establish generalisability and limit health inequalities. Triangulating causal inference methods could further explore the role of other established public health targets, informing approaches to promote healthy ageing globally.

Date of Award	13 May 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Laura D Howe (Supervisor), Kate M Tilling (Supervisor), Yoav Ben-Shlomo (Supervisor) & Neil Davies (Supervisor)