Understanding the mechanisms behind accelerated ageing and their impact on neurodegenerative disease: a multivariate genomic approach

Age-related diseases account for over half of the disease burden in adults, which is projected to rise as the global population ages. The “Geroscience Hypothesis” posits that developing therapies that reduce biological ageing will also broadly prevent age-related diseases, including neurodegenerative diseases. However, the pace of biological ageing varies dramatically between individuals, and even when two individuals age at a similar pace they may exhibit very different characteristics. Understanding why this variation occurs is crucial to identifying biological ageing aetiology and developing targeted treatments. Frailty is a commonly used measure of accelerated ageing, but our understanding of its genetic architecture is severely lacking for two key reasons. Firstly, previous studies have been limited to populations of European ancestry limiting the generalisability of findings, and secondly, they have used single aggregate scores that combine highly heterogeneous features, severely reducing our power to detect individual risk pathways. In my fellowship, I will apply new multivariate genomic methods to characterise the mechanisms and key drivers of frailty across multiple ancestries, including an exploration of sex-specific differences. Using these results, I will then explore how accelerated ageing impacts neurodegenerative disease risk to identify promising drug targets that might prevent both accelerated ageing and neurodegeneration.