Men and women age differently at the molecular level, and this fellowship will map those differences to explain why one sex faces higher risks of kidney disease and other age-related conditions. Most ageing research treats sex as an afterthought, creating data gaps that skew results and miss biological mechanisms that drive health inequalities. This project targets that gap by combining datasets on sex chromosome loss, telomere shortening, hormone profiles, and social factors across large longitudinal studies in the UK, Ireland, and the US. The researcher will use long-read sequencing to measure telomere length at individual chromosome ends—a technique that reveals detail standard methods miss—and study mosaic loss of sex chromosomes, the most common genetic alteration acquired over a lifetime. If successful, the work will identify disrupted biological pathways and biomarkers that classify individuals by kidney disease risk, enabling earlier intervention. It will also pinpoint social determinants that affect men and women differently, building evidence for targeted healthcare policies. The core aim is fundamental: to understand how lifetime exposures alter ageing biology in sex-specific ways. That knowledge could eventually guide therapeutic development and make clinical trials more equitable, but the immediate output is better biological models, not a bedside test.
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Background Our global population is ageing. The number of individuals over the age of 60 years is set to double by 2050[1], subsequently increasing the prevalence of age-related disease[2, 3]. The underlying molecular mechanisms which cause individuals to age at different rates, or alter their likelihood of disease, are poorly understood. More specifically, sex-inequalities are often overlooked, producing data-gaps and biased research. I will improve fundamental knowledge surrounding ageing sex-differences, determining how lifetime exposures impact individuals on a biological level to alter their risk of age-related disease. My research will build biological evidence to support the need for targeted interventions which promote health equity across the life-course. Current unmet needs Outcomes from this Fellowship will inform more equitable research, trials, and healthcare. I will use an interdisciplinary approach to investigate molecular markers of ageing, harnessing historically under-utilised data, generating new data, and building collaborations to advance the knowledge required to improve the lives of older individuals. Kidney disease will be used as an exemplar, due to its emergence as a public health emergency[4]. Sex inequalities are an area of significant inequality in molecular ageing research. I will examine sex-differences in age-related molecular markers to understand biological mechanisms influencing sex-differences in longevity[5, 6] and kidney disease[7–12], aligning with the DMT Strategic Priorities. Methods I will identify novel interactions and sex-specific features by combining datasets exploring sex chromosome degradation, (epi)genetics, telomere length, hormonal profiles, social demographics, comorbidities and health outcomes across the life-course. I will utilise innovative approaches, such as long-read sequencing to determine telomere length at individual chromosome ends[13]. I will study mosaic loss of sex chromosomes[14–19], the most common chromosomal alteration acquired over the life-course[17, 20, 21], to better understand its causes and consequences. I have established collaborations with a machine-learning expert, to facilitate the integration of longitudinal data to provide novel insights into the biological complexity of ageing. Workflows and best practice guidelines will be shared, facilitating their use in ethnically diverse cohorts and wider ageing phenotypes. Longitudinal cohort studies of ageing, NICOLA (Northern Ireland), TILDA (Republic of Ireland), and Health and Retirement Study (USA), are core collaborators, with input from Our Future Health, UK Biobank, All of Us, and kidney disease networks. I will leverage existing datasets, generate new data and enhance collaborations to expedite global impact. Benefits I will identify differentially disrupted pathways and biomarkers to aid the classification of individuals based on their kidney disease risk, with potential to improve patient care. Crucially, it will identify targets for future work to develop therapeutic interventions. Furthermore, my work holds potential to identify social determinants of health which impact males and females differently, providing evidence to support targeted interventions for equitable healthcare. Workflows and best-practice guidelines will be shared, facilitating their use in ethnically diverse cohorts and wider age-related phenotypes. I will disseminate my research to diverse audiences and stakeholders to maximise impact
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