Project 457493

Our healthcare system is overburdened by the increasing prevalence of metabolic multimorbidity, a condition characterized by the co-occurrence of different, yet related, metabolic diseases. Approximately 3.5% of Canadians above the age of 50 live with cardiometabolic multimorbidity and 19% of Canadian adults are diagnosed with metabolic syndrome which increases the risk of developing multimorbidity. While traditional therapies have been developed to treat diseases separately, there is an emergent need for therapies that can target underlying factors causing interrelated metabolic diseases. Many biomarkers have been discovered as potential pharmacotherapy candidates, yet past studies have failed to distinguish between causality and association due to methodological and resource limitations. Recently, two molecular biomarkers of aging, namely clonal hematopoiesis of indeterminate potential and epigenetic age, have been discovered to predict all-cause mortality, cardiovascular diseases, and type 2 diabetes. These biomarkers are characterized by unique genetic mutations and epigenetic patterns. However, the strength of their relationship to metabolic multimorbidity as it pertains to causality remains unknown. The proposed study will employ a rare multimodal strategy using a comprehensive set of cutting-edge molecular data, integrated with clinical and demographic data, from two international epidemiological studies (PURE and ORIGIN) totaling over 200,000 participants to characterize the relationship between molecular biomarkers of aging and combinations of metabolic multimorbidity. The demographic heterogeneity of our large study population, including both healthy and unhealthy populations, will broaden the relevance of our findings among the general population. Should our hypothesis be confirmed, these novel biomarkers will inform risk stratification for patients and form the basis for new therapies that can comprehensively treat or prevent metabolic multimorbidity.