Overweight as a heterogeneous phenotype: Leveraging differences in adiposity-related traits to understand effects on age-related disease

Research problem and specific questions The purpose of this project is to leverage the heterogeneity of overweight to understand how overweight increases the risk of cardiovascular disease, type 2 diabetes, and dementia.

We will study adiposity in general and specific adiposity-related traits:Metabolically unhealthy vs healthy adiposityEnvironmentally vs genetically driven adiposityAdiposity measured in midlife vs late-lifeThus, we can study differences in how the adiposity-related traits associate with the age-related diseases, and if these differences are explained by mediating factors or by an acceleration of aging.

We will study:Overweight in general, to highlight genes and biological pathways shared between adiposity and the age-related diseases, and seek to identify factors driving the associations.How metabolic biomarkers (e.g. cholesterol levels, inflammatory markers) and other potential mediators (e.g. depressive symptoms) differ among the adiposity-related traits, and if these factors influence the associations with the age-related diseases.If cellular or multisystem aging (telomere length, epigenetic clocks, and frailty) differ among the adiposity-related traits, and influence the association with the age-related diseases.Data and methodAim 1 uses genetic designs and public data.

Aim 2-3 applies advanced epidemiological designs to large longitudinal data from the Health and Retirement Study (USA; n=37,494) and twin cohorts in the IGEMS consortium (Australia, Denmark, Sweden, and USA; n=89-136).Plan for project realizationThe data are already available, and the realization and costs concern analyses to answer the research questions.

The project is led by an interdisciplinary team of researchers in Sweden, China, and the USA.

We will recruit a PhD student, who will conduct four studies within the project, and budget for partial financing of a present PhD student, whose work falls within the proposed project.RelevancePreliminary analyses indicate important differences among the adiposity-related traits, and by examining these differences the project will advance our understanding of the heterogeneity of overweight, and of what drives the negative health effects of adiposity in general.

It thereby has the potential to identify preventive strategies reducing the risk of several of our most common causes of morbidity and mortality, and promote a healthier aging.