APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics

Ellis, D. S., Watanabe, K., Wilmanski, T., Lustgarten, M. S., Ardisson Korat, A. V., Glusman, G., Hadlock, J. J., Fiehn, O., Sebastiani, P., Price, N. D., Hood, L., Magis, A. T., Evans, S. J., Pflieger, L., Lovejoy, J. C., Gibbons, S. M., Funk, C. C., Baloni, P., Rappaport, N.

Institute for Systems Biology, Seattle, WA 98109, USA; Phenome Health, Seattle, WA 98109, USA; Buck Institute for Research on Aging, Novato, CA · biorxiv

Paper

Abstract

Apolipoprotein E (APOE) modifies human aging; specifically, the {varepsilon}2 and {varepsilon}4 alleles are among the strongest genetic predictors of longevity and Alzheimers disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. Herein, we analyzed inter-omic, context-dependent association patterns across APOE genotypes, sex, and health axes in 2,229 community-dwelling individuals to test APOE genotypes for variation in metabolites and metabolite-associations tied to a previously-validated metric of biological aging (BA) based on blood biomarkers. Our analysis, supported by validation in an independent cohort, identified top APOE-associated plasma metabolites as diacylglycerols, which were increased in {varepsilon}2-carriers and trended higher in {varepsilon}4-carriers compared to {varepsilon}3-homozygotes, despite the known opposing aging effects of the allele variants. Omics association patterns of {varepsilon}2-carriers and increased biological age were also counter-intuitively similar, displaying increased associations between insulin resistance markers and energy-generating pathway metabolites. These results provide an atlas of APOE-related omic associations and support the involvement of bioenergetic pathways in mediating the impact of APOE on aging.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper investigates the role of APOE genotypes in biological aging and their association with metabolites, which is relevant to understanding the mechanisms of aging and longevity. However, while it provides insights into bioenergetic pathways and their relation to aging, the findings appear to be more of a solid contribution rather than a groundbreaking advance in the field. The study's focus on associations rather than direct interventions or mechanisms that could lead to lifespan extension limits its overall impact.

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