APOE genotype and biological age impact inter-omic associations related to bioenergetics
Apolipoprotein E (<i>APOE</i>) modifies human aging; specifically, the ε2 and ε4 alleles are among the strongest genetic predictors of longevity and Alzheimer's disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. In the present study, we analyzed multi-omic association patterns across <i>APOE</i> genotypes, sex, and biological age (BA) axes in 2,229 community dwelling individuals. Our analysis, supported by validation in an independent cohort, identified diacylglycerols as the top <i>APOE</i>-associated plasma metabolites. However, despite the known opposing aging effects of the allele variants, both ε2- and ε4-carriers showed higher diacylglycerols compared to ε3-homozygotes. 'Omics association patterns of ε2-carriers and increased biological age were also counter-intuitively similar, displaying significantly increased associations between insulin resistance markers and energy-generating pathway metabolites. These results demonstrate the context-dependence of the influence of <i>APOE</i>, with ε2 potentially strengthening insulin resistance-like pathways in the decades prior to imparting its longevity benefits. Additionally, they provide an atlas of <i>APOE</i>-related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of <i>APOE</i> on aging.
Authors
- Dylan Ellis (ORCID: https://orcid.org/0000-0001-9984-5158)
- Andres V Ardisson Korat (ORCID: https://orcid.org/0000-0003-4599-2245)
- Paola Sebastiani (ORCID: https://orcid.org/0000-0001-6419-1545)
- Gustavo Glusman (ORCID: https://orcid.org/0000-0001-8060-5955)
- Kengo Watanabe (ORCID: https://orcid.org/0000-0002-0348-1634)
- Nathan D. Price (ORCID: https://orcid.org/0000-0002-4157-0267)
- Andrew T. Magis (ORCID: https://orcid.org/0000-0003-0576-677X)
- Tomasz Wilmanski (ORCID: https://orcid.org/0000-0003-1059-073X)
- Priyanka Baloni (ORCID: https://orcid.org/0000-0002-3382-4941)
- Jennifer Hadlock (ORCID: https://orcid.org/0000-0001-6103-7606)
- Noa Rappaport (ORCID: https://orcid.org/0000-0001-8643-2055)
- Michael S. Lustgarten (ORCID: https://orcid.org/0000-0003-1262-784X)
- Lance Pflieger (ORCID: https://orcid.org/0000-0003-2237-5674)
- Sean M. Gibbons (ORCID: https://orcid.org/0000-0002-8724-7916)
- Simon J. Evans (ORCID: https://orcid.org/0000-0001-8112-9487)
- Leroy Hood (ORCID: https://orcid.org/0000-0001-7158-3678)
- Cory C. Funk (ORCID: https://orcid.org/0000-0002-5229-9011)
- Oliver Fiehn (ORCID: https://orcid.org/0000-0002-6261-8928)
- Jennifer C. Lovejoy
Institutions
- Tufts University (US)
- Tufts Medical Center (US)
- Buck Institute for Research on Aging (US)
- University of Washington (US)
- Purdue University West Lafayette (US)
- University of Washington Medical Center (US)
- Institute for Systems Biology (US)
- Jean Mayer Human Nutrition Research Center on Aging (US)
- Hamilton Thorne (United States) (US)
- University of California, Davis (US)
- Tokushima University (JP)
Publication Details
- Journal
- Aging
- Published
- 2025-05-03
- DOI
- https://doi.org/10.18632/aging.206243
- Citations
- 2
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- U.S. Department of Agriculture
- Wellcome Trust
- National Institute for Health and Care Research
- King's College London
- European Commission
- Versus Arthritis
- National Institutes of Health
- Agricultural Research Service
- Medical Research Council
- Japan Science and Technology Agency
- Precursory Research for Embryonic Science and Technology