A metabolomic signature of the APOE2 allele.

Qingyan Xiang, Thomas T Perls, Gary J Patti, Noa Rappaport, Luigi Ferrucci, Sofiya Milman, Nir Barzilai, Stefano Monti, Marcia Haigis, Jose M Ordovas, Oliver Fiehn, Mette Soerensen, Svetlana Ukraintseva, Mary F Feitosa, Stacy L Andersen, Paola Sebastiani, Anastasia Leshchyk, Mengze Li, Anastasia Gurinovich, Megan M Marron, Shakchhi Joshi, Cong-Hui Yao, Priyanka Baloni, Cory C Funk, Michael S Lustgarten, Ethan Stancliffe, Michaela Schwaiger-Haber, Qu Tian, Dylan Ellis, Zeyuan Song

Journal: GeroScience 2023;45(1):415-426

PMID: 35997888

Abstract

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.

© 2022. The Author(s), under exclusive licence to American Aging Association.

Address: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. [email protected].; Department of Biostatistics, Boston University, Boston, MA, USA.; Institute for Systems Biology, Seattle, WA, USA.; Longitudinal Studies Section, Translational Gerontology Branch, National Institute On Aging, Baltimore, MD, USA.; Department of Chemistry, Department of Medicine, Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, USA.; Nutrition, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center On Aging at Tufts University, Boston, MA, USA.; Department of Cell Biology at Harvard Medical School, Boston, MA, USA.; Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.; Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA.; Bioinformatics Program, Boston University, Boston, MA, USA.; Department of Medicine, Boston University School of Medicine, Boston, MA, USA.; Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MI, USA.; Biodemography of Aging Research Unit, Social Science Research, Duke University, Durham, NC, USA.; Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark.; West Coast Metabolomics Center, University of California, Davis, CA, USA.; Nutrition and Genomics Team, Jean Mayer USDA Human Nutrition Research Center On Aging and Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MB, USA.; Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
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