A metabolomic signature of the APOE2 allele

Authors: SEBASTIANI, PAOLA - Tufts Medical Center; SONG, ZEYUAN - Boston University; ELLIS, DYLAN - Institute For Systems Biology; TIAN, QU - National Institute On Aging (NIA, NIH); SCHWAIGER-HABER, MICHAELA - Washington University; STANCLIFFE, ETHAN - Washington University; LUSTGARTEN, MICHAEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FUNK, CORY - Institute For Systems Biology; BALONI, PRIYANKA - Institute For Systems Biology; MARRON, MEGAN - University Of Pittsburgh; GURINOVICH, ANASTASIA - Tufts Medical Center; LI, MENGZE - Boston University; LESCHYK, ANASTASIA - Boston University; MONTI, STEFANO - Boston University; MONTASSER, MAY - University Of Maryland; FEITOSA, MARY - Washington University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HAIGIS, MARCIA - Harvard Medical School; MILMAN, SOFIYA - Albert Einstein College Of Medicine; BARZILAI, NIR - Albert Einstein College Of Medicine; FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH); RAPPAPORT, NOA - Institute For Systems Biology; PATTI, GARY - Washington University; PERLS, THOMAS - Boston University

Submitted to: GeroScience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/9/2022
Publication Date: 8/15/2022
Citation: Sebastiani, P., Song, Z., Ellis, D., Tian, Q., Schwaiger-Haber, M., Stancliffe, E., Lustgarten, M., Funk, C., Baloni, P., Marron, M.M., Gurinovich, A., Li, M., Leschyk, A., Monti, S., Montasser, M., Feitosa, M.F., Ordovas, J.M., Haigis, M., Milman, S., Barzilai, N., Ferrucci, L., Rappaport, N., Patti, G.J., Perls, T.T. 2022. A metabolomic signature of the APOE2 allele. GeroScience. https://doi.org/10.1007/s11357-022-00646-9.
DOI: https://doi.org/10.1007/s11357-022-00646-9

Interpretive Summary: Aging is associated with changes at multiple physiological levels. Research is required to enable us to predict, identify, and, where necessary, address these changes. Towards this goal, a consortium of investigators, including scientists at the HNRCA in Boston, was created to identify biomarkers associated with healthy aging using state-of-the-art molecular techniques and large cohorts of elderly subjects. This research revealed a molecular fingerprint related to successful aging. Moreover, a significant connection between gut and brain health was identified. These findings will facilitate the identification of individual paths of aging and the possibility of implementing more efficacious and personalized prevention approaches to maximize health along the life span.

Technical 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 of Ashkenazi Jewish centenarians, 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 16 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 11 glycerolipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.14 to 1.25. The organic acid 6-hydroxyindole sulfate, which is a marker of gut health, 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. 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 a link between the e2 allele and the gut-brain axis.