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An aging clock using metabolomic CSF

Nathan Hwangbo, Xinyu Zhang, Daniel Raftery, Haiwei Gu, Shu-Ching Hu, Thomas J. Montine, Joseph F. Quinn, Kathryn A. Chung, Amie L. Hiller, Dongfang Wang, Qiang Fei, Lisa Bettcher, Cyrus P. Zabetian, Elaine Peskind, Gail Li, Daniel E.L. Promislow, Alexander Franks
doi: https://doi.org/10.1101/2021.04.04.438397
Nathan Hwangbo
1Department of Statistics and Applied Probability, University of California, Santa Barbara, Santa Barbara, CA
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Xinyu Zhang
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Daniel Raftery
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Haiwei Gu
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Shu-Ching Hu
3Veterans Affairs Puget Sound Health Care System, Seattle, WA
4Department of Neurology, University of Washington School of Medicine, Seattle, WA
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Thomas J. Montine
5Department of Pathology, Stanford University School of Medicine, Palo Alto, CA
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Joseph F. Quinn
6Portland Veterans Affairs Medical Center, Portland, OR
7Department of Neurology, Oregon Health and Science University, Portland, OR
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Kathryn A. Chung
6Portland Veterans Affairs Medical Center, Portland, OR
7Department of Neurology, Oregon Health and Science University, Portland, OR
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Amie L. Hiller
6Portland Veterans Affairs Medical Center, Portland, OR
7Department of Neurology, Oregon Health and Science University, Portland, OR
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Dongfang Wang
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Qiang Fei
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Lisa Bettcher
2Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle WA
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Cyrus P. Zabetian
3Veterans Affairs Puget Sound Health Care System, Seattle, WA
4Department of Neurology, University of Washington School of Medicine, Seattle, WA
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Elaine Peskind
3Veterans Affairs Puget Sound Health Care System, Seattle, WA
8Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA
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Gail Li
3Veterans Affairs Puget Sound Health Care System, Seattle, WA
8Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA
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Daniel E.L. Promislow
9Department of Biology, University of Washington, Seattle WA
10Department of Lab Medicine & Pathology, University of Washington School of Medicine, Seattle WA
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Alexander Franks
1Department of Statistics and Applied Probability, University of California, Santa Barbara, Santa Barbara, CA
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  • For correspondence: afranks@pstat.ucsb.edu
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Abstract

Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using “-omic” platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these “omic clocks” provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid from healthy human subjects, and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer’s and Parkinson’s disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small dataset (n = 85), and discuss techniques for drift correction, missing data imputation, and regularized regression which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of cerebrospinal fluid.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 05, 2021.
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An aging clock using metabolomic CSF
Nathan Hwangbo, Xinyu Zhang, Daniel Raftery, Haiwei Gu, Shu-Ching Hu, Thomas J. Montine, Joseph F. Quinn, Kathryn A. Chung, Amie L. Hiller, Dongfang Wang, Qiang Fei, Lisa Bettcher, Cyrus P. Zabetian, Elaine Peskind, Gail Li, Daniel E.L. Promislow, Alexander Franks
bioRxiv 2021.04.04.438397; doi: https://doi.org/10.1101/2021.04.04.438397
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An aging clock using metabolomic CSF
Nathan Hwangbo, Xinyu Zhang, Daniel Raftery, Haiwei Gu, Shu-Ching Hu, Thomas J. Montine, Joseph F. Quinn, Kathryn A. Chung, Amie L. Hiller, Dongfang Wang, Qiang Fei, Lisa Bettcher, Cyrus P. Zabetian, Elaine Peskind, Gail Li, Daniel E.L. Promislow, Alexander Franks
bioRxiv 2021.04.04.438397; doi: https://doi.org/10.1101/2021.04.04.438397

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