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Validation of biomarkers of aging

Nature Medicine volume 30, pages 360–372 (2024)Cite this article

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Abstract

The search for biomarkers that quantify biological aging (particularly ‘omic’-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.

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Fig. 1: Different approaches to cohort study design in the context of biomarkers of aging.
Fig. 2: Validation of biomarkers of aging with different numbers of cohorts or biomarkers.

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Acknowledgements

This work was supported in part by the Intramural Research Program of the National Institute on Aging, NIH, and grants from the National Institute on Aging and Hevolution Foundation. D.P.K. was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041398). We are very grateful to D.M. Wilson III for many suggestions during the writing of this paper. We express our gratitude to all members of the Biomarkers of Aging Consortium Roadmap Group (https://www.agingconsortium.org/) for their fruitful discussions that helped to define the scope and direction of this work. The list of authors reflects Roadmap Group members who directly contributed to or refined the manuscript.

Author information

Author notes

  1. These authors contributed equally: Mahdi Moqri, Chiara Herzog, Jesse R. Poganik.

Authors and Affiliations

  1. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mahdi Moqri, Jesse R. Poganik, Kejun Ying & Vadim N. Gladyshev

  2. Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA

    Mahdi Moqri & Michael P. Snyder

  3. Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, CA, USA

    Mahdi Moqri & Vittorio Sebastiano

  4. European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria

    Chiara Herzog & Martin Widschwendter

  5. T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Kejun Ying

  6. Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Jamie N. Justice

  7. Department of Epidemiology, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA

    Daniel W. Belsky

  8. Department of Psychiatry, Yale University, New Haven, CT, USA

    Albert T. Higgins-Chen

  9. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, San Diego, CA, USA

    Brian H. Chen

  10. Department of Environmental Health Sciences, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA

    Alan A. Cohen

  11. Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany

    Georg Fuellen

  12. School of Medicine, University College Dublin, Dublin, Ireland

    Georg Fuellen

  13. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Sara Hägg

  14. Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK

    Riccardo E. Marioni

  15. Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, London, UK

    Martin Widschwendter

  16. Department of Women’s and Children’s Health, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden

    Martin Widschwendter

  17. BioAge Labs, Richmond, CA, USA

    Kristen Fortney

  18. Gero PTE, Singapore, Singapore

    Peter O. Fedichev

  19. Insilico Medicine Hong Kong, Hong Kong SAR, China

    Alex Zhavoronkov

  20. Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA

    Nir Barzilai

  21. Department of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jessica Lasky-Su

  22. Musculoskeletal Research Center, Hinda and Arthur Marcus Institute for Aging Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Douglas P. Kiel

  23. Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Brian K. Kennedy

  24. Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Healthy Longevity, @AgeSingapore, National University Health System, Singapore, Singapore

    Brian K. Kennedy & Andrea B. Maier

  25. San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA

    Steven Cummings

  26. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

    Steven Cummings

  27. Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands

    P. Eline Slagboom

  28. Buck Institute for Research on Aging, Novato, CA, USA

    Eric Verdin

  29. Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    Andrea B. Maier

  30. Altos Labs, San Diego, CA, USA

    Steve Horvath

  31. National Institute on Aging, Baltimore, MD, USA

    Luigi Ferrucci

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  1. Mahdi Moqri
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  2. Chiara Herzog
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  3. Jesse R. Poganik
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  4. Kejun Ying
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  5. Jamie N. Justice
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  6. Daniel W. Belsky
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  7. Albert T. Higgins-Chen
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  10. Georg Fuellen
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  27. Vadim N. Gladyshev
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Corresponding authors

Correspondence to Vadim N. Gladyshev, Steve Horvath or Luigi Ferrucci.

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M.M., V.S., M.P.S. and V.N.G. have filed a patent on measuring cellular aging. C.H. is also affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria and is an honorary research fellow at the Department of Women’s Cancer, EGA Institute for Women’s Health, University College London. C.H. is a shareholder of Sola Diagnostics and is named as an inventor on a patent on an epigenetic clock indicative of breast cancer risk. J.N.J. is also affiliated with the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine and the XPRIZE Foundation. J.N.J. serves on the advisory board for the American Federation for Aging Research’s Finding Aging Biomarkers by Searching Existing Trials Initiative and the editorial board of the Journals of Gerontology Series A Biological Sciences, eLife and Experimental Gerontology. D.W.B. is also affiliated with the Child Brain Development Network, Canadian Institute for Advanced Research and SocioMed Research Nucleus and Universidad Mayor. D.W.B. is an inventor of DunedinPACE, a Duke University and University of Otago invention licensed to TruDiagnostic. A.T.H.-C. is an inventor of epigenetic clocks that are the subject of a provisional patent and have been licensed to TruDiagnostic. A.T.H.-C. has also received consulting fees from TruDiagnostic and FOXO Biosciences. B.H.C. owns stock in Illumina, the manufacturer of the DNA methylation arrays used in epigenetic biomarkers of aging, and is listed as a co-inventor on filed patents on commercial applications of epigenetic prediction models. A.A.C. is a founder, president and majority shareholder at Oken Health. R.E.M. has received a speaker fee from Illumina and is an advisor to the Epigenetic Clock Development Foundation and Optima Partners. M.W. is also affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck. M.W. is a shareholder of Sola Diagnostics and is named as an inventor on a patent on an epigenetic clock indicative of breast cancer risk. K.F. is the CEO of BioAge Labs. P.O.F. is an employee and stakeholder of Gero. A.Z. is the founder and the CEO of Insilico Medicine, a clinical-stage generative AI and robotics biotechnology company specializing in aging research. N.B. is the scientific director of the American Federation for Aging Research, is on the board of the executive committee of the Longevity Biotech Association and is advisor on the board of the Academy for Health and Lifespan Research. D.P.K. has received a grant from Solarea Bio and royalties from Wolters Kluwer. D.P.K. sits on the scientific advisory boards of Solarea Bio, Pfizer, Radius Health and Reneo and has participated in the data safety monitoring board for the AgNovos Healthcare treatment trial. E.V. is a scientific cofounder of Napa Therapeutics and BHB Therapeutics, serves on the scientific advisory board of Seneque and is a named co-inventor on a patent relating to an epigenetic clock robust to cell composition changes. A.B.M. declares herself chief medical officer of NU and co-founder of Chi Longevity. V.S. is a cofounder, SAB chair and head of research of Turn Biotechnologies. M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, iollo, Marble Therapeutics, Crosshair Therapeutics and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza and Mitrix. S. Horvath is a founder of the nonprofit Epigenetic Clock Development Foundation that licenses patents surrounding epigenetic clocks. The Regents of the University of California is the sole owner of a patent application directed at GrimAge and other epigenetic clocks for which S. Horvath is a named inventor.

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Moqri, M., Herzog, C., Poganik, J.R. et al. Validation of biomarkers of aging. Nat Med 30, 360–372 (2024). https://doi.org/10.1038/s41591-023-02784-9

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