Review

. 2024 Feb;30(2):360-372.

doi: 10.1038/s41591-023-02784-9. Epub 2024 Feb 14.

Validation of biomarkers of aging

Mahdi Moqri^#^{1

2

3}, Chiara Herzog^#⁴, Jesse R Poganik^#¹, Kejun Ying^{1

5}, Jamie N Justice⁶, Daniel W Belsky⁷, Albert T Higgins-Chen⁸, Brian H Chen⁹, Alan A Cohen¹⁰, Georg Fuellen^{11

12}, Sara Hägg¹³, Riccardo E Marioni¹⁴, Martin Widschwendter^{4

15

16}, Kristen Fortney¹⁷, Peter O Fedichev¹⁸, Alex Zhavoronkov¹⁹, Nir Barzilai²⁰, Jessica Lasky-Su²¹, Douglas P Kiel²², Brian K Kennedy^{23

24}, Steven Cummings^{25

26}, P Eline Slagboom²⁷, Eric Verdin²⁸, Andrea B Maier^{24

29}, Vittorio Sebastiano³, Michael P Snyder², Vadim N Gladyshev³⁰, Steve Horvath³¹, Luigi Ferrucci³²

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
³ Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, CA, USA.
⁴ European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria.
⁵ T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁶ Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁷ Department of Epidemiology, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁸ Department of Psychiatry, Yale University, New Haven, CT, USA.
⁹ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, San Diego, CA, USA.
¹⁰ Department of Environmental Health Sciences, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹¹ Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.
¹² School of Medicine, University College Dublin, Dublin, Ireland.
¹³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁵ Department of Women's Cancer, EGA Institute for Women's Health, University College London, London, UK.
¹⁶ Department of Women's and Children's Health, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.
¹⁷ BioAge Labs, Richmond, CA, USA.
¹⁸ Gero PTE, Singapore, Singapore.
¹⁹ Insilico Medicine Hong Kong, Hong Kong SAR, China.
²⁰ Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
²¹ Department of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.
²³ Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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.
²⁵ San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA.
²⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
²⁷ Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
²⁸ Buck Institute for Research on Aging, Novato, CA, USA.
²⁹ Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³⁰ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. vgladyshev@rics.bwh.harvard.edu.
³¹ Altos Labs, San Diego, CA, USA. shorvath@altoslabs.com.
³² National Institute on Aging, Baltimore, MD, USA. ferruccilu@grc.nia.nih.gov.

^# Contributed equally.

PMID: 38355974
PMCID: PMC11090477
DOI: 10.1038/s41591-023-02784-9

Review

Validation of biomarkers of aging

Mahdi Moqri et al. Nat Med. 2024 Feb.

. 2024 Feb;30(2):360-372.

doi: 10.1038/s41591-023-02784-9. Epub 2024 Feb 14.

Authors

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
³ Department of Obstetrics and Gynecology, School of Medicine, Stanford University, Stanford, CA, USA.
⁴ European Translational Oncology Prevention and Screening Institute, Universität Innsbruck, Innsbruck, Austria.
⁵ T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁶ Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁷ Department of Epidemiology, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁸ Department of Psychiatry, Yale University, New Haven, CT, USA.
⁹ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, San Diego, CA, USA.
¹⁰ Department of Environmental Health Sciences, Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹¹ Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.
¹² School of Medicine, University College Dublin, Dublin, Ireland.
¹³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁴ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
¹⁵ Department of Women's Cancer, EGA Institute for Women's Health, University College London, London, UK.
¹⁶ Department of Women's and Children's Health, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.
¹⁷ BioAge Labs, Richmond, CA, USA.
¹⁸ Gero PTE, Singapore, Singapore.
¹⁹ Insilico Medicine Hong Kong, Hong Kong SAR, China.
²⁰ Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.
²¹ Department of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.
²³ Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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.
²⁵ San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA.
²⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
²⁷ Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.
²⁸ Buck Institute for Research on Aging, Novato, CA, USA.
²⁹ Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³⁰ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. vgladyshev@rics.bwh.harvard.edu.
³¹ Altos Labs, San Diego, CA, USA. shorvath@altoslabs.com.
³² National Institute on Aging, Baltimore, MD, USA. ferruccilu@grc.nia.nih.gov.

^# Contributed equally.

PMID: 38355974
PMCID: PMC11090477
DOI: 10.1038/s41591-023-02784-9

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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Conflict of interest statement

Conflict of Interest statement: 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, Universitat Innsbruck, Austria and an honorary research fellow at the Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, United Kingdom. C.H. is a shareholder of Sola Diagnostics GmbH, and named as 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, Winston-Salem, NC, USA and the XPRIZE Foundation, Culver City, CA, USA. J.N.J. serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences, eLife, and Experimental Gerontology. D.B. is also affiliated with the Child Brain Development Network, Canadian Institute for Advanced Research and SocioMed Research Nucleus, Universidad Mayor, Santiago, Chile. D.B. is an inventor of DunedinPACE, a Duke University and University of Otago invention licensed to TruDiagnostic. A.H.-C. has built epigenetic aging metrics that are licensed by Elysium Health through Yale University. B.H.C. owns stock in Illumina Inc., the manufacturer of the DNA methylation arrays used in epigenetic biomarkers of aging, and is listed as a co-inventor in 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, Austria. M.W. is a shareholder of Sola Diagnostics GmbH, and named as inventor on a patent on an epigenetic clock indicative of breast cancer risk. K.F. is CEO of BioAge Labs P.O.F. is an employee and stakeholder in Gero PTE. A.Z. is the founder and 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 (AFAR), on the board of the executive committee of the Longevity Biotech Association, and 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 and Reneo and has participated on the Data Safety Monitoring Board for the AgNovos Healthcare osteoporosis treatment trial. E.V. is a scientific co-founder of Napa Therapeutics and BHB Therapeutics, serves on the scientific advisory board of Seneque, and is named co-inventor on a patent relating to an epigenetic clock robust to cell composition changes. A.B.M. declares to be Chief Medical Officer of NU. V.S is 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, Mitrix. S.H. 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.H. is a named inventor.

Figures

**Figure 1.. Different approaches to cohort study design in the context of biomarkers of aging.**
Biomarkers of aging are commonly validated using cross-sectional or longitudinal study designs. Cross-sectional studies involve measurement of biomarkers and chronological age or aging-related outcome data at a single time point. These data can only support association of these measures at that time point. Longitudinal designs, on the other hand, allow for assessment of predictive validity of biomarkers measured at one time point and future aging-related outcomes.

**Figure 2.. Validation of biomarkers of aging with different numbers of cohorts or biomarkers.**
a) Most existing biomarkers have been developed using data from a single cohort and some have been validated in a second external cohort. Analysis of multiple biomarkers across multiple cohorts allows for a meta-analysis comparison across multiple cohorts. b) Biomarker validation studies need to consider different sources of variation, such as heterogeneity in population characteristics, sample collections, data preprocessing, analyses, and reporting.

See this image and copyright information in PMC

References

1. Moqri M. et al. Biomarkers of aging for the identification and evaluation of longevity interventions. Cell 186, 3758–3775 (2023). - PMC - PubMed
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Extended Data References

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1. Kristie J. et al. Glycans Are a Novel Biomarker of Chronological and Biological Ages. J. Gerontol. A. Biol. Sci. Med. Sci 69, 779–789 (2014). - PMC - PubMed

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Validation of biomarkers of aging

Affiliations

Validation of biomarkers of aging

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Extended Data References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical