Activated GDF11/8 subforms predict cardiovascular events and mortality in humans
Open accessAbstract
Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline. The predictive value of blood levels of GDF11/8 proteins in humans for future disease outcomes has been unclear. Here, the authors show that low levels of specific activated GDF11/8 subforms are strongly associated with future cardiovascular events, mortality, and dementia risk.
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Studying the impact of individual isoforms can be biologically informative in studies of disease, as established with GDF8/11 for cardiovascular events.
“When cis-pQTL do reflect differential binding to encoded isoforms, we note that studying the impact of individual isoforms can be biologically informative in studies of disease, as established with GDF8/11 for cardiovascular events34.”
From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [34]
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- Authors
- Walker, R. G., Kato, T., Ben Driss, L., Williams, S. A., Hinterberg, M. A., Janjic, N., Gelinas, A. D., Carpenter, M. A., Kattamuri, C., Walter, J. E., Mueller, C., Mendello, K. R., Gordon, J. V., Walker, K. A., Coresh, J., Bhasin, S., Rubin, L. L., Wagers, A. J., Thompson, T. B., Ganz, P., & Lee, R. T.
- Affiliations
- Harvard University (US)
- SomaLogic (United States) (US)
- University of Cincinnati (US)
- University of Basel (CH)
- National Institute on Aging (US)
- Johns Hopkins University (US)
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Joslin Diabetes Center (US)
- San Francisco General Hospital (US)
- Corresponding author
- Ganz, Peter
- Lee, Richard T.
- ORCID
- Walker, Ryan G.
- Kato, Tomohiro
- Ben Driss, Laura
- Williams, Stephen A.
- Hinterberg, Michael A.
- Janjic, Nebojsa
- Gelinas, Amy D.
- Kattamuri, Chandramohan
- Walter, Joan E.
- Mueller, Christian
- Mendello, Kourtney R.
- Walker, Keenan A.
- Coresh, Josef
- Bhasin, Shalender
- Rubin, Lee L.
- Wagers, Amy J.
- Thompson, Thomas B.
- Ganz, Peter
- Lee, Richard T.
- Venue
- Nature Communications
- Published
- 2025-07-15
- Volume
- 16
- Issue
- 1
- Pages
- 6534-6534
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12263990
- OpenAlex
- W4412436997
- Cited by
- 4
- References
- 39
- Citations by year
- 2026: 4
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (R01AG047131, HL169291, 4T32HL007208)
- Glenn Fondation NIA Intramural Research Program
- U.S. Department of Health & Human Services | NIH | Center for Information Technology (1R56AG052972, P30AG31679, R01AG072086, R35GM134923, R01AG072087, R01HL059367, R01HL153499-02)
- The Glenn Foundation
- Topics
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- GDF11, myostatin, aptamers, cardiovascular events, all-cause mortality, dementia risk, aging, cardiovascular risk prediction, biomarkers
- MeSH terms
- Aged, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Risk Factors, Biomarkers, Bone Morphogenetic Proteins, Aptamers, Nucleotide, Growth Differentiation Factors, Myostatin
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