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Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
Open accessAbstract
The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
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“the rejuvenation strategies based on the use of blood-borne systemic factors identified in parabiosis experiments (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Loffredo et al., 2013
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“Excitingly, proof of principle exists for rejuvenation through blood-borne systemic factors (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Loffredo et al., 2013
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“The first study42 focused on the monomeric forms of GDF11 and myostatin and showed that they cumulatively decrease in abundance in serum with aging42,44.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [44]
In the citing paper
“Intriguingly, at least part of the ‘rejuvenating’ effect of a young systemic environment appears related to the higher levels of circulating growth differentiation factor 11 (GDF11) and oxytocin present in young blood as compared to aged38,166,168,169.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [168]
In the citing paper
“Studies on heterochronic parabiosis and plasma exchange in animals have demonstrated that circulating proteins can have a causal influence on ageing phenotypes across the body, including in skeletal muscle107,108, heart109 and brain15,110–112.”
From Measuring biological age using omics data (2022) · cites this paper as [109]
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Cites
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InfluentialSelf-citationThe ageing systemic milieu negatively regulates neurogenesis and cognitive function
Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., et al. (2011) · Nature · doi:10.1038/nature10357 · Cited by 1,763 · cited 2×
“Conversely, exposing a young mouse to an old systemic environment can inhibit myogenesis (Brack et al., 2007) and neurogenesis (Villeda et al., 2011) in the young mouse.”
Aptamer-Based Multiplexed Proteomic Technology for Biomarker Discovery
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Self-citationHaematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium
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Self-citationIncreased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis
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“Conversely, exposing a young mouse to an old systemic environment can inhibit myogenesis (Brack et al., 2007) and neurogenesis (Villeda et al., 2011) in the young mouse.”
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Items 901–948 of 948
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Chen, R., Dai, X., Wang, H., Zhang, T., Zhang, Z., Liu, Y., & Fan, Z. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1736069
“…as a “youth factor,” with preliminary studies indicating a decline in its levels with age and suggesting that supplementation could rejuvenate cardiac and skeletal muscle function (Frohlich et al., 2022; Lehallier et al., 2019; Loffredo et al., 2013; Sinha et al., 2014; Jin et al., 2019).”
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“1,46,49 At low doses of GDF11, TGFBR3 enhances R-SMAD signaling in MCF10A cells, 41 suggesting a noncanonical +,– trend that contrasts the purely inhibitory effect of TGFBR3 on TGFβ1 signaling (Figure 3I).”
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BackgroundLe rôle de GDF11 dans les leucémies aiguës myéloïdes
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Self-citationGDF-11 triggers cold-induced browning and metabolic activation of adipose tissue
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Metadata
- Authors
- Loffredo, F. S., Steinhauser, M. L., Jay, S. M., Gannon, J., Pancoast, J. R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J. L., Miller, C. M., Singer, B. S., Stewart, A., Psychogios, N., Gerszten, R. E., Hartigan, A. J., Kim, M.-J., Serwold, T., Wagers, A. J., & Lee, R. T.
- Affiliations
- Brigham and Women's Hospital (US)
- SomaLogic (United States) (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Wagers, Amy J.
- Lee, Richard T.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 153
- Issue
- 4
- Pages
- 828-839
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3677132
- OpenAlex
- W2156589853
- Cited by
- 948
- References
- 64
- Citations by year
- 2026: 44 · 2025: 46 · 2024: 53 · 2023: 67 · 2022: 69 · 2021: 69 · 2020: 87 · 2019: 70 · 2018: 86 · 2017: 91 · 2016: 94 · 2015: 84 · 2014: 56 · 2013: 30
- FWCI
- 59.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association
- National Institutes of Health (1dp2od004345-01)
- Harvard Stem Cell Institute
- National Institute on Aging (R01AG033053, R01AG032977, R01AG040019)
- National Heart, Lung, and Blood Institute (U01HL100402, K99HL112905, R00HL112905)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK090147, P30DK036836)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- GDF11, cardiac hypertrophy, cardiac aging, heterochronic parabiosis, circulating factors, heart failure with preserved ejection fraction, cardiomyocyte size, TGF-beta superfamily, aptamer-based proteomics, regenerative therapy
- MeSH terms
- Aging, Animals, Blood Pressure, Female, Cardiomegaly, Humans, Male, Mice, Inbred C57BL, Parabiosis, Hypertrophy, Left Ventricular, Bone Morphogenetic Proteins, Myocytes, Cardiac, Mice, Forkhead Transcription Factors, Growth Differentiation Factors, Induced Pluripotent Stem Cells
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