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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
In the citing paper
“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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BackgroundBiological activity and in vivo half-life of pro-activin A in male rats
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Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice
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“Later on, heterochronic parabiosis was shown to rejuvenate aged skeletal muscle, liver, heart, pancreas, bone, spinal cord and brain, ultimately leading to an extension of life and healthspan 125–130 .”
Modulation of GDF11 expression and synaptic plasticity by age and training
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“Indeed, initial studies in rodent models exploiting heterochronic parabiosis (in which circulatory systems of young and aged animals are connected) or using recombinant protein treatment, identified GDF11 as a molecule capable of rejuvenating cerebral, cardiac, skeletal muscle functions and attributed the diminished r…”
Plasma from Young Rats Injected into Old Rats Induce Antiaging Effects
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“53,54 Among the organs, the spleen has high GDF11 concentration, and a secretory defect of the spleen reduces GDF11 concentration in circulation.”
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“…growth differentiation factor 11 (GDF11) has been identified using modified aptamer-based proteomic technology as one of the factors present in the serum of young mice, reduced in aged animals, and capable of restoring cardiac function upon supplementation of old mice (Loffredo et al., 2013).”
BackgroundTGFβ Superfamily Members Mediate Androgen Deprivation Therapy-Induced Obese Frailty in Male Mice
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BackgroundMethodResultTopical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models
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Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence
Gonzalez-Valdes, I. B., Hidalgo, I., Bujarrabal-Dueso, A., Lara‐Pezzi, E., Padrón-Barthe, L., García‐Pavía, P., Arco, P. G., Redondo, J. M., Ruı́z-Cabello, J., Jiménez‐Borreguero, L. J., et al. (2015) · Nature Communications · doi:10.1038/ncomms7473 · Cited by 19
RetractedThe Rejuvenation of Aged Stem Cells for Cardiac Repair
Lüdke, A., Li, R., & Weisel, R. D. (2014) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2014.03.021 · Cited by 19
Cardiac stem cell aging and heart failure
Cesselli, D., Aleksova, A., Mazzega, E., Caragnano, A., & Beltrami, A. P. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.01.013 · Cited by 20
Pregnancy protects the kidney from acute ischemic injury
Popkov, V. A., Andrianova, N. V., Манских, В. Н., Silachev, D. N., Pevzner, I. B., Zorova, L. D., Sukhikh, G. T., Plotnikov, E. Y., & Zorov, D. B. (2018) · Scientific Reports · doi:10.1038/s41598-018-32801-8 · Cited by 19
Muscle wasting in the presence of disease, why is it so variable?
Kemp, P. R., Griffiths, M., & Polkey, M. I. (2018) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12489 · Cited by 21
“Another member of this family that appears to contribute to muscle loss is GDF-11.”
BackgroundInfluentialYounger‐ vs Older‐Old Patients with Heart Failure with Preserved Ejection Fraction
Matsushita, K., Harada, K., Miyazaki, T., Miyamoto, T., Kohsaka, S., Iida, K., Yamamoto, Y., Nagatomo, Y., Yoshino, H., Yamamoto, T., et al. (2019) · Journal of the American Geriatrics Society · doi:10.1111/jgs.16050 · Cited by 20
“C-reactive protein, mg/L 7 (2-28) 7 (2-27) 8 (2-29) .”
A Tale from TGF-β Superfamily for Thymus Ontogeny and Function
Jurberg, A. D., Vasconcelos‐Fontes, L., & Cotta-de-Almeida, V. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00442 · Cited by 22
“, a surgical procedure that connects the circulatory systems of animals with different ages, was able to reverse age-related phenotypes as cardiac hypertrophy (132).”
BackgroundInfluentialVitucci, D., Imperlini, E., Arcone, R., Alfieri, A., Canciello, A., Russomando, L., Martone, D., Cola, A., Labruna, G., Orrù, S., et al. (2017) · Journal of Sports Sciences · doi:10.1080/02640414.2017.1407232 · Cited by 19
“Furthermore, other studies demonstrated that circulating blood factors favour synaptic plasticity in the brain of elderly mice, and reduce age-related cardiac hypertrophy (Loffredo et al., 2013; Villeda et al., 2014).”
BackgroundProlonged Fasting/Refeeding Promotes Hematopoietic Stem Cell Regeneration and Rejuvenation
Mendelsohn, A. R., & Larrick, J. W. (2014) · Rejuvenation Research · doi:10.1089/rej.2014.1595 · Cited by 19
“For example, is expression of growth differentiation factor-11 (GDF11), a factor known to promote rejuvenation in the heart, skeletal muscle, and the brain, 23–25 increased?”
GDF11 induces mild hepatic fibrosis independent of metabolic health
Fröhlich, J., Kovačovicova, K. L., Mazza, T., Emma, M. R., Cabibi, D., Foti, M., Sobolewski, C., Oben, J. A., Peyrou, M., Villarroya, F., et al. (2020) · Aging · doi:10.18632/aging.104182 · Cited by 19
“Over the past decade, seminal studies have shown that systemic restoration of GDF11 levels reverses age-related phenotypes in aged mice, rejuvenates heart and skeletal muscle [16, 17] and improves the vascular and neurogenic rejuvenation in the brain [18, 19].”
BackgroundThe Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease
Ayoub, M., Jaoude, C. A., Ayoub, M., Hamadé, A., & Rima, M. (2025) · Immunology · doi:10.1111/imm.70036 · Cited by 25
“At the molecular level, the decrease in AMPK and GDF11 expression linked to aging is a leading factor of heightened cardiac fibrosis observed during the process of aging [203, 204].”
Chen, H. H., Tesic, M. B., Nikolic, V. N., Pavlović, M., Vučić, R. M., Spasić, A., Jovanović, H., Jovanović, I., Town, S. E. L., Padula, M. P., et al. (2022) · Biomolecules · doi:10.3390/biom12101419 · Cited by 18
“Given that perturbation in the circulation is potentially an upstream pathogenic mechanism of HFpEF [23], understanding the differences in certain protein’s abundance between myocardial and blood-derived samples is important in evaluating the reliability of certain systemic biomarkers in reflecting pathogenesis of HFp…”
BackgroundResultA germline-to-soma signal triggers an age-related decline of mitochondrial stress response
Zhou, L., Jiang, L., Li, L., Ma, C., Xia, P., Ding, W., & Liu, Y. (2024) · Nature Communications · doi:10.1038/s41467-024-53064-0 · Cited by 18
“Inspired by previous studies demonstrating that establishing a shared circulatory system between young and aged mice can reverse speci fi c aging phenotypes in older animals through factors present in young mice ’ s blood 12,13 , we fed C. elegans embryo lysates to adultwormsto exploresimilareffects.”
Myzithras, M., Li, H., Bigwarfe, T., Waltz, E., Gupta, P., Low, S. H. H., Hayes, D., MacDonnell, S. M., Ahlberg, J., Franti, M., et al. (2016) · Bioanalysis · doi:10.4155/bio.16.17 · Cited by 18
GDF11 administration does not extend lifespan in a mouse model of premature aging
Freitas‐Rodríguez, S., Rodríguez, F. J., & Folgueras, A. R. (2016) · Oncotarget · doi:10.18632/oncotarget.11096 · Cited by 18
“Thus, it has been shown that GDF11 levels in blood decline with age, and that its supplementation to reach young physiological range in old mice improved the features and function of a number of age-deteriorated tissues, including heart, skeletal muscle and brain [5-8].”
BackgroundInfluentialDrechsler, S., Lynch, M. A., Novella, S., Navarro, H. G., Hecimovic, S. K., Barini, E., Tucci, V., Castro, R. E., Vandenbroucke, R. E., Osuchowski, M. F., et al. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.07.005 · Cited by 20
Growth differentiation factor 11 is involved in isoproterenol‑induced heart failure
Zhang, X., Tan, H., Shi, Z., Li, N., Jia, Y., & Hao, Z. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10077 · Cited by 18
“GDF11 is known as a rejuvenation factor that reverses aging and aging-associated dysfunction in muscles, nerves and the cardiovascular system (20,36,37).”
BackgroundYoung plasma ameliorates aging-related acute brain injury after intracerebral hemorrhage
Yuan, J., Zhang, Q., Gong, C., Wang, F., Huang, J., Yang, G., Liu, L., Zhou, K., Xu, R., Chen, Q., et al. (2019) · Bioscience Reports · doi:10.1042/bsr20190537 · Cited by 20
Role of circulating factors in cardiac aging
Cannata, A. N., Marcon, G., Cimmino, G., Camparini, L., Ciucci, G., Sinagra, G., & Loffredo, F. S. (2017) · Journal of Thoracic Disease · doi:10.21037/jtd.2017.03.95 · Cited by 20
“More recently, in a revival of this interesting oldfashioned technique, heterochronic parabiosis, a specific experimental procedure whereby two animals of different ages are joined together, allowed to study the role of shared circulation in several conditions, such as muscular atrophy, neurodegenerative disorders, ca…”
BackgroundSelf-citationSignaling networks governing skeletal muscle growth, atrophy, and cachexia
Joshi, A. S., da Silva, M. T., Kumar, S., & Kumar, A. (2025) · Skeletal Muscle · doi:10.1186/s13395-025-00397-z · Cited by 25
“A few earlier studies showed that levels of GDF11 decline with age and that restoration of systemic GDF11 provides beneficial effects for several age-related conditions [113, 114].”
Immunity to acute virus infections with advanced age
Nikolich‐Žugich, J., Bradshaw, C. M., Uhrlaub, J. L., & Watanabe, M. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.09.007 · Cited by 19
Wlodarek, L., Alibhai, F. J., Wu, J., Li, S., & Li, R. (2022) · Stem Cells · doi:10.1093/stmcls/sxac019 · Cited by 17
Sonar, S. A., Watanabe, M., & Nikolich‐Žugich, J. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101835 · Cited by 19
TGF-β pathways in aging and immunity: lessons from Caenorhabditis elegans
Yamamoto, K. K., & Savage‐Dunn, C. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1220068 · Cited by 16
“An enticing 2013 study found that TGF-β family member GDF11 could act as a circulating factor that reverses age-related decline (Loffredo et al., 2013).”
BackgroundCardiac Aging and Rejuvenation — A Sense of Humors?
Rando, T. A., & Finkel, T. (2013) · New England Journal of Medicine · doi:10.1056/nejmcibr1306063 · Cited by 17
Goletti, S., & Gruson, D. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.09.014 · Cited by 17
The Promise and Challenges of Cardiac Stem Cell Therapy
Ni, N. C., Li, R., & Weisel, R. D. (2014) · Seminars in Thoracic and Cardiovascular Surgery · doi:10.1053/j.semtcvs.2014.03.001 · Cited by 17
The Immateriality of Circulating GDF11
Rodgers, B. D. (2016) · Circulation Research · doi:10.1161/circresaha.116.308478 · Cited by 17
Yuan, X., Bhat, O. M., Lohner, H., Li, N., Zhang, Y., & Li, P. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00342.2018 · Cited by 17
Blood autophagy defect causes accelerated non-hematopoietic organ aging
Fang, Y., Zhu, L., An, N. A., Jiang, G., Qian, J., Zhao, R., Yuan, N., Zhang, S., & Wang, J. (2019) · Aging · doi:10.18632/aging.102086 · Cited by 17
de Lucia, C., Murphy, T., Maruszak, A., Wright, P., Powell, T. R., Hartopp, N., de Jong, S., O'Sullivan, M. J., Breen, G. D., Price, J., et al. (2021) · Aging and Disease · doi:10.14336/ad.2021.0409 · Cited by 16
“Several studies using heterochronic parabiosis – involving the surgical attachment of a young and old rodent so that they share a common vascular system - have demonstrated that age-related declines in stem cell function can be reversed throughout the body and central nervous system by exposure to a youthful systemic…”
BackgroundRejuvenating the senescent heart
Nguyen, N., & Sussman, M. A. (2015) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000161 · Cited by 17
Rejuvenation: Turning back the clock of aging kidney
Wei, S.-Y., Pan, S., Li, B., Chen, Y., & Lin, S. (2019) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2019.05.020 · Cited by 18
Pepinsky, B., Gong, B.-J., Gao, Y. L., Lehmann, A., Ferrant, J. L., Amatucci, J., Sun, Y., Bush, M. W., Walz, T., Pederson, N. E., et al. (2017) · Biochemistry · doi:10.1021/acs.biochem.7b00302 · Cited by 16
Peng, L., Gagliano‐Jucá, T., Pencina, K. M., Krishnan, S. C., Li, Z., Tracy, R. P., Jasuja, R., & Bhasin, S. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab146 · Cited by 19
Modifying enzyme replacement therapy – A perspective
Schaible, P. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17653 · Cited by 14
Tian, J., Li, X. J., Ma, Y., Mai, Z., Yang, Y., Luo, M., Xu, W., Chen, K., Chen, X., Tang, J., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-45747-3 · Cited by 21
“Studies have shown that plasma derived from human UCB or blood from young donors is a rich source of TIMP-2 and GDF11 and can be used to reverse the effects of certain age-related diseases 6,7,31,32 .”
Background
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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