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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]
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“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]
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“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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“ant of this phenomenon, since treating old mice with GDF11 to reach youthful levels reproduced the effects of parabiosis and also reversed age-related cardiac hypertrophy.(100)”
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BackgroundInfluentialThe Aging Heart: Figure 1.Preprint
Chiao, Y. A., & Rabinovitch, P. S. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025148 · Cited by 204
“Recently, Loffredo et al. (2013) showed, by heterochronic parabiosis, that the circulation of young mice can regress cardiac hypertrophy in aged mouse hearts.”
BackgroundInfluentialFujita, Y., Taniguchi, Y., Shinkai, S., Tanaka, M., & Ito, M. (2016) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12724 · Cited by 206
Circulating Growth Differentiation Factor 11/8 Levels Decline With Age
Poggioli, T., Vujić, A., Yang, P., Macias-Treviño, C., Uygur, A., Loffredo, F. S., Pancoast, J. R., Cho, M., Goldstein, J., Tandias, R. M., et al. (2015) · Circulation Research · doi:10.1161/circresaha.115.307521 · Cited by 192
“1 mg/kg per day for 28 consecutive days reduced cardiac hypertrophy in old mice.(6) To further characterize the antihypertrophic effect of GDF11, we performed a dose titration study in young and aged mice and observed a significant dose-dependent decrease of heart weight, normalized to tibia length, after only 9 days…”
BackgroundResultInfluentialSelf-citationHeart Failure With Preserved Ejection Fraction: Heterogeneous Syndrome, Diverse Preclinical Models
Roh, J. D., Hill, J. A., Singh, A. S. C., Valero‐Muñoz, M., & Sam, F. (2022) · Circulation Research · doi:10.1161/circresaha.122.320257 · Cited by 202
Buckley, M. T., Sun, E., George, B. M., Liu, L. A., Schaum, N., Xu, L., Reyes, J. M., Goodell, M. A., Weissman, I. L., Wyss‐Coray, T., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00335-4 · Cited by 201
Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency
Studer, L., Vera, E., & Cornacchia, D. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.05.004 · Cited by 192
“, 2011) as well as improved heart function (Loffredo et al., 2013) in old animals following parabiosis with a young host.”
BackgroundStenvinkel, P., Carrero, J. J., von Walden, F., Ikizler, T. A., & Nader, G. A. (2015) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfv122 · Cited by 193
“During parabiosis experiments with blood from young mice, GDF11 was shown to reverse age-related cardiac hypertrophy [89] and skeletal muscle function [47] in old mice.”
MethodActivin A more prominently regulates muscle mass in primates than does GDF8
Latres, E., Mastaitis, J., Fury, W., Miloscio, L., Trejos, J., Pangilinan, J., Okamoto, H., Cavino, K., Na, E., Papatheodorou, A., et al. (2017) · Nature Communications · doi:10.1038/ncomms15153 · Cited by 185
GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy
Smith, S., Zhang, X., Zhang, X., Gross, P., Starosta, T., Mohsin, S., Franti, M., Gupta, P., Hayes, D., Myzithras, M., et al. (2015) · Circulation Research · doi:10.1161/circresaha.115.307527 · Cited by 189
“A recent study suggests that disease-free aging induces pathological cardiac hypertrophy (PCH) in 24-month-old mice and that this results in large part from an age-related reduction in the circulating blood levels of growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β super family of…”
BackgroundMethodInfluentialExercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction
Pandey, A., Shah, S. J., Butler, J., Kellogg, D. L., Lewis, G. D., Forman, D. E., Mentz, R. J., Borlaug, B. A., Simon, M. A., Chirinos, J. A., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.07.014 · Cited by 184
Nfatc1 orchestrates aging in hair follicle stem cells
Keyes, B. E., Segal, J. P., Heller, E., Lien, W., Chang, C.-Y., Guo, X., Oristian, D., Zheng, D., & Fuchs, E. V. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320301110 · Cited by 185
“Most recently, it was shown that cardiomyocytes rely upon systemic growth and differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) superfamily, which declines with age (11).”
BackgroundHeart Failure With Preserved Ejection Fraction
Loffredo, F. S., Nikolova, A., Pancoast, J. R., & Lee, R. T. (2014) · Circulation Research · doi:10.1161/circresaha.115.302929 · Cited by 184
“Recently, growth differentiation factor 11, a member of the activin/TGF-β superfamily, has been identified as a factor that carries the potential to reverse aging-related cardiac remodeling.(163) Heterochronic parabiosis, an experimental procedure whereby 2 animals of different ages are joined together, identified gro…”
BackgroundSelf-citationNew insights into iron regulation and erythropoiesis
Kim, A., & Nemeth, E. (2015) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000132 · Cited by 180
Lei, Q., Gao, F., Liu, T., Ren, W., Chen, L., Cao, Y., Chen, W., Guo, S., Zhang, Q., Chen, W., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz8697 · Cited by 170
Cardiac ageing: extrinsic and intrinsic factors in cellular renewal and senescence
Gude, N. A., Broughton, K. M., Firouzi, F., & Sussman, M. A. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0061-5 · Cited by 172
Mesenchymal stem cell therapy: A promising cell‐based therapy for treatment of myocardial infarction
Shafei, A., ALI, M. A. M., Ghanem, H. G., Shehata, A. I., Abdelgawad, A. A., Handal, H. R., Talaat, K. A., Ashaal, A. E., & El‐Shal, A. S. (2017) · The Journal of Gene Medicine · doi:10.1002/jgm.2995 · Cited by 165
“factor for the aging heart by parabiosis experiments, actively prevents fibrosis following myocardial injury.(47) Effects on cardiac contractility and metabolism are also one of”
Turning back time with emerging rejuvenation strategies
Mahmoudi, S., Xu, L., & Brunet, A. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0206-0 · Cited by 171
The Role of Exercise in Cardiac Aging
Roh, J. D., Rhee, J., Chaudhari, V., & Rosenzweig, A. (2016) · Circulation Research · doi:10.1161/circresaha.115.305250 · Cited by 161
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 172
Myostatin as a Biomarker of Muscle Wasting and other Pathologies-State of the Art and Knowledge Gaps
Bączek, J., Silkiewicz, M., & Wojszel, Z. B. (2020) · Nutrients · doi:10.3390/nu12082401 · Cited by 166
Blood-to-brain communication in aging and rejuvenation
Bieri, G., Schroer, A. B., & Villeda, S. A. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01238-8 · Cited by 156
Liu, W., Zhou, L., Zhou, C., Zhang, S., Jing, J., Xie, L., Sun, N., Duan, X., Jing, W., Liang, X., et al. (2016) · Nature Communications · doi:10.1038/ncomms12794 · Cited by 159
Rejuvenating Strategies for Stem Cell-Based Therapies in Aging
Neves, J., Sousa‐Victor, P., & Jasper, H. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.01.008 · Cited by 160
“By joining the circulatory system of young and old animals it was shown that the regenerative capacity of the skeletal muscle, liver, brain, bone and pancreas of young parabionts is worsened by exposure to an old systemic environment, whereas young blood can improve regeneration in old animals, reduce cardiac hypertro…”
InfluentialObas, V., & Vasan, R. S. (2018) · Clinical Science · doi:10.1042/cs20171156 · Cited by 148
Emerging Anti-Aging Strategies - Scientific Basis and Efficacy
Shetty, A. K., Kodali, M., Upadhya, R., & Madhu, L. N. (2018) · Aging and Disease · doi:10.14336/ad.2018.1026 · Cited by 149
“[56] Loffredo FS, Steinhauser ML, Jay SM, Gannon J,”
BackgroundActivin type II receptor signaling in cardiac aging and heart failure
Roh, J. D., Hobson, R., Chaudhari, V., Quintero, P. A., Yeri, A., Benson, M. D., Xiao, C., Zlotoff, D. A., Bezzerides, V. J., Houstis, N. E., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau8680 · Cited by 148
Self-citationLatres, E., Pangilinan, J., Miloscio, L., Bauerlein, R., Na, E., Potocky, T. B., Huang, Y., Eckersdorff, M., Rafique, A., Mastaitis, J., et al. (2015) · Skeletal Muscle · doi:10.1186/s13395-015-0060-8 · Cited by 143
“The lack of cross-reactivity to GDF11 is important, since data suggest that GDF11 has beneficial effects in aged skeletal muscle and reverses age-related cardiac hypertrophy [26, 27], so that blockade of GDF11 would not be desirable.”
BackgroundCirculating Proteomic Signatures of Chronological Age
Menni, C., Kiddle, S. J., Mangino, M., Viñuela, A., Psatha, M., Steves, C., Sattlecker, M., Buil, A., Newhouse, S., Nelson, S., et al. (2015) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glu121 · Cited by 144
“Also, SOMAscan has been shown to be a very robust technology in previous studies (43).”
BackgroundStrategies and Challenges in Clinical Trials Targeting Human Aging
Newman, J. C., Milman, S., Hashmi, S. K., Austad, S. N., Kirkland, J. L., Halter, J. B., & Barzilai, N. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw149 · Cited by 141
“Together with the hundreds of single-gene mutations that extend life span (34), these include (nonexhaustively) calorie, protein, and methionine restriction (35); visceral fat removal (36); elimination of senescent cells (27,37); exposure to young serum (38); and serumderived proteins such as GDF-11 (23,24,39); GH and…”
BackgroundNeurogenesis in the aging brain
Apple, D. M., Fonseca, R. S., & Kokovay, E. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.06.116 · Cited by 145
“GDF11 has been implicated in improving function of skeletal muscle stem cells [73], cardiac stem cells [74], and renal tubular cells [75].”
Multi-omic rejuvenation and lifespan extension on exposure to youthful circulation
Zhang, B., Lee, D. E., Trapp, A., Tyshkovskiy, A., Lu, A. T., Bareja, A., Kerepesi, C., McKay, L. K., Shindyapina, A. V., Dmitriev, S. E., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00451-9 · Cited by 134
“Indeed, the effects of HPB on the amelioration of aging phenotypes are evident across tissues including muscle 19 , liver 19 , heart 20 , brain 21,22 and bone 18,23 .”
Sanz-Ros, J., Romero-García, N., Mas-Bargues, C., Monleón, D., Gordevicius, J., Brooke, R. T., Dromant, M., Díaz, A., Derevyanko, A., Guío-Carrión, A., et al. (2022) · Science Advances · doi:10.1126/sciadv.abq2226 · Cited by 131
Antibody‐based proteomics and biomarker research—Current status and limitations
Solier, C., & Langen, H. (2014) · PROTEOMICS · doi:10.1002/pmic.201300334 · Cited by 131
“This platform has been used in biomarker discovery campaigns across a variety of disease areas, including exploratory cardiovascular research [74], nonsmall-cell lung cancer [75], chronic kidney disease [76], and showed promise in cerebrospinal fluid proteomics [77].”
MethodIntertissue Control of the Nucleolus via a Myokine-Dependent Longevity Pathway
Demontis, F., Patel, V. K., Swindell, W. R., & Perrimon, N. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.001 · Cited by 133
“In agreement with this scenario, GDF11 has been recently shown to act systemically to delay heart aging in mice (Loffredo et al., 2013).”
Association of Blood Donor Age and Sex With Recipient Survival After Red Blood Cell Transfusion
Chassé, M., Tinmouth, A. T., English, S. W., Acker, J. P., Wilson, K. R., Knoll, G. A., Shehata, N., van Walraven, C., Forster, A. J., Ramsay, T., et al. (2016) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2016.3324 · Cited by 130
Paracrine signals regulate human liver organoid maturation from iPSC
Asai, A., Aihara, E., Watson, C. L., Mourya, R., Mizuochi, T., Shivakumar, P., Phelan, K. J., Mayhew, C. N., Helmrath, M. A., Takebe, T., et al. (2017) · Development · doi:10.1242/dev.142794 · Cited by 128
“Three biological replicates were collected and combined as equal volumes, then submitted to the high-throughput SOMAscan assay in the laboratories of SOMALogic to quantify proteins as previously described (Hathout et al., 2015; Loffredo et al., 2013; Nahid et al., 2014).”
MethodMANF regulates metabolic and immune homeostasis in ageing and protects against liver damage
Sousa‐Victor, P., Neves, J., Cedron-Craft, W., Ventura, P. B., Liao, C., Riley, R. R., Soifer, I., van Bruggen, N., Kolumam, G. A., Villeda, S., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-018-0023-6 · Cited by 129
Cellular reprogramming and epigenetic rejuvenation
Simpson, D. J., Olova, N. N., & Chandra, T. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01158-7 · Cited by 127
Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease
Wallin, A., Román, G. C., Esiri, M. M., Kettunen, P., Svensson, J., Paraskevas, G. P., & Kapaki, E. N. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170803 · Cited by 133
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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