The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
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
2013 ACCF/AHA Guideline for the Management of Heart Failure
Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Drazner, M. H., Fonarow, G. C., Geraci, S. A., Horwich, T., Januzzi, J. L., et al. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.05.019 · Cited by 12,536
Tuerk, C., & Gold, L. (1990) · Science · doi:10.1126/science.2200121 · Cited by 10,421 · cited 1×
“SOMAmers (Slow Off-rate Modified Aptamers) are nucleic acid-based protein binding reagents evolved through SELEX (Tuerk and Gold, 1990) to bind protein targets.”
Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B., & Castelli, W. P. (1990) · New England Journal of Medicine · doi:10.1056/nejm199005313222203 · Cited by 5,699
Hunt, S. A., Abraham, W. T., Chin, M. H., Feldman, A. M., Francis, G. S., Ganiats, T. G., Jessup, M. L., Konstam, M. A., MANCINI, D. M., Michl, K., et al. (2009) · Circulation · doi:10.1161/circulationaha.109.192065 · Cited by 3,739
Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., Walsh, K., Schiaffino, S., Lecker, S. H., & Goldberg, A. L. (2004) · Cell · doi:10.1016/s0092-8674(04)00400-3 · Cited by 3,012 · cited 1×
“Although it is plausible that the antihypertrophic effect of rGDF11 is mediated by FoxO-dependent proteasomemediated protein degradation (Sandri et al., 2004), our data do not explain the differential effects of rGDF11 and myostatin.”
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287 · cited 4×
“…can significantly impact the function of aging tissues, as indicated by the restoration of appropriate activation and function of endogenous, ''old'' skeletal muscle satellite cells and successful muscle repair after injury following exposure to a ''youthful'' systemic milieu (Conboy et al., 2005).”
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
Gold, L., Ayers, D., Bertino, J., Bock, C., Bock, A., Brody, E. N., Carter, J., Dalby, A. B., Eaton, B. E., Fitzwater, T., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015004 · Cited by 1,754 · cited 1×
“The SOMAmer quantity is measured by hybridization to microarrays (for a full description, see Gold et al., 2010).”
Self-citationHaematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium
Balsam, L. B., Wagers, A. J., Christensen, J. L., Kofidis, T., Weissman, I. L., & Robbins, R. C. (2004) · Nature · doi:10.1038/nature02460 · Cited by 1,737 · cited 2×
“…solely through their common circulation, parabiosis is a powerful model to determine whether circulating factors can alter tissue function (Balsam et al., 2004; Brack et al., 2007; Conboy et al., 2005; Eggan et al., 2006; Ruckh et al., 2012; Sherwood et al., 2004; Villeda et al., 2011;…”
Self-citationIncreased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis
Brack, A. S., Conboy, M. J., Roy, S., Lee, M., Kuo, C. J., Keller, C., & Rando, T. A. (2007) · Science · doi:10.1126/science.1144090 · Cited by 1,564 · cited 4×
“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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López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
“…in this regard are the DR approaches to extend healthy lifespan (Piper et al., 2011; Sanchez-Roman et al., 2012) and 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).”
BackgroundChronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
Franceschi, C., & Campisi, J. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu057 · Cited by 3,891
“Three prominent examples are the ability of a young blood supply to rejuvenate tissue repair in aged skeletal muscle (25) and the capability of young serum to rejuvenate the proliferative and differentiation capacity of human muscle stem cells (satellite cells) from old donors (26), the ability of systemic GDF11 (grow…”
BackgroundHallmarks of Cellular Senescence
Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.001 · Cited by 2,605
“In normal aging, the decline in growth factors, such as GDF11, might also contribute to the activation of mTORC1 and the hypertrophy observed, particularly in cardiac cells [114].”
Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797
TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology
Morikawa, M., Derynck, R., & Miyazono, K. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021873 · Cited by 1,321
“Recently, GDF-11 has been identified as a circulating factor in young mice, which reverses age-related dysfunction in mouse cardiac and skeletal muscle (Loffredo et al. 2013; Sinha et al. 2014).”
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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