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How does the growth differentiation factor 11 regulate lifespan?

Image credit: Adapted from: https://biology.stackexchange.com/questions/25890/circulating-factors-affecting-human-health-longevity

Shubhankar Kulkarni
Shubhankar Kulkarni Aug 11, 2020
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Question: There have been contradicting reports regarding the role of growth differentiation factor 11 (GDF11) in longevity. How does the GDF11 regulate lifespan?

The GDF11, a member of the activin/TGF-β superfamily, was reduced in the plasma of old isochronic compared to young isochronic mice and was restored to youthful levels in old mice after exposure to a young circulation. GDF11 boosted the growth of new blood vessels and neurons in the brain and skeletal muscle at the sites of injuries. GDF11 increased neurogenesis in old mice. In vitro exposure of aged satellite cells to GDF11 produced dose-responsive increases in satellite cell proliferation and differentiation, suggesting that GDF11 can act directly on satellite cells to alter their function. The treatment of aged mice with daily intraperitoneal injections of recombinant GDF11 for 4 weeks increased numbers of satellite cells with intact DNA, as compared with cells from aged mice receiving vehicle alone. In a model of muscle injury, GDF11 treatment of aged mice 28 days before the injury and continued for 7 days thereafter restored more youthful profiles of myofiber caliber in regenerating muscle. Aged mice treated with GDF11 also showed increased average exercise endurance and grip strength. GDF11 levels decreased with age and when injected externally in older animals, could restore olfactory and motor functions.

Contrary to rejuvenating reports regarding GDF11 and its low levels in old individuals, the total levels of GDF11 were shown to increase with age in another study. Also, GDF11 mRNA levels rose in rat muscle with increased age. In vitro experiments also showed that differentiation of human primary myoblasts into myotubes was inhibited by GDF11. Higher systemic levels of GDF11 were associated with impaired regeneration in young mice, as indicated by a greater number of very small myofibers in the GDF11-treated muscles. Also, the treatment with GDF11 decreased the growth of adult and aged satellite cell cultures in a dose-dependent manner. Blockade of GFD11 and its receptors can be administered to old individuals with very high levels of GDF11 and muscle loss.

These contradicting results could be due to multiple forms of GDF11 and only one could decrease with age.

What other reasons might lead to such contradicting results?

[1]Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, et al. Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors. Science (80- ) [Internet]. 2014 May 9;344(6184):630–4. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1251141

[2]Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, et al. Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle. Science (80- ) [Internet]. 2014 May 9;344(6184):649–52. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1251152

[3]Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell [Internet]. 2013 May 9;153(4):828–39. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23663781

[4]Poggioli T, Vujic A, Yang P, Macias-Trevino C, Uygur A, Loffredo FS, et al. Circulating Growth Differentiation Factor 11/8 Levels Decline With Age. Circ Res [Internet]. 2016 Jan 8;118(1):29–37. Available from: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.115.307521

[5]Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, et al. GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. Cell Metab [Internet]. 2015 Jul;22(1):164–74. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1550413115002223

[6]Trendelenburg A, Meyer A, Jacobi C, Feige JN, Glass DJ. TAK-1/p38/nNFκB signaling inhibits myoblast differentiation by increasing levels of Activin A. Skelet Muscle [Internet]. 2012;2(1):3. Available from: http://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-2-3

[7]Conese M, Carbone A, Beccia E, Angiolillo A. The Fountain of Youth: A tale of parabiosis, stem cells, and rejuvenation. Open Med [Internet]. 2017 Oct 28;12(1):376–83. Available from: https://www.degruyter.com/view/journals/med/12/1/article-p376.xml

[8]Grens K. Studies Conflict on Regenerative Molecule. The Scientist [Internet]. 2015; Available from: https://www.the-scientist.com/daily-news/studies-conflict-on-regenerative-molecule-35447

Creative contributions

GDF11 may promote a calorie restriction-like phenotype

Jamila Aug 18, 2020
In a recent study by hudobenko and colleagues, it was found that GDF11 levels were reduced as mice and humans aged. Furthermore, supplementation with GDF11 was able to decrease the risk of mortality in mice after an induced stroke. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244081/) As already mentioned, there are conflicting reports about GDF11. Egerman suggests that GDF11 levels increase in aged humans and rats. (https://pubmed.ncbi.nlm.nih.gov/26001423/) However, other researchers have suggested that the increased GDF11 level reported by Egerman was not GDF11 but was an immunoglobulin light chain that appeared due to the cross-reactivity of the specific antibody used. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748736/) Furthermore, GDF11 and GDF8 share high homology. Previous studies may not have used methods that could distinguish these two factors properly. Camparini and colleagues used LC‐MS/MS‐based assay in combination with immunoprecipitation (IP) to distinguish between the two factors, and they found that both GDF11 and GDF8 levels were reduced in aged female mice. (https://onlinelibrary.wiley.com/doi/full/10.1002/pmic.201900104). GDF11 may mimic/enhance calorie restriction-like effects to regulate lifespan. In a study, GDF11 was substantially enhanced in aged mice on calorie restriction compared to the controls. Furthermore, the usage of exogenous GDF11 was able to induce adiponectin production and improve insulin/IGF‐1 signaling. (https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13038) Therefore, GDF11 may regulate lifespan by inducing a calorie restriction-like phenotype.
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Shubhankar Kulkarni
Shubhankar Kulkarni4 years ago
So the primary role of GDF11 may be metabolic homeostasis and altering longevity might be a by-product.
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