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The influence of GDF11 on brain fate and function

  • Marissa J. SchaferEmail author
  • Nathan K. LeBrasseur
Review Article


Growth differentiation factor 11 (GDF11) is a transforming growth factor β (TGFβ) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. During development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action. In the aged brain, exogenous, peripherally delivered GDF11 may enhance neurogenesis and angiogenesis, as well as improve neuropathological outcomes. This is in contrast to a predominantly negative influence on neurogenesis in the developing CNS. Seemingly antithetical effects may correspond to the cell types and mechanisms activated by local versus circulating concentrations of GDF11. Yet undefined, distinct mechanisms of action in young and aged brains may also play a role, which could include differential receptor and binding partner interactions. Exogenously increasing circulating GDF11 concentrations may be a viable approach for improving deleterious aspects of brain aging and neuropathology. Caution is warranted, however, since GDF11 appears to negatively influence muscle health and body composition. Nevertheless, an expanding understanding of GDF11 biology suggests that it is an important regulator of CNS formation and fate, and its manipulation may improve aspects of brain health in older organisms.


Growth differentiation factor 11 GDF11 Brain aging Brain development Neurogenesis Stroke Alzheimer’s disease 



Research associated with this review was supported by the National Institutes of Health, National Institute on Aging through a Mayo Clinic Alzheimer's Research Center pilot grant from AG016574 (MJS) and grants AG055529 and AG052958 (NKL).


  1. Alvarez-Buylla A, Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41(5):683–686Google Scholar
  2. Andersson O, Reissmann E, Ibanez CF (2006) Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. EMBO Rep 7(8):831–837Google Scholar
  3. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8(9):963–970Google Scholar
  4. Augustin H, McGourty K, Steinert JR, Cochemé HM, Adcott J, Cabecinha M, Vincent A, Halff EF, Kittler JT, Boucrot E, Partridge L (2017) Myostatin-like proteins regulate synaptic function and neuronal morphology. Development 144(13):2445–2455Google Scholar
  5. Awasaki T, Huang Y, O'Connor MB, Lee T (2011) Glia instruct developmental neuronal remodeling through TGF-beta signaling. Nat Neurosci 14(7):821–823Google Scholar
  6. Cash JN, Rejon CA, McPherron AC, Bernard DJ, Thompson TB (2009) The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding. EMBO J 28(17):2662–2676Google Scholar
  7. Cash JN, Angerman EB, Kattamuri C, Nolan K, Zhao H, Sidis Y, Keutmann HT, Thompson TB (2012) Structure of myostatin. follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding. J Biol Chem 287(2):1043–1053Google Scholar
  8. De Domenico E et al (2017) Modulation of GDF11 expression and synaptic plasticity by age and training. Oncotarget 8(35):57991–58002Google Scholar
  9. Drannik A et al (2017) Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function. PLoS One 12(2):e0171668Google Scholar
  10. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, Mallozzi C, Jacobi C, Jennings LL, Clay I, Laurent G, Ma S, Brachat S, Lach-Trifilieff E, Shavlakadze T, Trendelenburg AU, Brack AS, Glass DJ (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22(1):164–174Google Scholar
  11. Franke AG, Gubbe C, Beier M, Duenker N (2006) Transforming growth factor-beta and bone morphogenetic proteins: cooperative players in chick and murine programmed retinal cell death. J Comp Neurol 495(3):263–278Google Scholar
  12. Gokoffski KK, Wu HH, Beites CL, Kim J, Kim EJ, Matzuk MM, Johnson JE, Lander AD, Calof AL (2011) Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate. Development 138(19):4131–4142Google Scholar
  13. Hammers DW, Merscham-Banda M, Hsiao JY, Engst S, Hartman JJ, Sweeney HL (2017) Supraphysiological levels of GDF11 induce striated muscle atrophy. EMBO Mol Med 9(4):531–544Google Scholar
  14. Hayashi T, Noshita N, Sugawara T, Chan PH (2003) Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 23(2):166–180Google Scholar
  15. Hayashi Y, Mikawa S, Masumoto K, Katou F, Sato K (2018a) GDF11 expression in the adult rat central nervous system. J Chem Neuroanat 89:21–36Google Scholar
  16. Hayashi Y, Mikawa S, Ogawa C, Masumoto K, Katou F, Sato K (2018b) Myostatin expression in the adult rat central nervous system. J Chem Neuroanat 94:125–138Google Scholar
  17. Hinken AC, Powers JM, Luo G, Holt JA, Billin AN, Russell AJ (2016) Lack of evidence for GDF11 as a rejuvenator of aged skeletal muscle satellite cells. Aging Cell 15:582–584Google Scholar
  18. Hocking JC, Hehr CL, Chang RY, Johnston J, McFarlane S (2008) TGFbeta ligands promote the initiation of retinal ganglion cell dendrites in vitro and in vivo. Mol Cell Neurosci 37(2):247–260Google Scholar
  19. Jaeger PA, Lucin KM, Britschgi M, Vardarajan B, Huang RP, Kirby ED, Abbey R, Boeve BF, Boxer AL, Farrer LA, Finch NC, Graff-Radford NR, Head E, Hofree M, Huang R, Johns H, Karydas A, Knopman DS, Loboda A, Masliah E, Narasimhan R, Petersen RC, Podtelezhnikov A, Pradhan S, Rademakers R, Sun CH, Younkin SG, Miller BL, Ideker T, Wyss-Coray T (2016) Network-driven plasma proteomics expose molecular changes in the Alzheimer’s brain. Mol Neurodegener 11:31Google Scholar
  20. Jones JE, Cadena SM, Gong C, Wang X, Chen Z, Wang SX, Vickers C, Chen H, Lach-Trifilieff E, Hadcock JR, Glass DJ (2018) Supraphysiologic administration of GDF11 induces Cachexia in part by upregulating GDF15. Cell Rep 22(12):3375Google Scholar
  21. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344(6184):630–634Google Scholar
  22. Kawauchi S, Kim J, Santos R, Wu HH, Lander AD, Calof AL (2009) Foxg1 promotes olfactory neurogenesis by antagonizing Gdf11. Development 136(9):1453–1464Google Scholar
  23. Khalil AM, Dotimas H, Kahn J, Lamerdin JE, Hayes DB, Gupta P, Franti M (2016) Differential binding activity of TGF-beta family proteins to select TGF-beta receptors. J Pharmacol Exp Ther 358(3):423–430Google Scholar
  24. Kim J et al (2005) GDF11 controls the timing of progenitor cell competence in developing retina. Science 308(5730):1927–1930Google Scholar
  25. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM (1994) Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 25(9):1794–1798Google Scholar
  26. Lee YS, Lee SJ (2013) Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proc Natl Acad Sci U S A 110(39):E3713–E3722Google Scholar
  27. Lee SJ, McPherron AC (2001) Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A 98(16):9306–9311Google Scholar
  28. Liu JP (2006) The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord. Development 133(15):2865–2874Google Scholar
  29. Lo PC, Frasch M (1999) Sequence and expression of myoglianin, a novel Drosophila gene of the TGF-beta superfamily. Mech Dev 86(1–2):171–175Google Scholar
  30. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall’Osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, Lee RT (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153(4):828–839Google Scholar
  31. Lu L, Bai X, Cao Y, Luo H, Yang X, Kang L, Shi MJ, Fan W, Zhao BQ (2018) Growth differentiation factor 11 promotes neurovascular recovery after stroke in mice. Front Cell Neurosci 12:205Google Scholar
  32. Ma J, Zhang L, He G, Tan X, Jin X, Li C (2016) Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats. J Neurol Sci 369:27–35Google Scholar
  33. Ma J, Zhang L, Niu T, Ai C, Jia G, Jin X, Wen L, Zhang K, Zhang Q, Li C (2018) Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion. Brain Res Bull 139:38–47Google Scholar
  34. McPherron AC, Lawler AM, Lee SJ (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387(6628):83–90Google Scholar
  35. McPherron AC, Lawler AM, Lee SJ (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet 22(3):260–264Google Scholar
  36. Nakashima M, Toyono T, Akamine A, Joyner A (1999) Expression of growth/differentiation factor 11, a new member of the BMP/TGFbeta superfamily during mouse embryogenesis. Mech Dev 80(2):185–189Google Scholar
  37. Oh SP et al (2002) Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev 16(21):2749–2754Google Scholar
  38. Osman AM, Porritt MJ, Nilsson M, Kuhn HG (2011) Long-term stimulation of neural progenitor cell migration after cortical ischemia in mice. Stroke 42(12):3559–3565Google Scholar
  39. Ozek C, Krolewski RC, Buchanan SM, Rubin LL (2018) Growth differentiation factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Sci Rep 8(1):17293Google Scholar
  40. Padyana AK et al (2016) Crystal structure of human GDF11. Acta crystallographica. Section F, Structural biology communications 72(Pt 3):160–164Google Scholar
  41. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425(4):479–494Google Scholar
  42. Philip B, Lu Z, Gao Y (2005) Regulation of GDF-8 signaling by the p38 MAPK. Cell Signal 17(3):365–375Google Scholar
  43. Rebbapragada A, Benchabane H, Wrana JL, Celeste AJ, Attisano L (2003) Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol Cell Biol 23(20):7230–7242Google Scholar
  44. Schafer MJ, Atkinson EJ, Vanderboom PM, Kotajarvi B, White TA, Moore MM, Bruce CJ, Greason KL, Suri RM, Khosla S, Miller JD, Bergen HR III, LeBrasseur NK (2016) Quantification of GDF11 and myostatin in human aging and cardiovascular disease. Cell Metab 23(6):1207–1215Google Scholar
  45. Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H, Krasney PA (2008) Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin. Endocrinology 149(9):4589–4595Google Scholar
  46. Semba RD, et al. (2018) Relationship of circulating growth/differentiation factors 8 and 11 and their antagonists as measured using liquid chromatography-tandem mass spectrometry with age and skeletal muscle strength in healthy adults. J Gerontol A Biol Sci Med SciGoogle Scholar
  47. Shi Y, Liu JP (2011) Gdf11 facilitates temporal progression of neurogenesis in the developing spinal cord. J Neurosci 31(3):883–893Google Scholar
  48. Smith SC, Zhang X, Zhang X, Gross P, Starosta T, Mohsin S, Franti M, Gupta P, Hayes D, Myzithras M, Kahn J, Tanner J, Weldon SM, Khalil A, Guo X, Sabri A, Chen X, MacDonnell S, Houser SR (2015) GDF11 does not rescue aging-related pathological hypertrophy. Circ Res 117(11):926–932Google Scholar
  49. Teng H, Zhang ZG, Wang L, Zhang RL, Zhang L, Morris D, Gregg SR, Wu Z, Jiang A, Lu M, Zlokovic BV, Chopp M (2008) Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke. J Cereb Blood Flow Metab 28(4):764–771Google Scholar
  50. Tsai PT et al (2006) A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 26(4):1269–1274Google Scholar
  51. Vanbekbergen N, Hendrickx M, Leyns L (2014) Growth differentiation factor 11 is an encephalic regionalizing factor in neural differentiated mouse embryonic stem cells. BMC Res Notes 7:766Google Scholar
  52. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90–94Google Scholar
  53. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20(6):659–663Google Scholar
  54. Walker RG, Czepnik M, Goebel EJ, McCoy JC, Vujic A, Cho M, Oh J, Aykul S, Walton KL, Schang G, Bernard DJ, Hinck AP, Harrison CA, Martinez-Hackert E, Wagers AJ, Lee RT, Thompson TB (2017) Structural basis for potency differences between GDF8 and GDF11. BMC Biol 15(1):19Google Scholar
  55. Walter J, Keiner S, Witte OW, Redecker C (2010) Differential stroke-induced proliferative response of distinct precursor cell subpopulations in the young and aged dentate gyrus. Neuroscience 169(3):1279–1286Google Scholar
  56. Wang F et al (2015) Splenocytes derived from young WT mice prevent AD progression in APPswe/PSENldE9 transgenic mice. Oncotarget 6(25):20851–20862Google Scholar
  57. Wang Z, Dou M, Liu F, Jiang P, Ye S, Ma L, Cao H, du X, Sun P, Su N, Lin F, Zhang R, Li C (2018) GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway. PeerJ 6:e5524Google Scholar
  58. Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, Calof AL (2003) Autoregulation of neurogenesis by GDF11. Neuron 37(2):197–207Google Scholar
  59. Yang R, Fu S, Zhao L, Zhen B, Ye L, Niu X, Li X, Zhang P, Bai J (2017) Quantitation of circulating GDF-11 and beta2-MG in aged patients with age-related impairment in cognitive function. Clin Sci (Lond) 131(15):1895–1904Google Scholar
  60. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947Google Scholar
  61. Zhang M, Jadavji NM, Yoo HS, Smith PD (2018a) Recombinant growth differentiation factor 11 influences short-term memory and enhances Sox2 expression in middle-aged mice. Behav Brain Res 341:45–49Google Scholar
  62. Zhang W, Guo Y, Li B, Zhang Q, Liu JH, Gu GJ, Wang JH, Bao RK, Chen YJ, Xu JR (2018b) GDF11 rejuvenates cerebrovascular structure and function in an animal model of Alzheimer’s disease. J Alzheimers Dis 62(2):807–819Google Scholar
  63. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132(4):645–660Google Scholar
  64. Zimmers TA, Jiang Y, Wang M, Liang TW, Rupert JE, Au ED, Marino FE, Couch ME, Koniaris LG (2017) Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Res Cardiol 112(4):48Google Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Robert and Arlene Kogod Center on AgingMayo ClinicRochesterUSA
  2. 2.Department of Physical Medicine and RehabilitationMayo ClinicRochesterUSA

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