, Volume 20, Issue 2, pp 225–239 | Cite as

Late-onset administration of GDF11 extends life span and delays development of age-related markers in the annual fish Nothobranchius guentheri

  • Yang Zhou
  • Shousheng Ni
  • Lili Song
  • Xia Wang
  • Yu Zhang
  • Shicui ZhangEmail author
Research Article


Current studies have generated disputes on the age-related change in the concentration of growth differentiation factor 11 (GDF11) and its role in the genesis of rejuvenation conditions. In this study we showed for the first time that both GDF11 gene expression and its protein abundance decreased with age in the fish Nothobranchius guentheri. We also showed that rGDF11 fed was indeed absorbed by the fish. Importantly, we demonstrated that dietary intake of recombinant GDF11 had little influences on the body weight and length of aging N. guentheri, but it delayed the development of age-related biomarkers and extended both the median and maximum life span of the fish. Our results clearly demonstrate that piscine GDF11 has rejuvenation and anti-aging capacity, the first data as such in non-mammalian vertebrates.


Annual fish Nothobranchius Aging GDF11 Lifespan 



This work was supported in part by the Grants of the Natural Science Foundation of China (31501856; 31772442) and the Blue Life Breakthrough Program (MS2017NO02) of the Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, China.

Compliance with ethical standards

Conflict of interest

No competing financial interests exist.

Supplementary material

10522_2018_9789_MOESM1_ESM.pdf (154 kb)
Supplementary material 1 (PDF 153 kb)
10522_2018_9789_MOESM2_ESM.pdf (911 kb)
Supplementary material 2 (PDF 911 kb)
10522_2018_9789_MOESM3_ESM.pdf (290 kb)
Supplementary material 3 (PDF 290 kb)


  1. Andersen RE, Lim DA (2014) An ingredient for the elixir of youth. Cell Res 24:1381–1382. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Biga PR, Roberts SB, Iliev DB, McCauley LAR, Moon JS, Collodi P, Goetz FW (2005) The isolation, characterization, and expression of a novel GDF11 gene and a second myostatin form in zebrafish, Danio rerio. Comp Biochem Physiol Part B 141:218–230. CrossRefGoogle Scholar
  3. Brack AS (2013) Ageing of the heart reversed by youthful systemic factors! EMBO J 32:2189–2190. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Burks TN, Cohn RD (2011) Role of TGF-beta signaling in inherited and acquired myopathies. Skelet Muscle 1:19. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Dance A (2016) Live fast, die young. Nature 535:453–455. CrossRefPubMedGoogle Scholar
  6. Egerman MA et al (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22:164–174. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Funkenstein B, Olekh E (2010) Growth/differentiation factor-11: an evolutionary conserved growth factor in vertebrates. Dev Genes Evol 220:129–137. CrossRefPubMedGoogle Scholar
  8. Gamer LW, Wolfman NM, Celeste AJ, Hattersley G, Hewick R, Rosen V (1999) A novel BMP expressed in developing mouse limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos. Dev Biol 208:222–232. CrossRefPubMedGoogle Scholar
  9. Genade T, Benedetti M, Terzibasi E, Roncaglia P, Valenzano DR, Cattaneo A, Cellerino A (2005) Annual fishes of the genus Nothobranchius as a model system for aging research. Aging Cell 4:223–233. CrossRefPubMedGoogle Scholar
  10. Hall SS (2014) Young blood. Science 345:1234–1237. CrossRefPubMedGoogle Scholar
  11. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300CrossRefPubMedGoogle Scholar
  12. Hsu C-Y, Chiu Y-C, Hsu W-L, Chan Y-P (2008) Age-related markers assayed at different developmental stages of the annual fish Nothobranchius rachovii. J Gerontol Ser A Biol Sci Med Sci 63:1267–1276CrossRefGoogle Scholar
  13. Kaiser J (2014) Aging. ‘Rejuvenation factor’ in blood turns back the clock in old mice. Science 344:570–571. CrossRefPubMedGoogle Scholar
  14. Kaiser J (2015) Regenerative medicine. ‘Rejuvenating’ protein doubted. Science 348:849. CrossRefPubMedGoogle Scholar
  15. Katsimpardi L et al (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kishi S, Uchiyama J, Baughman AM, Goto T, Lin MC, Tsai SB (2003) The zebrafish as a vertebrate model of functional aging and very gradual senescence. Exp Gerontol 38:777–786. CrossRefPubMedGoogle Scholar
  17. Lim Y, Zhong JH, Zhou XF (2015) Development of mature BDNF-specific sandwich ELISA. J Neurochem 134:75–85. CrossRefPubMedGoogle Scholar
  18. Liu M, Zhang S (2009) A kringle-containing protease with plasminogen-like activity in the basal chordate Branchiostoma belcheri. Biosci Rep 29:385–395. CrossRefPubMedGoogle Scholar
  19. Liu T et al (2015) Resveratrol attenuates oxidative stress and extends life span in the annual fish Nothobranchius guentheri. Rejuvenation Res 18:225–233. CrossRefPubMedGoogle Scholar
  20. Liu S et al (2018) Resveratrol reduces senescence-associated secretory phenotype by SIRT1/NF-κB pathway in gut of the annual fish Nothobranchius guentheri. Fish Shellfish Immunol 80:473–479. CrossRefPubMedGoogle Scholar
  21. Loffredo FS et al (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–839. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Lu CY, Hsu CY (2015) Ambient temperature reduction extends lifespan via activating cellular degradation activity in an annual fish (Nothobranchius rachovii). Age (Dordr) 37:33. CrossRefGoogle Scholar
  23. Markofsky JPA (1972) Age at sexual maturity and its relationship to longevity in the male annual cyprinodont fish, Nothobranchius guenther. Exp Gerontol 7:131–135CrossRefPubMedGoogle Scholar
  24. Markofsky J, Perlmutter A (1973) Growth differences in subgroups of varying longevities in a laboratory population of the male annual cyprinodont fish, Nothobranchius guentheri (Peters). Exp Gerontol 8:65–73CrossRefPubMedGoogle Scholar
  25. McPherron AC (2010) Metabolic functions of myostatin and Gdf11. Immunol Endocr Metab Agents Med Chem 10:217–231. CrossRefPubMedPubMedCentralGoogle Scholar
  26. McPherron AC, Lawler AM, Lee SJ (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet 22:260–264. CrossRefPubMedGoogle Scholar
  27. 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 80:185–189CrossRefPubMedGoogle Scholar
  28. Okutan H, Ozcelik N, Yilmaz HR, Uz E (2005) Effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart. Clin Biochem 38:191–196CrossRefPubMedGoogle Scholar
  29. Pardali E, Ten Dijke P (2012) TGFbeta signaling and cardiovascular diseases. Int J Biol Sci 8:195–213. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Poggioli T et al (2016) Circulating growth differentiation factor 11/8 levels decline with age. Circ Res 118:29–37. CrossRefPubMedGoogle Scholar
  31. Rodgers BD, Eldridge JA (2015) Reduced circulating GDF11 is unlikely responsible for age-dependent changes in mouse heart, muscle, and brain. Endocrinology 156:3885–3888. CrossRefPubMedGoogle Scholar
  32. Schafer MJ et al (2016) Quantification of GDF11 and myostatin in human aging and cardiovascular disease. Cell Metab 23:1207–1215. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Sinha M et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649–652. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Smith SC et al (2015) GDF11 does not rescue aging-related pathological hypertrophy. Circ Res 117:926–932. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Sohal RS, Agarwal S, Dubey A, Orr WC (1993) Protein oxidative damage is associated with life expectancy of houseflies. Proc Natl Acad Sci USA 90:7255–7259. CrossRefPubMedGoogle Scholar
  36. Spitz DR, Oberley LW (1989) An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal Biochem 179:8–18CrossRefPubMedGoogle Scholar
  37. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Terzibasi E, Lefrancois C, Domenici P, Hartmann N, Graf M, Cellerino A (2009) Effects of dietary restriction on mortality and age-related phenotypes in the short-lived fish Nothobranchius furzeri. Aging Cell 8:88–99. CrossRefPubMedGoogle Scholar
  39. Valenzano DR, Cellerino A (2006) Resveratrol and the pharmacology of aging: a new vertebrate model to validate an old molecule. Cell Cycle 5:1027–1032. CrossRefPubMedGoogle Scholar
  40. Valenzano DR et al (2015) The African Turquoise killifish genome provides insights into evolution and genetic architecture of lifespan. Cell 163:1539–1554. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Wang G, Zhang S, Wang Z (2009) Responses of alternative complement expression to challenge with different combinations of Vibrio anguillarum, Escherichia coli and Staphylococcus aureus: evidence for specific immune priming in amphioxus Branchiostoma belcheri. Fish Shellfish Immunol 26:33–39. CrossRefPubMedGoogle Scholar
  42. Wang X, Chang Q, Wang Y, Su F, Zhang S (2014) Late-onset temperature reduction can retard the aging process in aged fish via a combined action of an anti-oxidant system and the insulin/insulin-like growth factor 1 signaling pathway. Rejuvenation Res 17:507–517. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wang X, Du X, Zhou Y, Wang S, Su F, Zhang S (2017) Intermittent food restriction initiated late in life prolongs lifespan and retards the onset of age-related markers in the annual fish Nothobranchius guentheri. Biogerontology 18:383–396. CrossRefPubMedGoogle Scholar
  44. Wang X, Du X, Zhou Y, Wang S, Su F, Zhang S (2018) Time-dependent effects of late-onset dietary intake of salidroside on lifespan and age-related biomarkers of the annual fish Nothobranchius guentheri. Oncotarget 9:14882–14894. PubMedPubMedCentralGoogle Scholar
  45. Zhang YH et al (2016) GDF11/BMP11 activates both smad1/5/8 and smad2/3 signals but shows no significant effect on proliferation and migration of human umbilical vein endothelial cells. Oncotarget 7:12063–12074. PubMedPubMedCentralGoogle Scholar
  46. Zhou Y, Jiang Z, Harris EC, Reeves J, Chen X, Pazdro R (2016) Circulating concentrations of growth differentiation factor 11 are heritable and correlate with life span. J Gerontol A Biol Sci Med Sci 71:1560–1563. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Yang Zhou
    • 1
  • Shousheng Ni
    • 1
  • Lili Song
    • 1
  • Xia Wang
    • 3
  • Yu Zhang
    • 1
  • Shicui Zhang
    • 1
    • 2
    Email author
  1. 1.Institute of Evolution & Marine Biodiversity and Department of Marine BiologyOcean University of ChinaQingdaoChina
  2. 2.Laboratory for Marine Biology and BiotechnologyQingdao National Laboratory for Marine Science and TechnologyQingdaoChina
  3. 3.Shandong Provincial Key Laboratory of Biochemical EngineeringQingdao University of Science and TechnologyQingdaoChina

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