HHS Public Access Author manuscript Author Manuscript
Circ Res. Author manuscript; available in PMC 2016 November 06. Published in final edited form as: Circ Res. 2015 November 6; 117(11): 906–908. doi:10.1161/CIRCRESAHA.115.307645.
The Elusive Philosopher's Stone in Young Blood Haipeng Sun1,2 and Yibin Wang1,2 1Key
Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
2Departments
of Anesthesiology, Medicine and Physiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
Author Manuscript
Keywords Ageing; hypertrophy; GDF11; rejuvenation According to legend, soon after the first Chinese Qin Emperor united China around 250 BC, he sent out a troop of young men and women to search for the elixir of life in the eastern seas to extend his life forever. With great expectation and fanfare, the searching party departed but never returned. However, our quests for the elusive life-renewing Philosopher's Stone have never ceased either in Harry Potter's wizard world or in our biomedical research, and a sighting of the magical rejuvenating power continues to generate excitement and understandably high expectations.
Author Manuscript Author Manuscript
In 2005, a landmark study by Conboy et al first demonstrated the rejuvenating power of the blood of young animals using a heterochronic parabiosis approach where the circulation of a young and an old mouse was surgically joined together1. This finding set off a race to find the putative systemic circulating factor(s) that can reverse ageing. Since 2013, in a series of reports, researchers including Harvard scientists Amy Wagers and Richard Lee found that blood from young mice could reverse ageing-related pathological features in muscle and brain following a heterochronic parabiosis procedure 2, 3, 4. In particular, circulating growth differentiation factor 11 (GDF11) was identified as the serum factor responsible for the rejuvenating power in the young blood 23, 4. These reports generated a wave of commentaries from leading scientific journals and sensational reports from mainstream news outlets, relating these observations to the discovery of the mythic Elixir of Life given the apparent therapeutic implications for ageing related illnesses 5-10. GDF11 is a member of the transforming growth factor super-family, originally identified as a homologous gene of another well-known muscle-derived hormone, myostatin11. Early genetic studies in mice established that GDF11 is essential for post-natal survival and regulates anterior to posterior patterning of the axial skeleton11, 12, as well as the temporal
Correspondence to: Yibin Wang, PhD., 650 Charles E. Young Drive, Room CHS 569, Los Angeles, CA 90095, Tel: (310) 206-5197, [email protected]. Disclosures stating any financial, personal or professional relationships with other people or organizations that could reasonably be perceived as conflicts of interest or as potentially influencing or biasing this work: None.
Sun and Wang
Page 2
Author Manuscript Author Manuscript
differentiation of retinal ganglion cells 13. It is now known that GDF11 has widespread expression and function in multiple systems 14, 15. Two key pieces of data led to its identification as the humoral factor in young blood responsible for the rejuvenating effect on the paired older mice following the parabiosis procedure. First, GDF11 protein levels in plasma and mRNA levels in spleen were found to be lower in the old mice (2 years) relative to the young mice (2 months) 2. More directly, restoring serum level of GDF11 with intravenous injection of a recombinant form of GDF11 protein can significantly reverse agerelated cardiac hypertrophy and improve muscle and brain function2-4 . It is worth noting that GDF11 is not a panacea for all forms of human diseases. The original Cell report clearly indicated that GDF11 treatment had no impact on pressure-overload induced pathological hypertrophy in the heart2, highlighting the specific anti-ageing effect of GDF11. However, a recent study published in Cell Metabolism led by Novartis scientist David Glass raised significant questions regarding these two key conclusions with countering evidences16. First, they found that the proteomic and immunoblotting methods used by Loffredo et al in the Cell report actually not only detected GDF11 but also cross-reacted significantly with its homologous protein myostatin due to 90% sequence identity. In fact, the circulating GDF11, when measured using a new and more specific anti-GDF11 immunoassay, could not be detected in the plasma from either old or young mice but showed a trend toward higher levels in aged rats or humans16. Furthermore, treatment with GDF11 in vitro or injecting recombinant GDF11 in vivo inhibited myoblast differentiation and skeletal muscle regeneration, associated with very similar signaling and molecular signatures as treatment with myostatin16. Based on these observations, the Novartis group proposed that inhibiting GDF11, rather than enhancing its activity, is actually a potential strategy to promote skeletal muscle regeneration.
Author Manuscript Author Manuscript
In this current issue of Circulation Research, researchers led by Steve Houser from Temple University also report a largely negative observation of the effect of GDF11 on age-related cardiac hypertrophy 17. Similar to the observations made by the Glass lab, Smith et al found that the anti-GDF-11 antibody from Abcam used in the initial Cell report can cross-react with both GDF11 and myostatin. While another GDF11 antibody from R&D Systems appears to be more specific for GDF11, the detection sensitivity is too low to measure serum level GDF11 in mice from either young or old groups17. Therefore, the premise of reduced circulating GDF11 as an underlying contributor to the ageing process in older animal could not be validated in mice. Furthermore, when circulating GDF11 was elevated by daily injections of a recombinant form of GDF11 for 4 weeks, no significant impact could be detected in the aged mouse hearts in terms of weight, myocyte size, contractile function, and pathological genes induction 17. These two new studies add to another recent report 18 arguing against the validity of the initial claim that GDF11 is a circulating factor in young blood responsible for its effect to reverse age-related pathological changes in heart and muscle 19-21. These seemingly contradictory results highlight the need to address some of the key questions raised regarding the GDF11 hypothesis. Is GDF11 a specific anti-ageing circulating factor, and if so, how? From earlier genetic analysis, GDF11 and its close homologue myostatin function through a common receptor, activin receptor IIB (ActRIIB),
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
Page 3
Author Manuscript
and have redundant but not entirely overlapping functions in vivo 22. Indeed, a report by Egerman et al showed that GDF11 and myostatin had a nearly identical downstream signaling pattern and gene expression profile in cultured human skeletal muscle-derived myoblasts16. However, there is still a gap in our knowledge about the downstream molecular events specific for GDF11-mediated effects in either cells or intact animals. This concern is compounded by the lack of high-quality antibodies with sufficient specificity and sensitivity to accurately measure GDF11 levels across different animal models and laboratories. One potential approach is to rely on more definitive genetic evidence to prove or disprove the functional role of GDF11 in the ageing process. For example, the impact of genetic inactivation of GDF11 on ageing should be carefully examined in heterozygous GDF11 +/ null mice, or in tissue specific knockout models.
Author Manuscript
Is GDF11 sufficient to reverse the ageing process in heart, muscle, and brain? This was first demonstrated by intravenous injection for 4 weeks of a recombinant form of GDF11 protein in aged animals 2-4. However, there is no uniform quality control or quantitative comparison for the potency of the GDF11 recombinant proteins used in different studies from different laboratories. This issue is of particular importance as GDF11, like myostatin and other TGFβ family members, is processed via proteolytic maturation into a biologically active dimer form. As indicated in the original report by Loffredo et al, the anti-ageing effect of GDF11 appears to be dose-dependent 2. For example, only the highest tested concentration of GDF11 was shown to be able to prevent cardiomyocyte hypertrophy in vitro, and elevated plasma GDF11 was only reliably achieved with the highest dose tested 2. Again, more definitive genetic evidence is needed where elevated circulating GDF11 levels can be accomplished through inducible transgenic approaches so that the long-term functional impact on heart, muscle and brain can be evaluated.
Author Manuscript
Finally, there are important and potentially significant differences in the study design between the current report and the original study in Cell. While the Harvard team procured the recombinant GDF11 protein from PeproTech,2 the Temple lab obtained theirs from R&D Systems.17 Again, without quantitative measurements for GDF11 specific activity other than common downstream events shared with myostatin, it is not clear if these two products have the same anti-ageing potency at the given doses in vivo. Moreover, the Harvard study tested the effect of GDF11 injection on 2 year old FEMALE mice 2, whereas the Temple study examined the same treatment in 2 year old MALEs 17. It is well accepted that the ageing process is gender-dependent and can be influenced by sex hormones even in the heterochronic parabiosis procedure 23. It is therefore very surprising that neither study tested GDF11 treatment in both sexes.
Author Manuscript
It is important to note that none of these controversies questions the remarkable effect of young blood on aged progenitor cell function as observed in the original heterochronic parabiosis experiment a decade ago1. Clearly, the quest is still on to find the elusive Philosopher's Stone hidden in the young blood to retard tissue ageing via improved regeneration and repair 19. Until more studies are performed with more definitive evidence, the controversy and debate about GDF11 in ageing is likely to continue.
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
Page 4
Author Manuscript
Acknowledgments Sources of Funding: This work is in part supported by Ministry of Science and Technology of China Grant 2012BAI02B05; National Institute of Health grants HL108186, HL103205, HL098954, HL080111 (to Y. Wang). American Heart Association (AHA) Western States Affiliate Post-doctoral Fellowship Award and AHA Science Development Grant (to H. Sun).
References
Author Manuscript Author Manuscript Author Manuscript
1. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005; 433:760–764. [PubMed: 15716955] 2. 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. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013; 153:828–839. [PubMed: 23663781] 3. Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ. Restoring systemic gdf11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014; 344:649–652. [PubMed: 24797481] 4. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014; 344:630–634. [PubMed: 24797482] 5. 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, WyssCoray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014; 20:659–663. [PubMed: 24793238] 6. Laviano A. Young blood. N Engl J Med. 2014; 371:573–575. [PubMed: 25099584] 7. Hall SS. Young blood. Science. 2014; 345:1234–1237. [PubMed: 25214587] 8. Bitto A, Kaeberlein M. Rejuvenation: It's in our blood. Cell Metab. 2014; 20:2–4. [PubMed: 24988454] 9. Andersen RE, Lim DA. An ingredient for the elixir of youth. Cell Res. 2014; 24:1381–1382. [PubMed: 25112712] 10. Leinwand LA, Harrison BC. Young at heart. Cell. 2013; 153:743–745. [PubMed: 23663775] 11. McPherron AC, Lawler AM, Lee SJ. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet. 1999; 22:260–264. [PubMed: 10391213] 12. Oh SP, Yeo CY, Lee Y, Schrewe H, Whitman M, Li E. Activin type iia and iib receptors mediate gdf11 signaling in axial vertebral patterning. Genes Dev. 2002; 16:2749–2754. [PubMed: 12414726] 13. Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL. Gdf11 controls the timing of progenitor cell competence in developing retina. Science. 2005; 308:1927–1930. [PubMed: 15976303] 14. McPherron AC. Metabolic functions of myostatin and gdf11. Immunol Endocr Metab Agents Med Chem. 2010; 10:217–231. [PubMed: 21197386] 15. Esteve P, Bovolenta P. Secreted inducers in vertebrate eye development: More functions for old morphogens. Curr Opin Neurobiol. 2006; 16:13–19. [PubMed: 16413771] 16. 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. Gdf11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 2015; 22:164–174. [PubMed: 26001423] 17. 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. Gdf11 does not rescue aging-related pathological hypertrophy. Circ Res. 2015; 117:xxx–xxx. in this issue.
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
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18. Rodgers BD, Eldridge JA. Reduced circulating gdf11 is unlikely responsible for age-dependent changes in mouse heart, muscle, and brain. Endocrinology. 2015 en20151628. 19. Scudellari M. Ageing research: Blood to blood. Nature. 2015; 517:426–429. [PubMed: 25612035] 20. Kaiser J. Regenerative medicine. ‘Rejuvenating’ protein doubted. Science. 2015; 348:849. [PubMed: 25999487] 21. Brun CE, Rudnicki MA. Gdf11 and the mythical fountain of youth. Cell Metab. 2015; 22:54–56. [PubMed: 26003784] 22. McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol. 2009; 9:24. [PubMed: 19298661] 23. Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 2014; 357:815–821. [PubMed: 24859218]
Author Manuscript Author Manuscript Author Manuscript Circ Res. Author manuscript; available in PMC 2016 November 06.
Circ Res. Author manuscript; available in PMC 2016 November 06. Published in final edited form as: Circ Res. 2015 November 6; 117(11): 906–908. doi:10.1161/CIRCRESAHA.115.307645.
The Elusive Philosopher's Stone in Young Blood Haipeng Sun1,2 and Yibin Wang1,2 1Key
Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
2Departments
of Anesthesiology, Medicine and Physiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
Author Manuscript
Keywords Ageing; hypertrophy; GDF11; rejuvenation According to legend, soon after the first Chinese Qin Emperor united China around 250 BC, he sent out a troop of young men and women to search for the elixir of life in the eastern seas to extend his life forever. With great expectation and fanfare, the searching party departed but never returned. However, our quests for the elusive life-renewing Philosopher's Stone have never ceased either in Harry Potter's wizard world or in our biomedical research, and a sighting of the magical rejuvenating power continues to generate excitement and understandably high expectations.
Author Manuscript Author Manuscript
In 2005, a landmark study by Conboy et al first demonstrated the rejuvenating power of the blood of young animals using a heterochronic parabiosis approach where the circulation of a young and an old mouse was surgically joined together1. This finding set off a race to find the putative systemic circulating factor(s) that can reverse ageing. Since 2013, in a series of reports, researchers including Harvard scientists Amy Wagers and Richard Lee found that blood from young mice could reverse ageing-related pathological features in muscle and brain following a heterochronic parabiosis procedure 2, 3, 4. In particular, circulating growth differentiation factor 11 (GDF11) was identified as the serum factor responsible for the rejuvenating power in the young blood 23, 4. These reports generated a wave of commentaries from leading scientific journals and sensational reports from mainstream news outlets, relating these observations to the discovery of the mythic Elixir of Life given the apparent therapeutic implications for ageing related illnesses 5-10. GDF11 is a member of the transforming growth factor super-family, originally identified as a homologous gene of another well-known muscle-derived hormone, myostatin11. Early genetic studies in mice established that GDF11 is essential for post-natal survival and regulates anterior to posterior patterning of the axial skeleton11, 12, as well as the temporal
Correspondence to: Yibin Wang, PhD., 650 Charles E. Young Drive, Room CHS 569, Los Angeles, CA 90095, Tel: (310) 206-5197, [email protected]. Disclosures stating any financial, personal or professional relationships with other people or organizations that could reasonably be perceived as conflicts of interest or as potentially influencing or biasing this work: None.
Sun and Wang
Page 2
Author Manuscript Author Manuscript
differentiation of retinal ganglion cells 13. It is now known that GDF11 has widespread expression and function in multiple systems 14, 15. Two key pieces of data led to its identification as the humoral factor in young blood responsible for the rejuvenating effect on the paired older mice following the parabiosis procedure. First, GDF11 protein levels in plasma and mRNA levels in spleen were found to be lower in the old mice (2 years) relative to the young mice (2 months) 2. More directly, restoring serum level of GDF11 with intravenous injection of a recombinant form of GDF11 protein can significantly reverse agerelated cardiac hypertrophy and improve muscle and brain function2-4 . It is worth noting that GDF11 is not a panacea for all forms of human diseases. The original Cell report clearly indicated that GDF11 treatment had no impact on pressure-overload induced pathological hypertrophy in the heart2, highlighting the specific anti-ageing effect of GDF11. However, a recent study published in Cell Metabolism led by Novartis scientist David Glass raised significant questions regarding these two key conclusions with countering evidences16. First, they found that the proteomic and immunoblotting methods used by Loffredo et al in the Cell report actually not only detected GDF11 but also cross-reacted significantly with its homologous protein myostatin due to 90% sequence identity. In fact, the circulating GDF11, when measured using a new and more specific anti-GDF11 immunoassay, could not be detected in the plasma from either old or young mice but showed a trend toward higher levels in aged rats or humans16. Furthermore, treatment with GDF11 in vitro or injecting recombinant GDF11 in vivo inhibited myoblast differentiation and skeletal muscle regeneration, associated with very similar signaling and molecular signatures as treatment with myostatin16. Based on these observations, the Novartis group proposed that inhibiting GDF11, rather than enhancing its activity, is actually a potential strategy to promote skeletal muscle regeneration.
Author Manuscript Author Manuscript
In this current issue of Circulation Research, researchers led by Steve Houser from Temple University also report a largely negative observation of the effect of GDF11 on age-related cardiac hypertrophy 17. Similar to the observations made by the Glass lab, Smith et al found that the anti-GDF-11 antibody from Abcam used in the initial Cell report can cross-react with both GDF11 and myostatin. While another GDF11 antibody from R&D Systems appears to be more specific for GDF11, the detection sensitivity is too low to measure serum level GDF11 in mice from either young or old groups17. Therefore, the premise of reduced circulating GDF11 as an underlying contributor to the ageing process in older animal could not be validated in mice. Furthermore, when circulating GDF11 was elevated by daily injections of a recombinant form of GDF11 for 4 weeks, no significant impact could be detected in the aged mouse hearts in terms of weight, myocyte size, contractile function, and pathological genes induction 17. These two new studies add to another recent report 18 arguing against the validity of the initial claim that GDF11 is a circulating factor in young blood responsible for its effect to reverse age-related pathological changes in heart and muscle 19-21. These seemingly contradictory results highlight the need to address some of the key questions raised regarding the GDF11 hypothesis. Is GDF11 a specific anti-ageing circulating factor, and if so, how? From earlier genetic analysis, GDF11 and its close homologue myostatin function through a common receptor, activin receptor IIB (ActRIIB),
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
Page 3
Author Manuscript
and have redundant but not entirely overlapping functions in vivo 22. Indeed, a report by Egerman et al showed that GDF11 and myostatin had a nearly identical downstream signaling pattern and gene expression profile in cultured human skeletal muscle-derived myoblasts16. However, there is still a gap in our knowledge about the downstream molecular events specific for GDF11-mediated effects in either cells or intact animals. This concern is compounded by the lack of high-quality antibodies with sufficient specificity and sensitivity to accurately measure GDF11 levels across different animal models and laboratories. One potential approach is to rely on more definitive genetic evidence to prove or disprove the functional role of GDF11 in the ageing process. For example, the impact of genetic inactivation of GDF11 on ageing should be carefully examined in heterozygous GDF11 +/ null mice, or in tissue specific knockout models.
Author Manuscript
Is GDF11 sufficient to reverse the ageing process in heart, muscle, and brain? This was first demonstrated by intravenous injection for 4 weeks of a recombinant form of GDF11 protein in aged animals 2-4. However, there is no uniform quality control or quantitative comparison for the potency of the GDF11 recombinant proteins used in different studies from different laboratories. This issue is of particular importance as GDF11, like myostatin and other TGFβ family members, is processed via proteolytic maturation into a biologically active dimer form. As indicated in the original report by Loffredo et al, the anti-ageing effect of GDF11 appears to be dose-dependent 2. For example, only the highest tested concentration of GDF11 was shown to be able to prevent cardiomyocyte hypertrophy in vitro, and elevated plasma GDF11 was only reliably achieved with the highest dose tested 2. Again, more definitive genetic evidence is needed where elevated circulating GDF11 levels can be accomplished through inducible transgenic approaches so that the long-term functional impact on heart, muscle and brain can be evaluated.
Author Manuscript
Finally, there are important and potentially significant differences in the study design between the current report and the original study in Cell. While the Harvard team procured the recombinant GDF11 protein from PeproTech,2 the Temple lab obtained theirs from R&D Systems.17 Again, without quantitative measurements for GDF11 specific activity other than common downstream events shared with myostatin, it is not clear if these two products have the same anti-ageing potency at the given doses in vivo. Moreover, the Harvard study tested the effect of GDF11 injection on 2 year old FEMALE mice 2, whereas the Temple study examined the same treatment in 2 year old MALEs 17. It is well accepted that the ageing process is gender-dependent and can be influenced by sex hormones even in the heterochronic parabiosis procedure 23. It is therefore very surprising that neither study tested GDF11 treatment in both sexes.
Author Manuscript
It is important to note that none of these controversies questions the remarkable effect of young blood on aged progenitor cell function as observed in the original heterochronic parabiosis experiment a decade ago1. Clearly, the quest is still on to find the elusive Philosopher's Stone hidden in the young blood to retard tissue ageing via improved regeneration and repair 19. Until more studies are performed with more definitive evidence, the controversy and debate about GDF11 in ageing is likely to continue.
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
Page 4
Author Manuscript
Acknowledgments Sources of Funding: This work is in part supported by Ministry of Science and Technology of China Grant 2012BAI02B05; National Institute of Health grants HL108186, HL103205, HL098954, HL080111 (to Y. Wang). American Heart Association (AHA) Western States Affiliate Post-doctoral Fellowship Award and AHA Science Development Grant (to H. Sun).
References
Author Manuscript Author Manuscript Author Manuscript
1. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005; 433:760–764. [PubMed: 15716955] 2. 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. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013; 153:828–839. [PubMed: 23663781] 3. Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ. Restoring systemic gdf11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014; 344:649–652. [PubMed: 24797481] 4. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014; 344:630–634. [PubMed: 24797482] 5. 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, WyssCoray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014; 20:659–663. [PubMed: 24793238] 6. Laviano A. Young blood. N Engl J Med. 2014; 371:573–575. [PubMed: 25099584] 7. Hall SS. Young blood. Science. 2014; 345:1234–1237. [PubMed: 25214587] 8. Bitto A, Kaeberlein M. Rejuvenation: It's in our blood. Cell Metab. 2014; 20:2–4. [PubMed: 24988454] 9. Andersen RE, Lim DA. An ingredient for the elixir of youth. Cell Res. 2014; 24:1381–1382. [PubMed: 25112712] 10. Leinwand LA, Harrison BC. Young at heart. Cell. 2013; 153:743–745. [PubMed: 23663775] 11. McPherron AC, Lawler AM, Lee SJ. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nat Genet. 1999; 22:260–264. [PubMed: 10391213] 12. Oh SP, Yeo CY, Lee Y, Schrewe H, Whitman M, Li E. Activin type iia and iib receptors mediate gdf11 signaling in axial vertebral patterning. Genes Dev. 2002; 16:2749–2754. [PubMed: 12414726] 13. Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL. Gdf11 controls the timing of progenitor cell competence in developing retina. Science. 2005; 308:1927–1930. [PubMed: 15976303] 14. McPherron AC. Metabolic functions of myostatin and gdf11. Immunol Endocr Metab Agents Med Chem. 2010; 10:217–231. [PubMed: 21197386] 15. Esteve P, Bovolenta P. Secreted inducers in vertebrate eye development: More functions for old morphogens. Curr Opin Neurobiol. 2006; 16:13–19. [PubMed: 16413771] 16. 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. Gdf11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 2015; 22:164–174. [PubMed: 26001423] 17. 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. Gdf11 does not rescue aging-related pathological hypertrophy. Circ Res. 2015; 117:xxx–xxx. in this issue.
Circ Res. Author manuscript; available in PMC 2016 November 06.
Sun and Wang
Page 5
Author Manuscript
18. Rodgers BD, Eldridge JA. Reduced circulating gdf11 is unlikely responsible for age-dependent changes in mouse heart, muscle, and brain. Endocrinology. 2015 en20151628. 19. Scudellari M. Ageing research: Blood to blood. Nature. 2015; 517:426–429. [PubMed: 25612035] 20. Kaiser J. Regenerative medicine. ‘Rejuvenating’ protein doubted. Science. 2015; 348:849. [PubMed: 25999487] 21. Brun CE, Rudnicki MA. Gdf11 and the mythical fountain of youth. Cell Metab. 2015; 22:54–56. [PubMed: 26003784] 22. McPherron AC, Huynh TV, Lee SJ. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev Biol. 2009; 9:24. [PubMed: 19298661] 23. Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 2014; 357:815–821. [PubMed: 24859218]
Author Manuscript Author Manuscript Author Manuscript Circ Res. Author manuscript; available in PMC 2016 November 06.
