Circulating Growth Differentiation Factor 11/8 Levels Decline With Age.
BACKGROUND
Growth differentiation factor 11 (GDF11) and GDF8 are members of the transforming growth factor-β superfamily sharing 89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al reported that GDF11/8 levels increase with age in mouse serum.


OBJECTIVE
Here, we clarify the direction of change of circulating GDF11/8 levels with age and investigate the effects of GDF11 administration on the murine heart.


RESULTS
We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses, and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al, is attributable to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2-month-old) and old (22-month-old) mice in a dose-dependent manner after only 9 days.


CONCLUSIONS
Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Tommaso
T
Poggioli
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Ana
A
Vujic
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Peiguo
P
Yang
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Claudio
C
Macias-Trevino
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Aysu
A
Uygur
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Francesco S
FS
Loffredo
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
James R
JR
Pancoast
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Miook
M
Cho
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Jill
J
Goldstein
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Rachel M
RM
Tandias
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Emilia
E
Gonzalez
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Ryan G
RG
Walker
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Thomas B
TB
Thompson
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Amy J
AJ
Wagers
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.).
Yick W
YW
Fong
From the Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., M.C., J.G., R.M.T., E.G., A.J.W., Y.W.F., R.T.L.); Brigham Regenerative Medicine Center and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (T.P., A.V., P.Y., C.M.-T., A.U., F.S.L., J.R.P., R.M.T., E.G., Y.W.F., R.T.L.); Department of Molecular Genetics, College of Medicine, University of Cincinnati, OH (R.G.W., T.B.T.); and Howard Hughes Medical Institute, Section on Developmental and Stem Cell Biology, Joslin Diabetes Center, Boston, MA (M.C., J.G., A.J.W.). RLee@bwh.harvard.edu.
Richard T
RT
Lee
D000375:Aging / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000097:blood*; D055412:Growth Differentiation Factors / Q000097:blood*; D006736:Horses; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055435:Myostatin / Q000097:blood*; D051381:Rats; D012756:Sheep
D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; C525912:Mstn protein, mouse; D055435:Myostatin
Gdf11 protein, mouse; Mstn protein, mouse; aging; intercellular signaling peptides and proteins; transforming growth factor-β