title: Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.
abstract: The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
authors.affiliation: Harvard Stem Cell Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Loffredo
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Steinhauser
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jay
authors.forename: Joseph
authors.initials: J
authors.lastname: Gannon
authors.forename: James R
authors.initials: JR
authors.lastname: Pancoast
authors.forename: Pratyusha
authors.initials: P
authors.lastname: Yalamanchi
authors.forename: Manisha
authors.initials: M
authors.lastname: Sinha
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Osso
authors.forename: Danika
authors.initials: D
authors.lastname: Khong
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shadrach
authors.forename: Christine M
authors.initials: CM
authors.lastname: Miller
authors.forename: Britta S
authors.initials: BS
authors.lastname: Singer
authors.forename: Alex
authors.initials: A
authors.lastname: Stewart
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Hartigan
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Thomas
authors.initials: T
authors.lastname: Serwold
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000375:Aging; D000818:Animals; D001794:Blood Pressure; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055412:Growth Differentiation Factors / Q000378:metabolism*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010227:Parabiosis
chemical_list: D019485:Bone Morphogenetic Proteins; D051858:Forkhead Transcription Factors; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors