The Immateriality of Circulating GDF11.
Recent portrayals of growth differentiation factor (GDF) 11 as an endocrine fountain of youth fail to consider the competitive influences of myostatin, a homologous protein with true endocrine action that binds the identical receptor, activin receptor IIb (ActRIIb) Subsequent studies have disproven the original premise that circulating levels of GDF11, but not those of myostatin, decline with age as the exact opposite seems to be true. These latter studies also seriously question the validity of data presented in the previous reports and indicate that myostatin circulates at levels 500x greater than those of GDF11; yet, both ligands share nearly identical affinities for ActRIIb. The compromised striated muscle function, neurogenesis, and vascular remodeling that occur with advanced age are, therefore, not caused by reduced circulating GDF11 as it could never outcompete myostatin for shared receptor binding sites Demonstrating that a single circulating factor reverses the effects of aging, particularly in the heart, muscle, and brain, is beyond transformative as it could revolutionize geriatric medicine and the treatment of sarcopenia, cancer cachexia, heart failure, and even stroke. Such a story was recently told. Unfortunately, however, it is founded on a misunderstanding of competitive ligand interactions and on questionable science. With 2 high profile publications in Science Katsimpardi et al1 and Sinha et al,2 and another in Cell Loffredo et al,3 the same Harvard group suggested that the age associated decline in circulating levels of GDF11 can induce cardiac hypertrophy, skeletal muscle dysfunction, and compromised neurogenesis.1 3 They also suggested that restoring GDF11 in aged circulation rejuvenates these tissues and induces vascular remodeling. The cornerstone of these conclusions is their reported observation that circulating GDF11, but not myostatin (also known as GDF8) declines with age. This is an extremely important distinction because both ligands bind the identical receptor, ActRIIb,
Circulation research