Restoration of Systemic Growth and Differentiation Factor‐11 (GDF11) Levels Reverses Age‐Associated Dysfunction in Skeletal Muscle

Recent studies involving heterochronic parabiosis indicate that impaired regeneration in aged animals is in part systemically controlled and reversible by exposure to a young circulation. While prior studies have identified a handful of systemic “aging” factors, discovery of the humoral “rejuvenating” factors that act on tissue stem cells to restore regenerative function has been relatively more elusive. Here, we demonstrate that the circulating hormone Growth and Differentiation Factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, using either heterochronic parabiosis or systemic delivery of recombinant protein, is sufficient to reverse functional impairments and restore genomic integrity in skeletal muscle stem cells (satellite cells). Augmentation of GDF11 levels further improved structural and functional features of resting skeletal muscle, resulting in increased strength and enhanced endurance exercise capacity. Taken together, these data reveal critical mechanisms in the systemic regulation of aging and identify a promising candidate therapeutic for the reversal of age-related skeletal muscle and stem cell dysfunction.