RESEARCH MONOGRAPH · KDC-MN-1346
GDF-11
TGF-beta superfamily growth differentiation factor
A growth differentiation factor in the TGF-beta superfamily originally implicated in parabiosis-mediated rejuvenation and subsequently a focus of contested replication studies in cardiac and skeletal muscle aging.
Abstract
GDF-11 (growth differentiation factor 11; bone morphogenetic protein 11, BMP-11; CAS 268544-12-9; mature peptide molecular weight approximately 12.5 kDa as a homodimer) is a member of the transforming growth factor beta (TGF-beta) superfamily, closely related to myostatin (GDF-8) with which it shares approximately 90 percent amino acid identity in the mature C-terminal domain. The compound came to prominence in 2013 when a heterochronic parabiosis study by Amy Wagers and Richard Lee at the Harvard Stem Cell Institute identified GDF-11 as a putative young-blood-borne rejuvenation factor that reversed age-related cardiac hypertrophy when administered to old mice. Subsequent studies extended the proposed rejuvenation activity to skeletal muscle and the central nervous system. The original GDF-11 papers triggered substantial follow-up research and substantial contested replication: independent groups (notably the Glass laboratory at Eli Lilly and the Wagers laboratory's own subsequent work) reported that the original immunoassays did not adequately distinguish GDF-11 from myostatin, that circulating GDF-11 levels do not in fact decline with age, and that recombinant GDF-11 administered to old mice produces muscle wasting at high doses (consistent with the myostatin-like activity expected from the structural homology) rather than rejuvenation. The contested literature has not produced consensus; some groups continue to report modest pro-cardiac and pro-cognitive effects of GDF-11 at carefully titrated doses, while others find no effect or harmful effects. Mechanism is canonical TGF-beta superfamily signaling through ActRIIA/B receptors and downstream SMAD2/3 transcription factor activation; GDF-11 and myostatin share the same receptor and signaling pathway, distinguishing them principally through tissue-specific expression patterns and post-translational propeptide regulation. The compound is research-grade with no regulatory approval and no active clinical development. Investigators studying GDF-11 should be aware of the contested replication literature and the importance of distinguishing GDF-11 from myostatin in immunoassays.
Mechanism of action
TGF-beta superfamily signaling through ActRIIA and ActRIIB receptors with downstream SMAD2/3 activation. Same receptor pathway as myostatin (GDF-8); high amino acid identity in the mature C-terminal domain.
Reported research dose ranges
Rodent research-grade dosing 0.1 to 1 mg/kg intraperitoneal daily, with the strong caveat that effects above 0.3 mg/kg trend toward myostatin-like muscle wasting in published independent replications.
References
- Loffredo FS, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013.
- Egerman MA, et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 2015.
- Smith SC, et al. GDF11 does not rescue aging-related pathological hypertrophy. Circ Res 2015.
- Hammers DW, et al. Supraphysiological levels of GDF11 induce striated muscle atrophy. EMBO Mol Med 2017.
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