GDF11

Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a is_associated_with::protein that in humans is encoded by the GDF11 is_associated_with::gene.

This BMP group of proteins is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues. GDF11 is a myostatin-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of is_associated_with::myostatin, including stopping the progenitor is_associated_with::cell-cycle during G-phase. The similarities between GDF11 and myostatin imply a likelihood that the same regulatory mechanisms are used to control tissue size during both muscular and neural development. In 2014, GDF11 was described as an anti-aging factor in two publications that were chosen as Science's scientific breakthrough of the year. A 2015 publication re-assessed this hypothesis and concluded that GDF11 increases with age and has deleterious effects on skeletal muscle.

Effects on cell growth and differentiation
GDF11 belongs to the is_associated_with::transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of is_associated_with::Hox genes. It determines Hox gene expression domains and rostrocaudal identity in the caudal is_associated_with::spinal cord.

During mouse development, GDF11 expression begins in the tail bud and caudal is_associated_with::neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.

This is_associated_with::cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of is_associated_with::olfactory receptor neurons occurring in the is_associated_with::olfactory epithelium, and controls the competence of is_associated_with::progenitor cells to regulate numbers of retinal is_associated_with::ganglionic cells developing in the is_associated_with::retina. Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.

GDF11 can bind type I TGF-beta superfamily receptors is_associated_with::ACVR1B (ALK4), is_associated_with::TGFBR1 (ALK5) and is_associated_with::ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.

GDF11 is closely related to is_associated_with::myostatin, a negative regulator of muscle growth. Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis, the production of islet progenitor cells, the regulation of kidney organogenesis, pancreatic development, the rostro-caudal patterning in the development of spinal cords, and is a negative regulator of chondrogenesis.

Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by is_associated_with::WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains. WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.

Effect on cardiac and skeletal muscle aging
GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in is_associated_with::parabiosis procedures, causing youthful regeneration of is_associated_with::cardiomyocytes, a reduction in the is_associated_with::Brain natriuretic peptide (BNP) and in the is_associated_with::Atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of is_associated_with::SERCA-2, an enzyme necessary for relaxation during diastolic functions. GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent is_associated_with::hematopoietic stem cells and suppresses the phosphorylation of Forkhead (is_associated_with::FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes. In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of is_associated_with::skeletal muscle by rescuing the function of aged muscle is_associated_with::stem cells, claiming that GDF11 may be an anti-aging rejuvenation factor.

These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on is_associated_with::skeletal muscle regeneration, being a pro-aging factor, with very high levels in some aged individuals.