GDF11

Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene.^[5] GDF11 is a member of the Transforming growth factor beta family.^[6]

GDF11
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5E4G
Identifiers
Aliases	GDF11, BMP-11, BMP11, growth differentiation factor 11, VHO
External IDs	OMIM: 603936 MGI: 1338027 HomoloGene: 21183 GeneCards: GDF11
Gene location (Human) Chr. Chromosome 12 (human)^[1] Band 12q13.2 Start 55,743,122 bp^[1] End 55,757,264 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10|10 D3 Start 128,718,164 bp^[2] End 128,727,587 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in retinal pigment epithelium internal globus pallidus ventral tegmental area subthalamic nucleus superior vestibular nucleus vena cava endothelial cell pons stromal cell of endometrium external globus pallidus Top expressed in spinal ganglia superior cervical ganglion upper arm olfactory bulb trigeminal ganglion ureter quadriceps femoris muscle lens uterus ureteric bud More reference expression data BioGPS n/a
Gene ontology Molecular function cytokine activity transforming growth factor beta receptor binding growth factor activity protein binding Cellular component intracellular membrane-bounded organelle nucleoplasm extracellular region extracellular space cellular component protein-containing complex Biological process regulation of apoptotic process skeletal system development roof of mouth development ureteric bud development regulation of MAPK cascade spinal cord anterior/posterior patterning cell development negative regulation of cell differentiation positive regulation of pathway-restricted SMAD protein phosphorylation cell maturation nervous system development animal organ morphogenesis pancreas development mesoderm development metanephros development camera-type eye morphogenesis anterior/posterior pattern specification negative regulation of cell population proliferation SMAD protein signal transduction regulation of signaling receptor activity negative regulation of neuron differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10220 14561 Ensembl ENSG00000135414 ENSMUSG00000025352 UniProt O95390 Q9Z1W4 RefSeq (mRNA) NM_005811 NM_010272 RefSeq (protein) NP_005802 NP_034402 Location (UCSC) Chr 12: 55.74 – 55.76 Mb Chr 10: 128.72 – 128.73 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

GDF11 acts as a cytokine and its molecular structure is identical in humans, mice and rats.^[7] The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.^[8]

Tissue distribution

GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina.^[6]

Function

Gene deletion and over-expression studies indicate that GDF11 primarily regulates the embryological development of the skeletal system. It may also help regulate development of the central nervous system, blood vessels, the kidney and other tissues.^{[9][10][11][12][13]}

GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury.^[14]

Effects on cell growth and differentiation

GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.^[15] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.^[12]

During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.^[16] This cytokine also inhibits the proliferation of olfactory receptor neural progenitors to regulate the number of neurons in the olfactory epithelium,^[17] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.^[18] Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development.

GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.^[15] It is also closely related to myostatin, a negative regulator of muscle growth,^[19][20] both structurally and phylogenetically.^[21]

Though GDF11 is 90% structurally similar to myostatin, GDF11's mechanism of action is opposite that of myostatin since it declines with age and exerts anti-aging regenerative effects in skeletal muscle in mice^[22]

Human studies

GDF11 levels fall to zero in humans at a mean age of 73.71. No endogenous GDF11 production results in the cessation of stem cell DNA repair which causes stem cells to die off and their populations fall to zero at an even faster rate. Since one cannot survive without hematopoietic, mesenchymal, etc. stems cells, this suggests that GDF11 may play a key role in maximum lifespan determination.^[23]

Elevian, whose founders include Harvard Stem Cell Institute researchers Dr. Amy Wagers, Dr. Lee Rubin and Dr. Rich Lee, has raised $58 million in two rounds of funding to study GDF11. On June 19, 2022, the New York Times published an article about GDF11 and Elevian titled "Can a 'Magic' Protein Slow the Aging Process?". The article stated that Elevian will conduct clinical trials using GDF11 to repair stroke damage in humans starting in Q1 of 2023.^[24]

GDF11 levels in individuals with major depressive disorder are significantly lower compared to healthy controls. Administration of GDF11 in aged mice stimulates neuronal autophagy which improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner.^[25]

It has been reported that GDF11 is down-regulated in pancreatic cancer tissue, compared with surrounding tissue, and pancreatic cell lines exhibit a low expression of the growth factor (65). This group also reported that, in a cohort of 63 PC patients, those with high GDF11 expression had significantly better survival rates in comparison with those with low GDF11 expression. These effects were related to decreased proliferation, migration and invasion, and these observations are in agreement with those reported in HCC and TNBC. GDF11 is also capable of inducing apoptosis in pancreatic cancer cell lines.^[26]

However, In 130 patients with colorectal cancer (CRC), the expression of GDF11 was significantly higher compared with normal tissue (56). The classification of the patient cohort in low and high GDF11 expression revealed that those patients with high levels of GDF11 showed a higher frequency of lymph node metastasis, more deaths and lower survival.

Note that GDF11 levels can increase in response to various cellular stressors, including hypoxia (low oxygen levels) and inflammation. Tumor microenvironments often have low oxygen levels and increased inflammation, which could be the cause higher GDF11 expression in colon cancer patients..^[26]

Animal studies

In 2014, GDF11 was described as a life extension factor in two publications based on the results of parabiosis experiments in mice ^[27][28] that were chosen as Science's scientific breakthrough of the year.^[29] Later studies questioned these findings.^{[30][31][32][33]} Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources.^[34] The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.

GDF11 is a powerful senolytic and antioxidant. GDF11 fed mice saw 45.7% reduction in senescent liver cells and a 21.7% reduction in senescent kidney cells. GDF11 induces generation of antioxidant enzymes (CAT, SOD and GPX), which directly results in reduction of ROS levels, which then decelerates protein oxidation, lipid peroxidation and possibly LF and SA-β-Gal development, which in turn extends lifespan of aged mice.^[35]

GDF11 attenuates the senescence of ovarian and testicular cells, and contributes to the recovery of ovarian and testicular endocrine functions. Moreover, GDF11 could rescue the diminished ovarian reserve in female mice and enhance the activities of marker enzymes of testicular function (SDH and G6PD) in male mice, suggesting a potential improvement of fertility.^[36]

Systematic replenishment of GDF11 improved the survival and morphology of β-cells and improved glucose metabolism in both non genetic and genetic mouse models of type 2 diabetes.^[37]

GDF11 triggers a calorie restriction‐like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF‐1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain.^[38]

GDF11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, GDF11 gene transfer restores glucose metabolism and improves insulin resistance.^[39]

GDF11 contributes to limiting functional damage of mitochondria in cardiomyocytes (heart cells) following ischemic (lack of blood flow) injury or anoxia (oxygen deprivation) insult, and repressing apoptosis in mitochondria-dependent and mitochondria-independent manners by increasing telomerase activities. This suggests that GDF11 may be an effective treatment for post heart attack patients.^[40]

GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial Infarction. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.^[41]

GDF11 improves endothelial dysfunction, decreases endothelial apoptosis, and reduces inflammation, consequently decreases atherosclerotic plaques area in apolipoprotein E−/− mice.^[42]

GDF11 attenuates liver fibrosis via expansion of liver progenitor cells. The protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.^[43]

GDF11 improves tubular regeneration after acute kidney injury in elderly mice. Supplementing GDF11 increased tubular cell dedifferentiation and proliferation as well as improved the prognosis of old mice that underwent ischemia–reperfusion injury by upregulating the ERK1/2 signaling pathway.^[44]

GDF11 is a regulator of skin biology and has significant effects on the production of procollagen I and hyaluronic acid. GDF11 also activates the Smad2/3 phosphorylation pathway in skin endothelial cells and improves skin vasculature.^[45]

GDF11 exerts considerable anti-aging effects on skin. As the key member of the TGF-Beta superfamily, GDF11 represents a promising therapeutic agent for the treatment of a number of inflammatory skin diseases, including psoriasis.^[46]

This GDF11 paper summarizes GDF11 expression in various organs as well as a table showing effects of GDF11 in cardiac, muscle skeletal and nervous system disease.^[47]

Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity.^[27]

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.^[48]

GDF11 has been found to reduce oxidative stress and was able to reduce the levels of AGEs, protein oxidation and lipid peroxidation, and to slow down the accumulation of age-related histological markers. GDF11 significantly prevented the decrease in CAT, GPX and SOD activities,^[49]

Enhanced GDF11 expression promoted apoptosis and down-regulated GDF11 expression inhibited apoptosis in pancreatic cancer cell lines. These findings suggested that GDF11 acted as a tumor suppressor for pancreatic cancer.^[50]

GDF11 induces tumor suppressive properties in human hepatocellular carcinoma-derived cells, Huh7 and Hep3B cell lines, restricting spheroid formation and clonogenic capacity, an effect that is also observed in other liver cancer cell lines (SNU-182, Hepa1-6, and HepG2), decreasing proliferation, motogenesis, and invasion. Similarly, Bajikar et al. (23) identified a tumor-suppressive role of GDF11 in a triple-negative breast cancer (TNBC).^[26]

References

1. GRCh38: Ensembl release 89: ENSG00000135414 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025352 - Ensembl, May 2017
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4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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35. Song L, Wu F, Li C, Zhang S (June 2022). "Dietary intake of GDF11 delays the onset of several biomarkers of aging in male mice through anti-oxidant system via Smad2/3 pathway". Biogerontology. 23 (3): 341–362. doi:10.1007/s10522-022-09967-w. PMC 9125541. PMID 35604508.
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37. Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK (December 2004). "GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development". Development. 131 (24): 6163–6174. doi:10.1242/dev.01535. PMID 15548585.
38. Katsimpardi L, Kuperwasser N, Camus C, Moigneu C, Chiche A, Tolle V, et al. (January 2020). "Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice". Aging Cell. 19 (1): e13038. doi:10.1111/acel.13038. PMC 6974718. PMID 31637864.
39. Lu B, Zhong J, Pan J, Yuan X, Ren M, Jiang L, et al. (December 2019). "Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice". Journal of Translational Medicine. 17 (1): 422. doi:10.1186/s12967-019-02166-1. PMC 6915940. PMID 31847906.
40. Chen, Lin; Luo, Guangjin; Liu, Yameng; Lin, Hairuo; Zheng, Cankun; Xie, Dongxiao; Zhu, Yingqi; Chen, Lu; Huang, Xiaoxia; Hu, Donghong; Xie, Jiahe; Chen, Zhenhuan; Liao, Wangjun; Bin, Jianping; Wang, Qiancheng (2021-07-02). "Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity". Cell Death & Disease. 12 (7): 665. doi:10.1038/s41419-021-03954-8. ISSN 2041-4889. PMC 8253774. PMID 34215721.
41. Zhao Y, Zhu J, Zhang N, Liu Q, Wang Y, Hu X, et al. (October 2020). "GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing". Stem Cells Translational Medicine. 9 (10): 1257–1271. doi:10.1002/sctm.20-0005. PMC 7519765. PMID 32515551.
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Further reading

• Kondás K, Szláma G, Trexler M, Patthy L (August 2008). "Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11". The Journal of Biological Chemistry. 283 (35): 23677–23684. doi:10.1074/jbc.M803025200. PMC 3259755. PMID 18596030.
• Lee SJ, McPherron AC (October 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development. 9 (5): 604–607. doi:10.1016/S0959-437X(99)00004-0. PMID 10508689.
• Hocking JC, Hehr CL, Chang RY, Johnston J, McFarlane S (February 2008). "TGFbeta ligands promote the initiation of retinal ganglion cell dendrites in vitro and in vivo". Molecular and Cellular Neurosciences. 37 (2): 247–260. doi:10.1016/j.mcn.2007.09.011. PMID 17997109. S2CID 140209779.
• Hannan NR, Jamshidi P, Pera MF, Wolvetang EJ (September 2009). "BMP-11 and myostatin support undifferentiated growth of human embryonic stem cells in feeder-free cultures". Cloning and Stem Cells. 11 (3): 427–435. doi:10.1089/clo.2009.0024. PMID 19751112.
• Gamer LW, Wolfman NM, Celeste AJ, Hattersley G, Hewick R, Rosen V (April 1999). "A novel BMP expressed in developing mouse limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos". Developmental Biology. 208 (1): 222–232. doi:10.1006/dbio.1998.9191. PMID 10075854.
• Yokoe T, Ohmachi T, Inoue H, Mimori K, Tanaka F, Kusunoki M, Mori M (November 2007). "Clinical significance of growth differentiation factor 11 in colorectal cancer". International Journal of Oncology. 31 (5): 1097–1101. doi:10.3892/ijo.31.5.1097. PMID 17912435.
• Schneyer AL, Sidis Y, Gulati A, Sun JL, Keutmann H, Krasney PA (September 2008). "Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin". Endocrinology. 149 (9): 4589–4595. doi:10.1210/en.2008-0259. PMC 2553374. PMID 18535106.
• McPherron AC, Lawler AM, Lee SJ (July 1999). "Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11". Nature Genetics. 22 (3): 260–264. doi:10.1038/10320. PMID 10391213. S2CID 1172738.
• Szumska D, Pieles G, Essalmani R, Bilski M, Mesnard D, Kaur K, et al. (June 2008). "VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5". Genes & Development. 22 (11): 1465–1477. doi:10.1101/gad.479408. PMC 2418583. PMID 18519639.

External links

• GDF11 human gene location in the UCSC Genome Browser.
• GDF11 human gene details in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O95390 (Growth/differentiation factor 11) at the PDBe-KB.