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. GDF11 is a member of the Transforming growth factor beta family. GDF11 acts as a cytokine and its molecular structure is identical in humans, mice and rats. 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. Tissue distribution. GDF11 is expressed in many tissues, including skeletal muscle, pancreas, kidney, nervous system, and retina. Function. GDF11  expression is elevated in young animals. GDF11 has pro-neurogenic, pro-angiogenic properties, induces CNS patterning and has been proposed as a "rejuvenating factor" Animal and Human studies. Systemic GDF11 treatment improves vasculature in the hippocampus and cortex of old mice resulting in enhanced neurogenesis. This paper suggests that exogenous GDF11 may be effective in reversing stroke damage and vascular dementia in humans. Loss of GDF11 Shortens Telomere Length by Down Regulating Telomerase Activity 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. 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. 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. 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. Circulating Concentrations of GDF11 are Positively Associated with Thyroid Stimulating Hormone Levels in Humans 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. GDF11 improves endothelial dysfunction, decreases endothelial apoptosis, and reduces inflammation, consequently decreases atherosclerotic plaques area in apolipoprotein E−/− mice. 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. 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. 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. 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. 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. 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. 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, 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. 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). 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. 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. The study suggests that GDF11 could be a prognostic biomarker in patients with this disease In  2014, GDF11 was described as a life extension factor in two publications based on the results of a parabiosis experiments with mice that were chosen as "Science's" scientific breakthrough of the year. Later studies questioned these findings. Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources. 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. 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. It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord. 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. In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in  the olfactory epithelium, and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the 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 ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction. GDF11 is closely related to myostatin, a negative regulator of  muscle growth. Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is a regulator of kidney organogenesis, pancreatic development, the rostro-caudal patterning in the development of spinal cords, and of chondrogenesis. Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by 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 parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions. GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (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 skeletal muscle by rescuing the function of aged muscle stem cells. In humans, older males who had been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlated with leg power output when cycling. These results have led to claims 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 skeletal muscle regeneration, being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, a Harvard study showed these contrary results to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy. However the Harvard study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in  fact myostatin. Also, the Harvard study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters. In 2016 conflicting reviews from different research teams were published concerning the effects of GDF11 on skeletal and cardiac muscle.