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GDF11
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GDF11
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GDF11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGDF11, BMP-11, BMP11, growth differentiation factor 11, VHO
External IDsOMIM: 603936; MGI: 1338027; HomoloGene: 21183; GeneCards: GDF11; OMA:GDF11 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 10: 128.72 – 128.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 acts as a cytokine and its sequence is highly conserved between 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

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

Function

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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

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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

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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, a university spin-off company 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?".[24] The article stated that Elevian will conduct clinical trials using GDF11 to repair stroke damage in humans starting in Q1 of 2023.[24]

Physical fitness correlated with GDF11 levels in serum, which is in line with results of a previous study reporting higher serum GDF11 in lifelong exercising men compared to their lifelong sedentary peers. Physical fitness not only determines the tissue-specific expression and concentration of GDF11, but also the magnitude of its exercise-stimulated regulation.[25]

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.[26]

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.[27]

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..[27]

Animal studies

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In 2014, GDF11 was described as a life extension factor in two publications based on the results of parabiosis experiments in mice [28][29] that were chosen as Science's scientific breakthrough of the year.[30] Later studies questioned these findings.[31][32][33][34] Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially available sources.[35] 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.[36]

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.[37]

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.[38]

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.[39]

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.[40]

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.[41]

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.[42]

GDF11 improves endothelial dysfunction, decreases endothelial apoptosis, and reduces inflammation, consequently decreases atherosclerotic plaques area in apolipoprotein E−/− mice.[43]

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.[44]

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.[45]

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.[46]

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.[47]

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.[48]

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.[28]

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.[49]

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,[50]

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.[51]

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).[27]

References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

GDF11

View on Grokipedia
from Grokipedia
Growth differentiation factor 11 (GDF11), also known as (BMP11), is a secreted protein belonging to the (TGF-β) superfamily that regulates embryonic development, tissue patterning, and aspects of adult including potential roles in aging and regeneration. Discovered in 1999 through studies on mammalian development, GDF11 was identified independently by McPherron et al. using a probe and by Nakashima et al. from incisor dental pulp , highlighting its expression in developing tissues such as the tailbud, limbs, and . Structurally, it encodes a 407-amino-acid precursor protein that is proteolytically processed into a mature 12.5 kDa dimer with conserved residues forming bonds, sharing high (approximately 90% in the mature domain) with (GDF8) but differing in its prodomain. In embryonic development, GDF11 is essential for anterior-posterior axial patterning, as well as the formation and morphogenesis of organs including the kidney, spleen, stomach, pancreas, and olfactory system, with knockout mice exhibiting severe defects such as shortened bodies and absent kidneys. It signals through type I and II TGF-β receptors, activating Smad-dependent pathways to control cell proliferation, differentiation, and apoptosis in these processes. Beyond development, GDF11 is expressed in adult tissues like the brain, heart, skeletal muscle, and spinal cord, where it influences erythropoiesis by inhibiting terminal erythroid differentiation and has been implicated in vascular function and endothelial progenitor cell activity. Research has highlighted GDF11's potential in , with studies showing that in aged mice reduces cardiac , improves muscle regeneration, and enhances neurovascular outcomes, suggesting a decline in circulating levels with age may contribute to tissue dysfunction. For instance, GDF11 supplementation has been reported to reverse age-related loss, pulmonary issues, and in murine models, positioning it as a candidate for therapies in , neurodegeneration, and chronic wounds. Ongoing research as of 2025 continues to explore its therapeutic applications, including in and age-related . However, controversies persist regarding its precise role in aging and metabolism; conflicting studies dispute whether GDF11 levels truly decline with age, its effects on muscle regeneration (potentially inhibitory rather than rejuvenating), and the specificity of assays distinguishing it from , underscoring the need for further clarification.

Discovery and Molecular Structure

Gene Identification and Cloning

The GDF11 gene was identified in 1999 as a novel member of the TGF-β superfamily through low-stringency screening of cDNA libraries for sequences related to known BMPs and GDFs. Independently, researchers used RT-PCR with degenerate oligonucleotide primers designed from conserved TGF-β family motifs to amplify a partial rat Gdf11 sequence from incisor pulp RNA, followed by 5'-RACE PCR to extend the fragment; this rat probe was then used to isolate full-length mouse Gdf11 cDNA from a 15.5 days post-coitum embryonic library. In humans, the GDF11 gene is located on chromosome 12q13.2 and consists of 4 exons, encoding a 407-amino-acid preproprotein that includes a signal peptide, a prodomain, and a mature TGF-β-like domain. The mouse ortholog shares high sequence similarity, with the predicted preproprotein also comprising 407 amino acids. Early characterization included functional assays demonstrating BMP-like activity; injection of GDF11 mRNA into Xenopus embryos induced ventral mesoderm formation and inhibited neural tissue induction, consistent with TGF-β family mesoderm-inducing properties. GDF11 exhibits structural homology to GDF8 (myostatin), sharing approximately 90% amino acid identity in the mature C-terminal region.

Protein Structure and Similarities to TGF-β Family

GDF11 is synthesized as a precursor protein that undergoes proteolytic cleavage to produce a mature form consisting of a 25-kDa disulfide-linked homodimer, with each approximately 12.5 kDa in size. This maturation process involves the removal of an N-terminal and a prodomain, which maintains the in a latent state prior to activation. Like other members of the transforming growth factor-β (TGF-β) superfamily, the mature GDF11 structure features a conserved motif, where seven residues form intramolecular disulfide bonds that stabilize the core fold. GDF11 shares approximately 90% amino acid sequence identity with GDF8 (also known as ) within their mature domains, reflecting their close evolutionary relationship within the TGF-β superfamily. This high similarity extends to the characteristic TGF-β signature motif, including the and β-sheet structures that define the superfamily's ligand architecture. Insights into the three-dimensional structure of GDF11 have been derived from its , determined at 1.50 resolution, which reveals a canonical TGF-β domain fold conserved across the family. The monomer adopts a hand-like conformation, with a central cystine palm, finger-like β-strands, a wrist region comprising an α-helix involved in type II receptor interactions, and a knuckle on the convex surface for type I receptor binding. with related ligands further highlights subtle conformational differences in these regions that may influence receptor affinity.

Expression and Regulation

Tissue and Developmental Distribution

GDF11 exhibits dynamic expression patterns during embryogenesis, with high levels observed in the developing , -derived tissues such as the branchial arches and cranial cells, somites, paraxial , and limb buds from E8.5 to E15.5. In situ hybridization studies have revealed prominent transcripts in these regions, which contribute to formation and development. Expression in the developing is noted in the metanephric and Wolffian duct. In adult mice, GDF11 is expressed in the brain, heart, skeletal muscle, kidney, and spinal cord, with protein detected in the hippocampus and caudate. Northern blot analyses in rat tissues confirm detectable transcripts in brain and dental pulp, with no detectable signals in heart, liver, kidney, lung, spleen, or testis. This pattern aligns with GDF11's role as a member of the TGF-β superfamily, where tissue-specific persistence varies post-development. Temporal regulation of GDF11 expression is prominent during early to mid-gestation (around E8.5–E12.5), coinciding with , and subsequently declines postnatally in most tissues except those with sustained expression like . data further illustrate this progression, with strong signals in embryonic somites and neural structures diminishing by late gestation.

Factors Regulating Expression

The expression of GDF11 is regulated at the transcriptional level through elements in its promoter that respond to BMP signaling. As a member of the TGF-β superfamily, GDF11 regulation involves Smad-binding elements similar to those in other BMP family members, allowing for autoregulatory or cross-talk mechanisms that modulate its transcription in response to extracellular signals. Under low-oxygen conditions, GDF11 expression is influenced by hypoxia-inducible factors, though studies indicate a complex relationship where prolonged hypoxia often leads to decreased GDF11 levels via miRNA-mediated mechanisms. For instance, hypoxia induces miR-1260b, which targets the 3' UTR of GDF11 mRNA, thereby suppressing its post-transcriptional expression and promoting vascular . Post-transcriptional control of GDF11 is mediated by microRNAs that bind to its 3' UTR. An age-related decline in GDF11 expression is closely linked to epigenetic modifications, specifically increased methylation of CpG islands in its promoter region. In mesenchymal stem cells, the DNA demethylase TET2 maintains GDF11 levels by demethylating these CpG sites; TET2 mutations or targeted mutagenesis of these sites hypermethylate the promoter, blocking GDF11 transcription and accelerating cellular senescence. This establishes a mutual regulatory feedback loop where GDF11 upregulates TET2 to sustain its own expression, and age-dependent promoter hypermethylation disrupts this balance, contributing to reduced GDF11 in aging tissues.

Signaling Mechanisms

Receptor Interactions and Pathways

GDF11, a member of the transforming growth factor-β (TGF-β) superfamily, initiates signaling by binding to specific type II and type I kinase receptors on the cell surface. It primarily interacts with the type II receptor activin receptor type IIB (ActRIIB), and to a lesser extent ActRIIA, followed by recruitment of type I receptors such as ALK4, ALK5, and ALK7. This ligand-induced assembly forms a heterotetrameric complex consisting of two type II and two type I receptor molecules, where the type II receptors phosphorylate the type I receptors, activating their domains. The specificity of GDF11 for ALK4, ALK5, and ALK7 distinguishes it somewhat from related ligands like GDF8 (), which shows reduced affinity for ALK7. Upon receptor activation, GDF11 predominantly engages the canonical TGF-β signaling pathway through of receptor-regulated Smads (R-Smads), specifically Smad2 and Smad3. The phosphorylated Smad2/3 complexes associate with Smad4 and translocate to the nucleus, where they regulate target transcription in cooperation with other transcription factors. This Smad2/3-dependent pathway is central to GDF11's biological effects and has been confirmed in various cell types, including cardiomyocytes and myoblasts, where it modulates cellular responses such as prevention. In addition to the canonical pathway, GDF11 can activate non-canonical signaling cascades in a context-dependent manner, particularly in neural and microglial cells. These include the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, as well as the (PI3K)/Akt pathway, which are triggered downstream of ALK5 and contribute to processes like inhibition and polarization. For instance, in neural stem cells, GDF11 induces ERK and PI3K/Akt activation alongside p38 MAPK, promoting differentiation and while suppressing migration. GDF11 signaling exhibits dose-dependence, with effective concentrations varying by and but typically showing half-maximal (EC50) in the range of 1-10 ng/mL for Smad2/3 and activity. In luciferase-based using Smad-responsive elements, recombinant GDF11 achieves potent at low nanomolar levels, underscoring its high in cellular contexts.

Downstream Effects on Gene Expression

GDF11 signaling, primarily through the canonical Smad2/3 pathway, leads to of Smad3, which translocates to the nucleus and binds to specific promoter regions to regulate transcription of target genes involved in control and differentiation. Similar mechanisms contribute to the upregulation of other inhibitors, such as p15 (CDKN2B), in populations responsive to TGF-β superfamily members. These effects are critical for maintaining cellular quiescence during tissue . GDF11 represses the expression of inhibitor of DNA binding proteins Id1 and Id2, basic helix-loop-helix transcription factors that normally inhibit differentiation by sequestering pro-differentiation factors like E-proteins. In hepatic cells, increasing GDF11 concentrations progressively downregulate Id1 and Id2 mRNA levels through Smad-dependent antagonism of BMP signaling, thereby promoting lineage commitment and maturation in developmental and regenerative contexts. Epigenetic changes downstream of GDF11 involve recruitment of histone deacetylases (HDACs) by phosphorylated Smad3 complexes to developmental loci, leading to deacetylation of s and compaction that silences proliferation-associated genes while activating differentiation programs. For instance, Smad3 interacts with to alter accessibility at loci regulating cell fate, a mechanism conserved across TGF-β ligands including GDF11. Microarray analyses of neural cells treated with GDF11 reveal upregulation of -associated genes. In progenitors, GDF11 facilitates temporal progression of via Smad2/3 signaling, as evidenced by delayed neuronal differentiation in Gdf11-null models.

Roles in Development and Physiology

Embryonic and Organ Development

GDF11 plays a critical role in embryonic patterning, particularly along the anterior-posterior axis, as evidenced by the phenotypes observed in mice. Homozygous Gdf11-null mice exhibit severe anterior homeotic transformations in the vertebral column, characterized by an increased number of thoracic and decreased number of , along with shortened or absent tails due to disrupted posterior axial development. These axial defects arise from altered expression patterns of , which GDF11 regulates upstream to specify segmental identities during embryogenesis. Additionally, Gdf11-null mice display kidney agenesis, resulting from failed ureteric bud outgrowth and metanephric induction, leading to perinatal lethality. In somitogenesis, GDF11 contributes to proper vertebral segmentation by modulating expression in the presomitic , ensuring the timely formation and identity of somites that give rise to the . Disruption of this regulation in Gdf11 mutants leads to homeotic shifts and impaired rostrocaudal patterning, highlighting GDF11's local action in coordinating mesodermal segmentation rather than long-range effects. GDF11 is expressed in developing somites, supporting its involvement in these early patterning events. GDF11 also influences organ morphogenesis, including the palate and limbs. Gdf11-null mice frequently develop cleft palate, with defects in palatal shelf elevation and fusion mediated through activin type II receptors, underscoring GDF11's necessity for craniofacial integrity. In limb development, GDF11 acts as a negative regulator of chondrogenesis and , expressed in the distal of the limb bud where it inhibits skeletal element formation and promotes patterning through induction of distal Hoxd genes like Hoxd-11 and Hoxd-13. This inhibitory effect occurs via antagonism of BMP signaling, as GDF11 overexpression truncates limbs by suppressing BMP-driven differentiation while upregulating its own antagonist to fine-tune activity.

Functions in Adult Tissues

In adult , GDF11 exerts a regulatory role similar to by inhibiting and promoting fiber type balance through activation of the SMAD2/3 signaling pathway, which suppresses myoblast differentiation and limits excessive muscle growth. This function helps maintain muscle by preventing pathological overgrowth, as evidenced by studies showing that inhibition of GDF11 signaling leads to increased muscle mass and strength in murine models. Unlike its developmental roles, GDF11's adult activity in skeletal muscle focuses on fine-tuning fiber composition rather than gross . GDF11 supports vascular in the by promoting , particularly in response to hypoxia, through induction of (VEGF) expression and enhancement of endothelial function. In hypoxic tissues, such as those affected by ischemia, GDF11 stimulates endothelial , migration, and differentiation of mesenchymal stem cells into endothelial-like cells via the TGF-β receptor/ERK/ pathway, thereby facilitating neovascularization without disrupting normal vascular integrity. In hepatic tissue, particularly in models of liver diseases such as non-alcoholic fatty liver disease, GDF11 contributes to metabolic regulation by suppressing , which helps preserve lipid homeostasis. Specifically, GDF11 downregulates genes involved in de novo lipid synthesis, such as those in the AKT/ pathway, to mitigate aberrant fat accumulation in hepatocytes. GDF11 influences by inhibiting terminal erythroid differentiation, thereby regulating production in adult . In the heart, GDF11 helps maintain cardiac by modulating and in adult tissues. GDF11 provides in the adult hippocampus by enhancing under stress conditions, thereby supporting cognitive resilience and neuronal adaptability. Through mechanisms involving increased and restoration of presynaptic markers, GDF11 attenuates stress-induced impairments in synaptic remodeling and inhibits inflammatory pathways like /caspase-1-mediated , maintaining hippocampal circuit integrity without altering baseline neuronal development.

Research on Aging and Regeneration

Animal Model Studies

In heterochronic experiments conducted in 2013, joining the circulatory systems of young (2-month-old) and aged (23-month-old) mice for 4 weeks reversed age-related cardiac in the older animals, reducing heart weight-to-tibia length ratios from 9.61 mg/mm to 7.93 mg/mm and cardiomyocyte cross-sectional areas from 357.8 μm² to 220.4 μm². This effect was attributed to elevated levels of circulating GDF11 from the young partner, as GDF11 concentrations decline with age; daily infusions of recombinant GDF11 (0.1 mg/kg for 30 days) into aged mice independently recapitulated these benefits, restoring cardiomyocyte size and reducing molecular markers of such as ANP and BNP. Initial studies in aged mouse cohorts suggested that systemic administration of recombinant GDF11 enhanced regeneration by rejuvenating cells, the primary stem cells responsible for repair. Treatment with GDF11 (0.1 mg/kg daily for 4 weeks) in 24-month-old mice reportedly improved function, including DNA damage repair and proliferative capacity, leading to increased myofiber cross-sectional area post-injury and enhanced grip strength compared to vehicle-treated controls. Recent studies in models of permanent cerebral ischemia (2025) demonstrated that recombinant GDF11 improves outcomes in the subacute phase of . Intravenous administration of rGDF11 (1 mg/kg every 48 hours for three doses starting 24 hours post-ischemia) increased neuronal survival through enhanced , as evidenced by elevated Sox2-positive neural stem cells in the ventricular zone, and boosted vascular density via neovascularization, with significant gains in - and CD31-positive vessel junctions and length in the ischemic cortex. Functional recovery was also promoted, with improved sensorimotor performance in body swing and limb placement tests. Early enthusiasm for GDF11's anti-aging effects faced controversy due to assays that could not distinguish it from GDF8 (), leading to misattribution of benefits, particularly in muscle regeneration where GDF11 was later shown to inhibit myoblast differentiation and cell expansion. Studies in resolved this by developing GDF11-specific immunoassays, revealing that prior kits cross-reacted with GDF8, and showing GDF11 levels actually trend upward with age in and sera. This distinction clarified that GDF11's roles in cardiac and neural models are separable from GDF8's muscle-suppressive effects, though debates persist on circulating levels in non-muscle contexts; refining interpretations of anti-aging preclinical data.

Mechanisms in Rejuvenation and Tissue Repair

In models of pathological myocardial remodeling, GDF11 activates SIRT1-dependent pathways to mitigate oxidative stress and apoptosis. In tissue repair, GDF11 regulates odontogenic differentiation of dental pulp stem cells by activating the Wnt/β-catenin signaling pathway, suggesting a similar mechanism in cutaneous wound healing where GDF11 enhances endothelial progenitor cell mobilization and vascular remodeling. Such activation promotes regenerative responses, including angiogenesis and extracellular matrix deposition, essential for closing diabetic wounds. GDF11 exerts anti-aging effects by reducing the (SASP) through inhibition of signaling. Loss of GDF11 upregulates SASP-related genes like and Timp2 in excitatory neurons, driving pro-inflammatory secretomes that accelerate brain aging; conversely, GDF11 supplementation suppresses these profiles. By repressing activity, GDF11 dampens production and in macrophages and skin models, mitigating SASP-mediated tissue dysfunction. GDF11 supports via PGC-1α activation. Previous investigations demonstrate that GDF11 induces PGC-1α expression, enhancing mitochondrial protein control and function in stressed cells, which aids during regeneration. These effects have been noted in of cardiac ischemia, where GDF11 improves and activity.

Clinical and Pathological Implications

Human Clinical Studies

Human studies on GDF11 have primarily been observational, focusing on circulating levels in relation to aging, frailty, and cardiovascular health, with no large-scale interventional trials completed as of 2025. Early established that plasma GDF11 concentrations do not significantly decline with chronological age in healthy adults but are elevated in individuals with comorbidities, such as and postoperative complications. In a cohort of older surgical patients, higher GDF11 levels correlated with increased frailty scores, , and higher 90-day mortality risk, suggesting GDF11 as a marker of advanced biological aging rather than chronological decline. Subsequent observational data have shown mixed patterns in GDF11 levels across age groups and conditions. A study of community-dwelling adults aged 18-79 found that circulating GDF11 decreased modestly in older age groups (61-80 years), independent of or status, with overall mean levels around 0.126 ng/mL. However, in contrast, analyses of elderly cohorts with cardiovascular risk factors reported lower levels of activated GDF11/8, which predicted higher risk of future events like and cognitive decline over approximately 4-year follow-up, with hazard ratios of 0.75 for MI and 0.663 for in high versus low groups. These findings highlight GDF11's potential role in age-related , though causality remains unestablished without intervention data. Regarding frailty specifically, cross-sectional analyses in older surgical patients have linked higher serum GDF11 to frailty, including associations with clinical frailty criteria. Mixed findings exist across studies, with no comprehensive meta-analyses available by 2025. In cardiovascular contexts, observational cohorts of patients have detected altered GDF11 profiles. For instance, in 100 patients with acute , higher plasma GDF11 at admission was associated with larger infarct sizes but not with left ventricular function at 6 months. These data build on precedents but underscore GDF11's complex role in cardiac stress. No pilot interventional studies on GDF11 supplementation for were reported by 2025. Biomarker validation efforts have standardized assays for plasma GDF11 measurement, enabling reliable quantification across studies. Commercial and custom ELISAs detect GDF11 with sensitivities down to 10 pg/mL, showing strong correlation (r=0.95) with in aged samples, and have been validated in cohorts up to 500 participants for aging predictions. These assays confirm GDF11's stability in frozen plasma for up to 2 years, supporting its use as a longitudinal , though inter-assay variability remains a challenge without universal reference standards.

Associations with Diseases

GDF11 exhibits a dual role in cancer, acting as a tumor suppressor in hepatocellular carcinoma (HCC) by restricting aberrant lipogenesis and mitochondrial dysfunction in cancer cells, which inhibits tumor progression and clonal expansion. In contrast, GDF11 promotes colorectal cancer growth through contributions from lymphatic endothelium, where it enhances tumor cell proliferation and invasion, potentially via epithelial-mesenchymal transition (EMT) induction as observed in related TGF-β family signaling pathways. In inflammatory conditions, GDF11 demonstrates anti-inflammatory effects in models of by promoting macrophage polarization toward an M2 and upregulating IL-10 expression, which mitigates activation and reduces colonic inflammation. However, dysregulation of GDF11 can lead to pro-fibrotic outcomes in chronic wounds, as it stimulates fibroblast activation in skin tissue, exacerbating excessive deposition and impairing healing. Neurological associations of GDF11 include interactions with amyloid pathology in older adults, where higher circulating levels may attenuate amyloid-related cognitive decline across the spectrum. Recent genome-wide association studies (GWAS) have identified genetic variants near GDF11 linked to metabolic disorders, including and , suggesting alterations in the immune-thyroid axis that influence disease susceptibility.

References

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  12. https://pubmed.ncbi.nlm.nih.gov/28257634/
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  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC14793/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC7196185/
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  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC1525155/
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