Review Volume 13, Issue 8 pp 12258—12272
Growth differentiation factor 11: a “rejuvenation factor” involved in regulation of age-related diseases?
- 1 Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- 2 Department of Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- 3 Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
Received: December 8, 2020 Accepted: March 14, 2021 Published: April 22, 2021https://doi.org/10.18632/aging.202881
How to Cite
Copyright: © 2021 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β superfamily of cytokines, is a critical rejuvenation factor in aging cells. 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. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.
Aging is currently a source of considerable concern worldwide. The prevalence of age-related diseases increases rapidly with advancing age; these diseases include cardiovascular disease, cognitive impairment, cancer, Alzheimer's disease, arthritis, obesity, and diabetes [1–3]. Aging has been linked to the progressive accumulation of damage and loss of function, both of which contribute to the onset of chronic disease and eventual death. Thus, there is ongoing research concerning the extension of healthy life and potentially reversing the aging process. Currently, senescent cells have become an increasingly important therapeutic target for age-related diseases . Importantly, senescent cardiomyocytes contribute to cardiac fibrosis, while senescent neurons and glial cells led to neurodegenerative diseases . Senescent cells exhibit various age-related characteristics, including irreversible cell cycle arrest, DNA damage, inflammation and oncogenes , resistance to apoptosis, and the acquisition of a senescence-associated secretory phenotype . This phenotype involves the secretion of multiple signaling molecules, including transforming growth factor-β (TGF-β), which induce and maintain age-related pathological conditions .
TGF-β is a family of pleiotropic cytokines with more than 30 members; it includes growth differentiation factors, bone morphogenetic proteins, and activins . These cytokines regulate multiple cellular biological procedures such as embryogenesis, homeostasis, and various pathological states [10, 11], implying a relationship between TGF-β signaling and the onset of age-related diseases. TGF-β signaling impairment and elevated TGF-β ligand concentrations in certain cell types may contribute to cell degeneration, inflammation, reduced regeneration ability, and metabolic abnormalities associated with age-related diseases .
Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, has recently received attention because of its numerous functions in modulating the development and differentiation of various tissues and organs. It was initially identified by McPherron et al. as a new differentiation factor for odontoblasts . Studies regarding the role of GDF11 in the development of various diseases have been conducted in recent decades. GDF11 is reportedly beneficial with respect to controlling age-related cardiac hypertrophy, improving muscle tone, preventing degeneration in the central nervous system, enhancing cognitive function, and promoting tissue regeneration [13, 14]. Important parabiosis experiments involving two animals of different ages, performed in 2013 and 2014, revealed that GDF11 levels were disrupted in an age-related manner in vascular, neurogenic, and skeletal muscle tissues [15, 16]. Those findings suggested that GDF11 may be regarded as an honorable “rejuvenation” factor that could restore regenerative function, thus resisting aging and extending longevity. A study in fish conducted by Zhou et al. revealed that GDF11 has rejuvenation capacity to extend the lifespan . In 2020, a plasma proteomic dataset from Lehallier et al. demonstrated that the GDF11 protein can significantly extend the lifespan . The above studies demonstrated critical roles for GDF11 in the inhibition of aging. However, recent studies have yielded conflicting data regarding the ability of GDF11 to alleviate dysfunction in age-related diseases [19, 20]. Thus, the regeneration ability of GDF11 with respect to age-related dysfunction requires further investigation. This review provides an overview of GDF11 and its functions in age-related diseases. It also discusses potential underlying mechanisms for the effects of GDF11 in age-related diseases.
Structure and promotor of GDF11
In humans, the GDF11 gene is located on chromosome 12. The GDF11 protein comprises 407 amino acids; it contains a single peptide, an RXXR protein hydrolysis processing position, and a C-terminal domain with a highly conserved cysteine residue pattern . Precursors of TGF-β-like proteins require cleavage at site 1 to release the mature portion of the growth factor . The pro-protein convertase subtilisin/kexin 5 cleaves the GDF11 protein into an inactive latent complex, which contains an N-terminal inhibitory precursor domain and two disulfide-bonded active end domains [23, 24]. Bone morphogenetic protein-1/tolloid family astacin metalloproteases cleave the propeptide and activate non-covalently bound potential complexes, which are formed by the propeptide and mature protein dimers (disulfide-linked) in circulation [25, 26] (Figure 1).
Figure 1. Structure and Maturation process of GDF11. GDF11 is cleaved by PCSK5 to form an inactive latent complex, which contains an N-terminal inhibitory pro-domain and two disulfide-linked carboxyl-terminal active domains. Then, members of the BMP1/Tolloid family of metalloproteinases cleave the latent complex at a single specific site to form the mature GDF11 and pro-peptide.
Crystallography analysis of GDF11 has revealed a standardized homodimeric form; monomeric GDF11 exhibits constitutive activity. The human GDF11 protein exhibits a conserved tertiary structure, similar to a “hand” with a four-stranded β-sheet that constitutes the “fingers,” as well as a cystine-knot structure that occupies the “palm” and an α-helix that forms the “wrist.” (Figure 2). The interlaced accumulation of adjacent dimers results in contact between the β-folded fingers of nearby molecules, as well as contact between the primary helix wrist of the homodimer chaperone and the β-sheet finger of the adjacent molecule .
The promoter regions of the GDF gene contain multiple E-box and ROR/REV-ERB response elements, which bind to many transcriptional activators to form a heterodimer that controls various downstream genes . Two transcriptional products of the GDF11 gene have been identified, according to Ensembl . Despite GC enrichment (77%) in the promoter sequence of human GDF11, there are three well-concealed CCAAT boxes without a presumed stimulatory protein 1 site. These three CCAAT boxes are individually located at +87 bp and +171 bp (both downstream of the presumed transcription initiation point), and at -66 bp (upstream of the putative transcription start site). The CCAAT box at -66 bp is presumed to be sufficient and necessary for trichostatin A (TSA) to activate the GDF11 promoter . TSA, an inhibitor of histone deacetylase 3 (HDAC3), is known to upregulate the expression of the gene encoding GDF11 . According to a comprehensive survey of human HDAC3, treatment of cells with TSA leads to the inactivation of HDAC3 and reduction of GDF11 expression, revealing that HDAC3 is both necessary and sufficient for GDF11 promoter activity . A recent study suggested that the transcription factor zinc finger protein 740 (ZNF740) upregulates the hypoxia-induced expression of GDF11 . To verify the binding of transcription factors to the GDF11 promoter, Yu et al. obtained information regarding GDF11 promoter region transcription factors, including the nuclear factor of activated T cells 2, ZNF740, and specificity protein 1; these factors each target a separate motif . ZNF740 is the only factor with an upstream site that is present in the GDF11 initiation subsequence (-753/-744; CCCCCAC); it may participate in a growth factor pathway involved in the ZNF740/GDF11/Smad signaling axis .
GDF11 signaling pathway
Like other members of the TGF-β superfamily, GDF11 regulates cell signaling by binding to activin receptor types I (activin receptor-like kinase 4/5/7 [ALK4, ALK5 and ALK7]) and II (ActRIIA and ActRIIB) (Figure 3). Both types I and II receptors comprise a small extracellular ligand-binding domain and an intracellular kinase domain. Generally, type II receptors phosphorylate and activate type I receptors. The activated type I receptors then phosphorylate and activate the receptor-regulated SMAD dimer. This dimer recruits the co-SMAD, SMAD4, to form a trimeric complex, which eventually translocates to the nucleus and regulates gene expression . Specifically, GDF11 binds to the ectodomains of the high-affinity type II receptor ActRIIB and the low-affinity type I receptor Alk5 to form a class of activin-type ternary complex crystals . The ternary complex structure of GDF11/ActRIIB-ectodomain/Alk5-ectodomain then phosphorylates intracellular SMAD proteins. These SMAD proteins transduce the signal to the nucleus and act as transcription factors; thus, signal transduction outcomes are dependent on the ligand-receptor combination [33, 34]. There are two common SMAD signaling patterns, including the activation of SMAD 2/3 and SMAD 1/5/8 . In addition to the typical SMAD signals, other non-SMAD pathways have been reported [19, 36]. GDF11 activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway, but suppresses the c-Jun amino-terminal kinase and NF-κB pathways. GDF11 can also activate p38 and extracellular signal-regulated kinase . MitoTEMPO, a mitochondrion-targeted ROS inhibitor, inhibits the GDF11-induced activation of c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase; thus, the GDF11-induced activation of c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase can be modified by ROS status . Recently, ERK1/2 signaling was found to be activated by GDF11, which downregulated bone morphogenetic protein–SMAD signaling and hepcidin activity .
GDF11 is expressed in multiple tissues
After the initial discovery of GDF11 in odontoblasts, its distribution and expression were reported in other tissues . Analysis of adult rat tissues revealed the expression of GDF11 in the skeleton, muscle, mandibular arch, hyoid arch, nasal epithelium, eye, spinal cord, olfactory system, kidney, testis, dental pulp, heart, brain, lung, spleen, and liver  (Figure 4). Notably, GDF11 was expressed in embryonic and adult brain regions: in various nuclei in the anterior hindbrain and ventral midbrain, as well as the thalamus, preoptic area, hippocampus, striatum, and outer layer of the inferior colliculus. In particular, GDF11 was strongly expressed in the thalamus and Purkinje cell layer, weakly expressed in the hippocampus, and inconsistently expressed in the midbrain and hindbrain . Subsequently, GDF11 was expressed in the developing pancreatic epithelium, stomach, duodenum, and metanephros [39, 40]. Notably, GDF11 also comprises a circulating factor in blood . However, there is inconsistency in the literature regarding circulating concentrations of GDF11 with age: reduction [42, 43], elevation  or tendency for elevation , or no change .
Figure 4. GDF11 protein expression data. The color-coding is based on tissues with common functional features. The mouse-over function shows protein score for analyzed cell types found in a selected tissue (http://www.proteinatlas.org/ENSG00000135414-GDF11/tissue).
Additional contributors to the inconsistent conclusions include high structural homology between GDF11 and parabiosis resulting in difficulty distinguishing circulating GDF11 and GDF8, as well as the experimental contexts (e.g., serum sample manipulation, models, and assays to detect GDF11). These issues have been discussed exhaustively elsewhere [43, 45]. GDF11 has 90% amino acid sequence identity to GDF8 in its mature carboxyl-terminal domain. GDF8, also known as myostatin, is a specific negative regulator during skeletal muscle growth . Rat GDF11 has 88% identity to GDF8 in the mature region . However, the prodomains are only 52% identical between GDF8 and GDF11; these prodomains aid in the folding of mature dimeric ligand . Because there is 90% sequence identity between mature active forms of GDF11 and GDF8, the SOMAmer technology and western blot analysis are not suitable assays for the recognition of GDF11 . Importantly, Egerman et al. proposed an immunoassay that was specific for GDF11 and did not detect myostatin . This immunoassay revealed elevated GDF11 levels in aged rats and humans; importantly, endogenous GDF11 could not be detected in young or old mice when it was below the detection threshold . Katsimpardi et al. proposed another assay (sandwich ELISA) that demonstrated specificity for GDF11 by using recombinant myostatin, which was not detected at any concentration ; they also performed western blotting with an anti-GDF11 antibody that was fully validated for sensitivity and specificity to the GDF11 antigen . Overall, the antibodies in these assays have contributed to differences in the results. We conclude that the reagent specificity and sensitivity are essential factors in determining the levels of GDF11. New and reliable studies can help move the field forward.
In this review, we described the gene structure and signaling pathways of GDF11, as well as the roles of GDF11 in organ development, aging, cardiovascular disease, neurological disease, and other diseases. Notably, GDF11 exhibits extensive expression in multiple tissues. Because of differences in GDF11 expression and function in cardiac, neural, muscular, and other tissues, further research is needed to elucidate the roles of GDF11 in age-related diseases. Current theories suggest that various rejuvenation factors in young blood have beneficial effects on cognitive and cardiovascular functions; the presence of GDF11 in many pro-longevity signaling pathways indicates that it may possess an ancient role in the regeneration of organ function. In this review, we have emphasized that the “youthful” expression of GDF11 (demonstrated via parabiosis experiments) may have a beneficial function in age-related diseases. Therefore, GDF11 may serve as a promising therapeutic rejuvenation factor in age-related diseases when its levels are appropriate.
Ma Y, Liu Y and Han F: Conceptualization, Methodology, Data curation, Writing-Original draft preparation. Shi J, Qiu H, Huang N and Hou N: Data curation and Investigation. Sun X: Supervision, Writing-Reviewing and Editing, Funding acquisition.
We thank Ryan Chastain-Gross, Ph.D., from Liwen Bianji, Edanz Group China, for editing the English text of a draft of this manuscript.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
This work was supported by the National Natural Science Foundation of China (81870593), Natural Science Foundation of Shandong Province of China (ZR2018MH008), Shandong Province Higher Educational Science and Technology Program for Youth Innovation (2020KJL004).
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