Growth And Differentiation Factors Research Articles

Polymorphism of Myostatin Gene and its Association with Body Weight of Iraqi Local Ducks

Myostatin, or growth and differentiation factor-8(GDF-8) is a member of the transforming growth factor (TGF)-ß superfamily. The objective of this study was to investigate the association between genetic polymorphism of the myostatin gene with the body-weight of Iraqi local ducks by DNA sequence analysis. The results of DNA sequence showed nitrogen base change (G?A) at 129 base pair sites of the exon1 of MSTN gene. Therefore, two alleles, G and A and two patterns of genotypes, GG, AG were observed. The observed numbers of GG and AG genotypes were 25 and 6, respectively. The G allele was of the highest frequency (0.9) while A allele showed the lowest frequency (0.1). The GG genotype showed the highest frequency (80.65%) and AG genotype showed the lowest frequency (19.35%). Additionally, the percentages of observed and expected heterozygosity were 0.19 and 0.17 respectively. Moreover, the percentages of observed and expected homozygosity were 0.80 and 0.82, respectively. The average heterozygosity was 0.17. The results revealed no significant (P?0.05) effect of the MSTN gene on body weight.

TGFβ/BMP Signaling Pathway in Cartilage Homeostasis.

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

Effects of Exercise Training on Growth and Differentiation Factor 11 Expression in Aged Mice.

Exercise training is considered an effective way to prevent age-related skeletal muscle loss. However, the molecular mechanism has not been clarified. Growth and differentiation factor 11 (GDF11) has been controversially considered a regulator of skeletal muscle aging. In this study, we examined whether GDF11 is associated with skeletal muscle aging and the effects of exercise training on age-related skeletal muscle loss. First, we observed that Gdf11 mRNA and protein expression levels in young (5-month-old, n = 6) and aged (22-to 26-month-old, n = 5) mice were not significantly different. Aged mice were then divided into sedentary (n = 5) and exercise (n = 6) groups. The exercise group performed moderate-intensity treadmill running for 6 weeks. Treadmill exercise training increased Gdf11 mRNA expression in the soleus muscle, but its protein expression was not altered. In contrast, the GDF11 level in the plantaris muscle was not changed at either the mRNA or protein level. Collectively, our data demonstrate that GDF11 levels do not change during aging, and that treadmill exercise training increased Gdf11 mRNA expression in a predominantly slow-twitch muscle.

Growth differentiation factor 11 locally controls anterior–posterior patterning of the axial skeleton

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β family member that has been identified as the central player of anterior–posterior (A–P) axial skeletal patterning. Mice homozygous for Gdf11 deletion exhibit severe anterior homeotic transformations of the vertebrae and craniofacial defects. During early embryogenesis, Gdf11 is expressed predominantly in the primitive streak and tail bud regions, where new mesodermal cells arise. On the basis of this expression pattern of Gdf11 and the phenotype of Gdf11 mutant mice, it has been suggested that GDF11 acts to specify positional identity along the A–P axis either by local changes in levels of signaling as development proceeds or by acting as a morphogen. To further investigate the mechanism of action of GDF11 in the vertebral specification, we used a Cdx2‐Cre transgene to generate mosaic mice in which Gdf11 expression is removed in posterior regions including the tail bud, but not in anterior regions. The skeletal analysis revealed that these mosaic mice display patterning defects limited to posterior regions where Gdf11 expression is deficient, whereas displaying normal skeletal phenotype in anterior regions where Gdf11 is normally expressed. Specifically, the mosaic mice exhibited seven true ribs, a pattern observed in wild‐type (wt) mice (vs. 10 true ribs in Gdf11 −/− mice), in the anterior axis and nine lumbar vertebrae, a pattern observed in Gdf11 null mice (vs. six lumbar vertebrae in wt mice), in the posterior axis. Our findings suggest that GDF11, rather than globally acting as a morphogen secreted from the tail bud, locally regulates axial vertebral patterning.

Beyond the bone: Bone morphogenetic protein signaling in adipose tissue

The bone morphogenetic proteins (BMPs) belong to the same superfamily as related to transforming growth factor β (TGFβ), growth and differentiation factors (GDFs), and activins. They were initially described as inducers of bone formation but are now known to be involved in morphogenetic activities and cell differentiation throughout the body, including the development of adipose tissue and adipogenic differentiation. BMP4 and BMP7 are the most studied BMPs in adipose tissue, with major roles in white adipogenesis and brown adipogenesis, respectively, but other BMPs such as BMP2, BMP6, and BMP8b as well as some inhibitors and modulators have been shown to also affect adipogenesis. It has become ever more important to understand adipose regulation, including the BMP pathways, in light of the strong links between obesity and metabolic and cardiovascular disease. In this review, we summarize the available information on BMP signaling in adipose tissue using preferentially articles that have appeared in the last decade, which together demonstrate the importance of BMP signaling in adipose biology.

Regulation of follicular development and differentiation by intra-ovarian factors and endocrine hormones.

Primordial germ cell migration and homing within the gonadal ridge during early embryo development requires oocyte-secreted polypeptide, growth factors, growth and differentiation factors (GDFs), bone morphogenetic proteins, stem cell factor (SCF), and basic fibroblast growth factor (bFGF). During embryogenesis, the germ cells migrate into developing gonads and undergo intra-ovarian development which involves the contact of primordial germ cells with other cells. Further follicular development and differentiation is tightly regulated by hormones and by intraovarian regulators. Maturation of cumulus-oocyte complexes and ovulation are directly controlled by FSH and LH and requires activation of mitogen-activated protein kinase in granulosa cells. The selection of dominant follicles is driven by a series of proliferation and apoptotic events. Together, the available data suggests that follicular development is regulated both by systemic and local factors.

Abstract 17217: ActRIIA-Fc Rebalances Activin/GDF and BMP9 Signaling to Attenuate Experimental Pulmonary Hypertension

Introduction: Therapies targeting the underlying mechanisms of pulmonary arterial hypertension (PAH) might modify the natural history of disease. The genetics of heritable PAH implicate deficient BMP signaling as a pathogenetic driver. Lung tissues from experimental and human PAH exhibit deficient BMP & excessive TGFβ signaling. While previous studies suggest agonism of BMP9 signaling or inhibition of TGFβ signaling may prevent experimental PH, the roles of activin and growth and differentiation factor (GDF) ligand signaling are unclear. ACTRIIA-Fc (sotatercept) is an activin- and GDF8/11-specific ligand trap currently in Phase 2 studies for anemia and multiple myeloma. Hypothesis: ACTRIIA-Fc inhibits activin and GDF8/11 signaling in vascular cells to attenuate experimental PH and pulmonary vascular remodeling. Methods: Impact of ACTRIIA-Fc on BMP & TGFβ signaling was examined in human pulmonary microvascular endothelial (PMVEC) and pulmonary arterial smooth muscle cells (PASMC). ACTRIIA-Fc (15 mg/kg s.c. 2x/week), sildenafil (30 mg/kg p.o. BID) or vehicle were given prophylactically for 4 weeks to rats developing PH following a single injection of MCT (40 mg/kg s.c.), or via single injection of SU5416 (200 mg/kg s.c.) combined with hypoxia (FIO2=0.10, SU-Hx). Alternately, rats were allowed to develop PH following SU-Hx treatment for 3 weeks or MCT treatment for 4 weeks, and then treated with ACTRIIA-Fc (1, 3, or 10 mg/kg s.c. 2x/week) or isotype-matched control antibody (3 weeks under normoxia following SU-Hx, or 2 weeks following MCT). Invasive hemodynamics, RV mass and vascular remodeling were assessed. Results: In PMVEC, ACTRIIA-Fc enhanced BMP9-induced SMAD1/5/8 activation and transcriptional activity, and reversed inhibition of BMP9 signaling by GDF11. ACTRIIA-Fc inhibited GDF8-, GDF11- and activin A-mediated SMAD2 phosphorylation and myogenic differentiation of PASMC. In vivo , a standard dose of ACTRIIA-Fc prevented PH, RV hypertrophy and PV remodeling in MCT- and SU-Hx-rats, with more potency than sildenafil. All doses of ACTRIIA-Fc attenuated PH and RV hypertrophy when given in a delayed fashion after MCT- and SU-Hx-treatment, with graded effects on PV remodeling. Conclusions: ACTRIIA-Fc rebalances GDF11 vs. BMP9 signaling, with distinct effects in vascular endothelium vs. media, and potently inhibits experimental PH in several rodent models. Given its well-defined tolerability, dosing, and efficacy in previous human studies, ACTRIIA-Fc is an attractive candidate for PAH as a novel, mechanism-targeted therapy.

Endocrine Regulation of Energy Balance by Drosophila TGF-β/Activins.

The Transforming growth factor beta (TGF-β) family of secreted proteins regulates a variety of key events in normal development and physiology. In mammals, this family, represented by 33 ligands, including TGF-β, activins, nodal, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), regulate biological processes as diverse as cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine functions. In Drosophila, only 7 members of this family are present, with 4 TGF-β/BMP and 3 TGF-β/activin ligands. Studies in the fly have illustrated the role of TGF-β/BMP ligands during embryogenesis and organ patterning, while the TGF-β/activin ligands have been implicated in the control of wing growth and neuronal functions. In this review, we focus on the emerging roles of Drosophila TGF-β/activins in inter-organ communication via long-distance regulation, especially in systemic lipid and carbohydrate homeostasis, and discuss findings relevant to metabolic diseases in humans.

Differing Effects of Younger and Older Human Plasma on C2C12 Myocytes in Vitro.

Ageing is associated with a general reduction of physiological function and a reduction of muscle mass and strength. Endocrine factors such as myostatin, activin A, growth and differentiation factor 11 (GDF-11) and their inhibitory peptides influence muscle mass in health and disease. We hypothesised that myocytes cultured in plasma from older and younger individuals would show an ageing effect, with reduced proliferation and differentiation in older environments. C2C12 myoblasts were grown as standard and stimulated with media conditioned with 5% plasma from healthy male participants that were either younger (n = 6, 18–35 years of age) or older (n = 6, >57 years of age). Concentration of plasma myostatin (total and free), follistatin-like binding protein (FLRG), GDF-11 and activin A were quantified by ELISA. Both FLRG and activin A were elevated in older individuals (109.6 and 35.1% increase, respectively), whilst myostatin (free and total) and GDF-11 were not. Results indicated that plasma activin A and FLRG were increased in older vs. younger participants, GDF11 and myostatin did not differ. Myoblasts in vitro showed no difference in proliferation rate between ages, however scratch closure was greater in younger vs. older plasma stimulated myoblasts (78.2 vs. 87.2% of baseline scratch diameter, respectively). Myotube diameters were larger in cells stimulated with younger plasma than with older at 24 and 48 h, but not at 2 h. A significant negative correlation was noted between in vivo plasma FLRG concentration and in vitro myotube diameter 48 h following plasma stimulation (r2 = 0.392, p = 0.030). Here we show that myoblasts and myotubes cultured in media conditioned with plasma from younger or older individuals show an ageing effect, and further this effect moderately correlates with circulating FLRG concentration in vivo. The effect of ageing on muscle function may not be innate to the tissue, but involve a general cellular environment change. Further work is needed to examine the effect of increased FLRG concentration on muscle function in ageing populations.

The TGFβ superfamily in cardiac dysfunction.

TGFβ superfamily includes the transforming growth factor βs (TGFβs), bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and Activin/Inhibin families of ligands. Among the 33 members of TGFβ superfamily ligands, many act on multiple types of cells within the heart, including cardiomyocytes, cardiac fibroblasts/myofibroblasts, coronary endothelial cells, smooth muscle cells, and immune cells (e.g. monocytes/macrophages and neutrophils). In this review, we highlight recent discoveries on TGFβs, BMPs, and GDFs in different cardiac residential cellular components, in association with functional impacts in heart development, injury repair, and dysfunction. Specifically, we will review the roles of TGFβs, BMPs, and GDFs in cardiac hypertrophy, fibrosis, contractility, metabolism, angiogenesis, and regeneration.

Transcription factors-Intricate players of the bone morphogenetic protein signaling pathway.

Bone morphogenetic proteins (BMPs) are a family of growth factors, some of which are known by the name growth and differentiation factor (GDF). BMPs were discovered in the 1960s in an attempt to find factors capable of inducing bone formation. By the end of 1980s, several different BMPs had been found and to date, around 20 members are known. Together with TGFβ, nodal, and activins, they comprise the TGFβ superfamily. BMPs are known to regulate cell fate both in development and adult tissues, and as such they are also involved in many disease states. Understanding the impact of BMPs in these processes requires intimate knowledge of the regulation of the BMP signaling pathway. The intracellular BMP pathway has been studied extensively but the various transcription factors (TFs) necessary for the BMP-mediated gene expression changes have remained under less scrutiny. Most of the studies have focused on specific TFs in the context of differentiation or development. Varying cell types and BMPs have been used, but no large-scale studies have yet been performed. Here we aim to summarize the current knowledge on BMP pathway-related TFs, focusing on those involved in the canonical BMP signaling pathway through the SMAD proteins.

Molecular characterization and expression analysis of the myostatin gene and its association with growth traits in Noble scallop (Chlamys nobilis).

Myostatin (MSTN), also called growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β (TGF-β) superfamily and an inhibitor of muscle differentiation and growth. In this report, we identified and characterized a MSTN gene (CnMSTN) from the scallop Chlamys nobilis. The open reading frame of CnMSTN was 1374bp in length, encoding 457 amino acids. The structure of CnMSTN included a putative signal peptide, a TGF-β propeptide domain, and a conserved TGF-β domain. Phylogenetic analysis showed that the CnMSTN gene was clustered in the same subgroup with the MSTN gene found in Mollusca. Quantitative real-time PCR showed that the CnMSTN gene was widely expressed in all tissues tested, with the highest expression level observed in the adductor muscle. Six single nucleotide polymorphisms (SNPs) were identified in the promoter region, but no SNP was detected in the exon regions. Association analysis showed that SNP g.-579A/C had significant effects on body mass, soft-tissue mass, and adductor muscle mass. The CC and AC genotypes of g.-579A/C had significantly higher growth trait values than that of genotype AA (P<0.05). These results suggest that CnMSTN could be used as a candidate gene for the selective breeding of C. nobilis.

Heparin, Heparan Sulphate and the TGF-β Cytokine Superfamily

Of the circa 40 cytokines of the TGF-β superfamily, around a third are currently known to bind to heparin and heparan sulphate. This includes TGF-β1, TGF-β2, certain bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), as well as GDNF and two of its close homologues. Experimental studies of their heparin/HS binding sites reveal a diversity of locations around the shared cystine-knot protein fold. The activities of the TGF-β cytokines in controlling proliferation, differentiation and survival in a range of cell types are in part regulated by a number of specific, secreted BMP antagonist proteins. These vary in structure but seven belong to the CAN or DAN family, which shares the TGF-β type cystine-knot domain. Other antagonists are more distant members of the TGF-β superfamily. It is emerging that the majority, but not all, of the antagonists are also heparin binding proteins. Any future exploitation of the TGF-β cytokines in the therapy of chronic diseases will need to fully consider their interactions with glycosaminoglycans and the implications of this in terms of their bioavailability and biological activity.

Activin A more prominently regulates muscle mass in primates than does GDF8

Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.

Supraphysiological levels of GDF11 induce striated muscle atrophy

Growth and differentiation factor (GDF) 11 is a member of the transforming growth factor β superfamily recently identified as a potential therapeutic for age‐related cardiac and skeletal muscle decrements, despite high homology to myostatin (Mstn), a potent negative regulator of muscle mass. Though several reports have refuted these data, the in vivo effects of GDF11 on skeletal muscle mass have not been addressed. Using in vitro myoblast culture assays, we first demonstrate that GDF11 and Mstn have similar activities/potencies on activating p‐SMAD2/3 and induce comparable levels of differentiated myotube atrophy. We further demonstrate that adeno‐associated virus‐mediated systemic overexpression of GDF11 in C57BL/6 mice results in substantial atrophy of skeletal and cardiac muscle, inducing a cachexic phenotype not seen in mice expressing similar levels of Mstn. Greater cardiac expression of Tgfbr1 may explain this GDF11‐specific cardiac phenotype. These data indicate that bioactive GDF11 at supraphysiological levels cause wasting of both skeletal and cardiac muscle. Rather than a therapeutic agent, GDF11 should be viewed as a potential deleterious biomarker in muscle wasting diseases.

TGF-β Family Signaling in Epithelial Differentiation and Epithelial-Mesenchymal Transition.

Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or pathologically. Transforming growth factor-βs (TGF-βs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-β family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated epithelial cell types within an organ. TGF-β ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evidence that illustrates how TGF-β family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining.

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases.

The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.

Correlating single nucleotide polymorphisms in the myostatin gene with performance traits in rabbit

The Myostatin (MSTN), or Growth and Differentiation Factor 8 (GDF8), gene has been implicated in the double muscling phenomenon, in which a series of mutations render the gene inactive and unable to properly regulate muscle fibre deposition. Single nucleotide polymorphisms (SNPs) in the MSTN gene have been correlated to production traits, making it a candidate target gene to enhance livestock and fowl productivity. This study aimed to assess any association of three SNPs in the rabbit MSTN gene (c.713T&amp;gt;A in exon 2, c.747+34C&amp;gt;T in intron 2, and c.*194A&amp;gt;G in 3’-untranslated region) and their combinations, with carcass, production and reproductive traits. The investigated traits included individual body weight, daily body weight gain, carcass traits and reproductive traits. The 3 SNPs were screened using PCR-restriction fragment length polymorphism (RFLP)-based analysis and the effects of the different SNP genotypes and their combinations were estimated in a rabbit population. Additionally, additive and dominance effects were estimated for significant traits. The results found no significant association between the c.713 T&amp;gt;A SNP and all the examined traits. Allele T at the c.747+34C&amp;gt;T SNP was only significantly associated (P&amp;lt;0.05) with increased body weight at 12 wk of age. However, for the SNP residing in the 3’ untranslated region (c.*194A&amp;gt;G), allele G was significantly associated (P&amp;lt;0.05) with increased body weight and high growth rate. Genotype GG at the c.*194A&amp;gt;G SNP also had positive effects on most carcass traits. The estimated additive genetic effect for the c.*194A&amp;gt;G SNP was significant (P&amp;lt;0.05) with most body weight, daily gain and carcass traits. No significant association was obtained between any MSTN SNPs and reproductive traits. In the combinations analysis, regardless of the genotypes of SNPs at c.713T&amp;gt;A and c.747+34C&amp;gt;T, GG at the c.*194A&amp;gt;G SNP correlated with highest values in body weight and daily weight gain. In conclusion, the ‘G’ allele at the c.*194A&amp;gt;G SNP had positive effects on growth and carcass traits and so could be used as a favourable allele in planning rabbit selection. Further population-wide studies are necessary to test the association of the c.*194A&amp;gt;G SNP with carcass traits. We also recommend evaluation of the potential effects of the c.*194A&amp;gt;G SNP on MSTN gene expression.

Molecular characterization, expression analysis of the myostatin gene and its association with growth traits in sea cucumber (Apostichopus japonicus).

Myostatin (MSTN), also referred to as growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily (TGF-β) and an important negative regulator for skeletal muscle development and growth in vertebrates. However, its function is not clear in invertebrates. In this study, we cloned and analyzed the MSTN gene (Aj-MSTN) from sea cucumber (Apostichopus japonicus). The full-length cDNA sequence of Aj-MSTN gene was composed of 2912bp, which contained a 5' UTR of 487bp, an ORF of 1356bp encoding 452 amino acids and a 3' UTR of 1069bp. The structure of Aj-MSTN included a putative signal peptide, a TGF-β propeptide domain and a conserved TGF-β domain. Phylogenetic analysis showed that the Aj-MSTN gene was clustered in the same subgroup with the MSTN-like gene found in Strongylocentrotus purpuratus. Quantitative real-time PCR detection results indicated that the Aj-MSTN gene expressed widely in adult tissues and the highest expression level was observed in the body wall. At different developmental stages, the expression levels were increased significantly at early auricularia and doliolaria stages, and reached the peak at juvenile stage. Six SNPs were identified in 5' flanking region and exons of the Aj-MSTN gene. Association analysis showed that SNP-1, SNP-2 and SNP-4 had significant effects on dry body weight. The results suggested that Aj-MSTN gene could be used as a candidate gene for the selective breeding of A. japonicus.

Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes. We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homolog, myostatin (MSTN), based on unique amino acid sequence features. Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women. In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, higher GDF11 at surgical baseline was associated with rehospitalization and multiple adverse events. Cumulatively, our results show that GDF11 levels do not decline throughout aging but are associated with comorbidity, frailty, and greater operative risk in older adults with cardiovascular disease.