Is GDF11 a Rejuvenating Factor?
The growth differentiation factor 11 (GDF11) or bone morphogenetic protein 11 (BMP-11) is a protein that belongs to the transforming growth factor-beta family (TGF-b) that is involved in cell proliferation and differentiation, wound healing, and the immune system [1].
GDF11 has been proposed as a rejuvenating factor as it was reported that it restores skeletal muscle stem cell function and enhances muscle repair after injury. In this blog, scientific literature on GDF11 is explored to clarify the potential role of this factor in tissue regeneration and longevity.
What Is the Function of GDF11 in the Body?
Before discussing the role of GDF11 in the body, it is important to provide information on its expression in adults and during embryogenesis.
A- Where Is GDF11 Expressed in Humans?
1- Where is GDF11 Expressed in Human Adults?
GDF11In humans, the GDF11 protein is highly expressed in the brain, testis, soft tissue, breast, placenta, prostate, stomach, epididymis, and gallbladder. It is mildly expressed in the intestines, salivary gland, the thyroid, the parathyroid, the adrenal gland, the liver, and the tonsils.
However, it appears that there is no protein expression in the other organs and tissues such as the heart, the skin, skeletal and smooth muscles, or the bone marrow [2].
2- Where is GDF11 Expressed During Human Embryogenesis?
Although based on RNA studies in mice, Gdf11 is mostly expressed in the primitive streak and tailbud regions. The primitive streak is a structure that generates new mesodermal progenitors (stem cells) migrate and differentiate into the mesoderm germ layer that generate future cells such as cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, and smooth muscle cells (in the gut).
The Tail bud or caudal cell mass is the embryonic structure that is later responsible for the generation of the lower end of the spinal cord [3].
B- How does GDF11 Function?
As a member of the superfamily of the Transforming Growth Factor beta (TGF-β) and the subfamily of the BMP, GDF11 induces cellular signaling through the canonical (classical) signal transduction pathways involving R-SMADS and SMAD4.
However, GDF11 also induces cellular signaling through non-canonical pathways such as the MAPK (Mitogen-Activated Protein Kinase) pathway. Both signalings require the binding of GDF11 to the activin receptors type II A or B [4].
The activation of the canonical and non-canonical pathways results in the transcriptional induction of the expression of genes that control cell proliferation and differentiation, wound healing, and the immune system [5].
C- How Is GDF11 Activated?
Although little is known about the mechanisms that induce the expression of GDF11, a study showed that histone deacetylase 3 (HDAC3), might be involved. The inhibition of HDAC3 using the drug trichostatin A (TSA) promoted the expression of GDF11 [6].
D- What Is the Role of GDF11 in Regeneration?
Although performed in mice, several studies reported that GDF11 can reverse age-related cardiac hypertrophy, and dysfunction of skeletal muscles, accelerate skin wound healing, improve the neuronal activity in the hippocampus, and enhances angiogenesis by promoting the therapeutic functions of mesenchymal stem cells.
1- Does GDF11 Improve Age-Related Vascular and Neuronal Activity in the Hippocampus?
A study reported that bloodstream delivery of GDF11 to older mice improves vasculature and promotes neurogenesis in the hippocampus. The authors suggest that GDF11 could be used to improve the central nervous system function [7].
2- Does GDF11 Reverse Age-Related Dysfunction of the Skeletal Muscle?
A study reported that the systemic delivery of GDF11 in older mice reverses functional deficiencies and restores the genomic integrity of muscle stem cells. The authors suggest that systemic delivery of GDF11 could be therapeutically used to reverse age-related skeletal muscle and stem cell dysfunction [8].
3- Does GDF11 Reverse Age-Related Cardiac Hypertrophy?
In aged individuals, heart hypertrophy is frequently associated with heart failure. Using a technique called parabiosis which consists in sharing circulation between younger and older mice with cardiac hypertrophy, a study reported that the hypertrophy was completely reversed in the older mice.
The authors identified GDF11 as the factor responsible and suggest that it could be used in therapy to reverse age-related cardiac hypertrophy [9].
4- Does GDF11 Accelerate Skin Wound Healing?
A study investigated the effects of topically applying truncated GDF11 on wound healing of diabetes mellitus (DM) mice models and reported that truncated GDF11 promotes skin wound healing by stimulating dermal fibrosis. They suggest truncated GDF11 could be used as a potential agent for treating skin wounds in the diabetic population [10].
5- Does GDF11 enhance Angiogenesis?
A study investigated the potential use of GDF11 capacity in inducing proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy. They found that GDF11 promotes the therapeutic functions of MSCs that could be used for ischemic diseases [11].
Conclusion
A rejuvenating function of GDF11 has been reported by several studies that involved different organs and tissues. However, all these investigations were performed in mice which may not result in similar outcomes in humans. Therefore, clinical trials using GDF11 would certainly determine if this factor is really the “Mythical Fountain of Youth”.
References
[2] https://www.proteinatlas.org/ENSG00000135414-GDF11/tissue
