TRANSFORMING GROWTH FACTOR BETA-1

Transforming Growth Factor beta-1 (TGFβ1)

(WikiLinks: Oxytocin) - (WikiLinks: TGF-β) - (Last Revision: 10/14/2022)

TGFβ1

Oxytocin

◉ This page focuses on Transforming Growth Factor Beta-1 as one of two determinate of aging when combined with Oxytocin. To review the Oxytocin specific information please go to: Oxytocin.

◉ We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age.

YOUNG VS OLD CHANGES IN TGF SIGNALING

TGF-β signals through two serine/threonine kinase receptors, the type I (TGFβR-I) and type II (TGFβR-II) receptors. The type I receptor is inactive in the absence of ligand while type II receptor is constitutively active. [52]

Transforming growth factor beta1 (TGF- beta1) becomes up regulated with age systemically and locally, and experimental attenuation of the age-increased TGF-beta/pSmad3 reduces B2M in muscle and brain 1,8,22. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. [15, [i]]

[i] TGFβ1-induced SMAD2/3 and SMAD1/5 phosphorylation are both ALK5-kinase-dependent in primary chondrocytes and mediated by TAK1 kinase activity

TGFβ1 Natural and Small Molecule Inhibitors of ALK5 pathway

A large number of supplements and small molecules exists that effectively inhibit TGFbeta-1 via the ALK5 kinase pathway. The image on the right provides a few examples.

Dosing Consideration:

⫸ There are other considerations for not overly diminishing TGF- beta signaling include the need for this pathway in the balance between tissue damage and host defense [53], immune modulation through attenuation of MHC genes and concomitant activation of NK cells [54, 55], and regulation of proliferation, differentiation, and growth of various cell types [20]. These reasons and our experimental observations in sum support the notion of minimizing the dose of pathway modulating drugs such as Alk5i, which as shown here, does not restrict but broadens the positive multi-tissue effects through combination with OT. OT alone has been shown to enhance the regeneration of old injured muscle in a 9- day protocol [12]. However, we shortened the treatment to 7 days and expanded the positive outcomes to brain and liver, by combining OT with Alk5i. ⫷ [1]

Curcumin worked synchronously with EGCG and considerably interfered with tumor conditioned media-induced transition of normal endothelial cells toward tumor endothelial cells by inhibition of the JAK/STAT3 signaling pathway. • EGCG has emerged as a master-regulator of epigenetic-associated machinery. • EGCG was noted to completely block the phosphorylation of SMAD2/3 and nuclear accumulation of SMAD4 [41]. In addition to essential nutrients and amino acids, select phytochemicals (such as EGCG described above) have become of great interest for treating/preventing chronic disease, including diseases linked to mitochondrial malfunction. [13, 14, 15, 10]

Epigallocatechin gallate (EGCG), curcumin, and quercetin have all been identified as polyphenolic modulators of DNA methyl transferases (DNMT). [18]

Reversal of Epigenetic Age with Diet and Lifestyle in a Pilot Randomized Clinical Trial Interventional Agents: [PhytoGanix® and UltraFlora® Intensive Care, Metagenics, alpha ketoglutarate, vitamin C and vitamin A) (Hore, 2017) and (e.g. , luteolin)]

Sensing of the environment by cells relies extensively on receptors that bind extracellular molecules and trigger intracellular responses. The TGF-b pathway transduces a broad range of extracellular signals into transcriptional responses that affect many cellular processes, including cell growth, apoptosis, differentiation, homeostasis, and morphogenesis. It is used, for instance, to control the precise patterns and forms that arise during development, and its malfunction contributes to a wide variety of diseases and developmental disorders. Here the authors develop a concise computational model of the TGF-b pathway and show that the first layer of communication with the environment, the ligand-receptor network, is not merely a passive transducer of signals but rather embeds properties that makes it a signal processing unit. Receptors traffic between different cellular compartments from which they signal distinctly, leading to an unexpected richness of types of behavior that is not apparent from the simplicity of the typical cartoon representations of this pathway. At the receptor level, the system can select among different functioning modes to sense absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This extra level of regulation can explain a wide variety of phenomena and leads to a unified interpretation of seemingly disparate experimental observations.[?]

Figure 1. The transforming growth factor- (TGFß) family signaling pathways contribute to the context-dependent regulation of basic cellular processes though their interplay with the MEK/ERK, phosphatidylinositol 3'-kinase (PI3K)/ protein kinase B (Akt) (purple), WNT/GSK (brown), JAK/STAT (yellow), NOTCH (light blue), and NF-KB (orange) signaling pathways. TGFß family ligands (TGFß, Activins, Nodal, Lefties, bone morphogenic proteins (BMPs), and GDFs) bind to type I and type Il transmembrane eceptors and form an activated receptor complex, which phosphorylates R-Smads (Smad1-3,5,8) proteins. R-Smads- Smad4 complexes are translocated into the nucleus and directly or indirectly regulate the expression of numerous transcriptional factors that support proliferation, differentiation, the epithelial-mesenchymal transition, cell death, and survival. Smad6 and Smad7 agonize signaling activation by binding to R-Smads and preventing their interaction with Smad4. The canonical TGFß family signaling pathway contains two branches, TGFß/ActivinA/Nodal/Smad2/3(red) and BMP/GDF/Smad1/5/8 (blue), whereas non-canonical TGFß cascades act through pathways activated by MAPKs (MKK/Jun/p38) (black). TGFß family signaling pathways are modulated by various agonists and antagonists at different cellular levels.

TRANSFORMING GROWTH FACTOR BETA 1 / OXYTOCIN AXIS

⫸ A paper from the Cowboy lab in 2015 demonstrates dramatically the primary aging paradigm this site ascribes to. That is you can impact aging by addressing chronokines that control the systemic aging directive. Putting this in a simplistic framework; decreasing key biological targets that increase with age, and increasing those targets that decrease with aging. The paper they published describes and exemplifies this stratgie to a T. If you are perusing an anti-aging stratgie or are a student of age regression science, I would strongly recommend that you read the entire article “Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age” ⫷ [1]

Transforming growth factor-beta proteins are multifunctional cytokines, secreted by numerous cell types. They are capable of signaling to virtually every cell type and broadly control cell proliferation, differentiation, apoptosis, inflammation and scarring in various tissues [1], [2]

Youthful calibration of TGF-β1/pSmad2,3 pathway by a systemically administered inhibitor of TGF-β receptor kinase activity reduced tissue inflammation in brain and muscle, as indicated by normalized levels of B2M, and robustly rejuvenated hippocampal neurogenesis and skeletal myogenesis in the same old animal. [1]

Derynck and Zhang pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. Alk5-inhibitor (i) plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging.

TGF-b receptor complexes are nodal points for multiprotein assemblies that regulate receptor function, routing, and Smad and non-Smad signaling pathways. These interactions are likely to depend on the activation and subcellular localization of the receptors and vary throughout the ‘life cycle’ of the receptor complex. [1]

These findings also suggest that young sera may contain a functional and natural decoy of TGF-b1, or a competitor of TGF-b1 signaling pathway (either endocrine or released by platelets). Lastly, our results demonstrate that Wnt antagonizes, rather than synergizes with TGF-b1-mediated satellite cell response inhibition. [3], [1]

Low dose of Alk5i that is combined with OT increases the levels of OTR in old animals, and OTR signaling is needed for the health of the brain, as well as, peripheral tissues. Thus, a low dose of Alk5i that is combined with OT has greater potential clinical advantages. Other considerations for not overly diminishing TGFbeta signaling include the need for this pathway in the balance between tissue damage and host defense [53], immune modulation through attenuation of MHC genes and concomitant activation of NK cells [54, 55], and regulation of proliferation, differentiation, and growth of various cell types [20]. These reasons and our experimental observations in sum support the notion of minimizing the dose of pathway modulating drugs such as Alk5i, which as shown here, does not restrict but broadens the positive multi-tissue effects through combination with OT. OT alone has been shown to enhance the regeneration of old injured muscle in a 9- day protocol [12]. However, we shortened the treatment to 7 days and expanded the positive outcomes to brain and liver, by combining OT with Alk5i

YOUNG VS OLD CHANGES IN TGF SIGNALING

TGF-β signals through two serine/threonine kinase receptors, the type I (TGFβR-I) and type II (TGFβR-II) receptors. The type I receptor is inactive in the absence of ligand while type II receptor is constitutively active. [52]

Transforming growth factor beta1 (TGF- beta1) becomes up regulated with age systemically and locally, and experimental attenuation of the age-increased TGF-beta/pSmad3 reduces B2M in muscle and brain 1,8,22. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. [15, [5]

Image Source: [2020] Resveratrol Modulates Transforming Growth Factor-Beta (TGF-β) Signaling Pathway for Disease Therapy: A New Insight into Its Pharmacological Activities [12]

◉ Resveratrol: effectively inhibits SMAD proteins by either affecting post translational modifications by different enzymes to target SMAD proteins for degradation or by inhibiting the phosphorylation and activation of SMADs. either affecting post translational modifications by different enzymes to target degradation or by inhibiting the phosphorylation and activation of SMADs[3, AND 4 - 12].

◉ EGCG: TGF-b1 stimulates Egr-1 protein expression in normal BMFs. At a concentration of 10mM, EGCG almost completely abrogated the TGF-b1-stimulated production of collagens. EGCG inhibited TGF-b1 in a does dependent manor. EGCG has demonstrated synergistic activity with Curcumin, which also inhibitory activity inhibiting Egr-1 protein expression at 20 mM [13].

◉ Curcumin: TGF-b signaling isinitiated by TGF-b binding to its cell membrane receptorand formation of the activated receptor complex, whichthen phosphorylates intracellular messenger moleculeslike SMAD proteins [2]. Our data show that curcumindecreased TGF-b receptor II protein levels. This was associated with reduced SMAD2/3 phosphorylation after curcumin treatment, indicating reduced biological activity of the activated TGF-b receptor complex [14].

◉ Selenium: combined with EGCG is synergistic for inducing

⫸ Very interestingly, the productive myogenic proliferation of young and old muscle stem cells was robust in TGF-b1-depleted serum, only when low levels of recombinant TGF-b1 were introduced (Fig. 1A–C). At 1–5 ng mL)1 (and higher), TGF-b1 alone sufficed for the inhibition of satellite cell responses, while myogenesis was positively regulated at 0.2 ng mL)1 (Fig. 1A–C).Similarly, myogenic differentiation responses from young cells also peaked in TGF-b1-depleted serum, which received low levels of exogenous recombinant TGF-b1 (Supporting Fig. S2A). In contrast, old cell differentiation was improved by TGF-b1 depletion from serum alone, as well as in a low range of recombinantTGF-b1 addition (Supporting Fig. S2B). The overall differentiation response from old cells was also diminished, compared to young cells (Supporting Fig. S2A,B). As myogenic differentiation was assayed at 48–72 h of culture, and aged satellite cells have elevated TGF-b1 production (Carlson et al., 2008), these data suggest that endogenous TGF-b1 production by old cells, in vitro, counteracts the pro-myogenic effect of TGF-b1 depletion from mouse serum (Figs 1, S1A–D and S2A,B). Together, these data demonstrate that sera-derived TGF-b1 inhibits satellite cell responses, and that specific levels of TGF-b1 are required for productive myogenic responses. Even with complete TGF-b1 depletion, old serum remained less myogenic than young (by 10–20%), suggesting that while TGF-b1 is a main inhibitor of satellite cell responses, it is not the only suppressor of regeneration present in old sera (Figs 1A–C, S2A,B). Correlating the inhibitory range of TGF-b1 with physiological levels found in young and old seraTo further substantiate these conclusions, we correlated the inhibitory range of TGF-b1 with its levels found in young vs aged sera. Specifically, we analyzed TGF-b1 levels as a function of age in mice and in humans (Fig. 2A,B). In mice, TGF-b1 levels sharply increased between 12 months (early post reproductive age, analogous to 5th–6th decades in humans) and 24 months(analogous to 8th–9th decades in humans), Fig. 2A. More over, this systemic age-related rise was found to be conserved in humans (Fig. 2B), where TGF-b1 plateaus at its highest systemic levels between the 6th and 9th decades of life (i.e. roughly at the onset and progression of age-imposed regenerative decline). Sera TGF-b1 for both species thus becomes elevated from the end of the reproductive period, to the end of lifespan. ⫷[3]