Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer’s disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases.
Given the pro and anti-geronic roles of the TGF-β superfamily in aging, we hypothesized that human longevity involves genetic variation in TGF-β signaling genes. Here we utilized a candidate functional genomic approach to identify and characterize functional variants in TGF- β signaling associated with human longevity. Targeted sequencing of 113 genes involved in aging- associated TGF- β signaling in an Ashkenazi Jewish centenarian cohort identified genetic variants robustly associated with human longevity. In particular, a centenarian-enriched intronic variant residing in a cell-type specific enhancer in SMAD3, a critical receptor-regulated TGF- β signal transducer, was identified. This non-coding SMAD3 variant (rs8040709) altered binding of ELK1, a member of the ETS family of transcription factor important for enhancer activity in certain cell types, resulting in reduced SMAD3 expression. Analysis of the variant in cell types derived from gene edited iPSCs demonstrated the variant reduced SMAD3 expression, senescence and inflammation in endothelial cells. In addition, heterozygosity in SMAD3 improved healthspan and reduced senescence in the Ercc1 -/Δ progeroid mouse model of accelerated aging. Taken together, these experiments demonstrate that variants in a cell type specific enhancer of SMAD3 resulted in reduced expression, senescence and inflammation and contributes to human longevity. Thus, SMAD3 represents a validated targeted for drug development for extending human healthspan.
Thank you for bringing up TGF beta. How to optimize THFb has been on my mind for quite some time. Someone, any ideas?
I have seen thoughts, that TGF beta just like mTOR is critical in some stages/situations in life. But that with advancing age, it can be considered overactive and act as a driver of the ageing processes.
I get ideas from this speculative paper.
In my regim, I already employ some of the supplements mentioned. But I the importance of inhibiting TGF beta, in a specific way, is illusive to me.
" Conclusion
In summary, spirulina/PhyCB, phase II inducers such as lipoic acid, ferulic acid or broccoli sprout powder, melatonin, berberine, high-dose biotin, soy isoflavones, taurine and NAC may have potential for downregulating TGFβ signalling, and thereby decreasing risk for, or improving clinical control of, a wide range of pro-fibrotic pathologies. Suggested dose schedules for these agents are presented in box 1. With regard to post-COVID-19 syndrome specifically, the antioxidant/anti-inflammatory effects of PhyCB, phase II inducers, melatonin and NAC might address neurological aspects of this syndrome thought likely to reflect chronic inflammation of cerebrovascular endothelial cells and microglia.269–272 Further studies are needed to confirm the benefit and safety of this potential nutraceutical strategy in COVID-19."
I was interested to see if I could find any natural ALK5 inhibitors, so I asked
Dr.Oracle: “Several natural compounds have been studied for their potential to modulate the TGF-β pathway, which includes ALK5 signaling. Some of these include resveratrol, found in grapes and red wine; curcumin, derived from turmeric; epigallocatechin gallate (EGCG), a component of green tea; and various flavonoids present in fruits and vegetables. Genistein, found in soy products, has also shown promise in this area. However, it’s important to note that while these compounds have demonstrated effects on TGF-β signaling in laboratory studies, their specific action on ALK5 and their clinical efficacy as ALK5 inhibitors require further research and validation.”
Interestingly, epigallocatechin gallate (EGCG), a green tea extract, has been mentioned in
many other threads for other benefits. Perhaps I should add it back again into my already too-long supplement stack.
“Flavonoids, a ubiquitous dietary phenolic subclass,
exert extensive in vitro anti-invasive and in vivo
anti-metastatic activities”
https://sci-hub.se/10.1007/s10555-012-9347-y
But none of those substances worked in the cancer-prone ITP mice.
I thought the ITP only used wild-type (genetically heterogeneous) mice.
Having said that, mice are, of course, more prone to cancer than humans.
Intriguingly, like RepSox, colchicine also seems to inhibit TGFβ1/ALK5.
The genomics and bioinformatics analysis indicated that the TGFβ1/ALK5 signaling pathway may be involved in the therapeutic mechanism of colchicine on AF. We then verified the expression of key proteins in the classic TGFβ1/ALK5 fibrosis pathway by WB. The results suggested that colchicine did act on the TGFβ1/ALK5 fibrosis pathway. To identify other possible pathways by which colchicine might alleviate myocardial fibrosis, we validated the activin A/ALK4 fibrosis pathway by WB, and it was also found to play an important role in the pathogenic fibrotic mechanism of AF. Similarly, colchicine was found to act on the activin A/ALK4 fibrosis pathway to reduce myocardial fibrosis.
I guess you can use the orally available drug galunisertib (instead of RepSox) together with tranylcypromine for partial chemical reprogramming.
The drug is probably quite safe when taken for a short period for chemical reprogramming.
Based on the role of TGF-β in patients with malignant GB, evidence of antitumor effects of TGF-β inhibitors such as galunisertib (including in a monotherapy study in glioblastoma), and a favorable short- and long-term toxicity profile, a multicenter Phase 1b/2a clinical trial was initiated to investigate the clinical benefit of combining galunisertib with standard TMZ-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma.
I was at the Bay Area Aging meeting and one of Irina Conboy’s PostDocs gave a presentation on TGF-Beta and the research they were doing on it. I forget the details of that exact presentation, but doing a google search it seems to be an area the Conboys’ have done a fair amount of work and I’ve heard Irina talk about it quite a bit.
“We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle,” said co-author David Schaffer, director of the Berkeley Stem Cell Center and a professor of chemical and biomolecular engineering. “That is good news, because if every tissue had a different molecular mechanism for aging, we wouldn’t be able to have a single intervention that rescues the function of multiple tissues.”
The drug interferes with the activity of a growth factor, transforming growth factor beta 1 (TGF-beta1), that Schaffer’s UC Berkeley colleague Irina Conboy showed over the past 10 years depresses the ability of various types of stem cells to renew tissue.
“Based on our earlier papers, the TGF-beta1 pathway seemed to be one of the main culprits in multi-tissue aging,” said Conboy, an associate professor of bioengineering. “That one protein, when upregulated, ages multiple stem cells in distinct organs, such as the brain, pancreas, heart and muscle. This is really the first demonstration that we can find a drug that makes the key TGF-beta1 pathway, which is elevated by aging, behave younger, thereby rejuvenating multiple organ systems.”
Drug makes old tissue cleverer
The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever, Conboy said.
These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.
and a related query to ChatGPT:
What are all the drugs that may be classified as Alk5 kinase inhibitors
ChatGPT
ALK5 kinase inhibitors are a subset of drugs designed to target and inhibit the activity of the ALK5 (Activin Receptor-Like Kinase 5) protein, which is part of the TGF-beta superfamily of receptors involved in various cellular processes, including cell growth and differentiation. These inhibitors are primarily used in research and have potential applications in treating diseases related to aberrant TGF-beta signaling.
Here are some notable ALK5 kinase inhibitors:
- SB-431542: This is one of the most well-known ALK5 inhibitors and is often used in research to study TGF-beta signaling pathways.
- LY2157299 (also known as TGF-β Receptor I Inhibitor): This compound has been studied for its potential in treating cancer and fibrosis by targeting TGF-beta signaling.
- GW788388: Another selective ALK5 inhibitor, which has been investigated for its effects on cancer and fibrotic diseases.
- RepSox (also known as N-[4-(4-phenylthiazol-2-yl)phenyl]methanesulfonamide): This is a small molecule inhibitor that targets ALK5 and has been used in research to investigate its impact on various cellular processes.
These inhibitors are primarily utilized in research settings to explore the role of TGF-beta signaling in diseases and to develop potential therapeutic strategies.
It’s important for AGA too.
Background: Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}.
Methods: For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-β-induced Smad2/3 phosphorylation in A549 cells and TGF-β-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation.
Results: TP0427736 inhibited ALK5 kinase activity with an IC50 of 2.72nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase.
Conclusions: TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA.
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Tgf beta is also an anti-inflammatory interleukin like interleukin 10, IL-13, IL-19, IL-35. In other words, they reduce inflammation. We already know the connection between inflammation and aging, aging itself is actually a chronic inflammation. Recently, a study has come out showing that there is a significant connection between interleukins and aging. When viewed from this perspective, in addition to the inhibition of mTOR and MAPK pathways that increase growth and development unnecessarily, the inhibition of interleukins that increase chronic inflammation and the strengthening of anti-inflammatory interleukins that stop chronic inflammation will slow down aging even more.
The pathophysiology of aneurysm development in MFS is a complex, multifactorial process. Upregulated p‐Erk1/2 and p‐Smad2 signaling in both MFS human and mouse aortic specimens suggests a pathogenic role for TGF‐β.
To define a mechanistic link between androgens, TGF‐β‐dependent Erk/Smad signaling and increased MMP activity, MMP‐2 activity levels were measured with gelatin zymography (Figure 4C: n=6 each group). MMP‐2 activity was significantly increased after TGF‐β stimulation compared with vehicle control (TGF‐β=1.56 [1.45–1.81] fold increase/vehicle control, P=0.002). TGF‐β+DHT further increased MMP‐2 activity levels (TGF‐β+DHT=2.47 [2.27–2.89] versus TGF‐β=1.56 [1.45–1.81] fold increase/vehicle control, P=0.009). The enhanced activity was reduced with flutamide treatment (TGF‐β+DHT=2.47 [2.27–2.89] versus TGF‐β+DHT+flutamide=1.69 [1.58–1.78] fold increase/vehicle control, P=0.008).
Although TGF‐β and DHT both enhance androgen receptor activity in prostatic stromal cells,27, 28, 29 the mechanistic link between androgen receptors, TGF‐β and DHT in aortic SMCs remains unclear. Androgen receptor protein levels were measured with western blotting from SMC lysates following either TGF‐β or DHT treatment for 24 hours. Both TGF‐β and DHT treatment significantly increased androgen receptor levels in Fbn1C1039G/+ male SMCs (TGF‐β=1.33 [1.29–1.35] fold increase/vehicle control, P=0.046) (Figure 5A: n=6 each group). Confirming these results, immunocytochemistry revealed that SMC androgen receptor expression was increased following either TGF‐β or DHT treatment after 48 hours (Figure 5B).
The major findings of this study are (1) Fbn1C1039G/+ male mice have enhanced aortic aneurysm growth compared with females; (2) ASC aorta p‐Erk1/2 and p‐Smad2 signaling is increased in MFS male mice and corresponds with enhanced MMP‐2 activity; (3) androgens potentiate TGF‐β‐induced p‐Erk1/2 and p‐Smad2 activation and SMC MMP‐2 activity, in vitro; and (4) androgen blockade with flutamide treatment attenuates ASC aneurysm growth in Fbn1C1039G/+ male mice, in vivo.
Matching increased aortic size, increased elastin breaks in MFS male mice compared with females provided histologic confirmation of enhanced proteolysis, in vivo. Furthermore, in vitro mechanistic assays confirm the synergistic effects of androgen and TGF‐β as inducers of Smad/Erk activation and ultimately MMP‐2 activity. Interestingly, female Fbn1C1039G/+ derived SMCs showed a muted p‐Erk1/2 response to TGF‐β with and without DHT in vitro, as well as more modest p‐Erk1/2 levels from ASC aortic tissue samples compared with males.
Noteworthy, Bowen et al recently identified a role for androgens in aortic aneurysm rupture using a vascular Ehlers‐Danlos mouse model, likely via the protein kinase C (PKC)/Erk pathway.33 In addition, we also noted that TGF‐β and DHT treatment significantly increased androgen receptor levels in Fbn1C1039G/+ male SMCs. Several studies have described the progression of abdominal aortic aneurysm pathology in male mice, demonstrating that castration or androgen receptor blockade attenuates abdominal aortic aneurysm development.13, 34 Although the mechanistic link between TGF‐β signaling and androgens in vascular SMCs still remains undefined, TGF‐β activates androgen receptors in prostatic stromal cells,23 whereas androgens modulate the TGF‐β/SMAD pathway in cardiomyocytes.21 Moreover, there are several studies demonstrating that androgens affect apoptosis, proliferation, and migration via p‐Erk1/2 activation in vascular SMC,35, 36, 37 all biological processes that potentially play a role during aneurysm formation.
Administration (flutamide, spironolactone) may play a role in inhibition of MFS aneurysm progression and prolong time to definitive repair, although there are several unwanted side effects in young men, including gynecomastia and decreased muscle mass.
Empagliflozin was shown to prevent TGFβ1-induced activation of human fibroblasts isolated from right cardiac atrium. These cells didn’t transcribe SLC5A2, which suggest that the effect is independent of empa’s SGLT2i activity.
TGFβ is implicated in 5-HT2B agonist valvulopathies (e.g fenfluramine, cabergoline), which suggests that empagliflozin might be protective in combination with these drugs.
I use wobenzym daily to lower TGF-beta (2 pills on an empty stomach). It’s very safe, and has pleasant effects overall.
Many longevity meds seem to have antifibrotic effects (we don’t really know if it’s organ-specific or not, the researchers don’t care enough to conduct studies on ‘healthy’ aging skin). I’m kind of concerned about my TGF-β levels dropping too low and causing thin skin.