Reviewing the Relationship Between TGF-β and Cellular Senescence

A rising level of TGF-β has long been associated with numerous aspects of aging. More modern research has shown it to encourage cells to become senescent. Further, TGF-β is an important component of the inflammatory mix of signals secreted by senescent cells, making it a part of the mechanism by which senescent cells can encourage their neighbors to also become senescent. When senescent cells fail to clear quickly, as happens in older individuals, this leads to a feedback loop of continually rising chronic inflammation and ever greater numbers of senescent cells. This is an important contribution to degenerative aging and the progressive failure of tissue and organ function throughout the body.

TGF-β exerts diverse functions by modulating the expression of downstream target genes via transcriptional and post-transcriptional mechanisms as well as protein modulation in a context-dependent manner. Importantly, the downstream targets of TGF-β signaling include many regulators involved in multiple aspects of aging processes, such as cell proliferation, cell cycle regulation, the production of reactive oxygen species (ROS), DNA damage repair, telomere regulation, unfolded protein response (UPR), and autophagy. Due to a large overlap between the two pathways, TGF-β signaling exhibits multifaceted crosstalk with aging processes. At the cellular level, TGF-β signaling has been shown to play an important role in cellular senescence and stem cell aging. Furthermore, the alteration of TGF-β signaling pathways has been frequently observed in various age-related diseases, including cardiovascular disease, Alzheimer's disease (AD), osteoarthritis, and obesity.

TGF-β has been shown to have dual functions in cancer biology: An early tumor suppressor and a late tumor promoter. The cytostatic effects of TGF-β are mediated by inducing the cyclin-dependent kinase inhibitors p15Ink4b, p21, and p27, and by suppressing several proliferation factors including c-Myc. This suggests a senescence promoting role of TGF-β under normal conditions and also coincides with the tumor suppressing role of cell senescence. TGF-β has been shown to induce or accelerate senescence and senescence-associated features in various cell types. In addition, the TGF-β-mediated accumulation of senescent cells has been suggested in idiopathic pulmonary fibrosis (IPF).

In addition to the cytostatic mechanisms, the senescence-promoting role of TGF-β might be explained by the effects on other modulators of senescent phenotypes. TGF-β reportedly induces ROS production in the mitochondria in several cell types. In addition, TGF-β suppresses telomerase activities by downregulating the expression of telomerase reverse transcriptase (TERT) in various cell types. Further, the senescence-associated secretory phenotype (SASP) yields the production and secretion of various signaling molecules, importantly including TGF-β. Thus, TGF-β is secreted as one of the SASP factors and can induce and maintain senescent phenotype and age-related pathological conditions in an autocrine/paracrine manner.

Link: https://doi.org/10.3390/ijms20205002

Comments

It's also the main reason our faces and bodies become older looking. TGF-B causes us to lose dermal fat, the good kind under the skin that keeps skin firm and young.
https://www.fightaging.org/archives/2018/12/tgf-β-is-involved-in-the-loss-of-fat-and-bacterial-defenses-in-aging-skin/

I would love thoughts on the following biohack:
The diabetes drug pioglitazone has been shown to help increase dermal fat in those who have lost it due to HIV drugs. A couple studies show a healthy increase in dermal fat with a decrease in viscarel fat in healthy people taking it low dose. This is interesting as it relates to the above study because ppar-gamma reduces TGF-β expression. Pioglitazone is the safest drug that can meaningfully increase ppar-gamma. Perhaps the anti-aging appearance effects of low dose ( 7.5 mg per day - https://www.hindawi.com/journals/aen/2015/782530/ ) Pioglitazone are related to TGF-β suppression via ppar-gamma activation.

https://www.sciencedirect.com/science/article/pii/S0531556517305569

"We hypothesized that oral pioglitazone treatment would inhibit TGF-β-driven renal fibrosis and its progression, by modulating profibrotic transcription factors in TGF-β1 transgenic mice." https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-019-1431-x

Posted by: August33 at January 8th, 2020 8:26 AM

@Reason, chronic inflamation seems a common cause of aging, doesn't it? It is maybe the 8th cause of aging? Or is it a consequence of the other 7? Thanks

Posted by: Josep at January 8th, 2020 12:04 PM

@Josep: It is a downstream consequence of damage, not damage itself. E.g. it is produced by senescent cells, among other causes.

Posted by: Reason at January 8th, 2020 5:59 PM

August33 - an interesting idea. I ran a cycle of pioglitazone years ago with the aim to increase subQ fat. It seemed to be successful, but I was scared off further experiments rightly or wrongly by bladder cancer worries. I expect there is a danger of telomere erosion with excessive stimulation of adipocyte progenitors, so you may not want to do this as a monotherapy.

Posted by: Mark at January 10th, 2020 6:10 AM

Thank you Mark, I wasn't as concerned about bladder cancer from such a small dose but telomere erosion definitely makes me look elsewhere. Finding a way to slow/stop dermal fat erosion is a huge deal. Now that we know that excessive TGF-b is the main culprit there must be a clearer path. Unfortunately it's not that simple as we also need TGF-b...where to find balance? Last year Reason stayed on this blog " fight aging says TGF-β1is a good example. It can increase or decrease inflammatory activity in specific contexts, and while it is definitely a prominent part of the problem of chronic inflammation in later life, it cannot simply be suppressed without unwelcome side-effects, the loss of activities that are still beneficial even in the context of a damaged immune system."

Here are the most interesting quotes I've found:

From selfhacked " A significant cause of increasing TGF levels is advanced glycation end products and in particular glucosepane, we can see what benefits may occur if glucosepane is removed by looking at the Conboy experiments in particular their 2015 paper which showed rejuvenation of stem cells by inhibiting TGF-beta. So if we remove glucosepane from tissue we can potentially expect increased stem cell mobility/repair plus reduction of ECM stiffening and more. It seems obvious to me that the best thing to target is glucosepane."

From Sience Direct: "One compund - Ursolic Acid actually prevents binding rather than reduces - ursolic acid competes with TGF-β1 binding to its receptor, and thereby neutralizes anti-proliferative effects of TGF-β1 and suppresses TGF-β1-induced collagen production."
https://www.sciencedirect.com/science/article/pii/S0014579304004429

another study: https://news.berkeley.edu/2015/05/13/drug-perks-up-old-muscles-and-aging-brains/. on Alk5 kinase inhibitor
" As the body ages, however, the TGF-beta1 begins to overexpress itself and become a deterrent for yet unknown reasons. What the Alk5 kinase inhibitor sought to do was not rid the body of the pathway but rather regulate it by attaching itself to the pathway and dulling its signal asking for more expression. Now with the TGF-beta1 down to youthful levels, stem cells are able to freely repair the body."
"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."

natural inhibitors? compound EGCG and myricetin reduced the mRNA expression of TGFβR1 at 80 μM conscentration. Also - The results showed that myricetin significantly ameliorated TGF-β1-

Posted by: August33 at January 26th, 2020 9:39 PM

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