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.



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.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 - ) Pioglitazone are related to TGF-β suppression via ppar-gamma activation.

"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."

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

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