More Evidence for TGF-β as an Important Factor in the Spread of Cellular Senescence

Senescent cells accumulate with age in tissues throughout the body, but their numbers remain small in comparison to somatic cells that continue to function. Nonetheless, lingering senescent cells produce a sizable harmful effect on cell and tissue function via the signaling molecules that they generate, the senescence-associated secretory phenotype (SASP). The SASP promotes growth and inflammation, and is beneficial in the short term scenarios of wound healing or cancer suppression. When present for the long term, these same signals become very disruptive.

The SASP is far from fully mapped, consisting of many different molecules, some secreted directly and many more packaged into extracellular vesicles. Researchers have so far largely focused their work on a few obvious suspects that seem likely to be more important. Of particular interest are a number of inflammatory cytokines, such as TGF-β, well-studied in other contexts. TGF-β is already a target for anti-inflammatory therapies. The connection to cellular senescence only makes it more attractive.

Today's open access preprint paper presents evidence for TGF-β to be important in one of the more insidious characteristics of senescent cells, their ability to encourage other cells to also become senescent. This isn't just a local phenomenon. Given sufficient TGF-β signalling, the burden of cellular senescence can be increased in distant tissues. This form of systemic inflammatory signaling is thought to be an important factor in the progression of aging, and researchers are looking into ways to disrupt TGF-β-induced senescence and inflammation.

Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFβ signalling pathway

Cellular senescence is a state of permanent cell cycle arrest accompanied by a hyper-secretory phenotype (Senescence-Associate Secretory Phenotype, or SASP), and is associated with both injury and aging-related pathologies within affected organs. Removal of senescent cells is beneficial to both organ function and organism survival. Severe acute injury of any large organ is associated with systemic effects including multi-organ failure, of which acute liver failure (ALF) is a paradigm. ALF is itself associated with senescence induction and subsequent regenerative failure. Studies both in vitro and in vivo have shown that senescence can be transmitted in a paracrine manner within affected organs, however whether senescence can spread systemically to more distant organs remains unknown.

Here we use acute liver senescence as an exemplar model, independent of systemic aging, to test whether senescence can be transmitted between organs in an endocrine manner. The SASP is a central mediator of the non-autonomous effects of senescent cells. We present evidence that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely-tuned mechanism with overall beneficial effects for wound healing. As described by others, SASP factors are able to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, through excessive SASP production, including senescence- and reprogramming-inducing factors. This excess of SASP factors may enter the circulation and induce widespread senescence and reprogramming to distant organs. In turn, this excessive stimulus for senescence, re-programming and regeneration can compromise organ function.

Systemic transmission of senescence may be relevant to several diseases. Here we use a model of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during ALF. ALF is itself characterised by sequential multi-organ failure typically beginning with the kidney and also involving the brain and lung in addition to other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The observation that TGFβ signalling is a central driver of systemic transmission of senescence paves the way for new therapeutic approaches in diseases where this phenomenon occurs. This is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies.


As a PPAR-γ agonist, Pioglitazone has inhibitory effects on TGF-β1/Smad2/3 and TGF-β1/TRAF6/TAK1 signaling pathways.
Does anyone know of any other TGFB inhibitor that is more effective?

Pioglitazone, a ligand of PPARg, is used to treat diabetes and possesses anti- inflammatory properties.

Besides the study here implicating TGFB with senescence, "TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models."

Pioglitazone is also a known inducer of adiponectin in adipose tissue, possibly staving off the unwanted loss of youthful dermal fat as we age.β-is-involved-in-the-loss-of-fat-and-bacterial-defenses-in-aging-skin/

Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ. Pioglitazone increases secretion of high-molecular-weight adi- ponectin from adipocytes. Am J Physiol Endocrinol Metab 2006; 291:E1100-5.

Finally here are some pros and cons for TGFB

Posted by: August33 at February 2nd, 2022 9:56 PM
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