Senescent Cells Degrade Intestinal Stem Cell Function

Senescent cells are constantly created and destroyed in all tissues of the body throughout life, but the number present at any given time increases with age, in large part because the immune system ceases to clear senescent cells as efficiently as it should. Senescent cells secrete pro-growth, pro-inflammatory factors that are useful in the short term, such as during wound healing, or to draw attention to potentially cancerous cells. When kept up for the long term, however, the signaling of senescent cells is highly disruptive to tissue structure and function. The example given here, of disrupted intestinal stem cell function resulting from specific molecules generated by senescent cells, is but one of many.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation.

The SASP (including factors like Ptk7, which are not technically secreted but are shed as a consequence of senescent cell surface remodeling) is believed to be a critical part of the contribution of senescent cells to age-related disease, primarily by influencing the tissue microenvironment and spreading senescence through a "bystander effect". Accordingly, selective elimination of senescent cells improves many aging symptoms and disease phenotypes. Our study identifies sPtk7 as a critical SASP factor that has a direct and reversible impact on intestinal stem cell proliferation and differentiation.

Our data show that Ptk7 is also expressed in fibroblasts and epithelial cells of the mouse small intestine, and that shedding of the N-terminal domain of Ptk7 is increased in the gut of old mice. Our co-culture experiments of intestinal organoids with senescent intestinal fibroblasts further show that fibroblast-derived Ptk7 impairs differentiation of intestinal stem cells. How this effect on intestinal stem cells influences epithelial homeostasis and regeneration remains to be established.



Here is an example of articles here where the cause and symptoms are discussed, without addressing the the obvious "so what should I do?" question. I new reader here would throw up their hands and nihilistically say "that's too bad".'

I'll suggest that one of the benefits of a full cleanse and 4 or 5 days of fasting is to give the gut lining a break to take care of some house cleaning. Of course, official science has no financial interest in knowing if this the case, and so we will never see the kind of studies that would prove it.

BTW: When I'm on my monthly 4 day fasts, twice a day, I add about 3 grams of fisetin to a splash of olive oil in the bottom of a glass and let it sit for an hour or two, then add 8 ounces of water and stir energetically. This mixture has got to be one of the worse tasting things I've ever downed, so I say to myself as I drink it "The wages of sin is death", and then quickly rinse my mouth out.

Posted by: Thomas Schaefer at January 25th, 2023 8:30 AM

Thomas, have you considered mixing some liquid DMSO with the fisetin or taking bioperine with it?

Posted by: august33 at January 25th, 2023 3:50 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.