Senescent Cells Increase Risk of Colon Cancer via Secretion of GDF15

Cells that enter a senescent state have many purposes in the body. They are involved in both wound healing and cancer suppression, for example. Senescence also serves to remove somatic cells that reach the Hayflick limit on replication. Senescent cells secrete a potent mix of signals to rouse the immune system and encourage local tissue regrowth and remodeling. This is all useful in the short term, where senescent cells accomplish the immediate task at hand and then self-destruct or are destroyed by immune cells. Wounds are healed, and potentially cancerous cells destroyed.

Yet cellular senescence is a cause of aging. The problems arise due to the tiny fraction of senescent cells that evade destruction and linger in the body in increasing numbers with advancing age. Signals that are useful in the short term become ever more destructive in the long term, producing chronic inflammation and actually encouraging the growth of cancerous cells. In the paper noted here, researchers dig into which of the many molecules secreted by senescent cells are responsible for their ability to increase the risk of colon cancer, identifying GDF15 as an important factor in this process.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP).

Given that CRC is an age- and diet-related disease and that the cellular and molecular mechanisms that underlie adenomatous polyp initiation and transformation are only partly understood, we carried out a series of studies to determine whether senescence-associated mechanisms may play a role in the polyp-to-CRC sequence. In this study, we provide both correlative and functional evidence that senescent fibroblasts and an essential SASP factor, GDF15, induce physiological and molecular changes that promote the adenoma-carcinoma initiation and progression sequence in the colon.

We assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.

Link: https://doi.org/10.1111/acel.13013

Comments

Based on a comment by LabRat a while back, I've ordered some CBD cream and am going to mix fisetine into it and apply it topically to my hands, forearms, and face in the hope I kill some cells that have not been taken care of by the oral doses during my fasts. After this article, I'm thinking about adding it to an enema mix.

Posted by: Tom Schaefer at August 16th, 2019 6:32 AM

@Tom

What sort of results are you experiencing? Loss of wrinkles and looking and feeling more youthful?

Posted by: Person1234 at August 16th, 2019 7:58 AM

First, I'm doing so many things to fight aging that it is impossible to properly attribute any benefits to anything I'm doing. 2nd: Doing 4-day fasts with fisetine is painful (3 of 10 compared to 2 of 10 without it) and it is difficult to sleep. I've developed more empathy for the chronically hungry poor. 3rd: I haven't received my CBD cream order yet.

The benefits are primarily in the intensity and recovery from my workouts. At 58, I lift more weight (bigger stacks and more reps) at Planet Fitness, than in any previous year. But like I said above, I'm also taking a powerful herbal endocrine enhancing blend that basically is a mix I made myself from stuff I ordered from Bulk Supplements that mimics the ingredients of the popular GNC product for men (and then some). I feel more will to deny my sloth instincts and do intense elliptical workouts at least 3 times a week, getting my resting heart rate down to 50bpm, and sleeping almost down to 40. This and deep breathing meditation has me at 3 or 4 breaths per minute. The dark spots on my hands are getting lighter, but the long and very skinny freak hairs I get every month or so still seem to appear somewhere (they must grow a cm per day). I think they are a harbinger and form of cancer.

For all I know, any fisetine benefits could be placebo, but I'm betting they are not and will continue to do (3 days X 2 times X 5 grams) ~30 grams during the last 3 days of my 4 day fasts.

Posted by: Tom Schaefer at August 16th, 2019 8:30 AM

@Tom, what do you mean the very skinny freak hairs are a harbinger and form of cancer? Got me scared because I get some of those once in a while.

Posted by: mcmp at August 17th, 2019 4:42 PM

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