A hypothesis about Senescent Cells
My hypothesis is that a large proportion of Senescent Cells are in fact Stem Cells which have not differentiated properly. What happens is they cause inflammation which causes a reduction in NF-κb which causes a reduction in SLC25A1 which reduces the number of citrate carriers which causes the differentiation of stem cells to fail more often and those turn in to senescent cells.
That therefore acts as a reinforcing error system that gets worse over time. The interesting point is that Naked Mole Rats have few senescent cells. I think that is because of HIF.
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Why would stem cells fail so often?
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Karl because of a shortage of acetyl coa
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I have done a blog post with further thoughts:
https://johnhemming.blogspot.com/2022/02/gompertz-interleukin-10-and-gradual.html
The Gompertz–Makeham law of mortality is a formula used to predict mortality. The Makeham element is the external part of this such as disease or accidents. The Gompertz part relates to the gradual deterioration of health of an entity. Not all animals follow the Gompertz formula, but Human Beings do. It is an exponential increase in death rates with age.
My view is that this implies that at the core of the issue of the gradual deterioration of health there is some relatively straight forward feedback loop which drives this. I have, therefore been studying the research to look for a hypothesis that has a potentially exponentially reinforcing feedback loop - which would start very small. I have a good candidate for this now. I will later edit this blog post to put all the references in, but I am now going to write the basic post and come back to that.
Many diseases have at the core of them the failure of Stem Cells to properly differentiate. For one disease last year (Osteoporosis) it was found that this was because some Stem Cells for the cell type that creates new bone did not have enough Acetyl-CoA in them. This was because there was not enough of a protein called "citrate carrier" in the mitochondria and the Acetyl-CoA that was created in the mitochondria was stuck there and did not get into the nucleus of the cell.
There is a gene (SLC25A1) which enables the cell to create citrate carrier. This gene is switched on by Nuclear Factor-κB. So if there is less NF-κB there will be less citrate carrier. Now there is a cytokine called Interleukin-10 (also known as human cytokine synthesis inhibitory factor (CSIF)) which inhibits NF-κB. This is generated by a type of cell which is called a Senescent Cell and is part of what is called SASP. Now I don't know if this is officially "known", but it is my view that when Stem Cells fail to differentiate they turn into Senescent Cells. Hence we now have a feedback loop. I think there is a good chance that this is the feedback loop that drives a lot of deterioration of health.
There is a good evolutionary reason for Interleukin-10 to be behind this. In the short term it reduces the inflammation caused by Senescent cells, but at the cost of long term health deterioration. There is a theory called Disposable Soma that what happens in evolution after an animal has reproduced does not really affect evolutionary selection that much. As far as I can see this hypothesis fits the evidence that is available.
There is for example Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10 a study which shows Sarcopenia is associated with higher levels of Interleukin 10. I will aim to update this post with links to the various bits of research that inform it. -
I have now looked at other research to see if it supports the hypothesis or not.
https://johnhemming.blogspot.com/2022/03/interleukin-10-review-of-research.html
Part of my hypothesis that there is a feedback mechanism between the failure of Stem Cells to Differentiate and the failure of more Stem cells to differentiate is that failed stem cells (senescent cells) issue a molecule as part of SASP into the blood which then affects other Stem Cells.
I think it is most likely that this molecule is Interleukin-10. (In fact having done the research I think it is reasonably certain)
I picked it because it is both an inhibitor of NF-κB and also part of SASP
My plan for this blog post is to hunt down papers on Interleukin-10 and see whether they support this hypothesis or not. That will, of course, be a work in progress. The portuguese research in red is particularly interesting
Inhibitors of NF-κB signaling: 785 and counting what is nice about this paper is that it has an appendix with 785 inhibitors of NF-κB.
Wikipedia on SASP this tells us what is in SASP and links to the research on this.
Research that supports the Hypothesis
Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10 a study which shows Sarcopenia is associated with higher levels of Interleukin 10. Sarcopenia is one of those diseases caused by a failure to differentiate.
Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathwayA
Hormesis and bone marrow stem cells: Enhancing cell proliferation, differentiation and resilience to inflammatory stress "However, at higher concentrations (10–100 ng/ml) IL-10 inhibited p38/MAPK signaling, by activating NF-κB with this response being blocked by the NF-κB inhibitor BAY11-7082." This one is not so clear as it seems to imply that IL-10 activates NF-κB when it inhibits it, but the mechanism is not the issue. What is the issue is that IL-10 inhibits differentiation at higher concentrations which is consistent as lower concentrations would not necessary hold back as much acetyl-coA.
Association between serum amyloid A and rheumatoid arthritis: A systematic review and meta-analysisThis has an association between IL-10 and Arthritis, not a massive one and it could be coincidental
Functional Characterization of Human IL-10. IL-10 affects also the ... differentiation of B cells (p12).
Risk of Late-Onset Depression and Cognitive Decline: Results From Inflammatory Proteome Analyses in a Prospective Population-Based Cohort Study Out of 78 biomarkers interleukin 10 (IL-10) and C-C chemokine ligand 4 (CCL4) were associated with significantly increased risk of LOD [Late Onset Depression] after multiple testing correction.
Cerebrospinal fluid IL-10 as an early stage discriminative marker between multiple sclerosis and neuro-Behçet disease the most relevant difference between these two disorders is observed in the CSF compartment as we identified a significant increase of IL-10 expression in patients who evolved to NBD as compared to those who evolved to RRMS. We also showed that IL-10 expression in CSF was independent from the one in PBMCs. This suggests that this anti-inflammatory cytokine may be produced within the CNS of patients with NBD
Increased frequency of Th17 cells and IL-17 levels are associated with low bone mineral density in postmenopausal women However, plasma levels of IL-10 along with IL-10+CD4+T cells were higher in post- compared to premenopausal women. T
Analysis of Cytokines and ATP in Plucked Hair Follicles Thus, we found that HF sheets in health and AGA contained detectable levels of IL-6, IL-10, and ATP.Content of IL-10 and ATP (but not IL-6) correlated with HF length and depended on pathogenetic factors (presumably, androgens). Directed Differentiation of Human Induced Pluripotent Stem Cells into Dendritic Cells Displaying Tolerogenic Properties and Resembling the CD141 + SubsetImportantly, IL-10 has been shown to interfere with the initiation of Th1 responses (38) and to favor the polarization of naïve T cells toward a Treg phenotype (39, 40).
Pathogenetic Characteristics of Mesenchymal Stem Cells in Hidradenitis Suppurativa Mesenchymal stem cells isolated from patients with HS (HS-MSCs) and from healthy controls (C-MSCs) met the International Society for Cellular Therapy minimal criteria. Compared with C-MSCs, cytokine analyses of HS-MSCs revealed statistically significant overexpression of interleukin (IL) 6 (median [interquartile range {IQR}], 8765.00 [7659.00-9123.00] vs 2849.00 [2609.00-3001.00] pg/mL; P = .008), IL-10 (median [IQR], 29.46 [26.35-35.79] vs 21.36 [19.89-23.33] pg/mL; P = .004), IL-12 (median [IQR], 15.25 [13.27-16.25] vs 11.89 [10.73-12.33] pg/mL; P = .03), IL-17A (median [IQR], 15.24 [13.23-17.24] vs 11.24 [10.28-11.95] pg/mL; P = .008), tumor necrosis factor (median [IQR], 42.54 [42.20-43.94] vs 32.55 [31.78-33.28] pg/mL; P = .004), transforming growth factor β1 (median [IQR], 1728.00 [1535.00-1979.00] vs 500.80 [465.00-634.50] pg/mL; P = .004), and interferon γ (median [IQR], 11.49 [10.71-12.35] vs 9.45 [9.29-10.01] pg/mL; P = .005).
The immune system in extreme longevity As a general trend, we observed an increase of type 1 (IL-2, IFN-c,TNF-a) and type 2 (IL-4, IL-6, IL-10) cytokines within the three CD8+ subsets in aged subjects.
Altered cytokine production in the elderly However, IL-2R expression on the cell surface is normal. Interferon (IFN)-γ as the main T-helper-1 (TH1) cytokine is produced less by lymphocytes of the elderly, whereas the TH2 cytokines IL-4 and IL-10 are produced in higher amounts as compared to stimulated lymphocytes of young donors.
Circulating Interleukin-10 and Risk of Cardiovascular Events Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.
Decoding the role of IL-10 in aging Finally, using an in vitro system, we gained evidence that IL-10 triggers cellular senescence in mouse adult fibroblasts. Together, these data disclosed IL-10 over- expression to induce multiple phenotypes that parallel premature aging and age-related diseases. In all, this thesis brings novel insight on the biology of IL-10, which might shed light into novel targets involved in aging and into the importance of immune-driven aging, showing that immune balances, rather than inflammaging play a role in this process.
IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure d IL-10 affects chromatin structure and C/EBPb and ATF occupancy at thermogenic genes
Research that does not really say anything either way, but I thought was interesting
Association of Interleukin 10 (IL-10) Gene Polymorphism (819T > C) with Susceptibility to Acute Myeloid Leukemia: A Meta-Analysis
Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy This is interesting because it implies SASP is tumour promoting
Peripheral Cytokine Levels as a Prognostic Indicator in Gastric Cancer: A Review of Existing Literature
Research that opposes the Hypothesis
Biomarkers of Metabolic Syndrome: Role in Pathogenesis and Pathophysiology Of Atrial Fibrillation This indicates that higher IL-10 makes metabolic syndrome less likely
The role of interleukin-10 family members in cardiovascular diseasesThis says a benefit exists from higher IL-10 in artherosclerosis
Association of interleukin-10 levels with age of onset and duration of illness in patients with major depressive disorder Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals.-
John Hemming Probably why plasma dilution sparks rejuvenation because you are diluting those suppressive cytokines.
Personally I am hitting senescent cells with foxo4-dri to stop SASP and then taking GDF11 to stimulate stem locked cells to differentiate again.
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Fred Cloud The differentiation problems appear to link to a shortage of acetyl-coA.
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John Hemming Thanks for your exhaustive research so far. Like you mentioned in your blog, there are likely many factors involved in producing the essential citrate carriers (of Acetyl-CoA) required for healthy stem cell proliferation. What is your approach in enhancing this process?...how are supplementing for it?
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