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
Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity "Targeted clearance of p16Ink4 -expressing cells in p16-INK-ATTAC (p16Ink4a apoptosis through targeted activation of caspase) mice in the presence of AP20187 (a synthetic drug that dimerizes a membrane-bound myristoylated FK506-binding protein-caspase-8 [FKBP–Casp8] fusion protein) has been successfully used as a strategy to understand the effect of clearing p16Ink4a-expressing senescent cells on multiple age-related conditions, including osteoporosis, frailty, cardiovascular disease, and metabolic dysfunction (for reviews, see (Tchkonia et al., 2013) and (Khosla et al., 2020)). However, although the roles of p21Cip1 or p16Ink4a as markers of senescence have been well described (Baker et al., 2011, 2013), their individual contributions in driving senescence more generally are largely unknown.
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.
Edit: 2/6/23
Senescence and senotherapies in biliary atresia and biliary cirrhosis Linking Bile Duct Blockage and Cellular Senescence Physical damage appears to lead to a hallmark of aging.
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
Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity "Targeted clearance of p16Ink4 -expressing cells in p16-INK-ATTAC (p16Ink4a apoptosis through targeted activation of caspase) mice in the presence of AP20187 (a synthetic drug that dimerizes a membrane-bound myristoylated FK506-binding protein-caspase-8 [FKBP–Casp8] fusion protein) has been successfully used as a strategy to understand the effect of clearing p16Ink4a-expressing senescent cells on multiple age-related conditions, including osteoporosis, frailty, cardiovascular disease, and metabolic dysfunction (for reviews, see (Tchkonia et al., 2013) and (Khosla et al., 2020)). However, although the roles of p21Cip1 or p16Ink4a as markers of senescence have been well described (Baker et al., 2011, 2013), their individual contributions in driving senescence more generally are largely unknown.
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.
Edit: 2/6/23
Senescence and senotherapies in biliary atresia and biliary cirrhosis Linking Bile Duct Blockage and Cellular Senescence Physical damage appears to lead to a hallmark of aging.
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