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. (link)
There is a gene (SLC25A1) which enables the cell to create citrate carrier. (link) The activity of this gene is increased by Nuclear Factor-ÎşB. (link) (second link) So if there is less NF-ÎşB 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-ÎşB. (link) This is generated by a type of cell which is called a Senescent Cell and is part of what is called SASP.(link) 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. (If it quacks its probably a duck) 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. Oddly enough it also conforms with Antagonistic Pleiotropy
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.
An interesting point in support of Interleukin-10 being the key molecule in SASP is that because it is anti-inflammatory it is counterintuitive to conclude that it is the cause of the failure of stem cells to differentiate. Hence few tests will have occurred.
Since originally writing this I have written this page which looks at the research on Interleukin-10. I think it confirms the hypothesis.
The above does not mean that this is the only thing that affects deteriorating cellular health. Clearly anything relating to inflammation has a role and hence issues like ensuring the quality of mitochondria is high and avoiding too much oxidative stress remain important. The key to me is that a feedback loop linking Senescent Cells to the failure of Stem Cells to differentiate is at the core of this. I have picked reasonably good candidates for the particular molecules, but that may not be right. The process for creating citrate carrier is like many things multifactorial. I would expect that chronic inflammation itself would also cause a reduction in citrate carriers in Stem Cells (through some form of homeostatic system). This could be through Interleukin-4, but I think that is less likely. I am still trying identify what might be the best candidate for this.
When we consider what is known to be of benefit with aging most of those interventions relate to improving how the mitochondria function so that the maintenance systems of the body (including those for DNA) operate effectively. There is something called "Heterochronic Parabiosis" which involves conjoining the circulatory system of two animals. The above hypothesis explains why that works and why things like plasma dilution and senolytics in isolation only have a temporary effect. Obviously if you combine senolytics and plasma dilution then that can have a bigger effect. However, there are still other things (like chronic inflammation) that are likely to have a similar effect on the citrate carrier.
Edit: 3/3/2022
Yesterday a paper was published in Nature. Molecular hallmarks of heterochronic parabiosis at single-cell resolution is the paper and it confirms that heterochronic parabiosis works by making various types of stem cells differentiate properly. Now that means "it is something in the blood." I think the circumstantial evidence for Interleukin-10 is stronger. Interleukin-10 is really hard to test for as the blood sample has to be frozen after taking it. It is also quite expensive to test for. Additionally it is counterintuitive because it acts in an anti-inflammatory manner. We still, however, don't have the proof.
Misexpression of genes lacking CpG islands drives degenerative changes during aging is a paper from December 2021 which looks more at which Genes may be subject to misexpression. Interestingly they say "Together, our findings suggest that disorganization of the nuclear periphery in aged cells results in misexpression of CGI− genes that are a direct source of systemic inflammatory mediators associated with aging." That fits with the idea that Stem Cells that have failed to differentiate properly are issuing SASP and in essence are senescent. They also find that some interventions resolve these issues which makes the interesting suggestion that changing the molecular environment of the Stem cells that have failed to differentiate turns them into cells that are functioning properly.
Heterochronic Parabiosis reduces senescense which is particularly interesting as it means that the burden of senescent cells can be reduced possibly by making them active rather than killing them off. Senescent cells inhibit their own removal 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-ÎşB with this response being blocked by the NF-ÎşB inhibitor BAY11-7082."
Edit: 9/3/2022
Obviously the first question to ask given the above is what to do. Personally I would not try to reduce Interleukin-10 without great care as it is clearly doing something to cut down the effect of inflammation from sensecent cells. However, there is an alternative which is to try to increase the amount of citrate in the cytosol.
Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis was a paper published last October (2021). Looking at the charts what is increasing is healthspan rather than lifespan (I now think the main lifespan constraint is stem cell exhaustion). However, it points out that 0.1% citrate in the diet does prevent a lot of the deterioration that from the above we know to be caused by differentiation problems.
As far as I know citrate has not yet been tested by the interventions testing program. I did ask some months ago as I thought citric acid was of some merit. The stem cells issue is something that can be influenced by HIF which the the subject of another of my blog posts. What we don't know is a mechanism to safely increase cytosolic citrate for human beings. It appears tofacitinib increases Cytosolic Citrate by inhibiting Janus Kinase, but it has some nasty side effects.
This is the key table set from the linked report above:
Cytosolic citrate and the consequentional increase in Acetyl-CoA will enables acetylation of the histone, but will inhibit autophagy and mitophagy and inhibits HIF. It might also increase Cholesterol, but there is a rate limiting enzyme.
Low Plasma Citrate Levels and Specific Transcriptional Signatures Associated with Quiescence of CD34+ Progenitors Predict Azacitidine Therapy Failure in MDS/AML Patients "Decreased citrate plasma levels, downregulated expression of the (ATP)-citrate lyase and other transcriptional/metabolic networks indicate metabolism-driven histone modifications in PD HSPCs. Observed histone deacetylation is consistent with transcription-nonpermissive chromatin configuration and quiescence of PD HSPCs." This confirms the importance of plasma citrate levels in human hematopoietic stem/progenitor cells.
Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis "we found that serum levels of citrate were negatively associated with osteophytes at the femoral site, cartilage defects, BMLs and serum MMP-13, and also had a trend of negative association with IPFP signal intensity alteration." This looks at citrate levels from 0.05 mmol/L through to 0.2 and finds fewer defects for more citrate in the blood serum.
Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis " Plasma citrate levels as a potential biomarker for glaucoma " The mean plasma citrate (104.8±23.2 vs. 128.2±31.1 ÎĽmol/L; P=0.01) concentrations were significantly lower among the patients with glaucoma, whereas the mean urine citrate concentrations (1.7±0.9 vs. 2.8±1.9 ÎĽmol/L; P=0.07) were slightly lower."
Periodontal status and blood citrate levels in women before and after the menopause indicates more gum inflammation with higher citrate levels (not surprising).
Edit: 18/3/2022
A non-canonical tricarboxylic acid cycle underlies cellular identity is a nicely done paper published on 9th March which confirms much of the above. I have done a separate blog post looking at the research on Interleukin-10 which makes it very likely that this is the key cytokine. That blog post is here.
Edit 24/3/22
Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity is good news for blackberry growers. Blackberries contain anthocyanins and also citric acid. I will put Ferulic acid into one of my testing cycles.
Edit 2/4/2022
Muscle is a stage, and cells and factors are merely players is also compatible with this "Several studies demonstrate that aged satellite cells accumulate intrinsic dysfunctions, such as apoptosis and senescence, and decreased self-renewal, all of which lead to diminished regenerative capabilities"
Edit 3/4/2022
Geriatric muscle stem cells switch reversible quiescence into senescence"Skeletal muscle homeostasis and regeneration require a population ofmuscle-specific Pax7-expresing adult stem cells, named satellite cells, which are normally quiescent5. When stimulated by damage or stress, these G0-arrested satellite cells are activated and enter the cell cycle, to proliferate further and formnew fibres or self-renewto reconstitute the satellite cell pool6,7. Hetero-parabiosis and hetero-grafting experiments between young and (non-geriatric) old rodents have led to the prevalent view that the satellite-cell-dependent muscle regeneration decline with ageing can be reversed by exposure to an external youthful environment (reviewed in refs 3,8–11). Notably, in very old (geriatric) mice with sarcopenia, we observed amarked drop in themuscle regenerative capacity compared to old non-sarcopenic mice. Whether this regenerative decline is ascribed to satellite cell intrinsic changes or to changes in the systemic environment is unknown."
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. (link)
There is a gene (SLC25A1) which enables the cell to create citrate carrier. (link) The activity of this gene is increased by Nuclear Factor-ÎşB. (link) (second link) So if there is less NF-ÎşB 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-ÎşB. (link) This is generated by a type of cell which is called a Senescent Cell and is part of what is called SASP.(link) 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. (If it quacks its probably a duck) 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. Oddly enough it also conforms with Antagonistic Pleiotropy
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.
An interesting point in support of Interleukin-10 being the key molecule in SASP is that because it is anti-inflammatory it is counterintuitive to conclude that it is the cause of the failure of stem cells to differentiate. Hence few tests will have occurred.
Since originally writing this I have written this page which looks at the research on Interleukin-10. I think it confirms the hypothesis.
The above does not mean that this is the only thing that affects deteriorating cellular health. Clearly anything relating to inflammation has a role and hence issues like ensuring the quality of mitochondria is high and avoiding too much oxidative stress remain important. The key to me is that a feedback loop linking Senescent Cells to the failure of Stem Cells to differentiate is at the core of this. I have picked reasonably good candidates for the particular molecules, but that may not be right. The process for creating citrate carrier is like many things multifactorial. I would expect that chronic inflammation itself would also cause a reduction in citrate carriers in Stem Cells (through some form of homeostatic system). This could be through Interleukin-4, but I think that is less likely. I am still trying identify what might be the best candidate for this.
When we consider what is known to be of benefit with aging most of those interventions relate to improving how the mitochondria function so that the maintenance systems of the body (including those for DNA) operate effectively. There is something called "Heterochronic Parabiosis" which involves conjoining the circulatory system of two animals. The above hypothesis explains why that works and why things like plasma dilution and senolytics in isolation only have a temporary effect. Obviously if you combine senolytics and plasma dilution then that can have a bigger effect. However, there are still other things (like chronic inflammation) that are likely to have a similar effect on the citrate carrier.
Edit: 3/3/2022
Yesterday a paper was published in Nature. Molecular hallmarks of heterochronic parabiosis at single-cell resolution is the paper and it confirms that heterochronic parabiosis works by making various types of stem cells differentiate properly. Now that means "it is something in the blood." I think the circumstantial evidence for Interleukin-10 is stronger. Interleukin-10 is really hard to test for as the blood sample has to be frozen after taking it. It is also quite expensive to test for. Additionally it is counterintuitive because it acts in an anti-inflammatory manner. We still, however, don't have the proof.
Misexpression of genes lacking CpG islands drives degenerative changes during aging is a paper from December 2021 which looks more at which Genes may be subject to misexpression. Interestingly they say "Together, our findings suggest that disorganization of the nuclear periphery in aged cells results in misexpression of CGI− genes that are a direct source of systemic inflammatory mediators associated with aging." That fits with the idea that Stem Cells that have failed to differentiate properly are issuing SASP and in essence are senescent. They also find that some interventions resolve these issues which makes the interesting suggestion that changing the molecular environment of the Stem cells that have failed to differentiate turns them into cells that are functioning properly.
Heterochronic Parabiosis reduces senescense which is particularly interesting as it means that the burden of senescent cells can be reduced possibly by making them active rather than killing them off. Senescent cells inhibit their own removal 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-ÎşB with this response being blocked by the NF-ÎşB inhibitor BAY11-7082."
Edit: 9/3/2022
Obviously the first question to ask given the above is what to do. Personally I would not try to reduce Interleukin-10 without great care as it is clearly doing something to cut down the effect of inflammation from sensecent cells. However, there is an alternative which is to try to increase the amount of citrate in the cytosol.
Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis was a paper published last October (2021). Looking at the charts what is increasing is healthspan rather than lifespan (I now think the main lifespan constraint is stem cell exhaustion). However, it points out that 0.1% citrate in the diet does prevent a lot of the deterioration that from the above we know to be caused by differentiation problems.
As far as I know citrate has not yet been tested by the interventions testing program. I did ask some months ago as I thought citric acid was of some merit. The stem cells issue is something that can be influenced by HIF which the the subject of another of my blog posts. What we don't know is a mechanism to safely increase cytosolic citrate for human beings. It appears tofacitinib increases Cytosolic Citrate by inhibiting Janus Kinase, but it has some nasty side effects.
This is the key table set from the linked report above:
Cytosolic citrate and the consequentional increase in Acetyl-CoA will enables acetylation of the histone, but will inhibit autophagy and mitophagy and inhibits HIF. It might also increase Cholesterol, but there is a rate limiting enzyme.
Low Plasma Citrate Levels and Specific Transcriptional Signatures Associated with Quiescence of CD34+ Progenitors Predict Azacitidine Therapy Failure in MDS/AML Patients "Decreased citrate plasma levels, downregulated expression of the (ATP)-citrate lyase and other transcriptional/metabolic networks indicate metabolism-driven histone modifications in PD HSPCs. Observed histone deacetylation is consistent with transcription-nonpermissive chromatin configuration and quiescence of PD HSPCs." This confirms the importance of plasma citrate levels in human hematopoietic stem/progenitor cells.
Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis "we found that serum levels of citrate were negatively associated with osteophytes at the femoral site, cartilage defects, BMLs and serum MMP-13, and also had a trend of negative association with IPFP signal intensity alteration." This looks at citrate levels from 0.05 mmol/L through to 0.2 and finds fewer defects for more citrate in the blood serum.
Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis " Plasma citrate levels as a potential biomarker for glaucoma " The mean plasma citrate (104.8±23.2 vs. 128.2±31.1 ÎĽmol/L; P=0.01) concentrations were significantly lower among the patients with glaucoma, whereas the mean urine citrate concentrations (1.7±0.9 vs. 2.8±1.9 ÎĽmol/L; P=0.07) were slightly lower."
Periodontal status and blood citrate levels in women before and after the menopause indicates more gum inflammation with higher citrate levels (not surprising).
Edit: 18/3/2022
A non-canonical tricarboxylic acid cycle underlies cellular identity is a nicely done paper published on 9th March which confirms much of the above. I have done a separate blog post looking at the research on Interleukin-10 which makes it very likely that this is the key cytokine. That blog post is here.
Edit 24/3/22
Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity is good news for blackberry growers. Blackberries contain anthocyanins and also citric acid. I will put Ferulic acid into one of my testing cycles.
Edit 2/4/2022
Muscle is a stage, and cells and factors are merely players is also compatible with this "Several studies demonstrate that aged satellite cells accumulate intrinsic dysfunctions, such as apoptosis and senescence, and decreased self-renewal, all of which lead to diminished regenerative capabilities"
Edit 3/4/2022
Geriatric muscle stem cells switch reversible quiescence into senescence"Skeletal muscle homeostasis and regeneration require a population ofmuscle-specific Pax7-expresing adult stem cells, named satellite cells, which are normally quiescent5. When stimulated by damage or stress, these G0-arrested satellite cells are activated and enter the cell cycle, to proliferate further and formnew fibres or self-renewto reconstitute the satellite cell pool6,7. Hetero-parabiosis and hetero-grafting experiments between young and (non-geriatric) old rodents have led to the prevalent view that the satellite-cell-dependent muscle regeneration decline with ageing can be reversed by exposure to an external youthful environment (reviewed in refs 3,8–11). Notably, in very old (geriatric) mice with sarcopenia, we observed amarked drop in themuscle regenerative capacity compared to old non-sarcopenic mice. Whether this regenerative decline is ascribed to satellite cell intrinsic changes or to changes in the systemic environment is unknown."
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