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-κB. (link) (second link) 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. (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 22/12/2022
I think there is also a feedback system based upon the Beclin 1 protein which affects autophagy and I have posted about that today Autophagy, Gene Length and Aging (why Senolytics don’t work that well)
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-κB. (link) (second link) 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. (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 22/12/2022
I think there is also a feedback system based upon the Beclin 1 protein which affects autophagy and I have posted about that today Autophagy, Gene Length and Aging (why Senolytics don’t work that well)
Comments
The Gompertz law can be viewed as an exponential probability distribution that models the failure rate of a large number of independent, repairable components in series without excessive amounts of redundancy, such as electronic systems.
Drenick established the convergence of a large number of independent sources of failure to an exponential probability distribution function.
Exponential probability distributions are additive; that is, the sum of a number of independent exponentially distributed variables is exponentially distributed. Thus, mortality by cancer, heart disease, diabetes and Alzheimer's, all of which increase exponentially, contribute to the Gompertz curve.
In simple terms, mortality is death by the weakest link.
“Failure time distributions for complex equipment” (2018) https://onlinelibrary.wiley.com/doi/full/10.1002/qre.2387
“The Failure Law of Complex Equipment” (1960) https://epubs.siam.org/doi/10.1137/0108051
https://drive.google.com/open?id=1noBRga5gp4rf8ZJT4PUf_Io6J1K51O31
Ross Lampe
The real issue here is inferring causality from the Gompertz model. It is tempting to think that if a curve is exponential then it is driven by an exponential process or by a linear parameter of that exponential. But if the underlying failure process is a series of components, any one of which could fail, then the outcome will be approximately exponential.
This concept does not just apply to the highest level measure - mortality. Consider other cellular declines that are also exponential:
ATP/AMP(t) ∝ exp(-0.04 t)
GSH/GSSG(t) ∝ exp(-0.043 t)
Thymic T cell production rate, R(t) ∝ exp(-0.044 t)
Hair follicle melanocyte stem cell decline leading to gray hair, Melan(t) ∝ exp(-0.039 t)
All decline at similar rates but the reasons why are not known. The Drenick failure model suggests that exponential rates derive naturally from any complex, multicomponent system.
Causality is very difficult to tease out in cell biology.