17 replies to this topic

[johnhemming]

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.

[johnhemming]

This is an interesting paper

https://pubmed.ncbi....h.gov/35032339/

 

Abstract

Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs stemness and osteogenic differentiation, but the key regulators for senescence and the related osteogenesis are not well defined. Herein, we screened the gene expression profiles of human BMSCs from young and old donors and identified that elevation of the nucleosome assembly protein 1-like 2 (NAP1L2) expression was correlated with BMSC senescence and impaired osteogenesis. Elevated NAP1L2 expression was observed in replicative cell senescence and induced cell senescence in vitro, and in age-related senescent human and mouse BMSCs in vivo, concomitant with significantly augmented chromatin accessibility detected by ATAC-seq. Loss- and gain-of-functions of NAP1L2 affected activation of NF-κB pathway, status of histone 3 lysine 14 acetylation (H3K14ac), and chromatin accessibility on osteogenic genes in BMSCs. Mechanistic studies revealed that NAP1L2, a histone chaperone, recruited SIRT1 to deacetylate H3K14ac on promoters of osteogenic genes such as Runx2, Sp7, and Bglap and suppressed the osteogenic differentiation of BMSCs. Importantly, molecular docking analysis showed a possible bond between NAP1L2 and an anti-aging reagent, the nicotinamide mononucleotide (NMN), and indeed, administration of NMN alleviated senescent phenotypes of BMSCs. In vivo and clinical evidence from aging mice and patients with senile osteoporosis also confirmed that elevation of NAP1L2 expression was associated with suppressed osteoblastogenesis. Taken together, our findings suggest that NAP1L2 is a regulator of both BMSC cell senescence and osteogenic differentiation, and provide a new theoretical basis for aging-related disease.

It points at the same route of acetylation as being the issue for failure to differentiation.

This was last September's paper

https://www.nature.c...587-021-00105-8

Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial–nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.

 

Give that this is consistent with heterochronic parabiosis working and programmed aging (I would argue) is not I think it can be said that this is a more likely hypothesis.

 

 

 

 

 

Edited by johnhemming, 20 February 2022 - 02:50 PM.

[Phoebus]

Interesting that acetate supplementation seemed to have stem cell renewal properties. 

 

 

Acetate is a short-chain fatty acid (SCFA) produced by colonic bacteria through the saccharolytic fermentation of fibres (e.g., resistant starch, polysaccharides and simple sugars), which escape digestion and absorption (Topping and Clifton, 2001). The molar ratio of acetate in the colon is three times larger than that of the two other major SCFAs, butyrate and propionate (Cummings et al., 1987). Enteric bacteria, including Ruminococcus spp., Prevotella spp., Bifidobacterium spp., and Akkermansia muciniphila are suggested to be the main acetate-producing bacteria (Rey et al., 2010).

Recently SCFAs have received increasing attention as they have been shown to play an important role in cardio-metabolic diseases (CMD), including obesity, type-2 diabetes (T2D), arterial stiffness and atherosclerosis (Den Besten et al., 2013). Once these bacteria-derived metabolites are synthetised, they have the capacity to reach different systematic tissues, improving the gut barrier integrity, glucose, cholesterol and lipid metabolism, and regulating the immune system and anti-inflammatory response, energy intake, and blood pressure (Martin-Gallausiaux et al., 2020). For instance, acetate was shown to decrease appetite by impacting directly on the hypothalamus (Frost et al., 2014), inhibit endogenous lipolysis (Hron et al., 1978), enhance hepatic uptake of blood cholesterol (Zhao Y. et al., 2017) and reduce hyperglycaemia (Sakakibara et al., 2006). However, to gain further insight into the host-microbial cross-talk involving circulating acetate levels and its implications in cardio-metabolic health (CMH), it is important to integrate different types of data.

https://www.frontier...Clifton, 2001).

 

Resistant starch in the diet is broken down into acetate by the gut bacteria. A good sources of resistant starch are beans, oats, legumes, cooked and cooled rice. etc. 

Edited by Phoebus, 20 February 2022 - 03:20 PM.

[Phoebus]

 

Aging brings with it thinner bones, more fractures, and an increased likelihood of osteoporosis. One reason for these aging ailments is the impaired function of the bone-marrow stem cells, which are required for the maintenance of bone integrity. Now, researchers have shown that changes in the epigenome are one reason for the reduction in stem cell function. The team from the the Max Planck Institute for Biology of Aging and CECAD Cluster of Excellence for Aging Research at the University of Cologne found that acetate was a key factor in the reversal of these changes in isolated stem cells. These findings could be relevant for the treatment of diseases such as osteoporosis.

This work is published in Nature Aging in the paper, “Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.”

 

 

:text=Epigenetic%20Changes%20in%20Aging%20Stem%20Cells%20Rejuvenated%20by%20Acetate,-September%2015%2C%202021&text=Aging%20brings%20with%20it%20thinner,the%20maintenance%20of%20bone%20integrity' class='bbc_url' title='External link' rel='nofollow external'>https://www.genengne... bone integrity.

[Phoebus]

 

 

In a complementary approach, we added sodium acetate directly to the medium of aged cells. Sodium acetate is an exogenous source of acetyl-CoA and can be converted into acetyl-CoA in the cytoplasm by the ACS enzyme41 (Fig. 3b), whose levels did not change with age (Fig. 3e). Impressively, supplementation of aged cells with sodium acetate rescued the loss of histone acetylation, resulting in levels similar to those of young cells (Fig. 4a,b). Collectively, these data corroborate our observation that loss of CiC upon aging is responsible for the reduction of histone acetylation levels, providing a mechanistic link between mitochondrial metabolism and histone acetylation upon aging.

 

https://www.nature.c...587-021-00105-8

[johnhemming]

The interesting thing about NF-κB is that it generally switches on the inflammatory genes (as well as the citrate carrier which is part of that really).  However, as inflammation generally goes up it is turned down. Hence one would assume in the Stem cells which were otherwise really dormant one would assume that it starts at a lower level and hence the general inflammation takes the citrate carrier down below what is needed. I would assume that the Stem cells themselves are not really inflamed.

[johnhemming]

On a separate point I have been looking at Dihydromyrecetin.  Interestingly that is thought to generate acetate faster from ethanol.

[johnhemming]

Having got a list of NF-κB inhibitors and looked at SASP.  I think the probable molecule that makes senescent cells inhibit NF-κB is Interleukin-10

 

This paper is consistent with that:

https://bmcgeriatr.b...2877-018-1007-9

 

 

[johnhemming]

I have done a blog post on this:

https://johnhemming....nd-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.

[s1lordi]

This goes in the cellular level as the loss of asymmetry during replication. The reason can be complicatet, one of which is the accumulation of ecRNA and this is an unsolvet issue worth exploring, another one is the size of vacuole, which also tend to increase with age and leads to cell swelling, seemingly a serious cause of senescence. We can communicate further with email if you have made progress in this direction.

[johnhemming]

I haven't really made any more progress than the above.   It does, however, appear to fit the evidence.

[s1lordi]

Never matter, start it now, and feel free to discuss. Few realize that we are confinet on earth permanently, the cell is the first obstacle that must be overcome, and no help from anywhere. There are many repeats and unknowt elements that cause excessive replication of certain DNA, but there are ways to tackle it. Either we can measure in detail(like taking stemcells from different parts of body), or we can study different animals with longer lifespan. And if the stemcell keep its stemness, the rest is just genetic problem(irreversible mutation). Basically these two are the bigest hindrance to immortality. First step is always the hardest.

[johnhemming]

There are obviously lessons to learn from species such as the Naked Mole Rat.

[s1lordi]

Eventually it comes down to the observation, i suggest you start with your own cell, and a fast growing on like planarian. But i don't know whether an optical microscope would do. And someone has to do the damn experiments, and by finding out what causes the swelling(gotta identify non functional RNAs and DNAs, but i dont know how to distinguish them from functional transcripts, so far the literature i read), you can then study long living animals successively, there are plenty of them, and plenty of time as well.

[johnhemming]

This paper is also consistent (published yesterday)

https://www.nature.c...586-022-04461-2

 

Molecular hallmarks of heterochronic parabiosis at single-cell resolution

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

 

[s1lordi]

There are many "elements" containt within a single genome, repeats are one of these. On the contrary, there are not so many means to manipulate the genes. It's a deadending, so please do the observation now, and through the phenomenon you can figure out countering method to tackle each. I hope you are not too old to do so. These paper mostly deal with exocrines(proteins) more exactly, which is just surface of the iceberg. Because most 'mass' who knows nothing about genetics dont want the knowledgeable survive. The situation is always threatening for an intellectual.

By the way, though we cannot figure out all the factors determining the asymmetry, it also is not needet, we only need to manage to maintain the stemness indefinitely.

[johnhemming]

I have done a review of the research on this issue and I think it confirms my hypothesis.

 

https://johnhemming....f-research.html

[johnhemming]

I have updated my original post to include this:

 

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. Thats about 1-2g of Citrate a day. That is something of the order of half a lemon a day. However, I would not suggest taking all the citrate as citric acid as that is quite acidic. It is the sort of thing to discuss with your doctor. We also don't know the effects of different quantities on human beings or whether it even has any effect in this way. People do, however, already consume quite a bit of citric acid and citrate

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.

Edited by johnhemming, 09 March 2022 - 07:24 AM.