Its the long genes that stop working

People who read my blog will be aware that I have for some time argued that most (if not all) diseases of aging are caused by cells not being able to produce enough of the right proteins. What happens is that certain genes stop functioning because of a metabolic imbalance. I was, however, mystified as to why it was always particular genes that stopped working.

Recently, however, there have been three papers produced:

Aging is associated with a systemic length-associated transcriptome imbalance
Age- or lifestyle-induced accumulation of genotoxicity is associated with a generalized shutdown of long gene transcription and
Gene Size Matters: An Analysis of Gene Length in the Human Genome


From these it is obvious to see that the genes that stop working are the longer ones.

To me it is therefore obvious that if there is a shortage of nuclear Acetyl-CoA then it would mean that the probability of longer Genes being transcribed would be reduced to a greater extent than shorter ones. That is because the availability of the whole of the gene will be reduced by a multiple of the probabilities of shorter genes being available. The process of acetylation for which Acetyl-CoA is required opens up the genes so that they can be transcribed. That does explain now why probability comes into so much of transcription and the balance of the probabilities of shorter genes being transcribed and longer genes being transcribed.

The interesting thing, however, is that my experimentation points to this as being at least to some extent a reversible process. What that means, of course, is that to some limited extent the effect of this can be mitigated improving people's healthspan even if it has no effect on the maximal life span.

I explain about this in this video:


Edit 15/12/2022
This paper published 14/12 Pan-cancer transcriptomic analysis reveals a tissue-specific loss of identity is also relevant " We found a loss of cell identity during ageing in around 40% of tissues."

This tweet gives an example of where genes have been encouraged to express at a higher level than ordinarily. It is an example of pigmented hair growing in a location which previously had no hair.

Edit 26/12/2022
What is interesting about Acetylation and DeAcetylation is that deacetylation is to some extent part of the transcription process. I have not, however, managed to find a paper which explains whether deacetylation is required for every creation of a transcript or whether it happens after the production of one or more transcripts. The principle remains the same, however, that if acetylation is less frequent then this will affect longer genes in to a greater extent than shorter ones. This may relate to the number of transcripts or both length and transcripts.
Edit 27/12/2022
The point about deacetylation being important, however, is that it would require NAD+ (hence the arguments about vitamin B3 and other NAD+ precursors) to occur. (Cue debate about NMN and NR).
Edit 28/12/2022
I have found some papers that go further into the mechanism for lower levels of acetylation resulting in longer genes not working.
Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing is a paper which confirms that for longer genes that are transcribed in two or more transcripts, the problem that arises from aging is that the splicing goes wrong more often.
When you combine that with this paper:
Where splicing joins chromatin it confirms that variations in acetylation control splicing. Obviously if a particular transcript is not acetylated (through a shortage of Acetyl-CoA) then it won't be transcribed. The paper says (as a section title) :"Histone Acetylation Induces Changes in the Alternative Splicing".
Edit 16/1/2023
Age-dependent loss of cohesion protection in human oocytes is another interesting paper which highlights that the shortage of a protein known as SGO2 is the main cause of fertility problems. Shugoshin_2 is an interesting gene because it is really really long. It runs at over 74,000 base pairs. Hence it is not surprising that one of the early changes as a result of age is that women run short on this protein. Obviously fixing this is quite significant (particularly to the women affected and the children that they may now have, but also to the fathers of those children), but we do need to be careful in improving human health that we don't overload the planet with human beings.
also ADAR1: a mast regulator of aging and immunity looks at ADAR1 which is about 47,000 base pairs long. That's long enough to cause difficulties
STAT3 promotes a youthful epigenetic state in articular chondrocytes This is about 75,000 base pairs long.
Edit 21/1/2023
Genome-wide RNA polymerase stalling shapes the transcriptome during aging is a paper which looks at how the RNA II Polymerase complex (which includes the acetylation enzyme) stalls "skewing transcriptional output in a gene-length-dependent faLong Genes Stop Working - Improving Cellular Healthshion". They hypothesise it is caused by DNA damage. I believe it is caused by a shortage of Acetyl-CoA. Figure 3(i) is a good one to look Talking to a father who was also picking up his son from school it is clear that if HAT/KAT is part of the RNA Pol II complex then the probabilty of longer genes being acetylated is likely to be linked to the first order of their length rather than exponential. Still harder for longer.
Edit 27/1/23
hTERT is the gene for Telomerase reverse transcriptase. Which is part of the process by which telomeres are extended. The gene is over 40,000 base pairs long. Hence it would not be surprising if older people's telomeres were shorter.
Edit 18/2/23 Relevant video

Edit 7/3/23
Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes looks at what happens when translation is stalled.
Histone deacetylase inhibitors prevent H2O2 from inducing stress granule formation indicates the role of deacetylation in forming stress granules
.
Mitochondrial Inhibition by Sodium Azide Induces Assembly of eIF2α Phosphorylation-Independent Stress Granules in Mammalian Cells So if you switch off the mitochondria the translation complex is turned into a stress granule

What I am still looking for, however, relates to the termination of transcription rather than what appears moreso to be the suspension of translation (creation of protein from mRNA). It appears that deacetylation links to the premature termination of the RNA Pol ii complex, but I have not found any research that directly confirms this.

What is clear from lots of research is that HDAC/KDAC inhibitors increase gene expression. The stronger the inhibition the greater the effect although really strong inhibition can deplete ATP. Edit 13/4/23
Ageing-associated changes in transcriptional elongation influence longevity is another paper looking at similar issues. Is it that the failure to transcribe the longer genes means that the shorter genes get transcribed more quickly?

Edit 14/4/23
Metabolism: Obviously if cells produce fewer proteins they require less energy. Hence it explains why younger people can eat more and don't get fat.
Edit 18/4/23
This article on Metabolic Influences on RNA Biology and Translation is interesting as to the next step after transcription.

Edit 13/8/23
Aging disrupts gene expression timing during muscle regeneration fits with the idea that transcription slows for longer genes.
Edit 25/8/23
Histone mark age of human tissues and cells is a paper which looks at histone variations as people age and concludes that it is possible to have an aging biomarker from histone values. That is obviously consistent with acetyl-CoA availability.

Edit 17/2/24
Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging is a paper from 2003 which showed that increased DNA damage did not cause aging.

Edit 31/3/24
Time is ticking faster for long genes in aging a paper in Cell which takes the issue on a bit.