Its the long genes that stop working (update)

I have updated my blog post about my hypothesis as to why long genes stop working as people get older

The update includes reference to the impact of acetylation on RNA splicing and cites two papers that evidence that as to being a rational conclusion.

In essence not all of the transcripts are spliced when there isn’t enough Acetyl-CoA.

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I have added a video to this now

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Hm I thought the issue was post-transcriptional + pre-translational, rather than pre-transcriptional.

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I attended a molecular biology conference earlier this week and it gave me some thoughts as to gene expression so I have written a blog post

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Doesn’t calorie restriction reduce the number of free acetyl groups?

RNA Pol II acts on DNA, not histones. The timecourses (and parts of the cell) that acetylation works on are different between DNA and histones.

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RNA Pol II itself works on the DNA and produces mRNA. However, there is complex around RNA Pol II that includes the Histone Acetyl Transferase (HAT). The process of enzymatic acetylation does not occur separately to transcription.

The HAT is not part of RNA Pol II, but is part of the complex.

Could vorinostat possess anti-aging capabilities? I’m pondering if HDAC inhibitors might enhance the process of learning a new accent. At present, my mastery of Chinese tones is not up to par.

I would be careful in taking a strong HDAC.

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https://www.pnas.org/doi/10.1073/pnas.1805436115

https://www.reddit.com/r/Nootropics/comments/5bqrpm/i_figured_out_prl853s_mechanism_of_action/

Sirtuins are HDACs…

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HDAC inhibitors really bring me back. I remember it being really interesting to read, there was this guy called musicman on reddit who was all about it, he might’ve been manic at the time he was writing about it, still very good.

Here is his gigachad of a post:
https://old.reddit.com/r/Nootropics/comments/596gbi/i_wrote_an_article_on_hdac_inhibitors_geared/

found from Longecity where his username still exists

Lmao that’s him again.

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From the post: "Examples of natural compounds that have HDAC inhibiting properties include resveratrol, EGCG and Curcumin. Though he warns that smokers shouldn’t take curcumin.
I don’t know how much he knows, but curcumin has many potential benefits.

Reducing gene transcription IN GENERAL is a “good thing” (that’s what CR does, it’s what rapamycin does, that’s what SIRT6 does). It’s only a bad thing when you reduce gene transcription of GOOD GENES like Nrf2 or lysosome TFs

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This is where i disagree. The phenotypes of aging arise in the main because of a reduction in the production of more complex proteins.

Furthermore I suggest people think why molecules such as resveratrol, pterostilbene, quercetin, berberine, EGCG and Curcumin which are generally thought to be good for health are also HDAC inhibitors.

Possibly they are good for health because they are HDAC inhibitors.

Incidentally I don’t want to inhibit cox-1. Hence I don’t myself take resveratrol because it is a cox-1 inhibitor.

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Modulators of gene transcription**

Excess undegraded/damaged protein (=> lipofuscin/aggregome) is easier to play into the “hallmarks of aging” (b/c it’s damage) than “insufficient production of essential proteins” [b/c we still don’t know *what* those proteins are) [this can still play into loss of homeostasis, but this is more subtle, and I dare say, this occurs at a much slower rate than actual damage from the aggregome]

Have you had a conversation with Rich Miller about the possibility of testing HDAC inhibitors?

I have not spoken to him about this.

Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence

Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the SASP through activation of the innate immunity cytosolic DNA sensing cGAS–STING pathway. However, the upstream signaling events that instigate CCF formation remain unknown. Here, we show that dysfunctional mitochondria, linked to down-regulation of nuclear-encoded mitochondrial oxidative phosphorylation genes, trigger a ROS–JNK retrograde signaling pathway that drives CCF formation and hence the SASP. JNK links to 53BP1, a nuclear protein that negatively regulates DNA double-strand break (DSB) end resection and CCF formation. Importantly, we show that low-dose HDAC inhibitors restore expression of most nuclear-encoded mitochondrial oxidative phosphorylation genes, improve mitochondrial function, and suppress CCFs and the SASP in senescent cells. In mouse models, HDAC inhibitors also suppress oxidative stress, CCF, inflammation, and tissue damage caused by senescence-inducing irradiation and/or acetaminophen-induced mitochondria dysfunction. Overall, our findings outline an extended mitochondria-to-nucleus retrograde signaling pathway that initiates formation of CCF during senescence and is a potential target for drug-based interventions to inhibit the proaging SASP.

http://m.genesdev.cshlp.org/content/34/5-6/428.full

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So perhaps one could summarize thus:

“Aging is the price we pay for NOT dying of cancer earlier.”

But the protection is not perfect and eventually we succumb either to cancer OR aging-related conditions.

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I would argue aging arises because evolution selects for the ability to survive varying food supplies in preference for a long healthspan with reliable sufficient food.

I think cancer also arises because of a failure of the anti-cancer systems in the body and that in improving the body’s response to the phenotypes of aging it also assists in fighting cancer.

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Is it likely that taking sodium butyrate supplements will have an impact? Or does it break down too rapidly to create any meaningful effects?