#1

Our dear @John_Hemming has a theory of aging: https://x.com/johnhemming4mp/status/1892163379478839516

hypothesis
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Analysis and suggestions of interventions by ChatGPT-4.5 Deep research: ChatGPT-4.5 Deep Research Genomic Failure Hypothesis Evaluation - Google Docs

I’ll cite ChatGPT:

In conclusion, the “genomic failure” hypothesis – that a failure in mitochondrial TCA/citrate output leads to loss of histone acetylation homeostasis, aberrant transcription, and translation, ultimately manifesting in aging – is well-grounded in current biochemical and genetic research. Numerous studies in model organisms and cell cultures demonstrate the tight coupling between metabolism and chromatin regulation. Aging cells do show combined metabolic and epigenomic dysregulation, lending credence to this model. However, aging is multifaceted, and this hypothesis captures only part of that picture. It is best viewed as a unifying mechanism that interacts with other aging processes: mitochondrial metabolites act as signals that can hasten or alleviate the genomic decline of aging​. Ongoing research – for example, using metabolite supplementation, epigenetic editing, or mitochondrial gene therapy in animals – will further test how reversible these linked processes are, and whether targeting the mito-epigenome axis can extend healthy lifespan in humans. For now, the weight of evidence supports the biochemical plausibility that a failing mitochondria can lead to failing gene expression, making the genomic failure hypothesis a compelling component of modern aging theory.
Genomic failure hypothesis of aging posits that aging stems from cumulative failures in maintaining genome integrity and regulation. This includes DNA damage accumulation, mitochondrial dysfunction (mtDNA damage, energy deficits), epigenetic drift (altered histone acetylation/methylation and DNA methylation), and loss of transcriptional homeostasis. The proposed interventions each target facets of this hypothesis – improving mitochondrial function, bolstering citrate/acetyl-CoA metabolism for histone acetylation, and stabilizing gene regulation or repair.

What do you think about this hypothesis? If correct, what would be the best interventions?

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#2

Any theory of ageing or biology for that matter needs to be multimodal that accounts for environmental variables as well.
Having said that I think biological theory does tend to be heavily mitochondrial centric.
This reminds me of Warburg Effect and all his postulates nearly a century ago.
Unfortunately, it has been mostly ignored in mainstream cancer biology and therapeutic research which is nucleus-centric. Sadly, Sid Mukherjee made no mention of Warburg in his “Emperor of maladies”.
If Richard Dawkins were to rewrite Selfish Genes…it could possibly be titled Selfish Mitochondria.
Elegant Somatic Cell Nuclear Transfer Experiments have demonstrated the power and dominance conferred to Mitochondria by evolution.
Here are some deep (albeit technical) reviews on what appears re surgent interest…

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#3

Another interesting article somewhat in the context just got published

A human brain map of mitochondrial respiratory capacity and diversity

https://www.nature.com/articles/s41586-025-08740-6

#4

Its an interesting article. I wonder if it finds that brain tissue closer to the third ventricle is younger/has higher mitochondrial energy levels.

This may be relevant, but it is not clear and most of the article is paywalled

Higher mitochondrial activity in phylogenetically younger brain areas.

https://www.nature.com/articles/s41586-025-08740-6/figures/14

I find “Phylogenetically younger” means evolved more recently.

Another word I learnt was “Voxel” a 3d equivalent of a pixel.

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#5

I am trying to get access to the entire article and will post it when I get it.
But Mitomap might turn out to be a at least as meaningful if not more than Human Genome project

https://www.nature.com/articles/s41586-025-08740-6

#6

Its an interesting and intriguing statement vis a vis mitochdrial density and phylogenic youth.
However, using that analogy proximal tubule of glomerulus which has one of highest energetic demands would be phylogenetically younger. What am I missing here unless you refer to energetic efficiency per mitochondrium?

#7

I would need to look at the paper in the round. There are differences between mitochondrial density and mitochondrial efficiency. My hypothesis is based around the ATP/O efficiency of the mitochondria which links to both the Mitochondrial Membrane Potential and Proton Gradient.

#8

Circling back to this question - any thoughts?

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#9

ChatGPT offers some answers:

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#10

See also: Question as to what to do with my protocol - #6 by John_Hemming

#11

@John_Hemming John, I read your protocol and now thinking about adding more citrate to my stack. I’m taking 2 mg of magnesium citrate now, which could be not enough. Which citrate is more beneficial for kidney health in your opinion - magnesium citrate or potassium citrate? Thanks

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#12

2 mg or 2 g? 2 mg is nothing. 2 g is a lot.

#13

It’s 2 mg (part of ONE multivitamin). Too little? That’s why thinking about adding more, but not sure which to choose.

#14

It is important to balance it. However, if you have limited kidney function it needs checking out with a specialist.

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#15

Unfortunately, at least in the States, specialists don’t advise on supplements. My kidneys function is pretty good for now.

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#16

Another approach is to start low and do relatively frequent measurements. If there appears to be a problem stop.

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