The reason acetylation is key is that it occurs as part of the RNA Polymerase II complex. AIUI it is a very basic energy availability control on transcription. There is I think a crosstalk between transcription and DNA methylation as well which means that if transcription successfully occurs demethylation occurs.
I think one of the key questions is what happens when RNA Pol II is stalled at a particular point awaiting acetylation and the histone in the neighbourhood is deacetylated.
ACSS2 is interesting because of the acetate metabolism and it may also feed into the effects of things like cider vinegar and alcohol metabolism. However, ACLY and the relationship between SLC25A1 and nuclear acetyl-CoA seem to be the key pathways involved in affecting transcription changes and particularly those which are part of aging.
AIUI ACCS2 is inhibited by acetylation levels so that it tends not to generate acetyl-CoA when the histone is highly acetylated.
The other histone modifications will have some effects and I am sure they are important in some circumstances, but the process of acetylation and deacetylation clearly rests at the centre of transcription control.
Several previous studies have demonstrated that acute ethanol has the ability to activate histone acetyltransferases (HATs) and inhibit histone deacetylases (HDACs) in the brain (Pandey et al., 2017; Figure 1). These properties may lead to increased histone acetylation (active epigenetic marks) that produces chromatin remodeling and changes in gene expression in the amygdala, a brain region responsible for comorbidity of anxiety and AUD (Pandey et al., 2008, 2017). Previous research has demonstrated that different alcohols and their metabolites can also induce changes to histone acetylation in hepatocytes (Choudhury and Shukla, 2008).
and “drugs”/psychedelics (incl possibly DOI, still need to see the paper more)
Actually looking at the paper it says ethanol has a direct effect. I have tended to think the effect is via acetate.
I will spent some time on this chasing down the original papers. Ethanol is complicated because its first metabolite (acetaldehyde) is really nasty, but the second one (acetate) is quite helpful.
The original post in this thread (please take a look) referred to a 2019 study from the Salk institute which reported that elevating acetyl-CoA levels reduces aspects of brain aging.
The abstract of this study follows:
Because old age is the greatest risk factor for dementia, a successful therapy will require an understanding of the physiological changes that occur in the brain with aging. Here, two structurally distinct Alzheimer’s disease (AD) drug candidates, CMS121 and J147, were used to identify a unique molecular pathway that is shared between the aging brain and AD. CMS121 and J147 reduced cognitive decline as well as metabolic and transcriptional markers of aging in the brain when administered to rapidly aging SAMP8 mice. Both compounds preserved mitochondrial homeostasis by regulating acetyl-coenzyme A (acetyl-CoA) metabolism. CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia.
CMS-121 | Acetyl-CoA Carboxylase 1 Inhibitor | MedChemExpress states that
CMS-121 is a quinolone derivative and an orally active acetyl-CoA carboxylase 1 (ACC1) inhibitor. CMS-121 protects HT22 cells against ischemia and oxidative damage with EC50 values of 7 nM and 200 nM, respectively. CMS-121 has strong neuroprotective, anti-inflammatory, antioxidative and renoprotective activities.
Moving on to 2025, it appears that a company identified as Neuro121 ( Neuroprotection & longevity in one capsule - NEURO 121 )
is now marketing “an experimental premium class molecule that protects your brain, enhances mitochondria, and stays ahead of its time. A limited batch for health pioneers.”
Pharma grade from the EU…30 x 100mg capsules for 89 Euros.
