Vinegar/sodium acetate rejuvenates blood vessels, another elixir of youth?

In my previous post, I pointed out a study in which scientists extended the lifespan of mice by up to five months, about 17%, through mechanical stress induced by ultrasound. I also mentioned that it would be beneficial to combine the therapy with the supplementation of sodium acetate or vinegar, as these activate the same pathways, namely SIRT1 and AMPK. Immediately afterward, I came across a study showing the successful suppression of cellular senescence using sodium acetate in vascular endothelial cell cultures — the inner lining of blood vessels. Almost as if on cue, the study was published just a few days ago, on May 12th of this year.

This is a fascinating study that combines the investigation of substances produced by gut bacteria that damage our blood vessels and accelerate the aging of the inner vascular lining. Researchers identified the compounds phenylacetic acid (PAA) and phenylacetylglutamine (PAGln), which are primarily produced by bacteria of the genus Clostridium. These compounds increase the production of hydrogen peroxide, which, in this environment, activates cellular senescence. However, hydrogen peroxide does not always trigger senescence — it can also induce energy dissipation through mitochondrial uncoupling or apoptosis, which involves dismantling dysfunctional cells into raw materials. In this case, however, it leads to cellular senescence, which manifests as a halt in the cell cycle and cessation of cell division, specifically in vascular cells, resulting in reduced vasodilation, stiffening of blood vessels, impaired angiogenesis (the formation of new blood vessels), and worsened blood supply. This is precisely where acetate/acetic acid in the bloodstream plays a role in suppressing these effects.

The compounds PAA and PAGln have been identified as factors causing endothelial cell senescence. Senescent cells produce cytokines that affect the function of neighboring cells.

As mice and humans age, the balance of different gut bacteria changes — some die out, while others proliferate. This shift affects the composition of bacterial metabolic byproducts. The concentration of the primary product, acetate, decreases in the colon and bloodstream, while other problematic compounds, like PAA and PAGln, emerge.

These compounds are produced by bacteria through the enzymatic activity of VOR and PPFOR.

These gut-derived compounds enter the bloodstream and influence vascular health, including the blood vessels' ability to respond to nitric oxide through vasodilation (expansion), adapting to physiological demands. Specifically, PAA molecules trigger cellular senescence, which can be identified using the marker p16. 

Markers of senescence, such as p16 and DNA damage indicator γ-H2A.X, confirm that the culprit in older individuals (Aged) is gut bacteria of the genus Clostridium (Clos). The therapy using D+Q (dasatinib + quercetin) acts as a senolytic, selectively toxic only to senescent cells.

Sodium acetate (Ac) suppresses senescence, as demonstrated by its ability to promote the formation of new blood vessels.

Sodium acetate (Ac) protects against the presence of PAA, maintains oxidative phosphorylation (OCR), and supports the activity of enzymes ACCS2 and IDH2.

Mitochondrial hydrogen peroxide (H₂O₂, generated via D-Ala) suppresses the activity of deacetylase SIRT1, thereby influencing the activity of other enzymes.

Mitochondrial H₂O₂ (generated via D-Ala) regulates vascular dilation sensitivity to nitric oxide through the IL-6 - HDAC4 pathway.

Acetate activates antioxidant protection (Nrf2) and shields against PAA molecules. If SIRT1 deacetylase is genetically disabled (siSirt1), this protective mechanism ceases to function.

Thus, the process leading to endothelial cell senescence begins in the gut, where bacterial composition gradually shifts over time, reducing the body's supply of acetic acid. Conversely, gut bacteria increasingly produce harmful toxins, leading some cells into senescence. As I previously mentioned, these senescent cells do not keep this information to themselves; they broadcast distress signals via chemical messengers (SASP), significantly affecting surrounding cells and the body's overall condition. One key effect is the increased production of H₂O₂ during ATP energy extraction in mitochondria.

Upon detailed analysis, activation of deacetylase SIRT1 through acetic acid/acetate appears to be an effective defense mechanism. This activation restores the metabolic function of senescent cells to normal oxidative phosphorylation, enabling them to generate more ATP energy for cellular activities.

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References:

Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging