Cellular Senescence Arises from Temporary SIRT1 Inactivity During Fat Cell Differentiation

I found a very interesting study linking the activity of deacetylase SIRT1 to cellular senescence in fat cells. It beautifully connects the effect of acetic acid/acetate in suppressing fat cell senescence and promoting healthy fat storage. Increasingly, we see that phenomena we consider negative are actually highly adaptive responses to specific conditions and are, in fact, beneficial. I’ve previously demonstrated this with insulin resistance. The same applies to weight gain — efficient fat storage is advantageous and does not cause obesity. On the contrary, impaired fat storage leads to weight gain. This results in permanent insulin resistance caused by senescent cells. Surprising, isn’t it?

SIRT1 deacetylase protects against cellular senescence in differentiated cells during the differentiation phase.

If we accept that occasionally storing energy reserves for periods of scarcity is beneficial, then safely depositing excess available calories into adipose tissue is a vital adaptation to environmental conditions. It appears fat storage can occur healthily without triggering cellular senescence — or poorly if senescence is activated in fat cells, as this restricts fat storage.  

Suppressing SIRT1 activity (using EX-527) specifically during differentiation (Inhib+Diff) induces cellular senescence (SA-β-Gal).

Let’s recap what overeating causes: When food is too easily accessible — especially more concentrated and rapidly absorbed — the body must quickly store it as fat. Natural calorie sources are typically less concentrated and have limited absorption, particularly carbohydrates, which aren’t fully absorbed in the small intestine and instead feed gut bacteria. At this stage, it’s critical for excess calories to convert them to acetate and lactate. Only elevated acetate levels during overeating ensure safe fat storage and proper activation of newly differentiated fat cells, because acetate activates SIRT1 precisely when new fat cell differentiation is needed. This is the only way to form healthy adipose tissue.

Adipocyte differentiation requires robust antioxidant protection via SOD2 and catalase.

In a prior post, I discussed a study where authors noted that deactivation, oxidation, and misfolding of superoxide dismutase (SOD1) heavily contribute to senescence. Here, they identified dysfunctional SOD2 as the primary cause. It seems antioxidant defense during fat cell differentiation is crucial: Differentiation generates superoxide, which must be dismutated into hydrogen peroxide — a role of SOD. If SOD is impaired, DNA damage and repair mechanism failure follow. This brings us back to excessive omega-6 PUFA consumption, which depletes antioxidant defenses and accelerates senescence. Yet, paradoxically, excess dietary PUFA enhances glucose fermentation into acetate, improving SIRT1 activation — so compensation can occur.

To summarize, I believe we now understand what damages adipose tissue. It's acetate deficiency and insufficient SIRT1 activation precisely when excess calories must be stored rapidly.  This damages fat tissue so severely that it loses the ability to differentiate new fat cells, and the existing ones become too large and can only store fat very slowly. To prevent this, short-chain fatty acids (especially acetate) must always be available during fat storage.  


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References:

SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence

Activation of Sirt1 by acetate alleviates silicofibrosis: Contribution of the gut microbiota

Akkermansia muciniphila-derived acetate activates the hepatic AMPK/SIRT1/PGC-1α axis to alleviate ferroptosis in metabolic-associated fatty liver disease


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