FGF21: Another Fighter Against Cellular Aging?

If you’re still unaware of what cellular senescence (cellular aging) is, check out older posts. In short, cellular senescence is emerging as a major trigger for chronic, hard-to-treat metabolic and health problems. The only difference lies in where senescent cells accumulate and stop obeying central commands — for example, to multiply or, conversely, to break down. These cells interfere with healthy ones, sending them misleading signals (SASP), but overall, it still appears that everything is functioning almost as before.

A typical trigger for cellular senescence is when the antioxidant system fails to break down hydrogen peroxide, leading to the release of signaling molecules from mitochondrial membranes. Depending on the state of the membranes, corresponding defense mechanisms are activated — for instance, oxidative metabolism (OxPhos) is halted and replaced by fermentation, which produces less hydrogen peroxide and doesn’t require oxygen. All this happens in an environment where oxygen is still abundant, creating pseudohypoxia. DNA repair and cell division stop to prevent the replication of damaged DNA.

Esteemed professors still repeat in their online lectures that fat cells first enlarge and then lose access to oxygen. But that can’t be the case. HIF1α activation must occur in small cells; otherwise, HIF1α deactivation wouldn’t work. But it works, it turns off cellular senescence. As the following study shows, it’s actually small adipose stem cells that activate cellular senescence — something these professors seem unaware of — and it’s also the main cause of the strange behavior of adipose tissue, i.e., pseudohypoxic behavior. But let’s continue.

If the DNA is still undamaged and repair mechanisms function, the cell can protect itself from peroxide damage by activating mitochondrial uncoupling — wasting energy as heat. This reduces the electrical potential across the mitochondrial membrane, lowering hydrogen peroxide production. There are many possibilities, and it’s always a response to a shortage of NADPH molecules. These are necessary for recycling GSSG into GSH (restoring mitochondrial antioxidant protection) and for fat synthesis. The line between triggering mitochondrial uncoupling (lean phenotype) and senescence (obese phenotype) is very thin.

ASC — adipocyte stem cell; FGF21 activates the GLUT1 and GLUT4 transporters, ensuring enough glucose for the PPP pathway, which recycles NADPH and the antioxidant GSH. This suppresses cellular aging/senescence, keeping adipose tissue healthy, with small and functional fat cells.

Now, to the topic. FGF21 molecules had somewhat eluded me — I couldn’t quite fit them into the model, which focuses mainly on oxidative metabolism, pseudohypoxia, and cellular senescence. Until I found this study, where these phenomena are directly linked and influenced by the hormone FGF21. It turns out that FGF21 works as a means to switch senescent cells back to oxidative phosphorylation. It’s another "youth elixir," functioning similarly to those I’ve described in previous posts — like acetate or mechanical stress (ultrasound). The method is interesting because it strikingly resembles the effects of acetate. It’s likely part of acetate’s pathway, though I don’t yet have proof that acetate activates FGF21 (medium-chain MCT fats do). I only know that FGF21’s effect can be turned off by deactivating SIRT1, just like with acetate. Interestingly, besides MCT fats, FGF21 can also be activated by sugar, alcohol, or even mildly oxidized oils — though I wouldn’t dare claim the effect is always positive. In some cases, these substances definitely cause cellular senescence.

So, how does FGF21 do it? The mechanism is directly tied to the pathway producing NADPH for glutathione (GSH) recycling — the PPP pathway. Here, glucose metabolism recycles NADP+ into NADPH. Thus enough glucose in the cytosol ensures sufficient antioxidant protection. I’ve previously illustrated how glucose can protect mitochondria during fat burning.

A combination of fats (FFA—oleate/palmitate) and fructose leads to fat accumulation and depletes antioxidant defenses, creating an acute NADPH shortage. Increased glucose (25 mM) can replenish missing NADPH and restore normal regulatory loop function (antioxidant protection).

I’ve also shown that fructose worsens antioxidant defense, blocks NADPH recycling (and thus GSH recycling), increases oxidative stress, and promotes fat storage over burning. By increasing KHK enzyme activity, fructose suppresses the deacetylase SIRT2, leading to G6PD acetylation and PPP pathway blockage. So, even though sugar activates FGF21, the outcome is only positive if there’s enough NADPH and oxidative stress doesn’t overwhelm PPP pathway.

The cited study directly addresses senescence in visceral adipose stem cells (around internal organs). I’ve mentioned before that obese individuals’ fat tissue contains a small number of senescent cells causing insulin resistance. This study reveals that these are stem cells, clearly marked by P16, P21, and P53 activation. The inability of adipose stem cells to differentiate into functional fat cells leads to hypertrophy in existing fat cells — new cells that would meet the central demand for fat storage simply don’t form, so old fat cells grow in size.

FGF21 forces these senescent fat cells to consume more glucose for NADPH production. It also activates GLUT4 transporters, which participate in insulin-stimulated glucose uptake. This restarts oxidative phosphorylation and allows differentiation into mature fat cells.

Researchers demonstrated in mice that supplementing small amounts of FGF21 corrects metabolism long before fat tissue size changes — before the mice lose weight. By the end of the experiment, FGF21-treated mice were just as fat as untreated ones, but their metabolism was significantly better. The fat tissue rejuvenates, starts functioning properly, and improves the processing of both glucose and fats.


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References:

FGF21 alleviates adipose stem cell senescence via CD90 glycosylation-dependent glucose influx in remodeling healthy white adipose tissue

FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway

Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury

Dietary medium-chain fatty acids reduce hepatic fat accumulation via activation of a CREBH-FGF21 axis

Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins


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