Is aspirin harmful to the mitochondria?

We certainly don’t want to harm our mitochondria, right?

Since the mitochondria control everything, from energy production, regeneration, longevity, etc., we should be protecting and optimizing it, not inhibiting it.

Certain “healthy” things that inhibit proper mitochondrial function include metformin and berberine for example.

Does aspirin also fall under that list?

Let’s take a look.

Aspirin and mitochondrial dysfunction

Mitochondrial dysfunction is thought to be involved in Reye’s syndrome (which I’ll address in another article) and aspirin is thought to cause it or at least contribute.

A few ways it is thought to do so is by 1) inhibiting fatty acid oxidation and contributing to fatty liver, 2) inhibiting various enzymes of the Kreb cycle, 3) inhibiting certain complexes of the electron transport chain (ETC), 4) causing fission of the mitochondria (creating smaller, more useless and dysfunction mitochondria) and 5) lowering ATP too much through excessive uncoupling.

Let’s start with the first 1.

1) Aspirin inhibiting fatty acid oxidation

There is no in vivo research that shows that aspirin inhibits fatty acid oxidation. In truth, there are a few studies showing that aspirin, at doses of 3-4g daily for weeks on end, didn’t affect or slightly lowered total free fatty acids and lowered triglycerides, while not affecting liver and kidney function.

A reduction is free fatty acids are many a result of a reduction in inflammation and stress hormones.

A reduction in triglycerides would indicate a reduction in excess lipolysis, a reduction in the synthesis of fat and/or an increase in fatty acid oxidation. Excess triglycerides, from excess lipolysis and/or lipid synthesis, would accumulate in tissue, such as the muscle, liver, heart, etc.

I’d yet have to see a study of a biopsy showing that aspirin caused fatty acid buildup in tissue from its ability to “inhibit fatty acid oxidation”.

Actually, aspirin has been shown to protect against fatty liver, not cause it.

There are only in vitro studies showing that aspirin can inhibit fatty acid oxidation. Here are one of them and some commentary about it.

Aspirin metabolites salicylate, hydroxyhippurate and gentisate, but not aspirin, directly inhibited palmitate oxidation in control and RS (Reye’s syndrome) cells. RS cells were significantly more sensitive to inhibition than controls at 0.5 to 5 mM salicylate. Inhibition was concentration-dependent and reversible. Inhibition did not occur in fibroblasts lacking activity of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of MTE. Salicylate was therefore inhibiting β-oxidation at this step. Hydroxyhippurate and salicylate reversibly inhibited HAD activities in extracts of control and RS cells.

(R)

And now commentary from BigYellowLemon:

Real, actual problems in beta-oxidation don’t actually start until 5mM or so, and even then they’re still not that strong. It only starts getting really intense at 10mM and upwards, in control cells. 5mM would be something like 10g-15g and 20g over the course of a day. You’d have other problems to worry about besides beta-oxidation at doses like that” (R, P).

This in vivo study in mice found that: “salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT. In addition, salsalate increased the expression of genes related to glucose and fatty acid transport and oxidation in skeletal muscle. Our results also showed that expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate. Moreover, sarcolipin (Sarcolipin (SLN), a regulator of SERCA activity in muscle, plays an important role in regulating muscle thermogenesis and metabolism) and sarcoplasmic reticulum Ca2+ ATPase 2 (Serca2) in skeletal muscle were enhanced in salsalate-treated mice” (R). Looks to me more like salicylate improves mitochondrial function, rather than inhibiting it. This is well in line with aspirin’s ability to help optimize the metabolism.

Last but not least, here’s a study that found that salicylate actually increased fat oxidation. “Intriguingly, energy expenditure was higher after administration of salsalate (∼18 and ∼16% under basal and clamp conditions, respectively) and was fueled by increased fat oxidation in the basal state and increased CHOox (carbohydrate oxidation) upon insulin stimulation (indicating improved metabolic flexibility). … Salsalate did not affect mitochondrial function and coupling” (R). The dose they used was 4g of salsalate.

2 & 3) Aspirin and inhibition of various enzymes of the Kreb cycle and ETC

The Kreb cycle is found in the mitochondria, which converts pyruvate to a variety of different compounds and eventually to oxaloacetate and then citrate again.

The most affected enzyme, by aspirin, is succinate dehydrogenase subunit C (SDHC; which is a part of the succinate dehydrogenase, aka complex II), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle (R).

But is that a bad thing? This is what the authors had to say about it:

The protein with the most significant difference between treatments was SDHC; plasma levels were lower after aspirin treatment. SDHC is a subunit of succinate dehydrogenase (SDH), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle, which oxidizes succinate to fumarate [38]. As one part of SDH (also called complex II), it also facilitates transfer of electrons to coenzyme Q (ubiquinone) [39]. Aspirin has been shown to interfere with mitochondrial function [40], as well as inhibit the activity of SDH in rats [41]. Further, repeated mild inhibition of oxidative phosphorylation via inhibition of SDH protects against the decrease in ATP that usually accompanies severe hypoxia and thus can act as neuroprotection [42]. Treatment with aspirin has also been shown in vivo to slow down the decline of intracellular ATP by this mechanism of inhibiting SDH [43] and therefore to protect against hypoxia, a common hallmark of tumors that promotes metabolic adaptations and angiogenesis [44]. Furthermore, accumulation of succinate, due to reduced efficiency of SDHC, results in the stabilization of HIF1-α, the degradation of which is promoted by the oncometabolite (R)-2-hydroxyglutarate [45].

Although aspirin appears to slightly inhibit succinate dehydrogenase, the study above found that: “expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate” (R).

Furthermore, aspirin has been shown to inhibit complex I in vitro (R). When CoQ10 levels are low, aspirin might inhibit complex I too much (complex I use CoQ10) and supplementing CoQ10 restores complex I activity, despite the intake of aspirin. I should add that in the study, they added NADH to the cells, which needs to be recycled back to NAD via CoQ10. So they already put the cell in a highly reduced state, making it more prone to ROS production. Plus, they used 50uM (micromolar), which is equivalent to 100-150mg of aspirin. Would 100-150mg of aspirin inhibit complex I by 50-60% (which would result in a significant increase in ROS and decrease in ATP production)? Clearly not, so we can most likely disregard this whole study as bogus, but it does show the importance of CoQ10 though.

#4 Aspirin and excess fission of the mitochondria

There is a balance between fission and fusion, which either breaks the mitochondria down into smaller bits or fuses it with another one to create bigger, more effective mitochondria, respectively. People with lots of oxidative stress and inflammation have a greater proportion of smaller fragmented mitochondria, whereas healther individuals have larger mitochondrias.

Large mitochondrias improve metabolic flexibility and total energy production.

Both fission and fusion are needed, but too much of either can also be bad.

As already mentioned, oxidative stress and inflammation promote fission. Too much inflammation and you have too much fission. This overwhelms mitophagy and autophagy, which can further worsen oxidative stress. “…abnormalities in mitochondrial fission in endothelial cells contribute to inflammation and oxidative stress in the cardiovascular system. These cells also produce less ATP and more ROS” (R).

Salicylate has been found to be protective in this regard. “Reductions in fission and inflammation were also observed in cells following NF-kB inhibition, anti-inflammatory drug salicylate could also reduce mitochondrial fragmentation. Salicylate works by blocking the activity of multiple inflammatory molecules, including NF-kB.” (R)

And also, aspirin doesn’t inhibit proper autophagy, it actually stimulates it. “Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300” (R, R).

Last but on least, aspirin-treated rats actually had larger mitochondria than the untreated animals, which indicates better metabolic flexibility and ability to produce energy. “Although it has been suggested that acetylsalicylate (ASA)-induced mitochondrial dysfunction plays an important role in the pathogenesis of Reye’s syndrome, administration of ASA alone does not cause this syndrome in therapeutic doses.  Furthermore, oral administration of ASA (150 mg/kg for 5 days running) to rats did not affect mitochondrial structure or liver function…” (R). And when you look at the actual data in the study, you’ll see that the aspirin-treated rats had bigger mitochondria, not smaller.

On a different note, aspirin reduces oxidative stress and muscle damage during exercises, while promoting proper mitochondrial function during exercise. This study (in elite Taekwondo athletes) shows that aspirin before exercises lowered post-workout lactate dehydrogenase (LDH) (R). Increased enzyme activity of LDH in the blood negatively affects pH, cellular ATP production, muscle cell membrane integrity, and is associated with increased levels of ROS production that can further exacerbate cellular damage.

So all in all, according to the study above, aspirin provides beneficial effects on exercise performance and recovery by 1) limiting exercise-induced muscle cell membrane and tissue damage by improving LDH and ROS clearance, and 2) by increasing oxygen delivery capacity to the skeletal muscle through reduced arterial stiffness following chronic high-intensity exercise.

#5 Aspirin, uncoupling and ATP depletion

Uncoupling is when protons enter the mitochondria through uncoupling proteins increased of through ATPase, thus creating heat instead of ATP.

Some uncoupling is good, since it speeds up the metabolic rate, increases core temps and CO2 production, lowers oxidative stress and inflammation, promotes fat loss and longevity, etc. Read more here on how to boost uncoupling.

But too much uncoupling could lower ATP levels too much, thus leading to death. However, too low ATP from excess uncoupling is actually very unlikely to be the case, since DNP (an illegal uncoupling fat loss drug typically used by bodybuilders and before that by Russian soldiers requiring heat in frigid areas) causes death through hyperthermia and not ATP depletion. Aspirin is a much less potent uncoupler than DNP and seems to uncouple most effectively at a starting dose of 1-1.5g. It doesn’t promote uncoupling in a linear fashion. In fact, it might even start to inhibit uncoupling in larger doses. That’s why people feel warm at 1-1.5g, but then start to feel colder after a few day, because the salicylate has had time to build up in the system (long half-life) and start to inhibit uncoupling. Or alternatively, the body enhances salicylate excretion, thus increasing the dose required.

In addition, uncoupling of oxidative phosphorylation decreases intracellular ATP formation and, consequently, induces the release of adenosine into extracellular fluids an effect that has been suggested to contribute to the anti-inflammatory actions of salicylate (R).

Lastly, many studies have been done of type I and II diabetics with aspirin, salsalate or sodium salicylate in the range of 3-9g for up to a full year without any incidents of hyperthermia or death from uncoupling.

Summary

Most of the fearmongering of aspirin destroying the mitochondria is unfound and bad science. Many human studies show that those taking 3-4g for many months on end or even 7-9g for a few weeks suffer little to no side effects.

But if you want to play it on the safe side, you can take compounds that support the electron transport chain to ensure energy production remains optimal. Compounds such as methylene blue, vitamin K2 (MK-4), succinic acid and CoQ10.

Also, there is evidence that salicylate might be harmful to the kidney in the presence of a zinc deficiency in very young animals (R). To prevent that, make sure to consume enough dairy, meat and oysters, all of which are great sources of zinc.

Just keep in mind that I’m not saying everyone should be taking 3-4g of salicylic acid daily, but most people actually feel improvements with doses of 81-325mg per day. Higher doses might be required to induce uncoupling if an increase in body temperature is required.

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2 Replies to “Is aspirin harmful to the mitochondria?”

  1. Hey Hans, i know you have your priorities but i just wanna tell you that i loved when you talked about BMR and mTOR in a newsletter and i’d love to see an article about the effects of an high vs low BMR on longevity and health!
    All the best,
    Ivan

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