Grade: Good

A cheap and safe treatment for inflammation, fever, and pain (commonly for a headache), aspirin is probably the most widely used drug in the world.  Before there was aspirin there were the leaves of willow trees which contain salicin.  If you can get past the unpleasant taste you can drink a tea made from willow leaves and your body will convert the salicin to salicylic acid.  Evidence shows this was done by many cultures for over 2,000 years before the modern form came along.

These days we take aspirin, or acetylsalicylic acid (ASA), which the body quickly breaks down to the same salicylic acid that we produced in vivo from willow leaves.  Our modern version was discovered in 1853 by a french chemist named Gerhardt.  For the next 4 decades chemists tinkered with the process of production until Bayer released a global marketing campaign in 1899 for their version of ASA which they called Aspirin.

Aspirin’s influence on Alzheimer’s is probably greatest as an anti-inflammatory.   The processes by which aspirin modulates inflammation are varied and still being discovered, but its role in COX-1 and COX-2 inhibition is fairly well studied.

Inflammation and COX

COX-1 and COX-2 (cyclooxygenases) are enzymes produced by genes of the same name that normally react with arachidonic acid (an omega-6 fatty acid – hold on to this as it will be important later) to form prostanoids, including thromboxane and prostaglandins such as prostacyclin. Aspirin inhibits COX-1 such that the generally inflammatory by-products of arachidonic acid, such as thromboxane, are not produced or at least produced in smaller quantities.

While aspirin inhibits COX-1 its effects on COX-2 are critically different in that it modifies the enzymatic activity of COX-2 and produces entirely new compounds.  COX-2 and omega-6 fatty acids normally produces prostanoids, most of which are proinflammatory, but aspirin-modified COX-2 produces lipoxins, a group of anti-inflammatory compounds known as specialized pro-resolving mediators (SPMs).

One of the many important things here is that omega-6 fatty acids are generally inflammatory and aspirin can tip the balance towards anti-inflammatory.  You can also double-down on the anti-inflammatories by switching some of your omega-6 consumption to omega-3.  But wait, what if you consume more omega-3’s AND take an aspirin?  You will gain the benefits of both.

A word of caution for anyone prone to bleeding – omega-3 fatty acids are mild anti-coagulants, as is low dose aspirin.  Alone or combined they may cause you to bleed more readily.

For a more detailed discussion of omega-3, omega-6 please read The Importance of Maintaining The Correct Ratio of Omega-3 to Omega-6 and Just What Is Omega-3.

Inflammation and NF-kB

Salicylic acid and its derivatives modulate signaling through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a transcription factor that plays a central role in inflammation.  NF-kB plays a role in many varied and complex processes in the body and any discussion feels like a gross oversimplification, but here goes.  NF-kB activates multiple cellular and viral genes involved in inflammation and infection including interleukin-1 (IL-1), IL-6, and adhesion molecules.  Aspirin short-circuits this activation of inflammation.  Aspirin can also be an activator of NF-kB pathways, which result in tumor death, but this article is about Alzheimer’s.

Lysosome Biogenesis and PPAR

Aspirin has been found to increase lysosomal biogenesis in brain cells.  This is huge and here’s why: lysosomes are organelles that break down and remove cellular waste products including misfolded proteins and are the workhorses in the process known as autophagy.  Wait, would that include misfolded proteins that create amyloid-beta plaques and tau tangles?  Yes!  Autophagy reduces the accumulation of both.  And aspirin increases the number of lysosomes in brain cells which is exactly where we want them!

The same study (see link above) found that aspirin stimulated the PPAR alpha pathway to upregulate Transcription factor EB (TFEB) which is the master regulator of lysosomal biogenesis.

PPAR alpha is activated during starvation (in the strictest sense of the word).  Don’t worry, you don’t need to be dying from lack of food for PPAR alpha to engage.  In fact, PPAR alpha is a necessary component of ketogenesis where it promotes uptake, utilization, and catabolism (break down) of fatty acids.




The Downside?

I mentioned before the bleeding risk associated with both large amounts of omega-3s and aspirin.  Aspirin can also be dangerous for children, but I assume if you are reading this you are not under the age of 10.  A trusted source mentioned in passing that aspirin can damage mitochondria, but I can find nothing in the literature to support that position.

Updated November 30, 2018:  There is another potential downside of long-term aspirin dosing as it relates to mucus production.  Thanks once again to the fine blogging of Emily Deans I began looking into the role of lectins in inflammation.  In short, lectins are produced by many fruits, vegetables, and grains to discourage us from eating them (sometimes until their seeds are ready), but we do anyway.  The result of ignoring the warnings is a long list of ailments, but the important one here is leaky gut.  One of the body’s first lines of defense against lectins is mucus (nose, throat, and gut).  The mucus binds to the lectin and escorts it through the digestive tract without incident.  The concern here is that aspirin (and really all NSAIDs) disrupt mucus production in the gut.  Here are the mixed results:

  • 1987:   “Non-steroidal anti-inflammatory drugs (NSAIDs) cause gross mucosal damage.”

However –

2012:  “Overall, gastric mucus secretion is increased in aspirin-takers, suggesting a functional adaptive response to long-term administration of the drug. However, it is possible that the adaptive response is impaired in some aspirin takers, who might be susceptible to severe upper gastrointestinal complication.”  In other words, not everyone reacts negatively to aspirin and tolerance can increase over time.

There is a form of aspirin that is much better tolerated.  Aspirin-PC or PhosphatidylCholine Associated Aspirin.

  • 2011:  “Overall, 42.2% of aspirin-treated subjects developed multiple erosions and/or ulcers, whereas 22.2% treated with [Aspirin-PC] developed such damage. Gastroduodenal ulcers were observed in 17.6% of aspirin-treated compared with 5.1% of subjects treated with [Aspirin-PC].”

It is important to note that subjects in the 2011 study began daily treatment with 325 mg of aspirin (the size of one normal pill) and were tested after 7 days, which hardly leaves time for the body to adapt.  My point is that the frightening number of 42.2% with multiple erosions likely drops over time.  That said, Aspirin-PC looks like a great alternative.

Here’s the catch: aspirin-PC is not commercially available yet.

I don’t know what the secret formula for aspirin-PC is or will be, but I know that Phosphatidylcholine is made from choline AFTER the body has preferentially produced acetylcholine and that reduced levels of choline and/or acetylcholine results in the body raiding stores of phosphatidylcholine to break them down into the smaller components that are now in short supply.  It stands to reason that supplementation would provide the raw materials needed for acetycholine and phosphatidlycholine (PC) and could provide protection against aspirin-induced gastric mucosal injury.

How does one supplement choline, you ask?  Well, “Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) or cytidine 5′-diphosphocholine” is a common form of supplementation.

An interesting source for phosphatidlycholine (PC) supplementation is krill oil.  Krill oil, like fish oil, contains omega-3 fatty acids such as EPA and DHA, and also a healthy does of phosphatidlycholine (PC).    This is pure speculation, but perhaps the answer here is to take krill oil with your aspirin.

Another thought is that the ketogenic diet eliminates many lectins and would therefore mitigate aspirin-induced gastric mucosal injury.

After much back and forth, my personal conclusion is that a daily aspirin is probably safe for most of us, and is likely safer when taken with citicoline and/or krill oil, and is probably safest when the above are combined with a ketogenic diet.