The Forgotten Chemistry Between Aspirin, Sardines, and How the Body Learns to End Inflammation

One of the coolest things I’ve learned in this space came from Dr. Seeds. He is an extraordinary thinker and an exceptionally generous teacher, and this insight fundamentally changed how I understand inflammation. What makes it so powerful is not just the biochemistry, but the way it reframes old, familiar tools in an entirely new light. This concept connects aspirin, omega-3s, and resolution biology in a way that is both elegant and practical, and it’s a perfect example of Dr. Seeds’ ability to share deep, clinically meaningful knowledge with clarity and humility.

At first glance, aspirin and fish oil look like simple, even old-fashioned tools. Aspirin has been around for more than a century, and fish consumption has been part of human diets far longer than supplements or pharmaceuticals. Yet when you zoom in to the molecular level, the interaction between aspirin and omega-3 fats reveals one of the clearest examples of how small biochemical changes can redirect entire inflammatory programs in the body. This is not about suppressing inflammation, but about teaching the body how to finish it.

To understand why this matters, it helps to reframe inflammation itself. Inflammation is not a mistake or a flaw. It is a necessary biological response to injury, infection, or stress. The problem is not that inflammation turns on, but that in many modern contexts it does not properly turn off. The shutdown phase of inflammation is not passive. It is an active, enzyme-driven process governed by a class of signaling molecules called pro-resolving mediators, often abbreviated PRMs or SPMs. These molecules are the biochemical equivalent of a cleanup crew. They signal immune cells to stop recruiting reinforcements, clear debris, and restore tissue to normal function.

The raw materials for these mediators come from fats stored in cell membranes. Specifically, long-chain fatty acids with 20 to 22 carbons. The most familiar of these are arachidonic acid, an omega-6 fat, and EPA and DHA, the omega-3 fats found in fish. These fats are not just calories. They are precursors to powerful signaling molecules. What determines whether they become inflammatory signals or resolving signals is the enzyme environment they encounter.

One of the most important enzyme systems in this story is the cyclooxygenase family, commonly called COX enzymes. There are two main types relevant here, COX-1 and COX-2. They perform similar chemistry but serve very different biological roles.

COX-1 is best understood as a maintenance enzyme. It is active most of the time in many tissues. In the stomach, it helps produce prostaglandins that protect the gut lining. In the kidneys, it supports normal blood flow. In platelets, COX-1 converts arachidonic acid into thromboxane A2, a molecule that promotes platelet aggregation and clot formation. This is normal and necessary physiology. Without COX-1 activity, bleeding risk rises and protective barriers weaken.

COX-2, by contrast, is more situational. It is often expressed at low levels at rest and increases when cells sense inflammation, injury, or immune activation. Immune cells, inflamed joints, and injured tissues commonly upregulate COX-2. COX-2 produces prostaglandins that amplify pain, swelling, and heat, which is why it is often labeled as “the inflammatory enzyme.” But this label is misleading. COX-2 is not inherently harmful. It is part of a larger program that includes both escalation and resolution. What matters is what COX-2 is allowed to produce.

This is where aspirin plays a unique role. Aspirin, chemically known as acetylsalicylic acid, has a distinctive mechanism of action. It irreversibly attaches an acetyl group to COX enzymes. This is not a temporary block; it permanently alters the enzyme until the cell replaces it. You can think of this as changing the shape of the machine itself rather than just turning it off.

When aspirin acetylates COX-1 in platelets, the result is relatively straightforward. COX-1 can no longer convert arachidonic acid into thromboxane A2. Platelets cannot easily make new COX-1, so this anti-clotting effect lasts for the lifespan of the platelet. This is why low-dose aspirin is used in cardiovascular medicine.

COX-2 behaves very differently. When aspirin acetylates COX-2, it does not simply shut the enzyme down. Instead, it changes the geometry of the enzyme’s active site. As a result, COX-2 can no longer efficiently make classic inflammatory prostaglandins, but it can still add oxygen to fatty acids in a different orientation. This subtle change redirects the enzyme’s output rather than eliminating it.

This redirection is the key to understanding how aspirin and omega-3 fats work together. When omega-3 fatty acids like EPA and DHA are available, aspirin-acetylated COX-2 converts them into specific hydroxy-fatty acids. From EPA, it produces 18R-HEPE. From DHA, it produces 17R-HDHA. These molecules are not the final signaling compounds. They are intermediates, or precursors, that mark the entry point into resolution pathways.

Once formed, these precursors are passed to another enzyme family, primarily lipoxygenases, especially 5-lipoxygenase in immune cells such as neutrophils and macrophages. These enzymes complete the conversion, producing aspirin-triggered resolvins. From EPA come aspirin-triggered E-series resolvins. From DHA come aspirin-triggered D-series resolvins. These mediators actively promote resolution by calming excessive immune cell activity, enhancing debris clearance, and restoring tissue balance.

An analogy that helps many people is to think of inflammation like a construction site. The initial inflammatory phase is demolition and repair preparation. Prostaglandins bring in workers and equipment. But without a foreman to signal when the job is done, the site stays chaotic. Pro-resolving mediators are that foreman. Aspirin does not fire the workers. It retrains the foreman so the job can be completed.

This brings us to an important practical question: where do the omega-3s come from? Supplements are one option, but they are not the only one, nor necessarily the most accessible. Sardines are a particularly interesting food in this context. They are inexpensive, widely available, and naturally rich in EPA and DHA. Unlike many larger fish, sardines are low on the food chain and therefore lower in mercury and other contaminants.

Sardines also contain omega-3s in a mix of lipid forms, including triglycerides and phospholipids. This matters because phospholipid-bound DHA, in particular, appears to integrate efficiently into cell membranes and may support delivery of DHA to neural tissues. Transport of DHA into the brain is a tightly regulated process, with specialized transport systems that favor certain lipid forms, such as lysophosphatidylcholine-DHA. While eating sardines does not directly deliver DHA in that exact form, regular intake supports the body’s ability to generate and maintain brain-relevant DHA pools more effectively than highly processed diets devoid of marine fats.

When you pair regular sardine consumption with low-dose aspirin, often referred to as baby aspirin, you create a biochemical environment that favors resolution signaling. The sardines provide the substrate, EPA and DHA. The aspirin modifies COX-2 so that when inflammation arises, those omega-3s are more likely to be routed toward pro-resolving mediator production rather than simply sitting unused in membranes.

This does not mean aspirin magically converts fish into resolvins. The context still matters. There must be some level of immune or inflammatory activation to induce COX-2 and lipoxygenase activity. But it does mean that the system is biased toward resolution rather than prolonged inflammation.

For beginners, the takeaway is simple. Eating oily fish regularly gives your body the raw materials to calm inflammation properly. Aspirin, in low doses and appropriate contexts, can help shift how those materials are used. For experts, the deeper insight is that enzyme acetylation, fatty acid stereochemistry, and immune cell cross-talk determine whether inflammation resolves cleanly or lingers.

For clinicians, this framework encourages a more nuanced view of aspirin and omega-3s. Aspirin is not just an anti-platelet drug, and omega-3s are not just lipid-lowering supplements. Together, they influence lipid mediator class switching, a process increasingly recognized as central to chronic inflammatory diseases. However, aspirin carries real risks, including gastrointestinal bleeding and interactions with other medications. This approach is not appropriate for everyone and should be individualized.

For strength coaches and performance professionals, the message is about timing and intent. Training creates inflammation by design. That inflammation drives adaptation. Blunting it indiscriminately with NSAIDs can impair progress. Supporting resolution, however, helps the body finish the adaptive process. Regular omega-3 intake from foods like sardines supports this without shutting down signaling. Aspirin should not be treated as a recovery supplement, but understanding its mechanism helps explain why chronic NSAID use can interfere with gains.

Ultimately, the story of aspirin and omega-3s is a story about systems biology. Small chemical changes can redirect entire signaling networks. Resolution is not the absence of inflammation, but the successful completion of it. When people understand that distinction, they stop asking how to eliminate inflammation and start asking how to teach the body to end it well. That shift in thinking is where real progress happens, whether you are a patient, a clinician, a coach, or simply someone trying to understand your own biology well enough to explain it to others.

11 comments