How does Aspirin Work?

 

Back in October, I reported on an article in Science Magazine claiming that daily aspirin can lower your risk of mortality by 13%.  I calculated this might add 2 years to life expectancy – and it’s easy and essentially free.  By the time it gets to Science Magazine, this is a mainstream position, meaning that although there is dissension (also here), the pro-aspirin view is now the majority.

The benefits of aspirin come from two quite different mechanisms, and my purpose in this column is to tease them apart.  One might legitimately be called “anti-aging”.  The other is more analogous to wearing seatbelts. Seatbelts lower your risk of dying but it would be a stretch to say that they make you younger.

The first benefit of aspirin is that it “thins the blood”.  (More technically, it inhibits the chemistry that makes blood clot.)  It turns out that, though chronic damage to the arteries sets the stage for heart attacks and strokes, the precipitating incident is usually a blood clot that gets snagged in the wrong place and denies blood supply to either the heart or the brain (“ischemia”), until, after just a minute or two, they suffocate.  Blood clots in the brain are the principal reason for stroke, and blood clots in the coronary artery can cause sudden cardiac death.  To the extent that these actions are responsible for its benefits, aspirin should be described as a “safety drug” rather than an anti-aging tonic.

The second mechanism, the one that I think of as “anti-aging” is to lower inflammation.  As we get older, our bodies slowly destroy themselves, and one of the principal mechanisms is to turn the inflammation process against healthy tissue.  All the diseases of old age are linked to chronic inflammation.

  • Inflammation can turn normal cells into cancer cells.

  • Inflammation in the arteries causes the damage that leads to plaques and then strokes and heart attacks.

  • Inflammation in the joints causes arthritis.  (There was a time when osteo-arthritis was distinguished from rheumatoid arthritis, and the former was blamed on abrasion building up over a lifetime, while only the latter was attributed to inflammation.  But the modern view is that they are not so different, and that osteo-arthritis is also an inflammatory disease.)

  • Inflammation is linked to brain damage and dementia.

So just by dialing down inflammation in a dumb, non-specific way, aspirin can lower risk of all these diseases.  In the young body, inflammation is an essential part of our immune defense, and has an important role in replacing damaged tissue.  But by the time we get to be 50+, inflammation is already causing more harm than good.  In this sense, anti-inflammatory is close to anti-aging.

If aspirin’s benefit comes from reducing inflammation then if you take aspirin from age 50 to age 80, say, then you are functionally a year or two younger than you might have been at the same age had you not taken aspirin.  If you stop taking aspirin on your 80th birthday, your body is that much younger, and the benefit stays with you still.  But if the only benefit comes from preventing fatal blood clots, then if you were to stop taking aspirin at age 80, your mortality risk would jump quickly back up where it would have been had you never taken aspirin at all.  You might attribute your survival for those 30 years in part to the benefit of aspirin, but you would not be better off than if you had survived to age 80 by sheer luck.

Separating these two effects of aspirin is not so easy because there is a strong physiological connection between the them.  Inflammation is suppressed by inhibiting COX-2, and blood clots are suppressed by inhibiting COX-1.  These are abbreviations for two forms of the enzyme cyclooxygenase.  Aspirin, like most NSAID drugs act on both COX-1 and COX-2.

(Rofecoxib=Vioxx is the only one that is completely specific to COX-2, without affecting COX-1.  Vioxx worked well against inflammation, but was found to increase risk of heart attack, and was withdrawn from the market in 2004.  But why should inhibiting COX-2 without COX-1 increase risk of heart attacks?  In the infamous VIGOR study, hidden data showed 4x as many heart attacks in patients taking Vioxx.  I have found no attempts to answer this question.)

Another interesting footnote:  Ibuprofen, the second most common NSAID, inhibits clotting in the same league with aspirin.  But the anti-clotting effect of aspirin lasts 5 days, and of ibuprofen just 1.  Here’s the curious part: if you take aspirin and ibuprofen together, the effect lasts just 1 day.  Evidently, ibuprofen blocks the long-term effects of aspirin.

By my reasoning, aspirin’s action in lowering heart risk ought to be a combination of these two kinds of actions.  But the message from Vioxx suggests that this benefit comes entirely from the first benefit, COX-1 and “blood thinning”.

But to the extent that aspirin lowers risk of cancer and Alzheimer’s disease, the effect must be due to COX-2 and the anti-inflammatory action.  There is powerful evidence that aspirin lowers risk of gastro-intestinal cancers and lung cancer.  There is also evidence for a less dramatic effect on other important cancers, including breast and prostate cancers.

Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung, and 39% for prostate cancer. Significant risk reductions were also observed for esophageal (73%), stomach (62%), and ovarian cancer (47%). NSAID effects became apparent after five or more years of use and were stronger with longer duration. Observed protective effects were also consistently stronger for gastrointestinal malignancies (esophagus, stomach, and colon). Results for pancreatic, urinary bladder, and renal cancer were inconsistent. Initial epidemiologic studies of malignant melanoma, Hodgkin’s disease, and adult leukemia also found that NSAIDs are protective. A few studies suggest that ibuprofen has stronger anticancer effects than aspirin, particularly against breast and lung cancer. – (from  R.E. Harris et al, 2005)

There are still researchers who claim that aspirin offers no benefit at all for cancer.  Here is a study that found no reduction in cancer risk for a low dose of 1 baby aspirin every other day.

Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.

Conclusion

Aspirin’s blood-thinning and anti-inflammatory effects both contribute substantially to disease prevention.  The first is primarily associated with COX-1 and roughly 10% reduction of heart disease and stroke.  The second is assoiated with COX-2 and roughly 40% reduction in risk of cancer.

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This article originally appeared in Josh’s blog here: http://joshmitteldorf.scienceblog.com/2013/08/06/how-does-aspirin-work/

6 Responses

  1. Julia says:

    Hi, I have a question. to the author and Mr. Rau. I am pregnant, 2nd month, and because of the arthritis that I’ve got during the first pregnancy and the following diagnosis “collagenose under question” the doctors want to prescribe me aspirin during the whole pregnancy (combined with heparin). Do you think it is really that what me and my baby needs?

    • Peter says:

      That sounds like a request for medical advice.

      I would consult your physician and obtain a second opinion if you are concerned. H+ Magazine, the author, and other commenters here can’t offer you specific or accurate advice.

  2. Hank Pellissier says:

    Great article Josh — I will go buy a bottle of aspirin today. Thanks

  3. P. Rau says:

    I’m very sad to read such a biased article here, partly because obviously the research done beforehand was quite narrow, and partly because this article may actually hurt people’s health. The regular intake of Aspirin will massively downregulate COX-1 and COX-2, which causes a decrease in gastric mucus production and leaves the gastric tissue open for acidic erosion. Gastric ulcera and malignancies (including cancer) are a very likely result.

    • P. Rau says:

      And another thing that just occurred to me:
      The permanent downregulation of COX-1 and COX-2 causes a build-up of arachidonic acid (which is usually metabolized by the COX enzymes). That increased supply will then be converted by another set of enzymes called LOX (lipoxygenase) into leukotrienes. And those substances strongly constrict the bronchial system.
      So asthmatic or COPD patients (of which there are LOTS in the industrial nations) are strongly advised to not regularly take aspirin.

      • MacSteve says:

        Thank you P. Rau for your reply. I completely agree with your assessment. My Grandmother suffered from rheumatoid arthritis at a time when Aspirin was the primary anti-inflammatory agent. The Aspirin did exactly as you describe and resulted in her contracting colon cancer and eventually dying from the cancer caused or exacerbated by the Aspirin regimen she was on. I also have succumbed to NSAIDs. I suffer from chronic pain due to injury, and the first thing the doctors did was put me on large doses of prescription NSAIDs. After taking that medication for over six months I can no longer take even an Advil without suffering stomach pain and other issues. I’m afraid I’ll find as I age that it did more damage than I’m aware of now. I realize that NSAIDs work for a great many things, but the chronic use of them and easy availability of them make them more of a danger than a help. We as a society, both lay and professional, have forgotten the meaning of moderation.

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