Aspirin is an old staple for life extension. Lately it has received bad press. For those who wish to replace aspirin, there are two actions that must be considered: anti-inflammatory and blood thinning. There are many good anti-inflammatories, all of which act through similar pathways, so that in the end we don’t know have optimal control over increasing inflammation. There are many prescription blood thinners, but no evidence that they increase life expectancy. Nattokinase and lumbrokinase are natural products, in a class by themselves. They show great promise, but there are no good studies.
Years ago, I wrote that aspirin and vitamin D were an easy, cheap way to buy a modicum of life extension. I still think that’s true.
It has been 4 years since the last time I wrote about aspirin. I’ve become more suspicious of ulterior motives in the medical literature during these years. Not only do they rig the trials of the drugs that they own and hope to profit from, they also fund research to try to discredit anything out-of-patent that might compete with their newest drugs. Witness the suppression two years ago of hydroxychloroquine and ivermectin, and chronic efforts against vitamin D.
There is an ongoing campaign to discredit daily low-dose aspirin as a generalized preventive, a lot of coverage in major media based on differences that are barely statistically significant.
This study was shut down after 3 years, based on a marginally significant indication of increased mortality in the aspirin arm. It has long been recognized that some studies must be discontinued if, along the way, it becomes overwhelmingly clear that one treatment branch is experiencing harm; but when ethics is invoked in alignment with the interests of pharmaceutical capital, I get suspicious, maybe cynical. Some of the benefits of aspirin become active only after 5 years of accumulated anti-inflammatory effects. Shutting down the trial assured that these benefits would never be reported.
Dual benefit
The benefits of aspirin fall into two categories: As a blood thinner, aspirin prevents heart attacks and strokes. As an anti-inflammatory, aspirin lowers the risk of all the diseases of old age, including AD, CVD, and cancer.
We know a great deal about aspirin because it has been in use since 1897, and daily low-dose aspirin has been prescribed to tens of millions of people since 1980. With 125 years of safety data, whatever risks there are must be very subtle indeed. The primary risk is for ulcers and bleeding of the upper GI tract. It is real, but affects a small percentage of people.
The anti-clotting benefits of aspirin are immediate, but the anti-inflammatory benefits unfold over many years. Short-term studies risk short-changing aspirin.
For those who experience GI bleeding or those who wish to avoid the risk, other NSAIDs are not an improvement. Better to replace aspirin with two separate strategies, one for blood thinning and one for inflammation.
Blood clotting is a balancing act
Blood must flow smoothly through capillaries that are no bigger than the red blood cells themselves. But when the body is injured, blood must be able to clot quickly and reliably to stem the loss of blood. The chemistry of blood clots is delicately balanced and tightly regulated, a marvelously adaptive system that we take for granted.
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All heart attacks are exacerbated by blood clotting, and for most, blood clots are the proximate cause. 87% of strokes are ischemic, caused by blood clots, with the remaining 13% hemorrhagic, caused by the opposite — uncontrolled bleeding in the brain. Thinning the blood can increase the risk of hemorrhagic stroke, while decreasing risk of heart attacks and ischemic strokes.
How does aspirin work
Platelets are the smallest cells in your blood, and there are about 1 for every 20 or 30 red blood cells. When platelets are activated, they clump together to form blood clots. Platelet activation is a self-reinforcing cascade, as activated platelets produce the enzyme thromboxane (or TxA2) which causes more activation, both within the same platelet and nearby. Producing TxA2 requires an intermediate step involving another enzyme, cyclooxygenase (COX2). Aspirin works by binding to COX2, effectively pulling it out of commission. Less COX2 means less TxA2, and less platelet activation.
Other blood thinners
P2Y12 antagonists are a class of prescription drugs that keep activated platelets from clumping together. The glue that binds platelets is adenosine diphosphate, or ADP, and P2Y12 antagonists bind to the same receptors on the surface of platelets where ADP normally goes, so they block the station and displace the ADP glue. Clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor are all P2Y12 antagonists.
Warfarin=Coumadin blocks the effect of vitamin K. Vitamin K, in turn, is a precursor of four enzymes which are necessary for blood clotting, including prothrombin and osteocalcin. Warfarin is the most dangerous of the prescription blood thinners.
Calcium, clotting and vitamin K
Vitamin K is not dangerous. Should you ingest too much vitamin K, it will not be turned into the clot-promoting enzymes.
Calcium is a structural component in bones, and calcium works with magnesium to create the signal that makes muscles contract. There is a dynamic and tightly-regulated steady state between calcium circulating in the blood and calcium bound in bones. Vitamin K tends to move calcium out of blood, into bones, and vitamin D does the opposite, moving calcium out of bones. This is the reason for the recommendation that vitamins D and K be taken together.
Excess calcium in the blood can lead to calcium deposits on artery walls, “hardening of the arteries”. Vitamin K is protective. The relevant form of K is vitamin K2, which is found in fermented vegetables and full fat yoghurts, and is also produced in the gut by a healthy microbiome.
Factor X is another pro-clotting enzyme that is downstream from vitamin K. A newer class of anti-clotting drugs targets factor X. Eliquis, Xarelto, Savaysa, and Betrixaban all work in this way. Inhibitionof factor X appears to be a potent path to dissolving persistent blood clots (deep vein thrombosis), but lower factor X does not correlate with long-term health benefits.
Nattokinase for preventing and dissolving blood clots
Nattokinase (NK) is an enzyme derived from fermented soy (Japanese natto), which thins blood by a different mechanism than aspirin. It is absorbed well when taken orally. There is reason to believe it does not cause ulcers or increase risk of hemorrhagic stroke. It may be superior in every way to expensive, patented blood thinners like Xarelto and Eliquis, but it is not patentable so drug companies are not motivated to do direct comparison studies (and NIH has not stepped up to fund such studies in their stead).
Nattokinase was misnamed by its discoverer (Hiroyuki Sumi) in 1980. It is not a kinase (energy enzyme) but a protease, an enzyme that breaks up proteins by dissolving peptide bonds. In particular, it works by degrading fibrinogen and serine.
Nattokinase works directly on blood clots, dissolving the fibrin bonds that hold platelets together. It does not work by tipping the scales of the body’s innate system that balances clotting and anti-clotting factors. In this respect, it is different from all the anti-clotting drugs mentioned above. It is short-acting and gets out of the system quickly.
Lumbrokinase, derived from earthworms, is a similar compound, and it has a long tradition in Oriental medicine. Gram for gram, lumbrokinase may be even more potent than nattokinase. Lumbrokinase has been used to treat Lyme disease.
For aspirin and other NSAIDs we have long-term data from millions of people who take the product daily. For nattokinase and lumbrokinase, there have been no such studies. Here is a trial currently underway that might begin to close the gap.
Bonus: For people with long COVID or ongoing damage from the mRNA vaccines, NK has a dual benefit. First, NK can dissolve blood clots, the most common problem associated with the virus’s spike protein. And, second, NK actually binds to the spike protein itself and causes it to degrade. Some percentage of vaccinated individuals retain the mRNA or integrate it into the genome, so that the toxic spike protein is still being produced in the body months after injection. NK can be part of a detox program for those with ongoing COVID vaccine injuries. There’s in vitro evidence that NK can inhibit viral growth, including SARS-CoV-2.
Anti-inflammatory drugs and supplements
There are many good options for dialing down inflammaging, though nothing we know can completely block the increase in systemic inflammation with age.
I’ve written in the past about omega 3 oils, curcumin, berberine, resveratrol, ashwagandha, and boswellia. These are all good alternatives if for any reason you are disinclined to take NSAIDs.
Starchy and sugary diets are pro-inflammatory. Exercise is the best anti-inflammatory of all.
Leafy greens, berries, and mushrooms are anti-inflammatory foods. Green tea, ginger, cloves, and rosemary can also be helpful.
The Bottom Line
As always, we wish we had more data, especially concerning the natural supplements and cheap, out-of-patent drugs for which there is insufficient financial incentive to perform expensive, long-term studies.
We don’t have evidence to support the role of blood thinning drugs as protection against long-term risk of heart disease or stroke, or for decreasing all-cause mortality. Nattokinase may be an exception, but we need better studies to know for sure.
Anti-inflammatories, however, are well-supported by animal studies, by longitudinal studies, and by theory. If we can dampen inflammaging, we can decrease risk of heart disease, stroke, cancer, and AD.
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THANK YOU for this educational report!
325 mg EOD + 81 mg EOD (opposite days), both enteric coated. I and my partner have been on this regimen for the last 20 years. Neither of us have had any GI problems or bleeding. Coincidentally, had my second colonoscopy on Friday. First one was 5 years ago. Clean as a whistle.
I agree that there is a large disinformation campaign to diminish competing drugs that have similar benefits at exponentially higher price points. Would love to see the agreements between the lead researchers and the funding agents of these studies.
Thanks, Josh, helpful information,
Michael
Thanks Josh,
Hello Josh! You forgot to mention bromelain, which has a history of use and a wealth of study far in excess of nattokinase. It also dissolves blood clots over time although reputedly slower than nattokinase. Importantly, it acts as an anti-inflammatory as well. Unlike aspirin, there is no indication that it will cause stomach ulcers.
Bromelain can clean out the arteries and veins over time, but it can also cause bleeding if you take too much of it and then cut or otherwise damage yourself. That’s because it strongly inhibits clotting. As a side benefit, it also is very effective at dissolving large kidney stones into kidney sand. If taken with large amounts of water and a antispasmotic (like peppermint oil pills, or the prescription chemical drug, drotaverine, it can relieve the pain from such stones in a day vs. several weeks without it.
I didn’t know about bromelain, and I’m not finding a lot of research at first google.
Bromelain is a compound found in pineapple that breaks down protein, called a protease. In the kitchen, bromelain is used to tenderize meat, but in the medical field, topically applied bromelain is an approved treatment to promote wound healing. Research shows that bromelain has anti-inflammatory and antithrombotic properties that may improve vascular function and reduce cardiovascular disease risk. Anthocyanins are blue- and purple-colored pigments found in fruits and vegetables that absorb free radicals in the blood stream, reduce inflammation, and reduce blood pressure.
Some useful references to get you started:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529416/
https://pubmed.ncbi.nlm.nih.gov/21749819/
https://pubmed.ncbi.nlm.nih.gov/17893836/
https://pubmed.ncbi.nlm.nih.gov/19339108/
The studies indicate that, in addition to being an anti-thrombotic, bromelain also induces apoptosis by increasing expression of p53 and Bax while decreases the activity of cell survival regulators such as Akt and Erk, thus promoting apoptotic cell death in tumors. Thus, it is probably also senolytic generally. Even if it does not kill off non-cancerous senile cells, it would still be considered a life-extender by, at minimum, the fact that it inhibits, and destroys cancer cells.
I should add one caution to anyone who is considering taking bromelain. I think these warnings would also apply to nattokinase, although I cannot speak for the dosages. It is supposed to be more powerful than bromelain, ounce for ounce, so one should keep that in mind.
It is dangerous to take too much of any proteolytic enzyme, over a short period of time. The manufacturers won’t tell you this. Their bottle recommendations are far too large. While, there don’t seem to be any obvious side effects at dosages that are commonly recommended, that is only so long as you don’t sustain any injury while under the influence of the enzyme. Keep in mind that bromelain is a VERY powerful anticoagulant. Much more powerful than aspirin.
About 25 years ago, I was in a martial arts competition match after taking bromelain for 4 days straight, 500 mg. 2x per day. I sustained a few mildly painful hits to the chest area during the match. Didn’t think anything of it. Normally, such hits would cause a small brown bump or two and would heal in a day or two. But, a few hours later, a huge area of my chest was completely blackened. Under the influence of the bromelain, my blood had continued leaking from my capillaries after the impact for much longer than normal. It became swollen and very painful for quite some time.
It took several days, after stopping the bromelain, for the anticoagulation effect to fully wear off and only then did the area begin to heal in earnest. Overall, it took much longer than usual for the area to heal. Since then, regardless of the recommendations on the bottle, in spite of the fact that I continue to use it for dissolving kidney stones, I never take more than 500 mg in a day and never for more than 3 days. If I were ever to take it as a “life extension drug”, on an everyday basis, I would take much less than that. Maybe, a maximum of 100 mg. per day (better 50 mg), in spite of the bottles which often recommend 500 mg. 3x per day with no time limitation.
These days, sadly, I’m too old for martial arts competitions. But, on the bright side, I am also much less likely to suffer from a bromelain induced excessive injury. 🙂
I’ll also add my experience of Serrapeptase, another proteolytic enzymes. I took this for a while after surgery at daily dosages that matched the manufacturers dosage recommendations. After about a month, my joints started to loosen up to the point where I things were popping out of joint. One day I was stretching my legs and my hip popped out of joint with only mild pressure. Hips should not do that, they are very stable (unlike shoulders). I immediately stopped taking everything, and things slowly went back to normal.
Curiously enough, my wife was also taking Serrapeptase, and she had exactly the same issue. Proteolytic enzymes will soften the connective tissue in the entire body, and too much is too much of a good thing.
That is interesting, Shaun
I have not experienced that side effect from Serrapeptase at about 15 mgs.
It is however known to increase joint mobility. Perhaps if you cut back the dose or take it every other day or twice a week, if you can not find a lower dose capsule or tablet.
I have experienced hypermobility from taking bio-identical hormones, particularly progesterone.
Progesterone can cause tendons and ligaments to be more flexible, which can loosen joints. Too much looseness can cause joint instability.
It resolved when I lowered the dosage. The joints are still flexible, but not to the point of instability. I did not want to eliminate the flexibility completely because flexible tendons and ligaments can prevent ruptures.
Are you taking Pregnenelone, that may increase progesterone levels in men and women? Also,DHEA can metabolize to Progesterone in men and women.
Progesterone counteracts high estrogen levels in men and is not necessarily undesirable. High Estrogen in men can adversely affect the heart. A beer belly is a sign of high estrogen. Beer contains estrogenic compounds.
Some people benefit from loose joints, such as ballet Dancers.
Also, joint hypermobility is known to be hereditary.
https://www.nhsinform.scot/illnesses-and-conditions/muscle-bone-and-joints/conditions/joint-hypermobility
https://pubmed.ncbi.nlm.nih.gov/12818469/
https://pubmed.ncbi.nlm.nih.gov/6295168/
Thanks for this. It’s a good reminder to add vitamin K to my D. I need a lot of D to maintain a good level, but haven’t been taking K.
Quote: “Not only do they rig the trials of the drugs that they own and hope to profit from, they also fund research to try to discredit anything out-of-patent that might compete with their newest drugs.”
This is absolutely, 100% true. When there is hundreds of billions of dollars at stake, the CEO’s of Pharma firms act in a way that would give a certified psycopath an attack of conscience when it looks in the mirror. We saw it with the smoking lobby, we saw it with big chemical firms like Du Pont, and we are have been seeing it for decades in in the market for patentable drugs.
Why haven’t you mentioned. FISH. OIL???
Yes, fish oil is where omega 3 fats come from, for most of us. I mentioned omega 3’s.
Dear Josh Mitteldorf
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You send me a photo of your aspirin, I informationally (in a word) activate this aspirin, let’s call it aspirin-A after activation. You will experience the properties of this aspirin-A and see its unique anti-inflammatory, blood-thinning properties, which make it possible to treat a huge number of diseases, including cancer, coronavirus, HIV, diabetes …
If we take ordinary water, we will get a similar effect, which is due to a change in the strength of the magnetic field of hydrogen atoms in these products after my words.
It will be interesting and useful for you, as a real scientist, to move to the level of informational space medicine.
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[email protected]
Josh
Thank you for an interesting post. I take a baby aspirin daily, I place it between my upper teeth and cheek and let it dissolve. It doesn’t go through the gut so no risk of bleeding. It works to fix my sore, stinging dry eyes.
Hope you are recovered from your accident Josh.
I’m miraculously recovered, thank you — no one thought I would have come so far so fast. I am doing yoga, hiking, bicycling, swimming — everything but running. My toes don’t work well enough yet.
This article is extremely helpful. Thank you very much.
I take Vitamin K2 separately from A, D, and E because of the 2015 study “Fat-soluble vitamin intestinal absorption: Absorption sites in the intestine and interactions for absorption”
“Significant competitive interactions for uptake were elucidated among vitamin D, E and K, supporting the hypothesis of common absorption pathways:
Vitamin A – Neither vitamin D nor K impacted vitamin A uptake. Vitamin E significantly improved vitamin A uptake at medium and high concentrations (up to 40%);
Vitamin D – Uptake was significantly reduced by vitamin E at medium and high concentrations (15% and 17% respectively), as well as by vitamin A at high concentration (30%);
Vitamin E – Vitamins A and D significantly reduced vitamin E uptake in a dose-dependent manner, while vitamin K had a negative effect only at the highest concentration; and
Vitamin K – Vitamins A, D, and E significantly decreased vitamin K uptake (from 34% to 58%).”
This work is interested in exploring the issues you indicate
Trust your gut: Bioavailability and bioaccessibility of dietary compounds
January 2022
https://www.sciencedirect.com/journal/current-research-in-food-science
Excellent points, Josh. Since there is insufficient financial incentive for private funding of expensive, long-term studies of natural supplements and cheap, out-of-patent drugs, it seems to me that government funding is appropriate.
Well not worms are equal Josh. For example the human liver fluke, a freshwater parasite endemic to areas of Thailand, Japan, and Siberia, triggers human liver cancer by creating harmful cell mutations, encouraging tumor growth. Cheers.
How can big proteins like proteases migrate through the endothelial layer on the gut’s inside if they are somehow yet not broken to amino acids in the stomach is a mistery to me. Are you serious while talking that natural proteases that are activated at neutral pH may get into the bloodstream? First that they may destroy on blood is albumin. To MHO proteases help to digest proteins in the colon as in older age much of protein from food is getting into the colon and rotting there. Rotting produce toxins. Acidity of gastric juice is dropping in older age. So, we may see “extended” digestion at higher pH with supplements of proteases.
Good point I don’t know how it is that some large molecules survive stomach acid. You’re certainly right that most do not.
Plant proteases such as papain from papaya, bromelain from pineapple, and ficin from figs are examples of natural proteases that are activated at neutral and alkaline pH [DOI:10.1111/j.1745-4514.1996.tb00561.x, Neutral and alkaline muscle proteases of marine fish and invertebrates. A review].
One study found that bromelain and papain can reversibly increase intestinal permeability [DOI:10.3390/metabo12111027, Effects of Proteases from Pineapple and Papaya on Protein Digestive Capacity and Gut Microbiota in Healthy C57BL/6 Mice and Dose-Manner Response on Mucosal Permeability in Human Reconstructed Intestinal 3D Tissue Model]. Yet, it is not clear if the proteases can get into the bloodstream even in the case of leaky gut syndrome. Also, because of the blood’s neutral pH, the proteases may destroy proteins in the blood cells.
Another study found that bromelain and papain can modulate the gut microbiota composition and improve the protein digestive capacity in healthy mice [DOI:10.3390/metabo12111027, (PDF) Effects of Proteases from Pineapple and Papaya on Protein Digestive Capacity and Gut Microbiota in Healthy C57BL/6 Mice and Dose-Manner Response on Mucosal Permeability in Human Reconstructed Intestinal 3D Tissue Model (researchgate.net)]. So, I believe that health improvement with natural protease intake is related to improved digestion of proteins.
It can also be interesting if the proteases are used similarly to fecal implants, that is, through the anus, to avoid splitting them into amino acids by gastric juice and enzymes in the stomach.
Adhering to dogma is always a dangerous thing. Over the years, “science”, especially medical science, has made a lot of assumptions that get established as unquestionable dogma, but are eventually proven wrong. This has been the case throughout history. It is also the case now. Two hundred years ago, for example, most doctors would have told you that, to cure a cold, one must attach leeches to the body, in order to “drain the bad blood”. That is what likely caused the death of our first President, George Washington.
Many medical scientists claimed, for a very long time, that proteolytic enzymes could not pass through the gut. At the moment, it is not exactly understand how they do it. However, the fact that they are absorbed, if and when taken in the correct manner, is without question, at this point. Both the personal experience of those who have taken them (including me), and many studies prove it.
Bromelain enzymes, for example, are theoretically “too big” to be absorbed, yet they do enter the bloodstream in large quantities. A lot of enzyme, for example, are excreted via urine. The quantity is measurable. That is why they can dissolve large kidney stones into calcium oxalate crystals, otherwise known as “kidney sand”, that can pass out of the body more quickly and easily. All the components of urine are collected from the blood.
There are certain procedures that must be followed to get any proteolytic enzymes into the bloodstream. Most importantly, they must be taken on an empty stomach AND with at lot of water. If your belly is full, the enzymes will help digest the food but will not last long enough to be absorbed. They will be destroyed by gastric acid eventually.
For more info on proteolytic enzymes in the bloodstream, check out the following small sampling of the wealth of studies out there. If you do your own research, you will find many more studies that prove the same thing.
https://www.researchgate.net/figure/Time-course-of-plasma-concentration-of-bromelain-after-oral-administration-expressed-as_fig3_223990679
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067380/
https://pubmed.ncbi.nlm.nih.gov/22517542/
This is very helpful, thank you!
Thanks for the references. 0.1-0.3% of bromelain bioavailability is not much, but more than 0. So, we have to consider it.
Based on web search results, bromelain is a proteolytic enzyme derived from pineapple stems that has various pharmacological effects [1]. However, its oral bioavailability is very low, meaning that only a small fraction of the ingested dose reaches the bloodstream. According to one study, rats that were given bromelain orally had plasma concentrations in the **ng/ml** region [2], [3], which indicates a very low absorption rate. Therefore, the bioavailability of bromelain with oral intake is estimated to be less than 0.003% [2].
Source:
(1)Bromelain a Potential Bioactive Compound: A Comprehensive Overview from …. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067380/.
(2) European public MRL assessment report for bromelain. https://www.ema.europa.eu/en/documents/mrl-report/bromelain-porcine-species-european-public-maximum-residue-limit-assessment-report-epmar-cvmp_en.pdf.
(3) Bromelain Loaded Lipid-Polymer Hybrid Nanoparticles for Oral Delivery …. https://link.springer.com/article/10.1007/s12010-022-03812-z .
(4) Potential role of bromelain in clinical and therapeutic applications. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998156/.
Sorry, corrections about the bioavailability of bromelain,
Based on web search results, bromelain is a proteolytic enzyme derived from pineapple stems that has various pharmacological effects [1]. The oral bioavailability of bromelain is very low, meaning that only a small fraction of the ingested dose reaches the bloodstream. According to one study, rats that were given bromelain orally had plasma concentrations in the **ng/ml** region [2], [3], which indicates a very low absorption rate. Therefore, the bioavailability of bromelain with oral intake is estimated to be less than 0.003% [2].
Source:
(1) Bromelain a Potential Bioactive Compound: A Comprehensive Overview from …. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067380/.
(2) European public MRL assessment report for bromelain. https://www.ema.europa.eu/en/documents/mrl-report/bromelain-porcine-species-european-public-maximum-residue-limit-assessment-report-epmar-cvmp_en.pdf.
(3) Bromelain Loaded Lipid-Polymer Hybrid Nanoparticles for Oral Delivery …. https://link.springer.com/article/10.1007/s12010-022-03812-z .
(4) Potential role of bromelain in clinical and therapeutic applications. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998156/.
I should also note that, because some proteolytic enzymes (though, perhaps, not all) are easily absorbed into the blood, it is very important to use them with caution. They can be very useful, but they can also be dangerous. If you are taking them simply to help you digest food, which is the most common use, make sure your stomach is not empty, to avoid absorption. Also, if you are taking aspirin, warfarin or some other drug that slows blood coagulation, you should not take proteolytic enzymes.
Thank you. Thinning the blood is a good thing on balance for most of us, reducing risk of heart attacks and strokes. But if you are injured, it increases risk of bleeding. And even if you don’t have other risk factors, moderation is imperative.
Hey guys!
Interesting discussion regarding Bromelain. I have been using other inflammation reducing substances such as Quercetin, Fistetin and Curcumin for a while but I have not tested Bromelain.
Now I have ordered NMN to add to the “combo”. Some say one should put it under the tongue to absorb it through the skin. I guess that would be to “bypass” the stomach. The capsules I use now I swallow whole which is very convenient.
Do any of you have any information regarding these types of substances whether it maybe is more efficient to let them be absorbed from under the tongue rather than swallow them ?