Aspirin, a Life Extension Drug

One of the most commonly used over-the-counter drugs, aspirin, has considerable potential as a life extension drug. While this has been known for awhile, at least in theory, some recent research adds support.

Aspirin deters the diseases of aging and civilization

In previous articles, we’ve seen that aspirin prevents cancer, including lung and prostate cancer. Cancer strikes mainly older people, and some 90% of cancer deaths are in people 65 years old and up. Cancer is therefore a disease of aging, and since aspirin prevents cancer, it might qualify as an anti-aging drug if it prevented the other diseases of aging and civilization.

Heart disease / atherosclerosis is another big killer that increases in incidence with age. Aspirin prevents heart attacks when used in primary prevention, that is, in people who have never had a previous heart attack, but, “In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds.” Worth noting here is that “the main risk factors for coronary disease were also risk factors for bleeding.” Aspirin is of greater value in secondary prevention.

In diabetics, aspirin at high doses dramatically decreases glucose (-25%) and triglycerides (-50%), and improves glucose tolerance and insulin sensitivity.

The fact that aspirin affects all of these diseases of aging and civilization suggests a common mechanism that may be involved in life extension.

Aspirin recapitulates features of calorie restriction

Autophagy, the cellular self-cleansing process that breaks down and recycles proteins and cellular components, is critical to maintaining a youthful state. Normally, autophagy declines to basal levels when an animal or human eats (is in the fed state) and increases when no food is available (in the fasted state). As we age, levels of autophagy decline and the process becomes more difficult to induce, and as a result, damage accumulates and cellular processes don’t work as well. Arguably, the increase in malfunctioning components just is aging, with the body increasingly susceptible to breakdown and infection.

Calorie restriction and intermittent fasting strongly up-regulate autophagy. Since calorie restriction has been found to be the most robust and effective life extension intervention known to science, increasing the rate or frequency of autophagy extends lifespan. In fact, mice that are genetically engineered to have higher rates of autophagy live longer than wild-type animals.

Autophagy plays an essential role in lifespan extension, and may be not only necessary, but sufficient, for lifespan extension.

It turns out that the effects of aspirin resemble those of calorie restriction, including the induction of autophagy.

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300… Altogether, these findings identify aspirin as an evolutionary conserved CRM.

EP300 is a cellular protein which functions as “a master repressor of autophagy”. By binding to EP300, aspirin de-represses autophagy.

When aspirin is ingested, it is rapidly (minutes) deacetylated and converted to salicylate. and in this case, the salicylate inactivates EP300, leading to increased autophagy.

Salicylate is one of the main components of willow bark, an ancient medicine. An extract of willow bark has been shown to be the most powerful life extension substance known to science.

So far, aspirin and/or salicylate look like potent life extension drugs.

One problem with using aspirin or salicylate for this purpose is the dose. Aspirin can cause stomach bleeding and bleeding in general, especially at high doses. While some patients such as those with rheumatoid arthritis may take large doses of aspirin, 3 grams or more daily (about 10 standard tablets), no one is going to recommend that to the general population. Many doctors even have misgivings about people taking low-dose (81 mg) aspirin due to its promotion of bleeding.

The above article states that “in patients taking up to 3 g aspirin/day, salicylate reaches 1–3 mM concentration in plasma, a dose range in which this molecule exhibits EP300 inhibitory and pro-autophagic properties, salicylate thus likely represents one of the principal metabolites responsible for aspirin activity.”

Given that we need a 1 mM concentration of salicylate to  see any degree of EP300 inhibition, and that level isn’t reached unless someone is taking a lot of aspirin, does the knowledge that aspirin is a calorie-restriction mimetic do us any good?

Diflunisal

Possibly. A different study found that salicylate inhibits p300 (same as EP300 above) at about the same concentration, above 1mM. The study also found that diflunisal, a prescription anti-inflammatory drug and a salicylate derivative, inhibits p300 at much lower concentrations. Diflunisal showed activity at 100 μM, and at 1 mM it cut the activity of p300 in half. Difunisal appears to be a relatively safe drug given in doses of 500 to 1000 mg and doesn’t appear to have the bleeding risk that aspirin does.

Both salicylate and diflunisal blocked the growth of cancer cells by inducing apoptosis, or programmed cell death, but diflunisal did so at concentrations less than 1/10 as high.

How else could the relatively high concentrations of salicylate required for life extension be overcome?

One way is potentiation.

Metformin potentiates aspirin, activates AMPK

Salicylate, the metabolite of aspirin, activates AMPK, the master regulator of lifespan, and it does this in common with exercise, fasting, metformin, polyphenols, and other interventions. Metformin, the anti-diabetes drug that extends lifespan in lab animals (and likely in humans), potentiates the effects of salicylate.

Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) [with] a mechanism that is distinct from metformin… A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway…  Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0 mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1 mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 μM)…  Pre-clinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.

Clinically achievable concentrations of salicylate and metformin killed cancer cells and activated AMPK.

Salicylate alone at clinically achievable levels, <1mM, activated AMPK and inhibited the growth of cancer cells, by blocking lipogenesis, the synthesis of lipid (fat) molecules necessary for growth of cancer. Metformin greatly potentiated the effect, such that, in my estimation, someone taking perhaps 2 standard aspirin tablets along with a standard metformin dose would achieve concentrations of these drugs that would kill cancer, as well as promote life extension.

A major caveat of many studies which have utilized metformin to inhibit cancer growth is that millimolar (mM) concentrations have been used, despite maximum concentrations observed clinically being 50–100 μM….

At clinical concentrations of salicylate achievable through the intake of regular strength aspirin (<1.0 mM) salicylate inhibited the survival of prostate and lung cancer cells by greater than 50%.

These data indicate that the salicylate-induced suppression of lipogenesis, taking place at clinically relevant doses of the drug, is mediated via the AMPK β1 subunit…

We found that the IC50 for clonogenic survival was dramatically reduced in all cell types when metformin and salicylate were used in combination.

We find that salicylate at concentrations as low as 0.25 mM inhibited de novo lipogenesis in prostate and lung cancer cells and this was associated with the inhibition of clonogenic survival.

A dose of .25 mM might be achievable with a standard aspirin tablet or two.

Metformin and aspirin together also significantly inhibit pancreatic cancer cells.

Aspirin inhibits mTOR

The mammalian (or mechanistic) target of rapamycin, mTOR, regulates growth and aging, and is repressed by AMPK. Many consider the deactivation of mTOR as the Holy Grail of anti-aging, and it certainly seems about the most potent anti-aging mechanism that we know about currently.

Aspirin inhibits mTOR, although the concentration here was 5mM, which is not clinically achievable.

Again, aspirin and metformin together hold promise in treating pancreatic cancer by targeting AMPK and mTOR.

A study that gets to the heart of the matter regarding mTOR and aspirin directly compared aspirin’s ability to inhibit mTOR with everolimus, an analog of rapamycin, the prototypical mTOR inhibitor. This study used tumor-bearing mice that were given low-dose or high-dose aspirin, or everolimus, or no treatment. Low-dose aspirin was 100 mg/kg, high-dose was 400 mg/kg.

The tumor growth inhibition rates induced by low and high‑dose aspirin and everolimus were 19.6, 33.6 and 53.7% (P<0.05) in H22 hepato­carcinoma, and 25.7, 40.6 and 48.7% (P<0.05) in S180 sarcoma….

We have demonstrated that aspirin may inhibit mTOR signaling associated with anti-angiogenesis and promoting autophagy on the protein expression level. We intend to continue with further experiments on the genetic level. Our study has significant clinical reference value and may potentially lead to therapeutic treatment options for hepatoma or sarcoma and other types of cancer.

According to my calculations, the human equivalent dose for the high-dose aspirin given to the mice is about 2.3 grams for a 70 kg man. (Divide mouse dose by 12 to account for higher mouse metabolism.) Still, not many people (including me) want to take 2 grams of aspirin daily, although some people with pain do so. Metformin and aspirin appear to potentiate each other in deactivating mTOR.

Atenolol is a beta blocker, a cheap, widely used anti-hypertensive drug which also promotes lifespan extension. Of interest, atenolol, aspirin, and metformin together all potentiate each other and target cancer cells by deactivating mTOR. Use of beta blockers is associated with lower rates of cancer.

Aspirin promotes nitric oxide production and reduces erectile dysfunction

Aspirin promotes endothelial function. Endothelial cells are those that line the insides of blood vessels, and their dysfunction is important in promoting atherosclerosis. Part of the protective effect of aspirin on endothelial function is due to its promotion of nitric oxide production, which relaxes blood vessel walls.

Possibly also due to increased nitric oxide production, low-dose aspirin can help treat erectile dysfunction. Men who took 100 mg of aspirin daily for 6 weeks showed significant improvement in erectile function.

Aspirin inhibits cellular senescence

Cellular senescence occurs when cells reach their growth limit (the Hayflick limit) and cannot divide any more. They go into a senescent state and emit inflammatory cytokines, which may be responsible for many of the ills of aging, and may promote cancer. Getting rid of senescent cells may actually reverse aging.

Perhaps even better than eliminating senescent cells is preventing cellular senescence in the first place. Aspirin delays endothelial cell senescence, increases nitric oxide, and reduces ADMA, a marker of atherosclerosis.

Aspirin: dose matters

Daily low-dose aspirin substantially decreases cancer risk. However, what got me onto the line of thinking leading to this article is the following: Aspirin Dose and Duration of Use and Risk of Colorectal Cancer in Men.

After adjustment for risk factors, men who regularly used aspirin (≥2 times per week) had a multivariate relative risk (RR) for colorectal cancer of 0.79 (95% confidence interval, [CI], 0.69–0.90) compared with nonregular users. However, significant risk reduction required at least 6–10 years of use (P for trend = .008) and was no longer evident within 4 years of discontinuing use (multivariate RR, 1.00; CI, 0.72–1.39). The benefit appeared related to increasing cumulative average dose: compared with men who denied any aspirin use, the multivariate RRs for cancer were 0.94 (CI, 0.75–1.18) for men who used 0.5–1.5 standard aspirin tablets per week, 0.80 (CI, 0.63–1.01) for 2–5 aspirin tablets per week, 0.72 (CI, 0.56–0.92) for 6–14 aspirin tablets per week, and 0.30 (CI, 0.11–0.81) for >14 aspirin tablets per week (P for trend = .004). Conclusions: Regular, long-term aspirin use reduces risk of colorectal cancer among men. However, the benefit of aspirin necessitates at least 6 years of consistent use, with maximal risk reduction at doses greater than 14 tablets per week. The potential hazards associated with long-term use of such doses should be carefully considered.

The higher the dose and the longer the duration of use, the less colorectal cancer risk these men had, with 14 tablets a week conferring a 70% decrease in risk. While that’s a large risk decrease, that’s also a lot of aspirin, a dosage that no one will recommend to healthy men who don’t need pain relief.

The other studies noted above suggest that lower doses can be effective, especially when used with metformin and/or beta blockers.

Aspirin: the risk

Aspirin can cause gastrointestinal ulcers and it increases bleeding risk by acetylating the COX-1 enzyme in platelets, the small blood cells that promote blood clotting. Platelets are incapable of generating more COX-2, hence aspirin permanently disables them; platelets have a life of about 10 days. For the cardiovascular protection effect of aspirin, it must be taken daily.

The most serious possible consequence of taking aspirin is bleeding into the brain, which can be fatal or severely disabling. This is known as a cerebral hemorrhage, and accounts for 5-10% of all strokes. Most cerebral hemorrhages are caused by aneurysms in the brain, and it turns out that aspirin could be protective against them. “… patients taking aspirin at least three times weekly had a significantly lower risk of SAH (OR, 0.27; 95% CI, 0.11–0.67; P=0.03) compared with those who never took aspirin.”

What about in the population in general and in other forms of bleeding risk, such as gastrointestinal bleeding? The title of a study tells the story:  Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk. Key to this is the word “fatal”.

Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding…. The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

The conclusion to the article:

Gastrointestinal bleeds constitute the majority of the adverse events caused by aspirin. The increase is about 60% overall, but there appears to be no increase in fatal GI bleeds attributable to low-dose aspirin, indeed prophylactic aspirin appear to be associated with a reduction in the fatality of GI bleeds. The undesirable effect of prophylactic aspirin which is of a severity comparable to a vascular disease event or a cancer is a bleed that leads to death, and low-dose aspirin appears to be associated with one death and one disabling haemorrhagic stroke per year in every 10,000 people taking low-dose aspirin. The available evidence makes it seems likely that these cerebral events would be reduced if hypertension is identified and adequately treated.

In addition, there will be one or two non-fatal GI bleeds per 1,000 people each year, but the frequency of these bleeds appears to fall rapidly, and there is no evidence of any increase in GI bleeds attributable to aspirin after three or four years of prophylaxis

All these conclusions are relevant to the risk-benefit balance of aspirin prophylaxis and should be communicated to subjects at risk of vascular disease and/or cancer, to enable them to make an informed decision about the protection of their own health.

Aspirin may not even really cause bleeding, hard as that may be to believe after the evidence laid out above. The bacterium Helicobacter pylori, which causes stomach ulcers, could be the true culprit.  If H. pylori is eradicated via antibiotics, then possibly no bleeding would occur, and studies are ongoing to find out.

A number of people (on the Ray Peat Forum) appear to believe that taking vitamin K2 will mitigate the bleeding risk of aspirin. Unfortunately, anyone with actual knowledge of blood clotting (hemostasis) knows that won’t work. Aspirin promotes bleeding by deactivating platelets, and vitamin K2 works by activating clotting factors, which are proteins, and the lack of which are responsible for disease like hemophilia. One won’t mitigate the other.

Aspirin may be under-used

One question about aspirin is whether there’s a basis in reality for the near paranoia among doctors about promoting its use. After all, the same medical establishment is still reluctant to promote a reasonable dose of vitamin D for fear of toxicity, a reluctance which appears to me to have little basis.

A study sought “to determine the long-term economic and population-health impact of broader use of aspirin by older Americans at higher risk for cardiovascular disease.”

These data reveal a large unmet need for daily aspirin, with over 40% of men and 10% of women aged 50 to 79 presenting high cardiovascular risk but not taking aspirin. We estimate that increased use by high-risk older Americans would improve national life expectancy at age 50 by 0.28 years (95% CI 0.08–0.50) and would add 900,000 people (95% CI 300,000–1,400,000) to the American population by 2036. After valuing the quality-adjusted life-years appropriately, Americans could expect $692 billion (95% CI 345–975) in net health benefits over that period.

Expanded use of aspirin by older Americans with elevated risk of cardiovascular disease could generate substantial population health benefits over the next twenty years and do so very cost-effectively.

The average increase in life expectancy if everyone who should use aspirin did use it is only 0.3 years, but that figure is for the entire population, i.e. everyone, even those who don’t take aspirin. You can be sure that if aspirin prevents a cancer or fatal heart attack, the number of years that life is lengthened will be longer, measured in years more likely.

At one time, the then oldest living person credited his long life to taking aspirin. He was 112 at the time.

Conclusion

Aspirin is staring us in the face as a cheap life extension drug. In combination with metformin and/or beta blockers, it may have great potential against cancer and in promoting longer life.

Aspirin is not without risks, and long-term use should be done in consultation with a physician to determine whether the benefits outweigh the risks for a given individual. For the record, I’m not promoting indiscriminate use of aspirin.

The noted scientist Mikhail Blagosklonny mentions aspirin in his list of proposed anti-aging drugs, along with rapamycin, metformin, beta blockers, and PDE5 inhibitors.

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Leave a Comment:

58 comments
Rob says April 1, 2018

I’ve been taking a daily low-dose aspirin (81 mg) for over a year now. Probably should have started doing it even earlier. In addition to reducing risk for cancers (especially colon and pancreatic cancer), the very small amount micro-bleeding that “may” occur in the GI tract may actually be a good thing, as it would be a way for the body to rid itself of excess iron (other than donating blood a few times each year, which I also do). With regard to beta blockers, I have been taking a very low-dose daily metaprolol for a couple years now (it was prescribed originally to correct a slightly irregular heartbeat – premature ventricular contraction). It fixed that issue right away, but I’ve continued to take the metaprolol because it lowers my blood pressure and pulse a small amount (a good thing in my case). Also, the fact that beta blockers may increase longevity is another factor that keeps me taking a very small amount of metaprolol daily.

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al becker says April 1, 2018

Thanks so much. Another very informative, and very helpful article.
You have previously written how berberine can act like metformin, so I am wondering if aspirin, in conjunction with berberine, might be very good.

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    P. D. Mangan says April 1, 2018

    I believe berberine should synergize with aspirin in the same way as metformin, and I thought I’d read a study that showed this, but I either can’t find it or it doesn’t exist.

    Reply
Paul Rivas says April 1, 2018

Great post. Very comprehensive. It’s clear that the combination of metformin with ASA is synergistic against pancreatic cancer, though much of the effect seems to be due to mTOR inhibition. The good news is that this effect can be achieved with as little as 500. Mg of metformin and 125 mg of ASA.
This is especially important since the latest trends are showing a decline in colon cancer rates while pancreatic cancer is on an upswing, probably secondary to obesity and diabetes.
So the post was very timely.

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Rob says April 1, 2018

PD – you have written in the past (2016) about willow bark extract being a potential anti-aging substance. I know that aspirin (salicylic acid) is basically derived from willow bark, but what is your opinion of taking the actual willow bark extract (in supplement form……..they are cheap)? I assume there is no risk of GI bleeding from taking willow bark extract either, although I have not read anything about that (one way or another). Seems like there shouldn’t be much downside from taking a small amount daily (and possibly a significant benefit). My other thought is to perhaps give willow bark extract a try for occasional pain (headache) relief, since the risks of taking ibuprofen are becoming more evident.

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    P. D. Mangan says April 1, 2018

    Hi Rob, I have taken willow bark myself, and it seems a very promising anti-aging supplement. However, as it relates to what I wrote in the article, willow bark has a relatively low concentration of salicylate. One would have to take a lot of it to get up to the concentrations mentioned here.

    Reply
Tom Clayton, MD says April 1, 2018

Flu deaths in 1918, aspirin use and vitamin c depletion (this was before supplementation of vitamin C).

There seems to be something missing in explanations why otherwise healthy and younger adults die from the flu. Does a dark angel just come visit these kids that die and take them? Fearing a repeat of the 1918 Spanish flu, which resulted in millions of deaths worldwide, what could be done to avert a similar deadly pandemic now?

Dr. Karen M. Starko MD provides us with some important clues. She hypothesizes the high mortality rates due to the 1918 Spanish flu resulted from the over-use of aspirin. The evidence Dr. Starko provides is compelling.

Physicians of the day were unaware that the recommended medication regimens (8.0—31.2 grams per day, or 8000 to 31,200 milligrams) during that time period produce aspirin levels associated with hyperventilation (33%) and fluid accumulation in the lungs (pulmonary edema 3%) of subjects.

Accumulation of fluid in the lungs was recently found in 46% of 26 aspirin-intoxicated adults. In lab experiments, aspirin increases lung fluid and impairs clearance of mucus.

In 1918 aspirin was recommend by the US Surgeon General, the US Navy, and the Journal of the American Medical Association just prior to the October death spike.
Bayer first introduced water-soluble aspirin tablets in 1900. Farbenfabriken Bayer’s worldwide distribution of aspirin had been accomplished in the same year as the flu pandemic. Aspirin sales more than doubled from 1918 to 1920.
The US Army camp with the highest mortality rate had ordered 100,000 aspirin tablets.

Young children were not given aspirin as widely as young adults, which may explain why the young had a lower mortality rate in the 1918 flu. [Clinical Infectious Diseases 2009; 49: online Sept. 29]

The descriptions of flu-related, aspirin-induced lung disease by Dr. Starko are gripping. She cites records of doctors describing aspirin lung as looking like “the lungs of the drowned.” There were small hemorrhages in the lungs which appeared “dark and red and wet, dripping wet.”

Dr. Starko cites doctors who described “frothy, blood-tinged fluid” in the lungs of patients who had died during the 1918 flu outbreak. There were also frank lung hemorrhages.

Dr. Starko goes on to describe aspirin-induced symptoms to include brain swelling, pinpoint red dots on the skin called petechiae, blue coloration of the skin and mucus membranes (cyanosis), along with vomiting and nose bleeds. These are not symptoms characteristic of the flu.

Another common finding among records of mortal flu cases in 1918 was brain swelling, called cerebral edema. Cerebral edema also occurs with the use of aspirin and in Reye’s syndrome. [Acta Neurologica Scandinavia Supplement 2007; 186:45—56]

This is exactly how a patient with severe vitamin C deficiency (scurvy) dies. In scurvy capillaries are weak and red blood cells leak into surrounding tissues, like the brain, lungs and eyes, which was observed among the 1918 flu victims.

Yes, aspirin depletes the body of vitamin C. Aspirin is known as one of the most powerful drugs at depleting vitamin C in normally healthy individuals. [Journal Clinical Pharmacology 1973; 13: 480] Modern medicine appears to have overlooked this well-documented fact.

The volume of literature that confirms aspirin depletes vitamin C is extensive.

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    Bill says April 1, 2018

    The information about aspirin and the Spanish Flu of 1919 is interesting. I note that at the time doctors were recommending “8 – 31.2 grams per day, or 8000 to 31,200 milligrams’.

    Now that is a huge daily dose ! And not one that i have ever taken. And one I doubt PD would recommend either.

    From memory the aspirin dose suggested for an anti-aging effect is around 70-80 mlgs.

    Reply
      P. D. Mangan says April 2, 2018

      Right, 8 to 31 grams a day is an overdose right there. Maximum recommended dose for pain currently is 4 grams.

      Reply
        Tom Clayton, MD says April 2, 2018

        I added the information about aspirin and vitamin C depletion and the 1918 flu epidemic deaths to show that it is not a benign drug and is not the answer to everything. As discussed here and elsewhere (http://drgalland.com/aspirin-and-vitamin-c-together-at-last/), “Aspirin side effects kill about a thousand people a year in the US. If aspirin were a new drug, it would have a tough time getting approved by the FDA and would only be available by prescription.

        Taking any dose of aspirin on a regular basis can triple your risk of dangerous gastrointestinal bleeding, according to some studies. The risk of this well-known aspirin side effect rises sharply when alcohol consumption is added.

        Additional research indicates that if you’re consuming just one serving of alcohol every day while taking aspirin on a regular basis, the risk of bleeding increases by another 250 percent. In other words, if you are one of the millions of Americans who have a glass of wine each day in the hope of improving your health, but are also taking aspirin, your risk of internal bleeding becomes seven times greater than if you didn’t drink or take aspirin.

        But surprising studies show that there are a few dietary supplements that can help protect the stomach from aspirin side effects. One of them is probably sitting on your shelf right now: vitamin C. This everyday vitamin acts as an antioxidant in the stomach to decrease aspirin-induced stomach damage.”

        [it continues…]

        Reply
          Tom Clayton, MD says April 2, 2018

          In order to be more complete, and knowing that there are significant problems with some members of the public taking too much of OTC medications, it helps me to have a detailed overview =

          https://www.fda.gov/ohrms/dockets/ac/02/briefing/3882B2_02_McNeil-NSAID.htm

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          Rob says April 2, 2018

          Tom, can you cite the studies that you refer to, that show that daily use of 81mg of aspirin often cause GI damage?

          Reply
          P. D. Mangan says April 2, 2018

          I addressed the risks of aspirin in my article – didn’t you read it? Aspirin side effects may kill a thousand people a year in the U.S., but far more lives are saved. Like any drug, it has risks and benefits, but I think I said that repeatedly in the article. Many of the studies I cited were at pains to say the benefits in terms of less cancer and heart disease far outweigh the risks.

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          Tom Clayton, MD says April 2, 2018

          Actually I did read most of it, but the overwhelming impression that most readers get (IMHO) is that aspirin is a wonder drug that is good for everything. But this is simply not the case. You are clearly invested in the belief that aspirin is a wonder drug and do what most people do, which is to try and find supporting evidence, ignoring or minimizing contrary evidence.

          This is called confirmation bias and I point it out simply to help keep things objective; without recognizing this, most people will charge on with incorrect beliefs, absolutely convinced that they are right. If you show them contrary evidence, they dig in their heels to defend the belief (called the backfire effect). But I digress.

          Let me say up front that I like your approach to proving your beliefs because it is logical and evidence based, but I personally am more skeptical than my formal medical training implies that I should be. Mainstream medicine resists change and much of medical care is caught up in making money first and foremost; anathema to objective and logical minds, including mine.

          Gastric bleeding is only one problem with aspirin. Demonstrating cause and effect for aspirin causing gastric bleeding is easy (it either happens or it doesn’t and can be measured directly), but it is extremely difficult to accurately establish cause and effect elsewhere simply because chronic diseases are more complicated than changing a single variable like aspirin and expecting a hallelujah effect.

          There are lots of studies that show that even low dose aspirin causes gastric bleeding and that the severity of the bleeding is proportional to the dose (easy to look up but you will have to Google academic articles instead of popular websites). These articles are just a few examples of acute bleeding versus aspirin taken on a chronic basis:

          http://www.amjmed.com/article/S0002-9343(11)00095-7/pdf
          https://www.health.harvard.edu/heart-health/answers-about-aspirin

          My goal is not to get into an argument with you; it is to caution people, especially old people, from thinking that aspirin is going to save them from a premature death and that they don’t really need to do much else.

          What may help save them is to stop eating refined carbohydrates and go on a high fat, moderate protein, low to very low carbohydrate diet because inflammation is directly related to carbohydrate consumption. Vitamin C supplementation is highly recommended.

          You may be interested in the fact that in the 19th century (1800s) there was some sugar in some diets but essentially no other refined carbohydrates. The caloric difference was taken up by meat and fat, particularly saturated animal fat (this was before technology created processed vegetable oils that do not occur in nature and are truly toxic). As I am sure you are aware, saturated animal fat is not related to CAD, as has been assumed since around 1950 (Ancel Keys).

          Old people of that era just did not get Type 2 diabetes and CAD for the most part although doctors knew about them; a sea change compared to today. More information is found in a great 2014 book by Nina Teicholz, “The Big Fat Surprise: why Meat Cheese and Butter belong in the diet,” [https://thebigfatsurprise.com/]. Eating fat and minimal carbs causes weight loss, test results normalize, and everything improves. The population is sicker than ever before with rampant obesity, Type 2 diabetes, and CAD thanks to the misguided dietary policy of the last 50 years that low fat high carb diets are best. Aspirin cannot reverse this because it is not part of the cause. High carbs elevate insulin, which stores fat and keeps fat from being burned as energy. Have you studied this?

          Reply
          Rob says April 2, 2018

          Tom – I think your diet advice is sound, and I certainly try to eat that way myself (minimize processed carbs, eliminate veg. oils, eat mostly whole foods). I also understand that taking aspirin, like any drug, comes with some risks. However, you fail to address the central question here, which is – do the potential benefits of taking low-dose aspirin exceed the risks? You talk a lot about the dangers of aspirin use, but do not seem to acknowledge that there COULD be some significant benefits as well. If you believe that those studies (showing reduced risk of some diseases in association with aspirin use) are flawed in some way, please let us know why you feel that way. I certainly don’t view aspirin as a panacea drug that will extend my lifespan by decades regardless of the rest of my diet and lifestyle. But I did conclude a while back (based on the studies I had read) that taking a daily low-dose aspirin probably provided more potential benefits than risks. If I was wrong in that determination, I’d like to know why. Thank you.

          Reply
          P. D. Mangan says April 2, 2018

          Yes, I’ve studied that, have read “Big Fat Surprise”, and all the rest, and agree with it. Meanwhile, heart disease and cancer are the two biggest killers in the country. As for that condescending “you will have to Google academic articles instead of popular websites”, everything linked in my article was from scientific/medical publications, which leads me again to think you didn’t read it. I’ve written plenty about the dangers of refined carbs, sugar, and seed oils (maybe you haven’t read them) but there are limits to writing about these all the time. For one thing, I’ve thoroughly incorporated low-carb, unprocessed foods into my own regimen, I’m 63 years old, and I’d like to avoid heart disease and cancer; avoiding them is a necessity if I want to live longer than the 19 years the CDC says I have left. Even people who refrain from eating refined carbs and sugar die, and I’d like to put that point off as long as possible, as I assume many of my readers would. Your stance on bleeding and aspirin is akin to if I said that automobiles cause 30,000 deaths a year in the US (which they do) so we should ban them. Again, I thoroughly discussed the risks of aspirin in my article. It should also be pointed out that many doctors and scientists disagree with your stance, and I linked to some of their papers above.

          Reply
          Tom Clayton, MD says April 2, 2018

          I didn’t mean to be condescending; I meant to point out that Google results give a lot of popular websites saying the same thing. But academic articles are often hard to read and frequently hide the truth, so I don’t jump up and down when somebody says that they have such articles as proof. Perhaps the most recent example of this crap is statins, where sponsoring drug companies have replaced absolute risk with relative risk; an unethical swap that most people do not understand. This type of crap goes on more frequently than one might expect, because research money does not flow unless there are specific questions that lead to products that can be sold. The hard questions that may interfere with this money making quest are ignored. So I didn’t read the source articles and do not have the time or real interest in doing so. This may change.

          At BEST statins may help a few people (no more than 1-2%) but there are too many side effects, are expensive, and there is no change in all-cause mortality. It pisses me off, because money should not be such a force that it interferes with the truth. I worked for Joseph Goldstein between my freshman and sophomore years in medical school and today I am 180 degrees opposite his conclusion that statins are great and should be put in the water supply. Who in their right mind would knowingly take a drug that interferes with the beginning of the mevalonate pathway?

          As my friend Duane Graveline (since deceased) said on https://spacedoc.com/articles/statins-and-the-mevalonate-pathway, “…all statins are reductase inhibitors. Unfortunately, the only reductase step in the entire 200 biochemical steps to the synthesis of cholesterol was right in the beginning of the mevalonate pathway, meaning that to get at cholesterol we had to interrupt many other vital functions sharing this same pathway such as CoQ10, dolichols, etc.”

          Another longtime friend, Uffe Ravnskov, MD, PhD, has done a superb job dissecting academic papers about statins for over 25 years; I believe that he was the first one to eat a bunch of eggs and prove that this caused cholesterol levels in the body to decrease, but of course LDL-C is now known to not cause heart disease, it is the apo(a) small dense particles that are genetically determined. I am 65 years old and take Pauling Therapy because I believe that Pauling and Rath are correct about the biochemistry of collagen repair and what to do to reverse existing plaque. http://www.ravnskov.nu/cholesterol/

          I noted that you wrote the book Dumping Iron, which is another topic I have long been interested in. I used to run an earlier version of the current “blog” early in the Internet years, done for hemochromatosis patients and their families at a time when the Harvard “expert” who was moderating his own list refused to let them say what they felt. That did not sit well with me, so I created a group where anybody could say anything. What started you down that path? Are you aware of Eugene Weinberg’s work? I knew Jerome Sullivan, MD, PhD, who introduced the concept that excessive stored iron is a culprit for atherosclerotic disease, and I dumped blood to keep my ferritin level low for 30 years as a result. He died at age 68 in 2013, a real shocker for me. You can send me a free copy if you want….

          My peripheral vessels are clear as they can be (via ultrasound) but I did not recognize the effect of local micro- trauma on the coronary arteries from the heart beating, an oversight that I take Pauling Therapy to address. And by the way, one will always be able to find people who disagree with one’s belief as well as those who agree. I don’t give a damn when somebody says something to the effect “How can 360 million Catholics be wrong?” because depending on the topic, most people can be and often are wrong because they do not recognize that they are not being objective (confirmation bias). What Catholic is objective about heaven and hell? They believe that these exist despite the fact that there is no objective evidence that they do, but I generally stay away from this type of discussion because it mostly goes nowhere. Remember the old adage that one should not discuss women, music, or politics.

          Finally, what I am most interested in is the molecular basis of disease. Although the pathways that you quote regarding the effect of aspirin make some sense, one big problem is like the Life Extension antioxidant supplementation craze of some years ago. Everything looks good on paper, but the main reason why the results were almost nil may be similar to the aspirin pathways; theoretically interesting, but subsequent follow-up showed that the effect was minimal because the antioxidants didn’t get to where they were needed when they were needed. That may not be the case with the aspirin pathways, but just identifying adverse effect of certain pathways does not mean that they occur frequently enough to overwhelm the body’s defenses (I am a big believer in the power of the immune system).

          At the end of the day, one has to decide what they want to do and do it. But when it comes to changing lifestyle, a lot of older people simply cannot do so.

          Reply
          Rob says April 2, 2018

          Tom – I think many of us who read PD’s blog would agree with you about the corrupt influence of money on the advice most doctors provide. You are preaching to the choir. But nobody (not Big Pharma, no doctor) is making any money promoting aspirin use, so I fail to see what a lot of what you have stated in your comments have to do with the risk/benefit ratio of low-dose aspirin use (?)

          Reply
          Tom Clayton, MD says April 2, 2018

          Just general and specific observations about other similar topics in the sense where claims are made but proof and truth is in short supply. Enjoyed taking about these things with you! Signing off.

          Reply
          P. D. Mangan says April 2, 2018

          Here’s my interview with Eugene Weinberg. My short bio of Jerome Sullivan. Luca Mascitelli. I’ll have more to say later.

          Reply
          Tom Clayton, MD says April 3, 2018

          Just curious; have you researched supplemental magnesium and cancer? This makes a lot more sense to me than aspirin.

          Reply
          P. D. Mangan says April 3, 2018

          Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials Deaths due to cancer down 21%, deaths due to GI cancer down 59%. “the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42–11·74) at age 65 years and older.”

          Aspirin has saved millions of lives.

          Reply
          Tom Clayton, MD says April 3, 2018

          You are misreading the decimal points.

          One of the first statements says, “On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths).” This means that the percentage of cancer deaths was 2.79% of all patients in all trials.

          “Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age—the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42–11·74) at age 65 years and older.” That means 7.08%.

          My main point in all of this is that aspirin is not a benign drug and there are significant risks, particularly for the elderly. And of course it is not a magic drug. Establishing cause and effect requires limiting the variables, which is almost never accomplished with human beings, who are not rats living in cages where every parameter (variable) can be controlled.

          Reply
          P. D. Mangan says April 3, 2018

          I’m not misreading anything. These were randomized controlled trials, and as close to proof that aspirin prevents cancer in humans as we’ll ever get.

          Reply
          Tom Clayton, MD says April 3, 2018

          When I say misreading, I am referring to their decimal representation of 0.68 which is .68 (I can’t make the period be in the middle as the article does). From where did you get a 59% reduction in GI cancers? This abstract says nothing of the kind.

          Reply
          P. D. Mangan says April 3, 2018

          Hazard ratio for GI cancers, 20 year follow-up, 0.41. 5 years follow-up, 0.46.

          Reply
          Tom Clayton, MD says April 3, 2018

          Do you have the full article to send me?

          Reply
          Tom Clayton, MD says April 3, 2018

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC478551/

          “Hazard ratios have also been used to describe the outcome of therapeutic trials where the question is to what extent treatment can shorten the duration of the illness. However, the hazard ratio, a type of RELATIVE RISK, does not always accurately portray the degree of abbreviation of the illness that occurred. In these circumstances, time-based parameters available from the time-to-event curve, such as the ratio of the median times of the placebo and drug groups, should be used to describe the magnitude of the benefit to the patient. The difference between hazard-based and time-based measures is analogous to the odds of winning a race and the margin of victory. The hazard ratio is the odds of a patient’s healing faster under treatment but does not convey any information about how much faster this event may occur.

          We have observed that there is substantial confusion among clinicians and clinical investigators about the difference between the hazard ratio and the median ratio. This report presents examples of this confusion, the exact distinction between the two statistics, and proper use of the hazard ratio and median ratio when interpreting the results of clinical trials to patients.”

          Recall that the use of relative risk instead of absolute risk in statin papers is as deceptive as it gets.

          Reply
          P. D. Mangan says April 3, 2018

          It’s available online, Google Scholar.

          Aspirin’s GI Risks May Be Overstated

          Reply
          Paul Rivas MD says April 2, 2018

          Your points are well taken, there is certainly a bleeding risk with ASA , and in reviewing the studies the relative risk looks pretty scary, but the absolute risk is about 2 persons per one thousand compared to controls. The interesting thing is that the risk wasn’t dependent on the dose or the duration. Also, the risk went way up with concomitant NSAID usage or age greater than 70.. Risk dropped with the proton pump inhibitors like nexium.

          I have a family history of GI cancers, so for me the risk is worth it, especially regarding pancreatic cancer. I probably wouldn’t risk it for primary prevention of CAD.

          Reply
          Rob says April 2, 2018

          Thanks, Paul. Two persons per thousand sounds like a pretty small risk, compared to the potential benefits. There is some history of prostate cancer and lung cancer in my family, so it sure seems to me like taking a low-dose aspirin is a risk worth taking.

          Reply
    Bill says April 7, 2018

    A late comment re aspirin as a major cause of mortality during the 1917-18 flu pandemic. : if one checks the number of deaths due to this flu pandemic, India ( then British India ) stands out. Between 5& 10% of the total population died due to the pandemic….17 million is one estimate !

    But in India at the time aspirin was a very rare & relatively expensive drug and certainly not affordable by ordinary poor Indians.

    I suggest that this completely undermines the theory that aspirin consumption by flu sufferers caused the high mortality.

    Reply
      Tom Clayton, MD says April 7, 2018

      This is a non sequitur. The theory about aspirin use in the 1918 epidemic increasing the death rate, ostensibly by vitamin c depletion (this was before vitamin c supplementation). It does NOT mean that all flu deaths were caused by excessive aspirin use. There were plenty of deaths from the flu having nothing to do with aspirin use, such as in India and other parts of the world. As stated earlier, within the locations inside the United States where there was excessive aspirin use, the mortality rate was significantly higher than other locations where aspirin was not used. This is still a consistent theory unaffected by deaths where aspirin was not used/available.

      Reply
        P. D. Mangan says April 7, 2018

        U.S. fatality rates in the flu epidemic of 1918-19 were strongly and negatively associated with amount of UVB radiation. Lowest rate, San Antonio, TX, highest, New London, CT. Now that’s a confounding factor. https://www.tandfonline.com/doi/full/10.4161/derm.1.4.9063

        Bill’s comment is not a non-sequitur. It depends on whether India had a greater percentage of its population or flu patients die than elsewhere. If they did, and no one there took aspirin, then aspirin could actually be protective.

        Anyway, the doses you claim cause this were upwards of 3 to 30 grams a day, and are irrelevant to the use of low-dose aspirin.

        Reply
          Tom Clayton, MD says April 7, 2018

          Never said or implied that low dose aspirin was bad. I take one baby aspirin every day. I did not set out to bore some readers with good solid information about other things to do to decrease the rate of premature death.

          The UVB article is nothing more than a theory, not confounding fact. It is much colder in Connecticut than in San Antonio in the winter. Does this mean that cold somehow figures in to the differences in death rates? Like most people, if you believe that something is true then you will defend the belief by finding evidence that “appears” to support the belief whilst ignoring evidence to the contrary, aka confirmation bias. Shall we assume that you are going to write another book about aspirin as a life extender? This seems to be your pattern.

          Reply
          P. D. Mangan says April 7, 2018

          I was wondering when you would get to ad hominem argument. That seems to be the pattern of people like you: when you find yourself losing, attack the other person.

          I already wrote about aspirin in a couple of my books. Do you make money from treating patients? Or do you treat everyone for free? And after all of your railing against both me and aspirin, saying how it’s so risky that no one should take it, it turns out *you* take it! Seems like we could have all saved ourselves a lot of trouble if we knew that in the first place.

          You’re banned.

          Reply
          Bill says April 9, 2018

          I have had an odd feeling about Clayton’s comments from the start PD. It seemed like an attempt to white ant your own blog with long extraneous comments.
          I think you did the right thing banning him from commenting.

          Reply
brbr says April 1, 2018

I hope this article is not an april fool’s joke lol.

Is beta blockers bad for T levels? Is it better than drugs such as losartan?

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Carl Rathlo says April 1, 2018

HERBAL

I am a 50 years old female diagnosed with Rheumatoid Arthritis 2 years ago but have had symptoms for at least 20 years. I was taking methotrexate and Cymbalta, as well as infusions of Remicade, nothing worked for me. All my pain was from my waist down and certainly not something I can stand. The only treatment that has been successful has been the taking of RA herbal remedy i purchased from Best Health herbal centre. I now wake up every morning without pain. I have been pain-free period for more than 4 months. I have regular blood tests and do not experience any of the side effects from taking the herbal remedy. Thank God this works for me. I feel great!.

Reply
    D says April 1, 2018

    What does this have to do with the blog post?

    Reply
Anon1 says April 2, 2018

Interesting study regarding aspirin if you have COPD.

https://www.ncbi.nlm.nih.gov/pubmed/29246770

CONCLUSIONS:

Regular aspirin use was associated with a more than 50% reduction in the rate of emphysema progression over 10 years. Further study of aspirin and platelets in emphysema may be warranted.

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Bill says April 2, 2018

@Tom Clayton, MD.
Tom you started off here with the comment about very high dose aspirin being prescribed in 1919 for sufferers of the Spanish Flu..And probably causing the high death rate among those sufferers…

The dose you mention as being prescribed was 4grams – 30 grams. As a comment it’s fair enough. At such doses it probably is toxic.

But nobody here, least of all PD , has suggested that any of us take it in such quantities.

After that you replied with 3 long grumpy tirades about other issues…In one of them you virtually accused PD of using only popular internet web sites to back up his statements. Now frankly that is false. It’s a false accusation Tom as you would already know if you had checked out even some of the links that PD has given for the numerous posts here …

I suggest that warrants an apology.

You have also made long comments about diet and lifestyle as if nobody commenting & reading here agreed with you…Tom you are preaching to the choir…And that’s a bit boring.

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Carole says April 3, 2018

This post, as all of yours, are excellent–replete with meticulously research. One question: what dosage of aspirin do you take daily? Thanks so much.

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    P. D. Mangan says April 3, 2018

    Thanks, Carole. I take a near daily low-dose aspirin, 81 mg.

    Reply
      peter connor says April 6, 2018

      Yes, really outstanding article P.D.! I have also been taking one daily low-dose aspirin for years, and I think that was based on my extrapolation of one of your earlier articles…Thank you!

      Reply
Carole says April 3, 2018

This post, as all of yours, are excellent–replete with meticulously research. One question: what dosage of aspirin do you take daily? Thanks so much.

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Brandon says April 3, 2018

PD, you have written some great stuff on aspirin.

I was wondering if you knew if the bleeding risk of aspirin is related to the acetyl or the salicylate?

I know of several other supplements that have acetyl such as N-Acetyl-Cysteine, Acetyl-L-Carnitine for example, would these increase bleeding risk? They are often taken in doses of 600mg+/day.

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    P. D. Mangan says April 3, 2018

    Thank you, Brandon. The bleeding risk is related to the acetyl group, but enzymes such as COX-1 and molecules like ASA have very specific structures and must fit together for a reaction to occur. To my knowledge, there’s no bleeding risk with NAC or for example, vinegar, which is acetic acid.

    That’s one reason I was interested in and wrote about the drug diflusinal, which is a salicylate derivative that’s more potent than aspirin in deactivating EP300, and without bleeding risk.

    Reply
Herman Rutner says April 3, 2018

Aspirin tablets disintegrate slowly and may cause localized gastric ulceration. Enteric coated aspirin may cause localized damage of the mucosa. The best form is chewable baby aspirin, 4 equaling 1 regular aspirin, at worst causing irritation of the stomach lining. Bismuth subsalicylate, best as aluminum and dye free , kaopectate with vanilla flavor destroys H pylori in a few days. It is more effective than antibiotics with less relapse than antibiotics which are active only in the stomach and gut. Why? Because kaopectate taken as a liquid also destroys Hp in the oral cavity and in the esophagus, both reservoirs for reinfection. Oral Hp can also be destroyed by daily gargling with a diluted kaopectate further slowing reinfection. Note that salicylate is released in stomach acidity and readily absorbed into the blood stream contributing to aspirin effectiveness.

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    P. D. Mangan says April 5, 2018

    Thanks, Herman. I note that Pepto-Bismol also contain bismuth subsalicylate and is antibacterial. Do you by any chance have a scientific source for this?

    Reply
Paul Rivas says April 4, 2018

A 2016 European study of 1720 people over a a three year period, all of whom used low dose aspirin, showed less bleeding and stroke incidence in those who took the drug occasionally as opposed to regular usage. The cancer incidence was about the same , so this would support the occasional use of aspirin over the regular use for both efficacy and risk

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    P. D. Mangan says April 5, 2018

    Thanks, Paul, I’d be very interested in that study. Did some looking on Google Scholar, couldn’t find it, as there are about a thousand studies a year on aspirin.

    Reply
      Paul Rivas says April 5, 2018

      Herehttps://www.ncbi.nlm.nih.gov/pubmed/26640116

      Reply
        paul rivas md says April 5, 2018

        A long term risk benefit analysis of low-dose aspirin in primary prevention

        Eur J clin Invest, 2016 Feb, 46 (2) , 130-40 . Wu IC

        Reply
        P. D. Mangan says April 5, 2018

        Thanks, Paul.

        Reply
jre says September 5, 2018

Gentlemen,

I appreciate your highly educated discourse and citing actual pubmed articles.

It is a breath of fresh air when talking about topics like anti-aging and nutrition.

Reply
    P. D. Mangan says September 5, 2018

    Thank you.

    Reply
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