Nattokinase and Reversal of Atherosclerotic Lesions

Atherosclerosis is one of the great killers. Fatty deposits form in blood vessels walls, narrowing and weakening the vessels. Eventually something ruptures, and the result is a stroke or heart attack, but even absent that the condition can narrow vessels sufficiently to cause fatal coronary artery disease. Even with modern medicine, the condition is inexorable: the toolkit doesn't yet include a way to more than slightly reverse the buildup of these plaques, and medical professionals must focus on ways to incrementally slow the progression of atherosclerosis rather than delivering any true cure.

One of the side-effects of starting a company, Repair Biotechnologies, that is working on a way to reverse atherosclerotic plaque is that I've been doing a great deal more reading on the topic of atherosclerosis than I would otherwise have done in the course of writing Fight Aging! Thus I turn up interesting items from the past few years that I missed at the time because I lacked the context to understand why they were worthy of notice, or just didn't have the sort of focus on atherosclerosis that I have at the moment. The papers I'll share today fall into this category, providing evidence for nattokinase, a very simple and readily available supplement, to have a surprisingly large effect on atherosclerotic lesions in humans. After six months of treatment, a third of the lesions were removed.

A clinical study on the effect of nattokinase on carotid artery atherosclerosis and hyperlipidaemia

All enrolled patients were from the Out-Patient Clinic of the Department of TCM at the 3rd Affiliated Hospital of Sun Yat-sen University. Using randomised picking method, all patients were randomly assigned to one of two groups, nattokinase (NK) and statin (ST) group. NK Group-patients were given NK at a daily dose of 6000 FU and ST Group-patients were treated with statin (simvastatin 20 mg) daily. The treatment course was 26 weeks. Common carotid artery intima media thickness (CCA-IMT), carotid plaque size and blood lipid profile of the patients were measured before and after treatment.

A total of 82 patients were enrolled in the study and 76 patients completed the study. Following the treatments for 26 weeks, there was a significant reduction in CCA-IMT and carotid plaque size in both groups compared with the baseline before treatment. The carotid plaque size and CCA-IMT reduced from 0.25±0.12cm2 to 0.16±0.10cm2 and from 1.13±0.12mm to 1.01±0.11mm, repectively. The reduction in the NK group was significantly profound, a 36.6% reduction in plaque size in NK group versus 11.5% change in ST group. Both treatments reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG).

Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases

Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in cardiovascular disease mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to cardiovascular disease.

This effect size on atherosclerotic lesions is big enough to be suspicious, given that nattokinase is a supplement in common use, and the dose used is not outrageously large. We seem to be seeing a lot of that sort of thing these days, however; sometimes significance goes unnoticed, but equally sometimes it is an issue with the study that will be corrected later. It is hard to tell which without meaningful further effort. Does bisphosphonate treatment actually extend life expectancy by five years, and did this really did go unnoticed despite its widespread use in older people? Is fisetin actually a significantly effective senolytic compound in humans despite being widely used; did the very high senolytic dose in comparison to the usual supplement dose successful hide this property? How did nearly twenty years of earnest development and use of the chemotherapeutic dasatinib go past without anyone noticing that it killed enough senescent cells to improve health and measures of aging in mice and people? And so forth.

Over the past few decades, hundreds of millions of dollars (at the very least) have been spent on clinical trials to try to reverse atherosclerosis - to give existing repair systems in the body sufficient breathing space or increased capacity, allowing them to break down the fatty deposits that form in blood vessels. The sponsors of any of those trials would have been ecstatic to find a reliable reversal of atherosclerotic plaque that was half the size of that noted in the nattokinase trial here. One might take a look at a 2012 review paper that surveys the degree to which treatments at the time could achieve the goal of reversing atherosclerosis. A reversal of 15-20% in an unreliable fraction of patients was about the best that could be done. Most approaches were considerably less effective than that. Not a lot has changed in this high level picture since then.

At present the dominant approach to treatment of atherosclerosis is reduction of blood cholesterol, the cholesterol attached to LDL particles, or LDL-C. Statins are the long-standing approach, and are now being joined by even more effective treatments such as PCSK9 inhibitors. This slows down atherosclerosis by (a) lowering overall cholesterol, and thus freeing up some fraction of the macrophage cells that would otherwise have had to shovel it out of blood vessel walls, but more importantly (b) lowering oxidized cholesterol, which is very damaging to macrophages. When considering atherosclerosis and its treatments it is important to consider macrophages: they are drawn to the fatty lesions, and their task once there is to mine cholesterol from the lesion, ingest it, and hand it off to HDL particles that carry it back to the liver for excretion. This is called reverse cholesterol transport.

Atherosclerosis exists because macrophages become overwhelmed, mostly by oxidized cholesterol, but also by sheer volume of cholesterol, or by an overly inflammatory environment. They become agitated, call for help, become foam cells (some of which become senescent, causing further issues) or die. Most of a plaque is made up of the debris of dead macrophages, and the plaque itself is a self-expanding disaster area that calls ever more macrophages to their doom. Reducing the LDL-C slows down this feedback loop, but it cannot do much for existing plaques. There is some regression (the aforementioned 15-20% at best) because macrophages are given some breathing room, but plaques continue to grow at the new slower pace, and people continue to die.

There has been a considerable amount of work undertaken over the years on alternatives to lowering LDL-C. Researchers have tried all sorts of ways to improve the ability of macrophages to mine cholesterol and send it back to the liver. They have tried increased numbers of HDL particles (which are formed from APOA1 protein). They have tried altered forms of APOA1 found in some human populations that are associated with lower levels of atherosclerosis. They have tried the introduction of artificial HDL particles to swell the numbers. They have tried upregulation of the ABCA1 and ABCG1 proteins that perform the actual handoff of cholesterol molecules to APOA1. There is more in the same vein.

All of these things work pretty well in mice; the current best approaches produce 50% reversion of atherosclerotic lesions in animal studies. Yet all of those tried in humans, meaning the HDL and APOA1 approaches, have failed miserably in clinical trials. What this means is that there is something that the research community doesn't yet understand in the low-level detailed differences between human and mouse reverse cholesterol transport. That is a big roadblock for anyone turning up to propose some form of enhanced cholesterol transport as a therapy, even if intending to try one of the varied effective-in-mice approaches that hasn't yet been trialed in humans.

In this context, one can see that evidence for a common supplement to manage 36% reversion of lesions in humans is both welcome and jarring. It will certainly have to be replicated before many researchers in the LDL-C-focused side of the scientific community are likely to take it all that seriously. Any simple, easily obtained improvement should be welcome. Nonetheless, it is still only reversion by a third. The disease will still progress, and will still kill people. The research community has to do better than this.

Comments

"Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation."

"PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year"

https://www.ncbi.nlm.nih.gov/pubmed/15158307/

Posted by: Lee at January 15th, 2019 4:48 PM

Another question to ask is why if a treatment is good at reducing the plaque by 50% it doesn't go to complete elimination ?

And apparently our mouse model is completely unrealistic. If it takes years, if not decades for the foam cells to calcify and grow the plaque how can we model it with mice that are a few months old ?

Posted by: cuberat at January 15th, 2019 5:12 PM

@Lee
was there a placebo control ?

Posted by: cuberat at January 15th, 2019 5:14 PM

@Cuberat
I don't think so.

Posted by: Lee at January 15th, 2019 5:48 PM

@Cuberat: Not as bad as Alzheimer's mice, but yes, you have to pay some attention to the details of the model in terms of what the plaques look like. You don't get the same distribution of plaque maturity and structure as in humans. There are various different models, some of which are supposedly better than others from that perspective.

Posted by: Reason at January 15th, 2019 6:05 PM

"Updating a 12-Year Experience With Arrest and Reversal Therapy for Coronary Heart Disease (An Overdue Requiem for Palliative Cardiology)"

"They agreed to follow a plant-based diet with <10% of calories derived from fat. They were asked to eliminate oil, dairy products (except skim milk and no-fat yogurt), fish, fowl, and meat. They were encouraged to eat grains, legumes, lentils, vegetables, and fruit. Cholesterol-lowering medication was individualized. The only goal was to achieve and maintain a total serum cholesterol of <150 mg/dl."

"Adherent patients have experienced no extension of clinical disease, no coronary events, and no interventions. This finding is all the more compelling when we consider that the original compliant 18 participants experienced 49 coronary events in the 8 years before the study."

http://www.dresselstyn.com/reversal01.htm

Posted by: Lee at January 15th, 2019 6:19 PM

It seems likely to me that the macrophages in plaque are there because they are just trying to do their job of fighting infection.
Nattokinase and other interventions may have limited effectiveness because the infection has not been resolved.

"Human oral, gut, and plaque microbiota in patients with atherosclerosis"

"We identified Chryseomonas in all atherosclerotic plaque samples, and Veillonella and Streptococcus in the majority."

"Interestingly, several bacterial taxa in the oral cavity and the gut correlated with plasma cholesterol levels. Taken together, our findings suggest that bacteria from the oral cavity, and perhaps even the gut, may correlate with disease markers of atherosclerosis."

https://www.pnas.org/content/108/Supplement_1/4592

Posted by: Lee at January 16th, 2019 8:23 AM

"The presence of biofilm structures in atherosclerotic plaques of arteries from legs amputated as a complication of diabetic foot ulcers."

"While the presence of bacterial biofilm structures in atherosclerotic plaque does not prove that biofilm is the proximate cause of atherosclerosis, it could contribute to the persistent inflammation associated with it. Second, the synergistic relationship between the atherosclerotic infection and the diabetic foot ulcer may ultimately contribute to higher amputation rates in diabetics."

https://www.ncbi.nlm.nih.gov/pubmed/26878370

Posted by: Lee at January 16th, 2019 8:43 AM

So not all supplements are snake oil? Interesting to see your opinions evolve. I eat natto regularly; I understand why some would prefer to get the active constituents in natto in supplement form (nattokinase, spermidine, K2, PQQ), as it is an acquired taste (I enjoy it with hot mustard and a bit of tamari). Also, for therapeutic use (as opposed to prevention) it is necessary to know the exact dose, and possibly get a much a higher dose than is available through a normal serving size.

Amazon is likely doing quite a bit of data mining on supplements in terms of Amazon.com customer purchase patterns and reviews, and now added to that all their PillPack Rx drug and supplement data -- it will be interesting to see how they apply the gleanings to their own brands (Amazon Elements and Solimo). My guess is they will learn a great deal about the efficacy of supplements/Rx drugs and supplement/Rx drug combinations.

While various lifestyle / DIY interventions are helpful for maintaining health and possibly achieving LEV, most of your readers ought agree, though, that for radical life extension SENS is necessary. Reversing hypothalamic aging, for example, will require likely both the control of hypothalamic inflammation and stem cell replenishment.

Posted by: CD at January 16th, 2019 11:45 AM

Hi CD! Just a 2 cents.

Currently, it'S true that lifestyle is large factor to maintain health, but there is not much possible for achieving LEV (I am of of opinion that currently there is nothing that can do LEV and that will be for a long time until) SENS could change, though even there, color me skeptic it is not snake oil and founded in biogerontology; but, biogerontology is more complicated than we thought and harder to decipher too. Until we see epigenetic changes and research, I am not sure anything is yet to make LEV (neither hypothalamic inflammation or stem cell replenishment, these are secondaries and have been shown not to reverse aging but slow it (it makes more than that); that'S because aging is more complicated and on many levels, the major one is genetic, epigenetics mostly that are a vicious circle with damages, that lead to more inflammation/deleterious gene activation (antagonistoc pleiotropy with age) and as such one day it'S over. Reversing hypothalamaic aging is only feasible if damages and epigenetic changes happen, otherwise it'S impossible. Many new studies show that why people liver longer is because they postpone the aging phases later, as such 'remain young' (this is epiclock signature), when you remain biologically young you level of mortality is much lower; and if you remain so, mortality does not rise (which equals LEV/eternal life). Just a 2 cents.

PS: having atherosclerotis lesions, I took nattokinase and it was quite helpful, it is a powerful anti-fibrotic and I likened it to other peptidases I took; but, in the end, it is only through continuous intake; nothing is good at the start (it's like trying to stop a 50m/h moving 150-wagon train for a total a 100,000 tons of momentum, impossible); it takes years of consuming that (this trial shows great improvement but it depends on the severity and events that happened before ('and the rest'/what you eat besides natto/do you take cholesterol food...etc), like if that person had cardio vascular event and clot did happen (as it did with me and destroyed my pulmonary artery and nearly died there from artery blood blockage, when it happened by ischemia when it lodged itself after my plaques ruptured). I feel I had more improvements from vitamins and whatnot, and by cutting food out then food itself saving me; it goes to show that food is medicine but not some magic either; it takes time to get healthy again changing lifestlye after a near death event. Sorry for typos.

Posted by: CANanonymity at January 16th, 2019 2:51 PM

PPS: I would like to add, that LEV is only possible if you remain young, it's impossible if you age (that's obvious, obviously), you would absolutely have to reverse to young state - by that, I mean, that LEV/eternal life can only be achieved by bringing mortality 'rising with age' to near-0, as such, by staying in a young state do you make intrinsic mortality nill ('age-caused') with time (excluding extrinsic factors like getting in accidents and whatnot). No therapy now or in the future would ever make LEV if it cannot keep a body in young state/phenotype/signature (this was demonstrated with CR, CR is one of the few life extending therapy, by reducing calorie there is damage accrual reduction and removal of junk (proteasome), methionine content reduction, NRF2/anti-ox improv, but, especially (orchestrating all this gene), reversal (just tempoarily) and slowing of clock aging; showing that CR is all under this gene control and if CR can 'rejuvenate you' by slowing aging of your tissues, and CR did reduce epigenetic aging rate/and even lowered a lil...by CR does not stop aging neither. Showing that to be able to live 500 years or LEV, only a young body will ever reach that (it's also visible in long lived bowhead whales, clams, greenland sharks, all live centuries and keep young 'slow growing' bodies (low mortality, young state, no death/post-pone it much later and post-pone 'aging/antagonistic pleitroypi entry' phase after puberty/reproduction, thus extreme lifespan).

Posted by: CANanonymity at January 16th, 2019 3:24 PM

PPPS: I will be sold on 'old people' can live forever only until they can make more than just iPSCs or centenarian cells be reverted to clock age 0, if they can do it in all cells, than I would definitely say that old people could reach LEV just as much; for, they would not 'stay old' they would revert to their young(er) state.

Posted by: CANanonymity at January 16th, 2019 3:27 PM

PPPPS: Last one, not doing 'ageism' or being against them or something, I really respect/admire old people (and that they reached this venerable age is achievement, like super-centenarians, they are survivors, and life survivors'/death post-poners, health/life/longevity is a gift we must protect and be graceful for) and if they get the therapy, it's only normal, time is amiss at an old age; thus, I more than understand/very agree that we need to extend their lives and improve their health, immediately and above all, they require immediate help, time is running out. Younger folks have more time left, but also matter of course (I'm one among millions who are in this 'early phase - let's do something while still young/for later will be better/still around, if act now'). Just a 2 cents.

Posted by: CANanonymity at January 16th, 2019 3:43 PM

If you look at the scale of new ideas coming out today in anti-aging compared to literally 2 years ago it is a very noticeable change. And we are at the 'year 0' of this opportunity. The industry is at the point of the first companies getting startup funding.

Posted by: aa3 at January 16th, 2019 7:41 PM

layman question here:

My reading of the article, "Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases," is essentially that it seems to very effective in reducing atherosclerosis via oral administration, but it's not clear if it is bioavailable.

How could it not be bioavailable if is is so effective?

Posted by: TysonsCorner at January 17th, 2019 3:47 AM

@TysonsCorner
"How could it not be bioavailable if is is so effective?"

Perhaps by altering the gut microbiome to reduce the number of bacteria that contribute to atherosclerosis.

Posted by: Lee at January 17th, 2019 7:03 AM

I take nattokinase among some other things. It has a low price point and 6000 FU a day is what was used in the study posted originally by Reason. There is a lot of snake oil in the supplement industry but some compounds do have merit, the devil is in the details and assessing the journal publications.

Posted by: Steve Hill at January 17th, 2019 10:45 AM

Btw, excuse my ignorance but what is the FU unit ?

Posted by: cuberat at January 17th, 2019 10:59 AM

Keep the analysis coming on atherosclerosis/CVD! That's public enemy number one. Heart attack and stroke together far outweigh the next killer, cancer. And everyone in the world is working on cancer -- not enough new approaches to CVD and the metabolic issues that drive CVD.

Posted by: Sebastian A at January 20th, 2019 2:18 PM

The difference between the mouse model and humans? One big one is that mice produce ascorbic acid whereas humans do not.

I would love to see the Pauling protocol tested for atheroclerosis but I guess that's fallen by the wayside. It's 3,000 mg of lysine and 3,000 mg of vitamin C (ascorbic acid). In his testing on guinea pigs (like humans they are one of 4 species on earth that do not produce their own ascorbic acid) plaques were reduced 25% in 5 weeks. But then, Linus Pauling was a freak, right?

Here's a few links .. http://www.internetwks.com/pauling/short.html
http://www.paulingtherapy.com/

Posted by: John Whitling at January 21st, 2019 9:26 AM

"The carotid plaque size and CCA-IMT reduced from 0.25±0.12cm2 to 0.16±0.10cm2 and from 1.13±0.12mm to 1.01±0.11mm, repectively. The reduction in the NK group was significantly profound, a 36.6% reduction in plaque size in NK group versus 11.5% change in ST group."

Why is the beginning plaque volume 0.25 so low in the NK group, while the initial plaque volume in the statin group is what you would expect in people in their 60's and older? 0.25 plaque volume is, I think what you might expect in a person 25-30.The initial plaque volumes of the 2 groups should be about the same, if people close in age were randomly chosen to be in each group. I can't make sense of this.

Posted by: alan at May 1st, 2019 2:05 PM

"Abstract
Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis."

https://stm.sciencemag.org/content/8/333/333ra50

Posted by: Susan C at May 16th, 2019 7:50 PM

@Susan
Very interesting. If it really works that wild be huge. And a nice can cow for the Big Pharma. If it doesn't have debilitating side effects it cold be taken periodically by everybody over 40. Huge markets. Huge promises.

Posted by: Cuberat at May 16th, 2019 8:01 PM

A few things that make me look less optimistic. First the mice were a special breed prone to arteriosclerosis. So CD might be just compensating for a broken pathway that is functioning in humans. The mice are not humans and humans have vastly different metabolism . The mice are a convenient to use but a very bad model for the human diseases that take decades to develop.

Posted by: Cuberat at May 16th, 2019 9:11 PM

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