Nuts over Nuts

By James P. Watson, with help and some additions by Vince Giuliano

Introduction

 Nuts have long been “labeled” as a bad source of nutrition due to their high fat content.  However, a growing body of scientific studies have shown that the health benefits of nuts are so strong that this “mislabeling” of nuts should be completely abolished.  These scientific studies have mostly occurred over the past two decades, beginning with four smaller studies between 1992 and 2002 (Adventist Health Study, Iowa Women’s Health Study, Nurses Health Study, and Physician’s Health Study) and ending with two landmark studies published this year (the 2013 PREDIMED Study and the recent 2013 Harvard NEJM report). When this research is viewed as a whole, the evidence is now clear that we should all go “Nuts over Nuts“!  There is a long list of reasons why you should go “Nuts over Nuts”.  The strongest reason is to reduce your cardiovascular disease risk (24-55% risk reduction, based on dose of nuts).  The 2nd strongest reason is probably to reduce your risk of cancer (9-40% risk reduction, based on dose of nuts).  What is so amazing about the data is that it also reduces your risk of a variety of other diverse diseases such as respiratory disease (10-19% risk reduction), infectious diseases (17-32%), and kidney disease (31-48%).

When “all cause mortality” is studied, there is a linear dose-response effect that correlates well with the number of servings of nuts per week.  Specifically, “all cause mortality” drops by 20% with 7 servings of nuts per week (one serving is defined in these studies as 28gms of nuts = one ounce).

Even more impressive was the PREDIMED study, where a Mediterranean diet was combined with 3 servings of mixed nuts per week.  Here there was a 39% reduction in “all cause mortality”.  This suggests that the health benefits of a Mediterranean diet and nuts is additive (or complimentary).  The combination of a Mediterranean diet and 3 servings of nuts per week has a greater health benefit than  than any of the FDA approved medications that have been advocated for general health, such as  statins, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, aspirin, and diuretics.  It even beats the heath benefit data for fish oil (Omega-3/Omega-6 fatty acid ratios), fruits and vegetables, and Vitamin D3 (25% reduction in breast and colon cancer incidence, as well as 75-77% reduction in mortality from breast and colon cancer).

We are not advocating that you stop taking your statin, your aspirin, your Vitamin D, or stop eating fish, fruits, vegetables. Instead, we are suggesting that you add one ounce of nuts to these other proven healthy foods.  An ounce of nuts a day may keep the doctor away much better than the proverbial apple.  This blog will first cover the  major recent scientific studies that have shown the health benefits of nuts. Then the blog will cover the “top 10 molecular mechanisms for the health benefits of nuts”.  While you read this blog, we ask you to please consume a few walnuts, some pistachios, some hazelnuts, some pine nuts, some Brazil nuts, some almonds, some pecans, and some peanuts.  By the time you finish reading this blog, you will likely be “Nuts about Nuts” too.

Image source

The Scientific Studies

The PREDIMED Study

Frequency of nut consumption and mortality risk in the PREDIMED nutrition intervention tria. (July, 2013)

This is a nut study that was done in Spain.  It is by far the best study to date that has been done on nuts, due to three reasons.  The first reason is that the PREDIMED study is the only study that was specifically devoted to nuts (The other studies mentioned in this blog were based on extracted data from large epidemiologic studies that were looking a many different dietary and lifestyle factors, not just nuts).  The 2nd reason the PREDIMED study is so significant is that it was a prospective, randomized study (The other studies were retrospective studies without randomized diet interventions).  Prospective, randomized studies are the strongest kind of scientific evidence.  It is very difficult to find reasons why such studies would be false.  The 3rd reason why the PREDIMED study is so significant is that it was a large study involving both men and women (7,216 Spanish men and women).  The statistical value of such a large study is very significant.

In short, the PREDIMED study randomized these volunteers to one of the following three diets:

1. Mediterranean diet + Extra Virgin Olive Oil (EVOO)

2. Mediterranean diet + mixed nuts

3. Low fat diet.

For standardizing the dose of nuts, one serving was defined as 28 gms of nuts (which is about 1 ounce). The type of nuts consumed in this study was a mixture of nuts easily available in Spain (almonds, peanuts, hazelnuts, pistachios, pine nuts, and walnuts).  Since walnuts seems to be such a great nut, the data was evaluated with and without walnuts in the reporting.  The follow-up for this study was good as well (4.8 years average follow-up).  The results were quite astounding!

There was a 39% reduction in “all cause mortality” for those who consumed > 3 servings of nuts per week and ate a Mediterranean diet.   For “non-walnuts”, there was a 34% mortality risk reduction for all cause mortality. For walnuts, there was an even greater reduction in all cause mortality (45% risk reduction). A similar effect was shown for cancer (40% risk reduction) and heart disease (55% risk reduction) in the group that combined a Mediterranean diet and 3 servings of mixed nuts per week.  A surprising result was that the volunteers who were already eating nuts (baseline nut consumption) who were assigned to the “nut eater” group showed a 63% reduction in all cause mortality, when compared to the low-fat diet group.  In summary, a Mediterranean diet with 3 servings of nuts per week is much better than a Mediterranean diet with EVOO and is much better than a low fat diet.

This study does leave some “hope for the nut haters”.  Specifically, several confounding variables in the data could have accounted for part of the “nut effect”.  The confounding variables included BMI, smoking, and exercise.  Those that consumed nuts and ate a Mediterranean diet also had a lower BMI, a lower waist circumference, were less likely to smoke, and were more physically active.  These factors may have “skewed” the results in favor of the “nut eaters.”  On the other hand, eating nuts may have contributed to the nut-eaters having these positive characteristics.

Conclusion:  This study was very important because it showed that other nuts besides walnuts are also very good for you.  Both walnuts and non-walnuts confer a global risk reduction in mortality that encompasses both cancer, heart disease, and other causes of mortality.  The risk reduction was the greatest in those who already were eating nuts (i.e. already had that type of diet prior to enrolling in the study).  When you compare these results with the fish oil or fish consumption studies, there is no comparison – nuts reduce mortality risk much greater than fish or fish oil.  This does not mean that fish oil or fish are not good for you.  It just means that there are probably other molecular mechanisms in play here.

Specifically, omega-3 fatty acids are found in nuts, but not nearly as much as with fish or fish oil. Walnuts are probably the type of nuts with the most omega-3 fatty acids and the type of nuts with the best ratio of omega-3 fatty acids to omega-6 fatty acids. However, this study showed non-walnuts to have a wonderful all cause mortality reduction of 34%.   The other nuts do not have than much omega-3s. For this reason, I do not believe that omega-3 fatty acids or the ratio of omega-3/omega-6 fatty acids can explain the PREDIMED results, especially since they showed that other nuts besides walnuts reduced mortality risks.  There must be other molecular mechanisms besides omega-3s in play here!  

Reference:

Antioxidant activity comparison of walnuts and fatty fish (2012).  Also see the discussion below regarding nuts and Omega fatty acids

This study suggests that walnuts and fatty fish work by different mechanisms to reduce coronary heart disease and it is a good idea to consume both: Walnuts and fatty fish influence different serum lipid fractions in normal to mildly hyperlipidemic individuals: a randomized controlled study (2009).

The Harvard Studies

Nurses Health Study and Health Professionals Follow-up Study – Association of Nut Consumption with Total and Cause-Specific Mortality (November 2013)

This is the paper that just came out in the NEJM and was featured in many news stories. It is by far the longest study (24-30 years) and the largest study ( 76,000 women and 42,000 men) of any study on nuts.

The study actually draws on “pooled data” from two very large longitudinal studies, the Nurses Health Study and the Health Professionals Follow-up Study. This pooled data was extracted from these two long-term studies which follow-up on specific individuals.  The data had been previously reported but with shorter duration follow-up (therefore not as strong as now). Unfortunately, this data is not a prospective, randomized study, like the PREDIMED study, but it is still a very significant study because of the 24-30 year follow-up and the very large group of subjects (almost 120,000 people in total). I like this paper because it broke down the data by three types of nut groups:  1)”any nut”, 2) “peanuts”, and 3) “tree nuts”

The New England Journal of Medicine has produced a fun YouTube video which explain the basic findings in the paper in lay terms.  You can view that video by clicking here.

Here is the summary:

The “nut data” in this paper was extracted from the following two large studies:

1. The Nurses Health Study – This is a 30-year follow-up study of 76, 464 women

2. The Health Professionals Follow-up Study – This is a 24-year follow-up study of 2,498 men. Nut consumption for both of these groups was evaluated every 2-4 years

Results:

  •  7 or more servings of nuts per week reduced “all cause mortality” by 20%  (p < 0.001)
  • 5-6 servings of nuts per week reduced “all cause mortality” by 15%
  • 2-4 servings of nuts per week reduced “all cause mortality” by 13%
  • 1 serving of nuts per week reduced “all cause mortality” by 10%

This type of data is called a “dose-response relationship” and strengthens the case that the consumption of nuts and the reduction in mortality is a  “cause-and-effect” relationship and not what is simply called a “correlation effect” which is not a “causal effect”

Details in risk reduction:  The table below summarizes the break down of the data.  Here is some of the details that I have summarized from the table:

  • 12-17% reduction in all cause mortality
  • 9-17% reduction in cancer
  • 24-26% reduction in heart disease
  • 10-19% reduction in respiratory disease
  • -2 to +5% reduction in neurodegenerative disease
  • 4-8% reduction in stroke risk
  • 17-32% reduction in infection risk
  • 31-48% reduction in kidney disease
  • 0-20% reduction in diabetes risk

 

harvstudytable

Conclusions:  This data cannot be ignored or dismissed.    The “dose-response” effect by the number of servings of nuts is very clear and cannot be dismissed.   The dramatic reduction in kidney disease and infection risk is unexplainable by the typical explanations for nut consumption (i.e. no cholesterol in nuts, good polyphenols, phytosterols, tocopherols, good omega-3/omega-6 fatty acid ratios, etc.).   There must be additional  molecular mechanisms at play here!  

I believe that the reduction in respiratory disease risk and infectious disease risk is probably due to a combination of polyphenols found in nuts as well as the selenoproteins (or selenium) found in certain nuts (Brazil nuts and walnuts are two of the best nuts for selenium).  These factors are discussed later in this blog

Pooled Data from Older studies

The publication is Health Benefits of Nut Consumption (2010) by Emilio Ros.

The Adventist Health Study paper on walnut consumption (1992) was one of the first scientific papers to show a unique benefit of nuts on heath.  This data as well as three others that followed this have provided the earliest evidence for the health benefits of nuts. These four older studies were summarized in this very fine 2010 paper written by Ros.   Here is a summary of Emilio Ros’s article published in the journal, Nutrients, July, 2010.

Studies:  The data from four studies was pooled and two specific things were looked at: heart disease (along with LDL and total cholesterol) and diabetes.  The four studies are:

1. Adventist health study – 1992

2. Iowa Women’s health study – 1993

3. Nurses Health Study – 1998

4. Physicians Health Study – 2002

Results:  The pooled data from these 4 large epidemiological studies showed a 37% reduction in multivariable-adjusted risk of fatal heart disease.  There was a “dose-response” effect on the number of servings of nuts with the greatest risk reduction occurring with > 5 servings of nuts per week.  There was a 47% risk reduction in sudden cardiac death as well. Here is a diagram from Emilio Ros’s article that shows the “dose-response” relationship between nuts and cardiovascular disease risk.   If you added the lines together, there is clearly an increasing risk reduction between 1-2 servings of nuts per month and greater than 5 servings of nuts per week.

Cardiovascular benefits of nuts

The specific things that Emilio Ros discusses is a total cholesterol lowering effect and a LDL-cholesterol lowering effect. There was clearly a reduction in total cholesterol and a reduction in LDL-cholesterol with nut consumption, but no effect on HDL. Nuts do not seem to raise HDL-cholesterol (the good type of cholesterol that can be most effectively raised with exercise).

Diabetes Benefits of nuts

The Emilio Ros article also looked at the issue of diabetes.  With diabetes, the consumption of nuts is not so clear.  Using the data from these 4 studies, Emilio Ros showed that the claims that nuts helped lower diabetes risk is NOT so clear. Here is a diagram illustrating that.  As you can see, the “dose-response” effect appears to be there but is not that strong.

Results of prospective studies on nut consumption and the risk of diabetes.

Mortality Rates And Life Expectancy (commentary by Vince Giuliano)

It is important to recognize that decreasing mortality by 20% or 40% is not the same as increasing life expectancy by 20% or 40%.  That is because mortality shoots up at an exponential rate with advancing age, and even taking 40% off of an exponentially rising curve still leaves an exponentially rising curve.  Mortality is something that can be measured year-to-year, whereas life expectancy can only be measured as such, empirically as a function of survival in the long term.   The relationship between mortality rates and life expectancy can be very complicated.  See How Changes in Age Specific Mortality Affects Life Expectancy .

Probability of death increases every year, more and more steeply with every passing year, particularly after age 60. Everything we know now suggests that this will continue to be so unless we can discover truly radical life extending innovations.  Historically and still currently, no one lives beyond the age of 122.

There is a strong tendency in advanced countries towards longer average life spans, a process called “rectangularization” of the survival curve.  At the same time there seems to be an effective upper bound to human age, about 122 years.

Fig. 1-1-10 Survival Curve for Number of Survivors Per 1,000 Births

Image source Examples of from-birth life expectancy from birth as a function age according to data from different time periods and places.  As history has progressed we are living longer and longer and the expected survival curve gets to be more and more rectangular in shape.  If this trend were to continue to where it seems to be going (as probably it won’t), except for trauma accidents everybody would drop dead at age 122   See the blog entries The Prospects that Emerging Science Offers us for Longer Healthy Lifespans, We are already evolving to live longer,  and Evolution and the prospect for much longer lifespans – a video blog.  If you are interested in the math involved, you can look into the Gompertz–Makeham law of mortality.

Thus, interventions that decrease mortality can be expected to impact on life expectancy depending on how they change the shape of the survival curve, something we cannot predict now.  I  can’t now imagine how a Mediterranean diet and nuts could get us beyond this 122 year limit, though I would be delighted to be wrong about that.  My current guess is that the 39% decrease in the reported “all cause mortality” reductions discussed above for nuts and the Mediterranean diet might at best lead to between 5 to at very most 10 years of average life extension, that is 7% to 12%.. This is not bad at all, but not necessarily earthshaking compared to other longevity interventions discussed in the literature, ones like calorie restriction,  mTOR inhibition via rapamycin, metformin, etc.  Even plain-old keeping fit can produce a comparable mortality reduction .   The 1995 study reported here, for example, indicates that being physically fit reduces mortality by 44%.

My personal view (Vince) is that it is best for me to “throw the whole book” at my aging, adopting as many mortality-reducing behaviors as I can.  That includes eating nuts daily, consuming plenty of olive oil, berries and fresh fruits and vegetables, a Mediterranean diet, fish oil and many other supplements, exercising daily, getting plenty of rest and sleep, keeping my mind and body adequately stressed, etc.  My view from a few months back is captured in the PowerPoint presentation that you can download from here.

Properties and benefits of different kinds of nuts.

The illustrated Healthy Nuts Go Nuts publication from the University of Michigan Health Service describes specific properties and health benefits of almonds, hazelnuts, pecans, walnuts, and peanuts, lists nutrients in various kinds of nuts, provides nut recipes, and other practical information.

Eating nuts and weight gain

Well-meaning friends warn that eating nuts will make me (Vince) gain weight.  They are wrong about that myth.  Although nuts are loaded with fat calories, the research evidence does NOT support the idea that adding nuts leads to weight gain.  More often, actual weight loss is connected with eating nuts.  See:

  • Nut consumption, weight gain and obesity: Epidemiologicalevidence  (2011):  “CONCLUSION: Consumption of nuts was not associated with a higher risk of weight gain in long-term epidemiologic studies and clinical trials.”
  • Health benefits of nut consumption (2010): “ Contrary to expectations, epidemiologic studies and clinical trials suggest that regular nut consumption is unlikely to contribute to obesity and may even help in weight loss.”
  • Nuts and health outcomes: new epidemiologic evidence (2009): “ Long-term nut consumption is linked with lower body weight and lower risk of obesity and weight gain.”
  • Nut consumption and body weight (2003): “In well-controlled nut-feeding trials, no changes in body weight were observed. Some studies on free-living subjects in which no constraints on body weight are imposed show a nonsignificant tendency to lower weight while subjects are on the nut diets. In another line of evidence, preliminary data indicate that subjects on nut-rich diets excrete more fat in stools. Further research is needed to study the effects of nut consumption on energy balance and body weight. In the meantime, the available cumulative data do not indicate that free-living people on self-selected diets including nuts frequently have a higher body mass index or a tendency to gain weight.”
  • A review of the evidence: nuts and body weight (2007): “This paper reviewed all the available evidence from the literature in relation to nut consumption and body weight. The findings show that the role of nut consumption in body weight management is varied. Nuts, when included as part of an energy-controlled diet, were found in some instances to assist with weight loss. However, when nuts were added to an existing diet without controlling for energy intake, body weight increased, although to a lesser extent than theoretically predicted. There is limited evidence on the effect nut consumption has on type 2 diabetes, although available evidence indicates that nuts as part of a healthy diet do not cause weight gain and can have a positive influence on the fatty acid profile of a person with diabetes. This review shows there is a lack of evidence to support the restriction of nut consumption in weight management, indicating that further research is needed to assess the role of nuts in weight management.”
  • Nut consumption and weight gain in a Mediterranean cohort: The SUN study (2007): “Frequent nut consumption was associated with a reduced risk of weight gain (5 kg or more). These results support the recommendation of nut consumption as an important component of a cardioprotective diet and also allay fears of possible weight gain.”

Molecular Mechanisms for the Health Benefits of Nuts

The scientific studies above are what is called “epidemiological evidence.”  In science, we try to discover the molecular mechanisms that account for such epidemiological effects.  I have read a lot about the molecular biology behind nuts and here is a list of mechanisms that I believe account for

the health benefits of nuts.  Yes, omega-3 fatty acids are one of the mechanisms, but there are many other mechanisms.  I have listed them in the order that I believe are in the order of importance.

1. No cholesterolThis is the Bill Clinton explanation – “It is the lack of cholesterol, stupid!”

 Nuts have no cholesterol since plants make cholesterol in very small amounts.  Cholesterol plays a large role in cardiovascular diseases. Therefore the lack of cholesterol in nuts is one possible explanation for the health benefits of nuts.  This explanation is so simple that is is like falling off a log!  As Bill Clinton said about the economy in the 1992 presidential race, “It is the Economy Stupid”.  Here we can use the Bill Clinton line of reasoning:   ”There is NO Cholesterol in nuts, stupid!”

I only partially “buy into” this explanation, however, since the majority of people studied in the PREDIMED study as well as the Harvard studies, the Nurses Health Study, the Iowa Women’s Health Study, and the Physicians Health Study were NOT vegetarians.  (Only the Adventist Health Study included a significant number of vegetarians).  The other reason why I do not “buy” the “no cholesterol hypothesis” is because the major source of cholesterol is not from a person’s diet but rather from de novo synthesis by the liver and gut.  This is why there are vegetarians who still have high cholesterol and require statin drug therapy to reduce their cholesterol.  Cholesterol is synthesized “de novo” in the human liver as well as other organs.  Specifically, for a man weighing 68 kg, the human body synthesizes about 1,000 mg of cholesterol per day.  The typical dietary intake of cholesterol per day is 200-300 mg.  Therefore, being a vegetarian only reduces the total cholesterol (diet + de novo synthesis) by 20-30%.   This is why HMG-CoA reductase inhibitors such as Lipitor and Crestor are so effective in reducing cholesterol (this reduces de novo synthesis of cholesterol in the liver).  Therefore, the “no cholesterol hypothesis”  for the health benefits of nuts is a good explanation, but not adequate to explain ALL of the benefits of nuts. The no cholesterol hypothesis probably contributes to the risk reduction in cardiovascular disease with nut consumption.  This hypothesis also does not explain the nut eater’s anti-cancer benefits and reduced risk of lung disease, infections, etc.  Phenolic compounds such as polyphenols are more likely to explain the anti-cancer effects of nuts.

References:

2. Phenolic compounds

This is the same explanation for the benefits of fruits and vegetables: It is the polyphenols, stupid!   - polyphenols have many molecular mechanisms of action, including anti-oxidant effects, transcription factor effects, and epigenetic effects on gene expression Nuts are rich in polyphenols.  Polyphenols are now thought to be the major molecular mediators of the health benefits of fruits and vegetables.  Although polyphenols were once thought to work as “anti-oxidants”, this is NOT the major mechanism of action based on the overwhelming scientific evidence. The strongest effects of polyphenols are probably via their epigenetic effects.  This has to do with gene expression.  Even though I believe that the primary mechanism of action of polyphenols is via these epigenetic effects, a lot of research went into the “antioxidant effects” of nuts, which showed dramatic reductions in CRP as well.  CRP is a marker of oxidative stress.  Therefore there is some effect of polyphenols on “oxidative stress” but it is most likely not directly as an “antioxidant”.

Instead, the oxidative stress effects may have more to do with reducing the production of free radicals or increasing endogenous antioxidant enzymes such as catalase, SOD, glutahione, periredoxin, and thioredoxin.   When it comes to nuts, however, few studies have been done so far to specifically look at the epigenetic effects of nuts, since this epigenetic effect of polyphenols is relatively recent research.  The main effects of polyphenols on epigenetics has to do with their anti-cancer effects (not their cardiovascular effects).  Thus it is probably the epigenetic effects of the polyphenols found in nuts that confers the 55% reduction in cancer risk that was seen with the PREDIMED study of mixed nuts in Spain. However based on the epigenetic research from fruits and vegetables, it is likely that the polyphenols in nuts have a similar epigenetic action, since many of the polyphenols found in nuts are on the “same list” of polyphenols that are found in all plants.  However, there may be some uniquely different polyphenols found in nuts that are not found in fruits and vegetables. Here are some polyphenols that are found in high concentrations in nuts:

  • quercetin
  • luteolin
  • eriodictyol
  • rutin
  • naringenin
  • apigenin
  • anthocyanins
  • cyanidin-3-galactoside
  • cyanidin-3-glucoside

References:

Nuts have other unique polyphenols not found in most fruits and vegetables.  Although they have not been studied for their epigenetic effects, these unique polyphenols may be unique HDAC inhibitors or they may affect DNMTs in unique ways.  Here are some unique polyphenols found in walnuts:

1. Hydrolysable tannins –  3 new ellagitannins have been found in walnuts

2. Glansreginins A and Glansreginins B – these are dicarboxylic acid derivatives

reference:  

Nuts, especially walnuts, have both antioxidant quantity and efficacy and exhibit significant potential health benefits (2012)

 General references on “antioxidant” effects of nuts:

Summary:  Both nuts in general and walnuts specifically have a lot of polyphenols in them.  The common polyphenols found in fruits and vegetables are also found in nuts, but there are also unique polyphenols found in nuts that are not found in fruits and vegetables. The include hydrolysable tannins and dicarboxylic acid derivatives (glansreginins A and B).

The most important mechanism of action of polyphenols is probably their effects on epigenetics.  Epigenetics involves the regulation of gene expression.  This is a powerful way that polyphenols can exert their health benefits and is likely the explanation for the anticancer effects of nuts.

3. Phytosterols - Another explanation for the reduction in cholesterol seen with nut consumption

 Phytosterols are similar in structure to cholesterol, having the same cyclopentanoperhydrophenanthrene ring structure, but differ in the side chain at C24 and/or the position and configuration of unsaturated double bonds.          Pistachio nuts and sunflower kernels are the richest in phytosterols .   Phytosterols  interfere with cholesterol absorption in the gut by replacing cholesterol in micelles created with digestion.  This reduces blood cholesterol. Here are some common phytosterols:

  • beta-sitosterol
  • avenasterol
  •  campestanol
  •  campesterol

Reference:   PHYTOSTEROLS IN HUMAN NUTRITION (2002)

 

Phytosterols2

phytosterols1

4. Folic acid

Nuts are a great source of folic acid.  Folic acid is very important for many reasons, including DNA synthesis, epigenetic “single-carbon metabolism”, etc.  It is a very important anti-cancer mechanism of action for nuts.  Folic acid is needed for DNA methylation, which is part of the epigenetic regulation of gene expression.  Thus, both folic acid and polyphenols found in nuts can both contribute to the explanation for the 55% cancer risk reduction seen with nuts.

Reference: Other relevant components of nuts: phytosterols, folate and minerals (2003)

 5.Tocopherols

 Most studies of tocopherols focus on alpha-tocopherol (Vit E).  However nuts have a lot of gamma-tocopherol, which is also a form of vitamin E.  gamma-tocopherol has several uniquely different effects from alpha-tocopherol, including the natriuretic effects.  In general, the main effects of these tocopherols appears to be an “antiatherogenic effect”

References:

6. Hydroxybutyrate – an epigenetic byproduct of dietary fiber fermentation by gut bacteria

 Nuts are a good source of dietary fiber.  Although dietary fiber in of itself has great health benefits for the colon in preventing colon cancer, it was not known until recently that gut bacteria fermented dietary fiber into a compound called sodium hydroxybutyrate.  Fermented dietary fiber is a great source of Sodium Hydroybutyrate.  Sodium Hydroxybutyrate is a very powerful epigenetic compound that inhibits the deacetylation of histone proteins (i.e. called HDAC inhibitors).  There are many different classes of HDAC inhibitors based on which enzyme they inhibit. Sodium hydroxybuturate is a broad spectrum HDAC inhibitor that inhibits most HDACs except the class II and class II HDACs.  HDAC inhibitors can also be classified by their molecular structure. In this classification system, sodium hydroxybutyrate is classified as a “fatty acid type” HDAC Inhibitor and is the most effective “fatty acid inhibitor” in this molecular class.  Sodium hydroxybutyrate has very little toxicity and can be purchased as a supplement very cheaply.  It has been very well studied and is not toxic. Sodium hydroxybutyrate has been studied in many scientific papers where it has been shown to have beneficial effects.   When used in cell culture, it inhibits about 2% of gene deacetylation.  This is an amazing quantitative effect. The reason for this specific, narrow function of sodium hydroxybutryrate may be because there is a “Butyrate response element” found in the promoter regions of many  genes.   Why would evolution create a response element for a fatty acid?  The story gets even more interesting.  There are actually two groups of genes affected by hydroxybutyrate response elements as follows:

a. Repressed genes - with these genes, Na hydroxybutyrate represses transcription via a                               transcription factor that binds to this site in the promoter.

b. Induced genes - with these genes, Na hydroxybutyrate induces transcription via the SAME TRANSCRIPTION FACTOR!   This is another example of the vital importance of a good gut micro biome.  However, I am not sure if the European/Western gut microbiome has bacteria in the colon that can ferment fiber and form Na hydroxybutyrate.  I know that cows can do this.  We have always been told that the major reason for dietary fiber had to do with GI motility, keeping stool soft, and the ability of dietary fiber to bind toxic, carginogenic bile salts.  However, I think all of those “lousy reasons” for taking dietary fiber are pretty weak and not very impressive.  Instead, I really like the idea that our gut micro biome are making an HDAC inhibitor for us that has “co-evolved” in evolution to inhibit the enzymes in our cell nuclei that are implicated in both cancer and aging!   If this is really true, it is an amazing story…….we have co-evolved to develop HDACs that are inhibited by the bacteria that live in our guts!  This is an amazing story of “co-evolution” that has not been told!  Here is the enzyme pocket of the HDAC1 that deacetylates histone lysine acetyl groups.

Reference and image source:    Inhibition of Histone Deacetylase Activity by Butyrate

FIGURE 5 – Schematic representation of histone deacetylase-like protein (HDLP, gray) interactions with trichostatin A (TSA, black) in the crystal structure of an HDAC homolog from the hyperthermophilic bacterium Aquifex aeolicus. HDLP residues are labeled in gray and their counterparts in HDAC1 are indicated in black [adapted with permission from Dr. Nikola P. Pavletich (43)]. Structures of TSA and butyrate are shown. (Nature 401: 188–193, with permission.)”

 Note that the enzyme pocket in this stick figure diagram has TSA in it, but that Na hydroxybutytrate potentially also binds to to the same place (although we don’t know this for sure).  The article suggests that it may bind to the zinc divalent cation in the HDAC enzyme pocket, but it is still unclear, since it is a noncompetitive inhibitor of HDACs, suggesting a non-enzyme pocket mechanism of action.

References:

7. L-arginine => high content of L-arginine => nitric oxide donor (i.e. cardiovascular effects)

Nuts are also a source of l-arginine, a nitric oxide donor, an important signaling molecule that can offer multiple vascular benefits including support of the health of your artery walls by making them more flexible and less prone to blood clots that can block blood flow. “Black walnuts rank highest among America’s domestic nuts, with 1.0 g of L-arginine per 1-oz. serving, according to the U.S. Department of Agriculture. Peanuts rank second with 0.9 g per serving. Almonds have 0.7 g, followed by pine nuts with 0.68 g. English walnuts have 0.64 g per serving, pistachio nuts have 0.62 g and filberts have 0.57 g per 1 oz. Macadamia nuts have 0.39 g per serving and pecans follow with 0.33 g. Brazil nuts and cashews provide 0.6 g of L-arginine per 1-oz. serving(ref)”.

8. Low sodium, high calcium, magnesium, potassium, etc. 

This chart lists mineral, protein and vitamin contents of a number of kinds of nuts and some grains.

 9. Good ratio of omega-3/omega-6  fatty acids (mostly in walnuts)

Of course, it is recognized that most Americans consume an unbalanced diet too high in Omega 6 fatty acids and too low in Omega 3s.  High meat consumption is one of the key factors responsible.  Previously, I commented that with the exception of walnuts, nuts tend not to be very rich in Omega 3s.  However, some of the extra mortality reduction associated with walnut cinsumption could be associated with high Omega 3 levels in these nuts.  See:

10. Selenoproteins

Selenium is a very important trace element that is not found in many grains (Ex: wheat, rice, barley, oats, etc.).  There are 26 proteins that require selenium and these are all critical proteins in immune function.  This could explain nut-consumption respiratory disease risk reduction (pneumonia is the most common respiratory disease) and infection risk reduction (selenium could possibly explain this).

According to the 2011 publication Nutrigenetics, nutrigenomics, and selenium, “Selenium (Se) is an important micronutrient that, as a component of selenoproteins, influences oxidative and inflammatory processes. Its’ levels vary considerably, with different ethnic and geographic population groups showing varied conditions, ranging from frank Se deficiencies to toxic effects. An optimum Se level is essential for the maintenance of homeostasis, and this optimum may vary according to life stage, general state of health, and genotype. Nutrigenetic studies of different Se levels, in the presence of genetic variants in selenoproteins, suggest that an effective dietary Se intake for one individual may be very different from that for others. However, we are just starting to learn the significance of various genes in selenoprotein pathways, functional variants in these, and how to combine such data from genes into pathways, alongside dietary intake or serum levels of Se. Advances in systems biology, genetics, and genomics technologies, including genetic/genomic, epigenetic/epigenomic, transcriptomic, proteomic, and metabolomic information, start to make it feasible to assess a comprehensive spectrum of the biological activity of Se.”

Brazil nuts appears to be the food that contains the highest level of unadulterated selenium.  It is also found in walnuts, hazelnuts, almonds and pistachios.

References:

 Brazilian nut consumption improves selenium status and glutathione peroxidase activity and reduces atherogenic risk in obese women (2012)

Some additional research publications on nuts:

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About James Watson

I am a physician with a keen interest in the molecular biology of aging. I have specific interests in the theories of antagonistic pleiotropy and hormesis as frameworks to understand cellular senescence and mechanisms for coping with cellular stress. The hormetic "stressors" that I am interested in exploiting at low doses include exercise, hypoxia, intermittent caloric restriction, radiation, etc. I also have a very strong interest in the epigenetic theory of aging and pharmacologic/dietary maintenance of histone acetylation and DNA methylation with age. I also am working on pharmacologic methods to destroy senescent cells and to reactivate quiescent endogenous stem cells. In cases where there is a "stem cell exhaustion" in the specific niche, I am very interested in stem cell therapy (Ex: OA)
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3 Responses to Nuts over Nuts

  1. MachineGhost says:

    Did the PREDIMED study look at whether the nuts were raw or roasted? And were any roasted nuts oil-roasted or dry-roasted? Raw nuts are full of anti-nutrients and leaky gut-inducing toxins and oil roasted nuts use toxic Omega-6. The devil is in the details.

    > 1. No cholesterol – This is the Bill Clinton explanation – “It is the lack of
    > cholesterol, stupid!”

    Cute, but the lipid infiltration hypothesis is now over 40-years old and has been discredited, so remotely unlikely to play a role here. Heck, statin therapy isn’t even recommended anymore for high LDL, but it hasn’t stopped the pharmaceutical industry and its three-lettered enforcers from revising guidelines recently so that 70% of currently healthy people would then be put on statins! They are getting more and more desparate to extract as much $ from the scam before it collapses.

    > 2. Phenolic compounds

    You overlooked phytic acid. While it is an anti-nutrient, it has some anti-cancer properties the FDA doesn’t like. As well as chelating too many important macro- and micro- minerals, but also toxic iron and uranium.

    > If this is really true, it is an amazing story…….we have co-evolved to develop
    > HDACs that are inhibited by the bacteria that live in our guts! This is an amazing
    > story of “co-evolution” that has not been told! Here is the enzyme pocket of the
    > HDAC1 that deacetylates histone lysine acetyl groups.

    It is true, but Western diets have very little of the third type of fiber that promotes specific microbiota to digest it into butyrate: resistant starch. It’s the next big thing in health and medicine as well as being the biggest shift in self-perceptions since Darwin’s theory of natural selection (we are 90% microbiota, only 10% mammal and its genes outnumber human’s by 350 to 1, nevermind epigenetic influence!).

    > 9. Good ratio of omega-3/omega-6 fatty acids (mostly in walnuts)

    Nuts universally contain too much toxic Omega-6, except for walnuts. Since Omega-6 is easily oxidized by digestion, heat, light and oxygen rending it toxic and thus oxidizing the LDL cell membrane (the real culprit), it is even more crucial to ferret out raw, oil and dry-roasted intakes as I mentioned earlier. I speculate the Spanish do not eat such massive quantities of toxic Omega-6 fats as SADers do, so a little extra from nuts may not take the dose out of the hormetic range, hence the positive benefits.

  2. peterz54 says:

    Here’s the thing – I haven’t seen one study which compared a control diet and control with nuts, calorie normalized, in which the control diet was a high quality vegan diet with no refined food products, no dairy, etc. heavy on legumes, green vegetables, and included brown rice, berries, fruit, garlic onions, ground flax seed, etc. A diet like this is truly low in fat (<15 %) and nutritionally dense and will drop cardiac disease markers like LDL cholesterol and triglycerides like a rock. Yes adding nuts to a marginal or poor diet would help and the science points to that, but is it optimum, the best we can do?

  3. jz99 says:

    new fullerene article showing further promise: “Liposome Formulation of Fullerene-Based Molecular Diagnostic and Therapeutic Agents.” http://www.ncbi.nlm.nih.gov/pubmed/24300561




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