If you haven’t heard about it by now, a new paper was released this week looking at the link between carnitine, gut bacteria, a molecule called TMAO, and atherosclerosis. The multi-part study was performed by researchers at the Cleveland Clinic, among other places, and was reported in the New York Times, Culprit in Heart Disease Goes Beyond Meat’s Fat, and today’s episode of Science Friday, Red Meat’s Heart Risk Goes Beyond the Fat (1).
The Science Friday episode is 13 minutes long and is a good overview of the research, though I will go over it here briefly.
Carnitine is an amino acid (but not a protein amino acid) that is used by the body to transport fatty acids into the cell’s mitochondria to be burned as energy. For this reason, there have been many trials of carnitine supplementation with hopes that it could increase fat loss and related conditions. The trails have been mixed (1). In food, carnitine is found in the highest amounts in beef (56-162 mg per 4 oz serving according to the NIH), while other foods have much lower amounts (a chicken breast has only 3-5 mg per 4 oz).
While humans can produce carnitine, and most people can produce all they need, only bacteria can break it down (1). Some bacteria convert carnitine into a molecule called trimethylamine (TMA) and when this happens, the liver converts TMA to trimethylamine-N-oxide (TMAO).
In 2011, in the VeganHealth.org article, Choline, I reported on a study by this same group of researchers that indicated that the metabolism of choline, by gut bacteria and then the liver, results in TMAO. The researchers found that high blood levels of TMAO were associated with cardiovascular disease.
This time, they studied carnitine rather than choline, and they came to a similar conclusions. They also found that vegetarians do not have the bacteria in their guts needed to produce TMAO out of carnitine; not that this really matters given that we eat little to no carnitine.
Based on their studies using mice , the researchers believe that TMAO prevents the metabolism of cholesterol by the liver and diverts it to the blood vessels where it becomes plaque.
In my series Of Meat and Mortality, I did not mention that the Harvard study found that saturated fat and cholesterol in red meat only moderately accounted for the increase in cardiovascular disease associated with red meat. This theory about TMAO causing heart disease might explain the finding by Harvard and also help explain why poultry has not had an association with mortality from cardiovascular disease while red meat has.
This is not the final word on carnitine and heart disease and it will be interesting to see what future research shows.
1. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 Apr 7. doi: 10.1038/nm.3145. [Epub ahead of print] | link
Of Meat and Mortality – Part 4 is a review of the results from a study combining the data on 37,698 men from of the Health Professionals Follow-up Study (1986-2008) and 83,644 women from the Nurses’ Health Study (1980-2008). This study was conducted by the Harvard School of Public Health and published one year ago (1).
There were some benefits this study had over the others. The inclusion criteria was a bit more stringent (you could not have had angina or a heart attack compared to just not having had a heart attack in the other studies (2)), the follow-up was long (22-28 years, the other studies either had much shorter follow-up or much less people to follow), and they assessed the diet regularly over time. Since they were all health professionals, it minimized income and lifestyle disparities.
The intake amount categories were divided into fifths, with the largest being about 2 servings per day for both men and women (unprocessed plus processed red meat).
They only reported two models: age-adjusted-only and multivariate. Once again, their multivariate model contained adjustments that likely interacted with red meat’s effect on mortality: history of diabetes, hypertension, or hypercholesterolemia, and energy intake. Even so, unprocessed red meat was associated with increased mortality (1.36, 1.25-1.47) as was processed red meat (1.27, 1.18-1.38). When men and women were separated, the findings held. The results also held for cardiovascular disease (no surprise) and for cancer (not a huge surprise, but the association was weaker).
The authors said:
“Compared with red meat, other dietary components, such as fish, poultry, nuts, legumes, low-fat dairy products, and whole grains, were associated with lower risk. These results indicate that replacement of red meat with alternative healthy dietary components may lower the mortality risk.”
Conclusion Of Meat and Mortality
Let’s sum up the 4 studies:
EPIC (3) – Large study, highest red meat intake category was about 2 servings per day, processed red meat was strongly associated with mortality, unprocessed was associated with mortality in the model that did not adjust for body mass index (BMI), removing first 2 years of follow-up didn’t change results.
NHANES (4) – Small but long study, highest intake category was roughly 1.5 times per day, unprocessed and processed meat was strongly associated with mortality until results were adjusted for many variables which could be influenced by red meat, strong reason to believe people in the lowest intake category had cut down on red meat due to previous disease.
Shanghai (5) – Only “red” meat was pork and very little processed meat, highest intake category was about 1 serving per day, red meat intake was positively associated with total mortality among men but not among women, results were likely adjusted for conditions that could be affected by red meat intake.
Harvard (1) – Highest quality study, largest intake category was 2 servings of red meat per day, red and processed meat strongly associated with mortality in both men and women even after adjusting for many factors that could be influenced by red meat intake.
My conclusion is that eating two servings of red meat per day mostly likely increases the risk of early death over eating a half serving or less, and especially if it’s processed. To be more certain, a model is needed that does not adjust for any of the factors that red meat likely influences while adjusting for all those that it doesn’t.
That said, it’s not a slam dunk and I’d rather people were eating cows and pigs than birds (because it takes so many more birds to produce the same amount of meat) so I don’t necessarily consider this good news.
My vote is for people to replace the red meat in their diet with legumes and nuts!
1. Pan A, Sun Q, Bernstein AM, Schulze MB, Manson JE, Stampfer MJ, Willett WC, Hu FB. Red meat consumption and mortality: results from 2 prospective cohort studies. Arch Intern Med. 2012 Apr 9;172(7):555-63. | link
2. van Dam RM, Willett WC, Rimm EB, Stampfer MJ, Hu FB. Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care. 2002 Mar;25(3):417-24. | link
3. Rohrmann S, et al. Meat consumption and mortality – results from the European Prospective Investigation into Cancer and Nutrition. BMC Med. 2013 Mar 7;11:63. | link
4. Kappeler R, Eichholzer M, Rohrmann S. Meat consumption and diet quality and mortality in NHANES III. Eur J Clin Nutr. 2013 Mar 13. | link
5. Takata Y, Shu X-O, Gao Y-T, Li H, Zhang X, et al.Red Meat and Poultry Intakes and Risk of Total and Cause-Specific Mortality: Results from Cohort Studies of Chinese Adults in Shanghai. PLoS ONE. 2013 Feb 18;8(2):e56963. doi:10.1371/journal.pone.0056963 | link
Part 3 of Meat and Mortality is a review of a study from China. Not “The China Study”, but “a China study.”
If you read Part 2: NHANES when it first came out, I have updated it as of April 10 2013, to reflect that the meat intake categories were times per month not per week (only partially my fault as they listed them as “per week” in Table 2) and some further analysis making a strong argument that there was reverse causation in which people with prior disease had changed their red meat intake habits before the study began.
Now, on to Part 3: A China Study –
This prospective cohort study included 73,162 women taking part in the Shanghai Women’s Health Study and 61,128 men from the Shanghai Men’s Health Study. These numbers make it much larger than NHANES and only about 1/4 as large as EPIC.
The meat intake groups were divided into fifths, with the lowest category eating 17 g for women and 21 g for men (less than 1 oz) and the highest category eating 103 g (3.6 oz) for women and 126 g (4.4 oz) for men. The highest red meat intake categories were even less than what was seen in EPIC.
The authors summarize the results:
“[W]e found that red meat intake was positively associated with total mortality among men, but not among women. This discrepant association was also observed for lung cancer mortality. Further, red meat intake was positively associated with the risk of ischemic heart disease mortality, which was statistically significant among men. In contrast, red meat intake was inversely associated with the risk of hemorrhagic stroke mortality, which was statistically significant among women. Among men, the positive association between red meat intake and total mortality was significant in the low-income group, but no association was observed in the high-income group….”
The finding that red meat prevents hemorrhagic stroke (caused by bleeding in the brain) is not surprising, as higher rates of hemorrhagic stroke have consistently been found with low cholesterol levels. The thinking has always been that the risk of dying of a high-cholesterol-related diseases is so much greater than the risk of dying of hemorrhagic stroke that you’re better off with low cholesterol levels.
No statistically significant associations were found for poultry intake.
In addition to adjusting for the typical variables (age, smoking, alcohol, fruit and vegetable intake, etc), they adjusted the results for total caloric intake and a comorbidity index, thus raising the possiiblity that they wiped out any effect red meat might have had on mortality due to causing a higher caloric intake or previous disease.
The reason for the difference between the men and women might be that a much higher percentage of men than women smoke in China, 70% vs. 3%, which could cause confounding despite the attempt to adjust for smoking. The authors also thought that perhaps iron-deficiency in the women protected them from iron overload that could be caused by red meat.
The Chinese eat very little processed meat and the red meat they eat comes mostly from pigs (very few cows). I’m not sure if this matters, but thought it worth noting.
In summary, it’s too bad that these studies do not start out with a healthy population and do not provide a model not adjusted for conditions that red meat might effect.
Part 4 coming up…
1. Takata Y, Shu X-O, Gao Y-T, Li H, Zhang X, et al.Red Meat and Poultry Intakes and Risk of Total and Cause-Specific Mortality: Results from Cohort Studies of Chinese Adults in Shanghai. PLoS ONE. 2013 Feb 18;8(2):e56963. doi:10.1371/journal.pone.0056963 | link
The second study comes from the National Health and Nutrition Examination Survey (NHANES) III. NHANES is a nutrition survey that is done every few years in the USA to see how the nation is eating (1). For this arm of the study, about 17,500 people were included, a number dwarfed by the over 448,000 people in the EPIC study reviewed in Part 1.
I was particularly interested in this study because I thought the meat intake categories would be much higher than in EPIC. That is not the case, as the highest red meat intake category was ≥ 45 times per month, which comes to about 1.5 times per day, as compared to about 2 servings per day in EPIC.
In the model that adjusted only for age, sex and ethnicity, high red meat and processed meat consumption was significantly associated with increased total mortality (red meat: 1.57, 1.07–2.30; processed meat: 1.27, 1.06–1.54). However, in the fully adjusted model there were no statistically significant associations for red meat, processed meat, or fish consumption with total mortality.
In the fully adjusted model, they adjusted for smoking, alcohol, physical activity, socioeconomic status, marital status, fruit and vegetables, use of aspirin and ibuprofen, hormone replacement therapy, oral contraceptives, mineral and vitamin supplements, family history of diabetes and high cholesterol, and – get this – body mass index (BMI), history of hypertension, diabetes, and hypercholesterolemia (high cholesterol).
Adjusting for these last few items would remove any association with mortality for meat if meat causes death through increasing BMI, raising blood pressure, increasing diabetes risk, or increasing cholesterol – the very things considered to be how meat would cause an increase in mortality.
But even more odd is that had they run such a model, it might have shown that more red meat decreases mortality. As red meat intake went from ≤ 6 times per month to over 45 times per month, BMI went down in men and women, the percentage with a history of high blood pressure went way down in men and women, the percentage with diabetes went way down in men and slightly up in women, and the percentage with high cholesterol went way down in men and women!
In other words, according to this study, adding red meat an extra 40 times per month lowers cholesterol, blood pressure, BMI, and a man’s chance of getting diabetes.
The lowest category of red meat had a fairly large number of participants (18% for men, 28% for women), whereas eating red meat ≥ 45 times per month had very few (3.3% for men, 1.4% for women). And except for BMI, that lowest category is where there is a high level of those diseases mentioned above.
It seems to me that there must be some sort of reverse causation going on here where the people with those diseases were eating less red meat in response to having those diseases and then dying sooner. It’s interesting to note that the low red meat eaters were not likely to eat more poultry.
This underlines the benefit of starting with a population that is free of disease for a prospective study.
I have tried to steer clear of writing about papers comparing high meat intakes to low meat intakes and the association with various diseases because there is no end to the flow of these studies and I don’t find them particularly relevant to vegan nutrition. But there have been quite a few papers released on meat and mortality recently and people, including myself, are feeling a bit confused.
So I have decided to review some of these papers in blog posts, one at a time, until it no longer seems useful to continue. Here is the first one…
The European Prospective Investigation into Cancer and Nutrition (EPIC) released a study in March looking at the association with mortality of red meat, processed meat, and poultry (1). There were 448,568 participants from 10 European countries, followed for a median of 12.7 years.
The highest intake categories were ≥ 160 g (5.6 oz) per day for red meat and processed meat, and ≥ 80 g (2.8 oz) per day for poultry. A serving of meat in the U.S. is considered to be 3 oz which is about the size of a deck of cards. The comparison categories were 10 to 19.9 g for red and processed meat, and 5 to 9.9 g for poultry (in other words, not much).
They looked at the data in a number of different ways, adjusting results for age, gender, education, body weight and height, total energy intake, alcohol consumption, physical activity, smoking status and duration, and intake of the other meat intake categories.
After all was said and done, processed meat was associated fairly strongly with all-cause mortality. Processed meat intake was also associated with dying from cardiovascular disease and dying from cancer.
Red meat and poultry were neutral in the fully adjusted models, though red meat had some trends towards increased mortality and poultry had some trends towards decreased.
Adjusting for fruit and vegetable intake didn’t affect the results nor did removing the first two years of follow-up.
The body mass index (BMI) of the participants in the highest red meat category was higher than in the rest of the categories combined (27.0 vs. 24.4 for men, 24.8 vs. 22.9 for women). There was a similar difference in BMI for poultry categories. So it seems reasonable that if they had not adjusted for body weight and height there might have been more of an association for red meat.
But what would cause a higher BMI for those who eat more red meat (or poultry)? That would most likely be explained by a higher energy intake. However, they did perform a model where they removed the energy adjustment and it didn’t affect the results. That said, in the basic model adjusting only for age, gender, and study center, they found a strong association with red meat (1.37, 1.23-1.54), so I’m not fully convinced that removing the body weight/height adjustments would not have produced a strong association with increased mortality for red meat.
On the other hand, recent studies have not found such a strong association between a BMI less than 30 and increased mortality, so perhaps this isn’t a good line of reasoning. I have written the lead author to ask about this.
Why would processed meat be so much worse than red meat or poultry? According to the authors:
• Processed meat has a higher saturated fat and cholesterol content.
• Processed meat is treated by salting, curing, or smoking which leads to more carcinogens and precursors to carcinogens.
I will add that processed meat is also higher in sodium (which has been in the news quite a bit lately as being linked with increased mortality).
The authors declared no conflicts of interest.
Other than my question about the body weight adjustments, my remaining question is whether the meat intake categories in this study were too low to detect more of an effect for red meat or poultry. Certainly, there must be a point at which eating too much red meat has to be bad – one would think.
Or, on the other hand, maybe these meat intakes are entirely too high! Some will point out that, of course, people who eat a standard American diet (or European diet in this case), but a little less or a little more poultry or red meat, aren’t going to have much different mortality outcomes. But people who eat a whole-foods-only, low-fat vegan diet will definitely have better health outcomes. They just cannot be measured in a study like this.
Perhaps. Stay tuned…
1. Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, Tjønneland A, Nailler L, Boutron-Ruault MC, Clavel-Chapelon F, Krogh V, Palli D, Panico S, Tumino R, Ricceri F, Bergmann MM, Boeing H, Li K, Kaaks R, Khaw KT, Wareham NJ, Crowe FL, Key TJ, Naska A, Trichopoulou A, Trichopoulos D, Leenders M, Peeters PH, Engeset D, Parr CL, Skeie G, Jakszyn P, Sánchez MJ, Huerta JM, Redondo ML, Barricarte A, Amiano P, Drake I, Sonestedt E, Hallmans G, Johansson I, Fedirko V, Romieux I, Ferrari P, Norat T, Vergnaud AC, Riboli E, Linseisen AJ. Meat consumption and mortality – results from the European Prospective Investigation into Cancer and Nutrition. BMC Med. 2013 Mar 7;11:63. | link
In March of 2012, a vegan woman wrote me saying that her serum ferritin levels were 8 ng/ml. The reference range for her laboratory was 10-232 ng/ml. Generally, a healthy level is above 18 ng/ml with levels as low as 12 ng/ml being associated with complete depletion of iron stores.
Instead of supplementing with iron, she:
• Increased beans and spinach from once every two weeks to two to three times a week (yes, she had been eating surprisingly few beans for a vegan)
• Replaced brown rice with quinoa (which has about twice the amount of iron)
• Stopped drinking coffee with meals
• Added a 500 mg vitamin C tablet or an orange to a couple of her high-iron meals a week
She just got her iron tested again and it was 28 ng/ml. A big increase which puts her well above iron deficiency!
1. On p. 8 of the Executive Summary for their 2010 Dietary Reference Intakes for Calcium and Vitamin D, the Institute of Medicine says that they are basing their recommendations on a vitamin D level of 16 to 20 ng/ml of 25(OH)D. I have been using that as the level to indicate adequate vitamin D. But later in the document (p. 14), they talk about ideal levels some more and conclude that less than 20 ng/dl might be potentially too low for some people and therefore they recommend at least 20 ng/ml.
I have changed the levels in my calcium and vitamin D articles to reflect this. (Thanks, Brandon!)
2. In the table of calcium in plant foods, I had listed the wrong amount of calcium in a 1/2 cup serving of “Mustard greens – frozen, cooked, boiled, drained, chopped” as 107 mg. It is actually 76 mg.
I do not take this lightly. A 7-year-old vegan boy from San Diego was found to have vitamin B12 deficiency severe enough to cause neurological problems (1).
In the months before he was admitted, he would engage in obsessive–compulsive behavior, including lining up his toys, repetitive stair climbing, and difficulty concentrating. Eventually he developed a widened gait (i.e., he couldn’t walk normally) and was taken to the hospital. His vitamin B12 level was 109 pg/ml (normal range is above 250 pg/ml).
Luckily, the child made an almost full neurological recovery after two months of vitamin B12 treatment.
The boy was also somewhat malnourished and had previously had teeth extracted due to “poor dentition.”
So where is the progress?
The progress is in the sensitive write-up performed by the researchers who did not disparage the vegan diet for children or try to convince the parents to feed the child animal products. Rather, they pointed out some benefits of a vegan diet for children, while cautioning that it needs fortification with vitamin B12.
Let’s hope this child makes a 100% recovery in both his neurological development and his teeth.
1. Crawford JR, Say D. Vitamin B12 deficiency presenting as acute ataxia. BMJ Case Rep. 2013 Mar 26;2013. | link
She has been told to get 1,200 mg of calcium per day. But if the calcium from greens in only absorbed at less than 50%, does that mean she needs to get a higher amount of calcium in her diet so that she absorbs a full 1,200 mg?
The answer is that dietary recommendations are made knowing that a nutrient is only partially absorbed from the diet. It depends on the nutrient and recommendations are made for each nutrient based on its typical absorption rate.
In extreme cases, such as the calcium from spinach that is absorbed at only about 5%, you would need to make modifications to rely only on spinach or foods with a similar absorption rate. But the recommendations for calcium assume that only about 1/3 is going to be absorbed from the best sources (not sure the exact number the Institute of Medicine uses).
But this is a reason why I never mention getting one’s calcium from legumes or nuts and seeds – when you combine their relatively low amounts of calcium and their low absorption rates, you cannot rely on them for the bulk of your calcium needs. They will supply some, but not nearly enough.
Focus on the greens with higher amounts of calcium that is moderate to highly absorbable, calcium-set tofu, and fortified foods or supplements.