The researchers carefully controlled for intakes of total energy, whole grains, fruits, and vegetables; age; body mass index; race (white or nonwhite); smoking status; alcohol intake; physical activity level; multivitamin use; aspirin use; family history of diabetes mellitus, myocardial infarction, or cancer; and baseline history of diabetes mellitus, hypertension, or hypercholesterolemia. In women, they also adjusted the data for postmenopausal status and menopausal hormone use.
Some in the cattle industry have questioned the validity of the food frequency questionnaires used in this type of study (here). The authors of the study responded:
"However, all the questionnaires used in this study have been validated against multiple-day food records—at least 14 days during a year—and have been found to be acceptable in terms of validation and reproducibility.
"Second, although there [are individual] day-to-day variations in food consumption, people are generally eating in a pattern that can be captured by the questionnaire. We were interested in between-person variation[s], and we were comparing people who eat a high amount of red meat to those who eat a low amount of red meat. Because we repeated the measurements every four years, the cumulative average used in the analysis represents a long-term dietary pattern. That is a strength of this study, because many other studies may have only a single measure at baseline.
"Last, but most importantly, the measurement error generally tends to attenuate the association, and if we corrected the measurement error using some statistical methods, the associations were much stronger!" [emphasis added]
Some have responded to this by claiming that "correlation doesn't equal causation" (as if the Harvard researchers don't realize this), or that the results only apply to consumption of conventional meat, not grass-finished.
Such a response ignores two important facts:
1) This study is only one among hundreds finding an association between red meat consumption and increased mortality from heart disease and cancer.
2) Basic research has shown that these hazards arise from components that occur in meat from grass-fed animals at levels equal to or greater than levels found in meat from grain-fed animals.
The following provide examples of the large number of studies finding positive associations between consumption of red meat and adverse health outcomes:
Meat consumption and colorectal cancer risk: Dose-response meta-analysis of epidemiological studies
Meat consumption and risk of colorectal cancer: A meta-analysis of prospective studies
Processed meat consumption and stomach cancer risk meta-analysis
Meat consumption and the risk of type 2 diabetes meta-analysis
Meat consumption and prostate cancer risk
Thus, this new study is not some isolated, rare, unusual finding. It resonates with a large body of corroborating epidemiological evidence finding a positive association between red meat consumption and risk of or mortality from disease. It adds to that growing body of evidence.
Of course, "correlation does not prove causation," so some scientists have taken the next step required, doing research to find out if there are any plausible mechanisms by which consumption of meat could increase the risk of mortality.
So far, researchers have found that a number of components of red meat have biological effects providing plausible mechanisms by which diets rich in meat could increase the risk of chronic diseases and mortality. The suspect components include animal protein, cholesterol, arachidonic acid, heme iron, and Neu5Cg sialic acid, all of which naturally occur in red meat. Further, the concentration of these components of meat is not markedly affected by feeding or pharmaceutical strategy used in raising the animals; meat from grass-fattened animals has practically the same amount of these components as meat from grain-fattened animals.
Animal protein typically forms a larger proportion of lean grass-fed than conventional fatty meat, and promotes increases in IGF-1 levels, which appears involved in promotion of breast, colon, and prostate cancers.
High animal protein intake raises serum IGF-1 levels. [Full text]
IGF-1 has roles in growth promotion and carcinogenesis. [Abstract]
Elevated IGF-1 levels were associated with a 49% increased risk of prostate cancer and a 65% increased risk of premenopausal breast cancer. [Abstract]
Elevated IGF-1 levels are associated with increased risk of prostate cancer, lung cancer, colorectal cancer, and premenopausal breast cancer. [Abstract]
Starting with a zero cholesterol diet, adding small increments of dietary cholesterol raises serum cholesterol levels, in a dose-response fashion.[Full text]
Elevated serum cholesterol increases the risk for cardiovascular disease. [National Cholesterol Education Program]
Elevated serum cholesterol increases risk of ischemic stroke in the general Japanese population.[Abstract]
Mice fed a high fat, high cholesterol diet and showing elevated serum cholesterol have increased mammary tumor growth and metastases compared to controls. [Abstract]
Emerging evidence indicates that oxidized cholesterol plays an important role in the angiogenesis process that supports tumor growth. [Abstract]
The more unnecessary LDL cholesterol in the blood, the more likely there will be oxidized cholesterol in the blood.
Individuals with elevated serum cholesterol found to have a 35% increased prostate cancer risk.[Abstract]
Cholesterol-depletion of breast and prostate cancer cell lines induces apoptosis whereas cholesterol-enrichment via elevated serum cholesterol (due to diet) supports tumor growth and progression.[Abstract, Full Text]
Elevated LDL positively correlates with increased risk of advanced stage colon cancer.[Abstract]
Patients with colon adenomas, the precursors of colon cancer, have elevated LDL.[Abstract]
Patients with distant metastases of colorectal cancer have significantly elevated serum cholesterol levels compared to those without metastases. "Elevated serum lipid levels may facilitate the development of distant metastasis in CRC [colorectal cancer] patients."[Abstract]
Heme Iron, Arachidonic Acid, HCAs, PHAs, and Neu5Gc
Heme iron, a form of iron found at the highest levels in red meats. I discussed some of the evidence linking iron intake and levels to inflammatory diseases (including heart disease and cancer) in this post.
Arachidonic acid, which occurs in meat from grass-fed animals at levels equal to or greater than found in meat from grain-fed animals, and is involved in cancer promotion, which I discussed in this post.
Neu5Gc, a type of sialic acid produced by non-human mammals but not by humans, which enters humans through consumption of mammalian meat and milk, is incorporated into epithelial and endothelial tissues, incites an auto-immune response and inflammation in those tissues, and has been found concentrated in malignant tumors (full text).
Of interest, this paper on Neu5Gc includes the following passage:
"Although earlier studies claimed the absence of Neu5Gc from normal human tissues, we showed thatit is also present in smaller amounts in normal human epithelial and endothelial cells in vivo (Tangvoranuntakul et al. 2003). Furthermore, we recently demonstrated that mice with a human-likedefect in the CMAH gene had no detectable Neu5Gc (Hedlund et al. 2007), effectively ruling out an alternate mammalian pathway for synthesis. This paradox is explained by our finding that humans can metabolically incorporate Neu5Gc via oral intake (Tangvoranuntakul et al. 2003). We have therefore suggested that the well-known epidemiological association of human cancers with consumption of red meat and milk (which happen to be the richest dietary sources of Neu5Gc) (Rose et al. 1986; Norat et al. 2002; Lewin et al. 2006) might be related to this unusual metabolic accumulation. Here, we have demonstrated another required component for this hypothesis – circulating antibodies that can recognize Neu5Gc on human tissues and can potentially generate chronic inflammation. To our knowledge, this is the first example wherein a nonhuman molecule becomes metabolically and covalently incorporated onto human cell surfaces, even in the face of an immune response against it. Further studies are needed to firmly establish a link between Neu5Gc expression in tumors and anti-Neu5Gc in the pathogenesis of carcinomas."[emphasis added]This passage illustrates that the epidemiological association of human cancers with consumption of red meat and milk is "well-known" among scientists and that they have moved beyond questioning the association (since it is scientifically well established) to elucidating the mechanisms responsible for this association, in this case Neu5Gc, the first nonhuman molecule proven to become part of human cell surfaces despite an immune response against it.
I first learned about Neu5Gc from this video by Plant Positive:
Cooking meat at high temperatures, particularly over open flames, produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) which are carcinogenic. These will form in meat cooked at high temperatures regardless of how the source animal was fed. The National Cancer Institute says "numerous epidemiologic studies have used detailed questionnaires to examine participants’ meat consumption and meat cooking methods to estimate HCA and PAH exposures. Researchers found that high consumption of well-done, fried, or barbecued meats was associated with increased risks of colorectal (14), pancreatic (15, 16), and prostate (17, 18) cancer."
Protein, cholesterol, iron, arachidonic acid, and Neu5Gc all occur naturally in meat, and HCAs and PAHs form in meat cooked at high temperatures, regardless of the feeding or pharmaceutical strategy used to raise the animals from which the meat is taken.
The studies I cited above only provide a small sampling of the laboratory data providing evidence of plausible mechanisms by which an excessive consumption of meat could increase one's risk of mortality. Epidemiological research generated both the lipid hypothesis and the hypothesis that red meat increases mortality risk, but we now have much stronger data to support these hypotheses.
We have evidence for specific mechanisms by which these naturally occuring substances can initiate (HCAs or PAHs) or promote (protein, cholesterol, iron, arachidonic acid, and Neu5Gc) fatal diseases, so only someone ignoring or ignorant of the above data could argue that the association of increased risks of mortality from cancer and heart disease apply only to people eating meat from grain-fed or drug-treated animals, or that the epidemiological associations have no plausible physiological basis.