An interesting research paper published on 17 June 2021 indicates there is a demonstrable link between consumption of red meat and incidences of colorectal cancer. This is not a new story, by the way, as the International Agency for Research on Cancer had already determined back in 2015 that processed meat was carcinogenic and red meat was probably carcinogenic to humans.
However, the way the mechanistic connection between red meat and colorectal cancer was established recently was a compelling read. In short, the research determined there is “an alkylating mutational signature in (cancerous) colon cells” which is directly linked to “red meat consumption and cancer driver mutations”.
Alkylation
The paper ‘Discovery and features of an alkylating signature in colorectal cancer’ was the result of a collaboration of several international institutes led by the Medical Oncology department of the Dana-Farber Cancer Institute and Harvard Medical School, USA.
It was a longitudinal study over many years covering 238, 130 women and 51, 529 men who repeatedly provided data on their diets, lifestyles, and other factors. To understand what a longitudinal study means, refer to my previous article A Diet of Plastics.
Out of the total group of 289, 659 women and men, there were 4, 855 cases of colorectal carcinoma (CRC) detected over the years of which 900 cases were examined in detail for genetic mutations. A common alkylating pattern was found in these cases affecting the genes known as KRAS p.G12D, KRAS p.G13D, and PIK3CA p.E5454K.
How these mutations occur is curious and one cause seems to be related to damage caused to an enzyme called O6-methylguanine-DNA methyltransferase (MGMT). MGMT is known as a DNA “suicide” repair enzyme, able to prevent gene mutation, cell death and formation of tumours due to alkylating agents.
It appeared that certain compounds in red meat (and processed meats) methylates MGMT (by substitution of certain atoms in MGMT by a CH3 methyl group of molecules) which causes the deactivation of normal MGMT functions.
Methylation is the most common type of alkylation, which is defined as the substitution of cell molecules by alkyl groups such as free radicals obtained from diets or the environment.
The inactivation of MGMT alone may not explain fully the role of red meat in CRC. The alkylation damage due to red meat is relatively small compared to other natural mutational processes. However, such small alkylation effects may end up having a higher carcinogenic potential because of the sensitivity of the target genes, i.e., KRAS and PIK3CA.
It is still unclear which compounds in red meat causes such alkylation effects. The most likely candidates are metabolites (by-products arising from digestion) called nitroso-compounds (NOC). Related NOCs such as nitrosamines are known to be significantly carcinogenic in test mammals and humans, and usually arise from eating processed meats treated with nitrites.
Depending on the circumstances, nitrosylation can also affect enzyme activity, including MGMT. This in turn allows alkylation in cells to happen more frequently, with post-digested alkylated cells passing further through the digestive tract.
The higher incidence of CRCs found near the rectum may be the result of more contact by colon tissue with alkylated cells stored as faeces in the distal colon (lower portion of the large intestine). It is suggested that although alkylation started earlier in the dietary tract, the movement of digested red meats through the intestine means that alkylated cells end up concentrated in the distal colon where they had the most impact on colorectal tissue due to constant contact.
The signature pattern of alkylated tumour genes found in CRCs appeared to be limited to people with a high consumption of red meats. No such alkylating signatures were found for people who consumed poultry or fish or have other lifestyle factors (such as high BMI, smoking, alcohol consumption or lack of activity). Curiously, no other significant mutational processes were associated with red meat; CRC patients appeared to only have alkylated cell damage.
Therefore, one would assume the level of alkylating cell damage would be an indicator for CRC, and indeed people with the highest levels of alkylating damage had a 47% greater risk of dying from CRC. As such, it was proposed that the identification of people who are genetically prone to acquiring alkylating damage may be helpful to prevent the onset of CRC via adjustments to their diets.
To put things into context, the lifetime risk of developing CRC is around 4% in the USA and is the third leading cause of cancer-related deaths. However, the number of deaths from CRC amongst people under the age of 55 has increased by 1% per year from 2008 to 2017 (where the data stopped). The evidence suggests diets may have had an impact in such an unusual persistent pattern of incremental deaths from CRC amongst younger people.
Other non-CRC curiosities
There are also often many media stories about how there is “no harm” in certain foods, based on research which are often skewed by the heavy presence of younger people in the studies. However, I am of an age (along with many people) where sensible dietary practices can make a significant improvement to well-being and life expectancy.
As an example, in the American Association of Retired Persons Diet and Health Study, an analysis of 416, 104 men and women found that substituting plant-based protein in place of animal protein for only 3% of calorie intake resulted in a 10% reduction in mortality.
Curiously, substituting plant protein for egg protein reduced cardiovascular risks by over 20% and replacing meat proteins by plant proteins cut the same risks by over 13%. More on this later.
The data is quite clear though, whatever the media say. Many similar studies had arrived at roughly the same positive findings regarding the consistent role of plant proteins in promoting general health and reduced mortality rates.
Covid-19 diets
Furthermore, a small 2020 international study conducted by Stamford Hospital in the USA on just under 3, 000 healthcare workers found that people following pescatarian-based and plant-based diets had respectively 59% and 73% lower risk of moderate-to-severe reactions to a Covid-19 infection.
In contrast, people on low-carbohydrate, high protein diets (e.g. keto diet) were estimated to have a 48% higher probability of moderate-to-severe reactions to a Covid-19 infection.
However, the data probably also indicated that a varied diet may be a significant factor. People who eat more plant-based and pescatarian-based diets often consume a wide variety of other foods such as fruits, nuts, and vegetables. And people on low-carb diets also tend to eat a lot of meat.
How such diets affect human responses to Covid-19 has not been established but it may be due to less inflammation in diets containing less animal protein.
Harmful constituents?
Regarding meat, a plausible hypothesis centres around carnitine. Red meat has four times as much carnitine as white meat, and carnitine can be processed by gut bacteria into TMAO. Furthermore, the digestion of meat, in particular red meat, can result in gut intestinal-generated toxic metabolites such as p-cresylsulfate, hippuric acid, indoxyl sulfate, p-cresylglucuronide, phenylacetylglutamine, and phenylsulfate.
They are produced from the decomposition of amino acids within meat proteins, so consumption of animal flesh raises their presence in blood plasma. These compounds then need to be filtered out by the kidneys.
Hence, overall health is strongly correlated with a good renal system. Sadly, kidney function declines with age and by age 80, the kidneys have a glomerular filtration rate (GFR) of around 60 mL/min or less, down from 90-120 mL/min for young adults. A decrease in GFR appears to be a function of aging, with GFR declining by 10 mL/min per decade of life.
This means the ability to excrete such metabolites declines significantly as one ages, resulting in such toxic compounds circulating in the body for longer thereby increasing the potential for causing harm to various organs.
Therefore, data suggests it would be a good idea to cut down on eggs and red meat to compensate for declining renal function as one gets older.
The views expressed here are entirely the writer’s own.
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