A recent study revealed the connection between high red meat consumption and an increased risk of colorectal cancer. — SERGEY KOTENEV/Unsplash
In a potentially groundbreaking Singaporean study published in June 2024 and again in October, researchers claim to have uncovered a startling link between iron consumption and colorectal cancer.
This research advanced an explanation for the long-observed connection between red meat intake and increased cancer risk. This discovery not only sheds light on the mechanisms behind one of the world’s most common cancers but also suggests new avenues for prevention and treatment.
The iron-cancer connection
For decades, health professionals have warned about the potential risks of overconsumption of red meat, particularly its association with colorectal cancer. However, the exact mechanisms behind this link remained elusive. Now, a team of scientists at the Institute of Molecular and Cell Biology in Singapore has plausibly identified a crucial piece of the puzzle: iron, specifically the form of iron known as Fe3+.
Colorectal cancer is the third most common cancer worldwide, affecting millions of people each year. While genetic factors play a role, diet and lifestyle have long been suspected to contribute significantly to its development. The new research provides compelling evidence that high levels of iron, particularly in its Fe3+ form, can directly drive the development of colorectal cancer by reactivating a key player in cellular immortality: telomerase.
The immortality enzyme
Telomerase is an enzyme often referred to as the “immortality enzyme” due to its ability to extend the lifespan of cells. It does this by maintaining or elongating the length of “telomeres”, the protective structures at the end of chromosomes. As cells replicate, telomeres tend to drop off the ends of chromosomes after each duplication cycle.
Over time, cells with shortened telomeres eventually cannot replicate themselves and either die off or become senescent (unable to function properly). In normal cells, telomerase is usually inactive. However, in about 90% of cancers, including colorectal cancers, telomerase production is provoked, allowing cancer cells to divide indefinitely.
The researchers found that iron, particularly in its Fe3+ form, can trigger the reactivation of telomerase through a protein called pirin which binds only with Fe3+. This iron-sensing protein acts as a mediator (or switch), which turns on the telomerase engine in cells when presented with high Fe3+ levels, potentially causing cancers. There is more on this later.
Iron absorption
When a human consumes iron-rich foods like red meat, the body absorbs and retains the iron for future use. Excess dietary iron is typically stored, because there is no dedicated mechanism for removing surplus iron from the body. Therefore, in some cases – due to genetic factors, overconsumption, or other health conditions – iron levels in the body can quickly become abnormally high.
Types of dietary iron
At this point, it should be noted that red meat contains iron in the Fe2+ (ferrous) form, known as heme iron. This is not the problematic Fe3+ (ferric) form identified in the Singapore study.
In fact, Fe3+ is the form of iron found in plants, known as non-heme iron, and several large-scale research papers have found that consuming plant-based iron can REDUCE the risk of colorectal cancers by around 20%.
Spinach is a rich plant-based source of iron and should be consumed as part of a healthy diet. — FOTIOS PHOTOS/Pexels
Another statistical finding is that substitution of heme iron from beef with non-heme iron from plant sources like beans reduced colorectal cancer risk by roughly 6% in men for every gram substituted. The density of Fe3+ in plant-based foods is also very much lower than the density of Fe2+ in red meats, around 50% less or lower.
Hence, the prominent role of Fe3+ as a claimed primary causative factor in colorectal cancer is curious. And an explanation may be as follows.
Fe2+ is roughly five times more biologically available for absorption, as it is more reactive than Fe3+ in the gut. As such, Fe2+ is readily converted into Fe3+, and consuming an excess of Fe2+ ferrous iron can result in an overload of Fe3+ ferric iron due to food reduction processes and oxidation in the digestive system.
Such metabolic processes may also cause collateral damage via lipid peroxidation (a process that creates damaging free radicals in cells) and DNA damage due to oxidation. This adjuvant activity may result in the newly created Fe3+ molecules having a bigger influence on pirin and telomerase activation. In normal circumstances, excess Fe3+ iron can be stored in cells as a compound called ferritin, when the molecules can get past the gut.
Pirin interaction
But before conversion of Fe3+ into ferritin by other cells outside the digestive tract, excess Fe3+ iron often interacts with pirin proteins in the cells lining the colon. Pirin, acting as an iron sensor, becomes active in an environment dense with Fe3+ molecules.
Activated pirin competes with a gene activation factor called NFAT1 and they both bind to a gene called FBXW7. By competing with NFAT1, pirin downgrades the normal function of the gene. FBXW7 is involved in the production of the E3 ligase enzyme, which is used to promote certain proteins for destruction, such as Sp1.
In an activated pirin environment, FBXW7 function is impaired, allowing more Sp1 to survive and aggregate, eventually triggering the production of a protein called hTERT (human Telomerase Reverse Transcriptase), which is a sub-component of telomerase.
Too much hTERT in cells can ultimately lead to the reactivation of telomerase in them. This appears to be the case with colon cells due to their direct proximity to excess Fe3+ and pirin. With telomerase active, cells that should normally die off continue to divide, potentially giving rise to tumours. This is the interesting and plausible link identified by the researchers in Singapore.
A tale of two tumours
The research team examined fresh tumour samples from 40 colorectal cancer patients. They found a striking correlation: tumours with high Fe3+ iron levels also tended to have high telomerase activity. In fact, 10 out of 11 samples with elevated iron levels also showed increased telomerase activity.
This discovery led the researchers to categorise tumours into two groups: TumourHigh (high Fe3+ iron and high telomerase activity) and “TumourLow” (low iron and low telomerase activity). Further analysis revealed that specific clusters of cells within the TumourHigh samples showed increased activity of genes related to Fe3+ metabolism and telomerase activation.
Other sources of iron overload
While the study highlights the risks associated with high red meat consumption, it is important to note that iron overload can occur from other sources as well. Hereditary hemochromatosis, a genetic disorder that causes the body to absorb too much iron from food, has been linked to higher rates of colorectal cancer.
Additionally, certain dietary supplements and even cooking in old iron pots can contribute to excessive iron intake.
A new treatment?
The identification of this iron-telomerase connection suggests not only a plausible cancer risk, but it also introduces new possibilities for treatment for colorectal cancers. The researchers have also identified an interesting molecule called “SP2509” that can inhibit the pirin-mediated reactivation of telomerase.
If you are curious, SP2509 is a compound which acts as the “reversible inhibitor of lysine-specific demethylase-1” and has been known to selectively induce apoptosis (cell death) in cancer cells. However, the study was interested in SP2509’s ability to reduce the expression of iron metabolism-related proteins, which can elevate telomerase activity in colorectal cells.
In laboratory tests, SP2509 showed promising results in reducing telomerase activity and inhibiting cancer cell growth. While it is still far from being a clinically approved drug, this discovery offers a new route for developing treatments that could potentially work for a range of cancers where telomerase activation plays a crucial role.
Implications for diet and health
Such research underscores the importance of maintaining a balanced diet and monitoring iron intake, especially for individuals with higher risks of colorectal cancer. But it is also crucial to remember that iron is an essential nutrient, vital for many bodily functions including oxygen transport in the blood.
The key takeaway is not to eliminate iron from the diet but to be mindful of overconsumption, particularly of rich Fe2+ sources like red meat which are very dense in iron which metabolises readily into Fe3+.
The paper does not mention it, but it is also possible that the metabolic pathway involved in converting Fe2+ to the Fe3+ form of iron may also have a bearing on cancer outcomes. This is because consumption of plant-based foods which are natively high only in Fe3+ does not increase the risk of colorectal cancer and is actually more likely to be protective against the disease.
People should limit their intake of meat, especially processed meats like sausages. — MALI MAEDER/Pexels
Hence, diversifying iron intake across different types of foods and maintaining a healthier plant-rich diet (with adequate dietary fibre) should help mitigate the risks of excess iron in diets. Some recommendations for iron management are as follows:
• Limiting red meat consumption, particularly processed meats
• Incorporating a variety of plant-based iron sources in the diet
• Regular check-ups and screenings, particularly for those with a family history of colorectal cancer or iron metabolism disorders
• Consulting healthcare provider before taking iron supplements.
A balanced perspective
It is important to view such findings in context. While the link between iron, telomerase, and colorectal cancer is highly significant, cancer development is complex and multifactorial. Idiosyncratic factors such as genetics, diets, environments, physical activity, lifestyle choices, etc, also play hugely important roles in cancer risk.
Such research also emphasises a simple fact: the power to influence health, and reduce negative outcomes, often lies in the everyday choices people make. From the food people eat to lifestyle habits, humans have more control over cancer risk than they probably know.
The views expressed here are entirely the writer’s own.
