The Irony of Iron

Healthy Aging

How iron is killing our cells (aka ferroptosis)

The countdown is on until Simon & Schuster’s March 25th release of The Longevity Nutrient. This book tracks our 20-year scientific journey – starting with an unexpected discovery of C15:0’s health benefits while helping dolphins – which has culminated in a movement to improve global health. And dare we say, humanity?

In this series of Science Says!, we provide a behind-the-scenes science peek relevant to each of the book’s chapters – from surprising dolphin discoveries to longevity molecule must-haves, from how essential fatty acids are discovered to the many ways C15:0 works, from how a newly found nutritional deficiency accelerates aging to how fixing and optimizing our C15:0 levels can slow aging to help us live healthier, longer.

This week, let’s talk about how nutritional C15:0 deficiencies cause fragile cell membranes + renegade iron that leads to ferroptosis, a new cell killer.

A quick disclaimer. We’re about to talk a lot about iron overload. Before diving in, however, it is important to note that iron is essential to our health, and iron deficiencies remain an ongoing problem. As such, it is critical that you work closely with your healthcare provider to understand your iron status.

Suddenly, iron overload is everywhere.

Iron overload is a condition where, just like it sounds, too much iron is deposited into our tissues. During the 1990s, the number of peer-reviewed studies on iron overload started climbing… and continued climbing. The winner for the most papers in a single year on iron overload was last year, with 1,025 papers (see graph below).

So, how relevant is iron overload to our health?

Iron overload can wreak damage throughout our bodies. Here are a few examples.

Our liver. As described by Pinyopornpanish et al., the heart of iron overload is, well, the liver. There are two types of liver iron overload:

• Primary iron overload. Some people have a genetic change that causes their gut to too-readily absorb dietary iron. The result is too much iron in the blood and iron in the tissues. This condition is called hereditary hemochromatosis.
• Secondary iron overload. Increasingly, people are developing secondary, non-hereditary iron overload. One of the fastest emerging conditions is called dysmetabolic iron overload syndrome (DIOS). Sachinidis et al. and Anastasopoulos et al. show how DIOS is closely linked to metabolic syndrome (including insulin resistance), hyperferritinemia, and fatty liver disease.

The bottom line of many of these studies? The greater the iron overload, the more severe the liver disease. As a reminder from one of our recent Science Says! issues, metabolic-dysfunction associated steatotic liver disease (MASLD) is now present in 1 in 3 people globally.

Our gut. Malesza et al. describe how excess iron can increase oxidative stress, inflammation, and impair our microbiome – all at the gut level. A result is the rise in inflammatory bowel diseases.

Our heart. In their review, Ru et al. describe how iron overload impairs mitochondrial function, increases the risk of heart failure, incites inflammation in vessels, and increases oxidation of LDL cholesterol.

Our brains. An increasing number of studies are showing that iron overload can happen in our brains, too. Mohammadi et al. discuss how excess iron can cause oxidative stress, neuroinflammation, and speed up neurodegeneration.

Ferroptosis: an increasing urgency.

We’ve covered ferroptosis before, but it’s well worth covering again. During 2012, Dixon et al. described an entirely new way that our cells are dying: they called it ferroptosis.

We do a deep-dive on ferroptosis in The Longevity Nutrient, but briefly, ferroptosis is caused by:

• Fragile fatty acids in our cell membranes, which increase lipid peroxidation.
• Abnormal free iron deposition in cells.
• Combined lipid peroxidation + free iron deposition, which result in massive reactive oxygen species (ROS), which take down mitochondria and kill cells.

Thanks to over 10,000 peer-reviewed papers since Dixon et al.’s discovery during 2012, and as more recently reviewed by Berndt et al., we now know that ferroptosis accelerates aging and impairs metabolic, heart, and cognitive diseases.

Got it. But what is causing this rise in iron overload and ferroptosis?

Well, that’s been the kabillion dollar question. As we published in the journal Metabolites, a decade of studies show that nutritional C15:0 deficiencies appear to be a primary driver of both iron overload and ferroptosis.

As a stable odd-chain saturated fatty acid, one of C15:0’s core roles is to stabilize our cell membranes. It ends up, if we have C15:0 levels less than 0.2% in our cell membranes, those cells become fragile – including red blood cells. Here’s what the science has shown:

• Low dietary intake of C15:0 results in low C15:0 levels in our cell membranes.
• Low C15:0 levels in our cell membranes result in fragile cells and increased lipid peroxidation.
• When red blood cells become fragile, Kupffer cells in the liver engulf them. Over time, increasing red blood cell corpses result in liver iron overload.
• Combined fragile cell membranes with iron overload results in ferroptosis. You know the rest of the story.

We called this nutritional C15:0 deficiency syndrome, Cellular Fragility Syndrome, which may be affecting as many as 1 in 3 people globally.

So, how does C15:0 help support healthy iron metabolism?

The good thing about nutritional deficiencies (like vitamin C deficiency and scurvy & vitamin D deficiency and rickets)? They are fixable. As described in our Metabolites paper, numerous studies have shown the following:

• C15:0 actively stabilizes red blood cells & supports healthy iron metabolism. C15:0 supplementation has been shown to improve red blood cell stability by as much as 80% and stop liver iron deposition. In a randomized clinical trial, C15:0 supplementation supported healthy red blood cells better than placebo controls.
• C15:0 stops ferroptosis and lowers lipid peroxidation. Studies have shown that C15:0 directly stabilizes cells, lowers lipid peroxidation, and stops ferroptosis.
• Maintaining healthy C15:0 levels translates into maintained metabolic, heart, and liver health. This evidence is provided across numerous large prospective cohort studies.
• C15:0 is clinically proven to treat C15:0 deficiencies and support health. Across two clinical trials, C15:0 supplementation raised C15:0 levels, resulting in improved liver, red blood cell, LDL cholesterol and gut microbiome health.

Thus, C15:0 deficiencies are not only helping to explain why our iron metabolism is out of whack, but we are also finding that C15:0 can fix Cellular Fragility Syndrome and regain healthy iron metabolism.

You can learn more about how the discoveries of ferroptosis, iron overload, and C15:0 deficiencies unfolded, including a giant initial clue from dolphins, in The Longevity Nutrient.