Fragile Red Blood Cells Mess Up Iron Metabolism

Healthy Aging

How fragile red blood cells cause metabolic hyperferritinemia

A few weeks back, we covered a metabolic storm that has been brewing for decades. In this series, we’re sharing the science behind the earliest igniters of metabolic dysfunction. Just as importantly, we are sharing studies supporting how we can take back control of our long-term health. In the last two issues, we shared how aging-related fragile red blood cells can cause whole-body frailty, and how too much iron can burden our metabolism. As the last part of this series, we’re covering how those fragile red blood cells actually cause imbalanced iron… and the condition now called metabolic hyperferritinemia.

Let’s start with the life of a normal red blood cell (that’s RBC, to you and me).

As covered previously, the primary role of RBCs is to deliver oxygen to tissues throughout our body. When happy, these cells live a good life of about 120 days. As reviewed by Korolnek et al., here’s how their life is typically spent:

• RBCs are born in our bone marrow. When we need more oxygen, our kidneys release a hormone called erythropoietin (aka, EPO). EPO tells “nursing” macrophages in our bone marrow to help make more RBCs. The youngest RBCs have a nucleus, but this nucleus gets swapped out for hemoglobin – the ultimate oxygen carrier.
• RBCs go to work. Once in the blood stream, adult RBCs spend their life picking up and delivering oxygen. Over time, RBCs become increasingly fragile and eventually retire.
• RBCs are recycled. When RBCs get too fragile, they are engulfed (yes, eaten) by macrophages. This includes special macrophages in the liver called Kupffer cells. Iron is sent back to the bone marrow to make more RBCs, amino acids are used to make more cells, and heme becomes bilirubin, which our liver kicks out into urine or our stool.

So, our bodies have a very efficient way of ensuring an ongoing supply of fresh and functioning RBCs to keep our tissues – from our feet to our hearts to our brains – well oxygenated. How efficient? Korolnek et al. share that about 2 million senescent RBCs are recycled each second. Wow.

How too many fragile RBCs  →  imbalanced iron  → ferroptosis.

If we have too many fragile RBCs, however, this puts the system above under stress.

While macrophages, including Kupffer cells, have special antioxidant powers that help protect them against damage from iron, there is a breaking point. As described by Recalcati et al., if there are too many fragile RBCs, this results in increased engulfment of RBCs. In turn, this high iron overwhelms the Kupffer cells’ natural defenses. The outcome? Ferroptosis, a new form of cell death.

As a reminder, ferroptosis was first discovered by Dixon et al. in 2012. Ferroptosis is described as follows:

• Fragile fatty acids in the cell membrane result in lipid peroxidation (aka oxidative stress).
• Lipid peroxidation combines with aberrant intracellular iron, resulting in massive production of reactive oxygen species (ROS).
• ROS attack the mitochondria, which kills the cellular energy supply… and the cells.

Today, there are over 20,000 peer-reviewed papers on ferroptosis. That’s a lot of papers. We now know that ferroptosis accelerates aging, speeds up the onset and progression of aging-related breakdown, and compromises metabolic, liver, heart, and cognitive function.

Summing it up: From fragile RBCs to metabolic hyperferritinemia.

To sum it all up, too many fragile fatty acids (defined as polyunsaturated fatty acids by Recalcati et al.) in cell membranes result in fragile cells, including RBCs. When we have too many fragile RBCs, this overwhelms the liver’s Kupffer cells, resulting in excess iron storage, ferroptosis, and accelerated aging – including our metabolism.

This is how fragile RBCs kick off iron imbalance and a metabolic storm, now called metabolic hyperferritinemia. As a reminder, metabolic hyperferritinemia is a condition formally defined in Nature’s 2023 consensus statement by Valenti et al. Subsequently, Gensluckner et al.’s study showed that approximately 1 in 10 people in a general population study had metabolic ferritinemia. Understanding all this, the next question is, what’s causing an increase in fragile RBCs?