What Happens to Red Blood Cells When They Age?

With an average lifespan of about 120 days, human red blood cells (RBCs) undergo a series of progressive changes that signal their eventual removal from circulation. As red blood cells age, their membranes become more rigid, and their metabolic activity declines, marking them for clearance by specialized immune cells. This natural process, known as erythrocyte senescence, is a vital part of maintaining blood homeostasis.

Quick Summary

As red blood cells age, they experience morphological and biochemical changes, including decreased membrane flexibility and altered surface proteins. These changes tag the cells for removal, primarily in the spleen and liver, by macrophages, a process called erythrophagocytosis, which ensures vital components are recycled.

Key Points

• Loss of Deformability: As red blood cells age, their membranes become more rigid, making it harder for them to squeeze through the narrow blood vessels of the spleen.

• Altered Surface Signals: Aged RBCs develop surface markers, including clustering of the protein Band 3 and exposure of phosphatidylserine, which are recognized by macrophages as signals for destruction.

• Macrophage Clearance: Macrophages in the spleen, liver, and bone marrow engulf and break down senescent red blood cells through a process called erythrophagocytosis.

• Iron Recycling: The iron from the hemoglobin of destroyed red blood cells is salvaged and transported back to the bone marrow for reuse in new red blood cells.

• Bilirubin Excretion: The heme component of hemoglobin is converted into bilirubin, which is processed by the liver and excreted in bile.

• Decreased Metabolic Activity: The absence of a nucleus means red blood cells cannot produce new proteins, leading to a gradual decline in key enzyme activity and energy production.

• Platelet Involvement: Recent research indicates that platelets may also play a role in marking senescent red blood cells for clearance by forming complexes with them.

The Journey of a Red Blood Cell: From Bone Marrow to Senescence

Red blood cells, or erythrocytes, are produced in the bone marrow in a process called erythropoiesis. Once mature, these biconcave, anucleated cells circulate in the bloodstream for roughly 120 days, delivering oxygen to tissues throughout the body. Over their long journey, which involves squeezing through countless capillaries and experiencing mechanical stress, red blood cells accumulate damage that marks them for the end of their life cycle.

Key Changes in Aged Red Blood Cells

Several physical and biochemical modifications occur in RBCs as they age, transforming them from supple, efficient oxygen carriers into damaged, rigid cells ready for removal. These changes collectively signal to the immune system that the cell is ready to be cleared.

• Loss of Membrane Flexibility: A major hallmark of aging is the loss of membrane deformability. This rigidity occurs due to cumulative oxidative damage and changes to the cell's membrane proteins and lipids. The inability to easily change shape makes it difficult for older RBCs to navigate the narrow sinusoids of the spleen, leading to their entrapment and destruction.
• Altered Membrane Proteins: Key proteins on the cell surface, such as Band 3, undergo aggregation and modification over time. This clumping of Band 3 can expose new surface antigens, which are then recognized by naturally occurring auto-antibodies (immunoglobulin G or IgG). The binding of IgG acts as an "eat me" signal for macrophages.
• Flipping of Phosphatidylserine: Normally, the phospholipid phosphatidylserine (PS) is kept on the inner surface of the cell membrane. However, in aged or stressed RBCs, PS can flip to the outer leaflet, acting as another potent signal for macrophages to initiate phagocytosis.
• Decreased Metabolic Activity: Without a nucleus, RBCs cannot synthesize new proteins. Over time, the activity of key metabolic enzymes, particularly those involved in glycolysis, declines. This leads to reduced ATP production, which is crucial for maintaining the cell's structure and ion gradients. Lower energy levels further compromise membrane integrity and flexibility.
• Loss of Water and Volume: Due to changes in ion pumps and metabolic activity, aged RBCs often lose water and shrink in size, increasing their density. This density change can be used to separate older RBCs in laboratory settings.

The Process of Erythrophagocytosis

The final act for an aged red blood cell is its clearance by macrophages, primarily in the spleen, liver, and bone marrow. This specialized form of phagocytosis is known as erythrophagocytosis.

1. Recognition: In the spleen's red pulp, macrophages survey circulating red blood cells. They recognize the senescence signals on the surface of old RBCs, such as aggregated Band 3 proteins coated with IgG or exposed phosphatidylserine.
2. Entrapment: The spleen's unique microvasculature, containing narrow inter-endothelial slits, traps the less deformable, older RBCs. Healthy, flexible RBCs pass through easily, but the rigid aged cells are retained in the macrophage-rich red pulp.
3. Engulfment and Destruction: Once recognized and trapped, macrophages engulf the senescent RBCs. Inside the macrophage, the RBC is broken down into its constituent parts.
4. Recycling: The components are efficiently recycled back into the body. Hemoglobin is split into its heme and globin components. The globin is broken down into amino acids, which are reused. The iron from the heme is bound to transferrin and transported back to the bone marrow to be incorporated into new red blood cells. The remaining heme is converted into biliverdin and then bilirubin, which is excreted by the liver in bile.

Comparison of Young vs. Aged Red Blood Cells

Feature	Young Red Blood Cells (RBCs)	Aged Red Blood Cells (RBCs)
Membrane Flexibility	High; easily deformable.	Decreased; more rigid.
Shape	Biconcave disc.	Spherocytic (more spherical) due to membrane loss.
Cell Volume & Density	Normal volume and lower density.	Reduced volume and higher density.
Metabolic Activity	High; active ATP production.	Low; decreased ATP and enzyme activity.
Surface Signals	High expression of "don't eat me" signal (CD47).	Low CD47; high exposure of "eat me" signals (e.g., PS, IgG-coated Band 3).
Lifespan	Circulates for approximately 120 days.	Tagged for removal; lifespan nearing its end.
Spleen Interaction	Easily passes through splenic sinusoids.	Trapped and retained in the spleen for clearance.

Conclusion

The aging of red blood cells is a tightly regulated and highly efficient process that maintains blood and iron homeostasis. As they circulate for 120 days, RBCs experience a gradual decline in function, characterized by increasing membrane rigidity, decreased metabolism, and altered surface signals. These changes culminate in their recognition and removal by macrophages in the spleen and liver. The recycling of iron and other components is a critical part of this process, ensuring that the body's resources are conserved for the production of new, healthy red blood cells. The precise molecular signals that trigger the clearance of senescent red blood cells are still an area of active research, but the overall mechanism demonstrates a finely tuned biological system for managing cellular turnover.

[What is the role of the spleen in red blood cell loss caused by malaria?](https://www.medrxiv.org/content/10.1101/2025.05.08.25327032v1.full-text)

Frequently Asked Questions

What is the primary site of red blood cell destruction?

The primary site for the destruction of old and damaged red blood cells is the spleen, where a specialized network of macrophages recognizes and removes senescent cells from circulation. The liver also plays a significant role, especially in conditions where the spleen is absent or dysfunctional.

What is the process called when macrophages eat red blood cells?

The process by which macrophages engulf and digest red blood cells is called erythrophagocytosis. This happens when macrophages identify specific senescence markers on the surface of aging or damaged red blood cells.

How does the body know when a red blood cell is old?

The body identifies old red blood cells through a combination of physical and biochemical changes. These include decreased membrane flexibility, the aggregation of membrane proteins like Band 3, the exposure of phosphatidylserine on the cell surface, and the binding of auto-antibodies (IgG) to the cell.

What happens to the iron from destroyed red blood cells?

When red blood cells are destroyed, the iron from their hemoglobin is recycled. Macrophages release the iron into the blood, where it is bound to the protein transferrin and transported back to the bone marrow for the production of new red blood cells.

What happens if old red blood cells are not removed properly?

If old red blood cells are not removed efficiently, it can lead to various health problems. Anemia can develop due to the loss of functional RBCs, and the accumulation of damaged cells can lead to organ damage. In severe cases, it can cause an enlarged spleen (splenomegaly) and other complications.

Do red blood cells undergo apoptosis like other cells?

While red blood cells do not have a nucleus and therefore cannot undergo standard programmed cell death (apoptosis), they go through a similar, specific process called eryptosis. This involves cellular shrinkage and externalization of phosphatidylserine, triggering their removal by phagocytosis.

What is the role of the spleen in filtering red blood cells?

The spleen acts as a specialized filter for the blood. Its red pulp contains a network of narrow slits and macrophages that act as a quality control mechanism. Flexible, healthy red blood cells can squeeze through, but rigid or damaged ones get trapped and are subsequently removed by macrophages.