What single feature of normal RBCs is most responsible for limiting their life span?

The life span of normal red blood cells (RBCs) is primarily limited by the loss of their nucleus. During erythropoiesis, RBCs expel their nucleus to make room for hemoglobin, which is crucial for their function of oxygen transport. This process, however, also means that mature RBCs lack the ability to synthesize new proteins or repair any damage that occurs over time. As a result, without a nucleus to direct cellular repairs and maintain cellular function, RBCs gradually accumulate damage and become less effective at performing their role, leading to a finite life span of about 120 days.

In contrast, while the loss of mitochondria does contribute to energy metabolism changes and the flexibility of the cell membrane aids in the movement of RBCs through the microvasculature, these features do not directly limit the cell's life span in the same way the absence of a nucleus does. The reduction of hemoglobin iron pertains more to the functionality and capacity of oxygen transport rather than directly causing an end to the RBC's life cycle.