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<p>In response to acute stress, nucleated cells undergo various regulated cell deaths (RCDs). Alternatively and in the long run, they permanently stop proliferating with the parallel acquisition of apoptosis resistance and the senescence-associated secretory phenotype. This particular long-term stress response is referred to as cellular senescence. Terminally differentiated, anucleate red blood cells (RBCs) cannot proliferate anymore and are incapable of synthesizing proteins. RBC senescence is therefore defined by phagocytosis-promoting age-related changes, such as band 3 protein-derived senescent erythrocyte-specific antigen (SESA)-mediated binding of autologous antibodies, desialylated glycoproteins, CD47 loss, and glycophorin depletion. Additionally, RBCs can undergo eryptosis, a Ca<sup>2+</sup>-driven RCD. Here, we consider the intracellular signals that drive RBC senescence and eryptosis to underscore how these pathways are intertwined. Our findings suggest that RBC senescence and eryptosis are distinct processes with their differences primarily lying in how fast senescent and eryptotic RBCs are removed from the circulation. Severe damage to RBCs promotes intense Ca<sup>2+</sup> influx, oxidative and nitrosative stress, as well as&#xa0;activation of caspase-3. This eventually leads to phosphatidylserine externalization and eryptosis. Phosphatidylserine externalization, in turn, ensures swift erythrophagocytosis of eryptotic RBCs thus preventing hemolysis. On the other hand, suberyptotic stress stimuli are not sufficient to trigger rapid cell death. However, they mediate the gradual and inevitable accumulation of senescence-associated injuries. Clearance of senescent RBCs with low-level phosphatidylserine exposure is slow-paced, and mature RBCs possess mechanisms to eradicate senescence markers that tag cells for phagocytosis to extend their lifespan (e.g., generation of vesicles). In this review, we highlight the physiological significance of RBC senescence and eryptosis, and provide practical guidelines to distinguish them thus avoiding misinterpretation of experimental data.</p> Graphical abstract <p></p>

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Redefining the concept of erythrocyte senescence: is eryptosis fundamentally different from erythrocyte senescence

  • 期刊论文

  • 发表日期：

    2025年11月19日

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  • Anton Tkachenko,
  • Ondrej Havranek,
  • Florian Lang,
  • Karl S. Lang,
  • Thomas Wieder

摘要

In response to acute stress, nucleated cells undergo various regulated cell deaths (RCDs). Alternatively and in the long run, they permanently stop proliferating with the parallel acquisition of apoptosis resistance and the senescence-associated secretory phenotype. This particular long-term stress response is referred to as cellular senescence. Terminally differentiated, anucleate red blood cells (RBCs) cannot proliferate anymore and are incapable of synthesizing proteins. RBC senescence is therefore defined by phagocytosis-promoting age-related changes, such as band 3 protein-derived senescent erythrocyte-specific antigen (SESA)-mediated binding of autologous antibodies, desialylated glycoproteins, CD47 loss, and glycophorin depletion. Additionally, RBCs can undergo eryptosis, a Ca2+-driven RCD. Here, we consider the intracellular signals that drive RBC senescence and eryptosis to underscore how these pathways are intertwined. Our findings suggest that RBC senescence and eryptosis are distinct processes with their differences primarily lying in how fast senescent and eryptotic RBCs are removed from the circulation. Severe damage to RBCs promotes intense Ca2+ influx, oxidative and nitrosative stress, as well as activation of caspase-3. This eventually leads to phosphatidylserine externalization and eryptosis. Phosphatidylserine externalization, in turn, ensures swift erythrophagocytosis of eryptotic RBCs thus preventing hemolysis. On the other hand, suberyptotic stress stimuli are not sufficient to trigger rapid cell death. However, they mediate the gradual and inevitable accumulation of senescence-associated injuries. Clearance of senescent RBCs with low-level phosphatidylserine exposure is slow-paced, and mature RBCs possess mechanisms to eradicate senescence markers that tag cells for phagocytosis to extend their lifespan (e.g., generation of vesicles). In this review, we highlight the physiological significance of RBC senescence and eryptosis, and provide practical guidelines to distinguish them thus avoiding misinterpretation of experimental data.

Graphical abstract