Abstract

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells' replicative capacity, leading to a decline in erythrocyte count (EC) in older individuals and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [≥]70 years in the Long Life Family Study, among whom lower EC further augmented the exponential age-dependent rise in mortality. We identified an EC threshold (ECT) (~3.8x1012/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT in older individuals emerged from modeling, independent of the WHO anemia definition based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [≤] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older individuals.