Erythrocyte Count, Anemia, and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study

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 adults 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 and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8x10 12 /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 emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5 th 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 adults.