The Magnitude of Telomere Shortening per Cell Division In Vivo: Implications for Lifelong Hematopoiesis in Humans

Abstract

The magnitude of telomere shortening per cell division in human somatic cells in vivo (MTSIV) is a fundamental but unquantified parameter. MTSIV is essential for understanding how telomere-length (TL)-dependent hematopoietic cell division influences age-related health and longevity. By leveraging sex differences in leukocyte TL and the differential dosage of DKC1, a telomerase-regulating gene, during early embryonic cell divisions, we estimate the MTSIV to be 28 base pairs per cell division (95% CI: 23 - 32). Using this estimate and leukocyte TL data from newborns and centenarians, we infer that hematopoietic stem cells (HSCs) undergo approximately 156 divisions (95% CI: 130 - 183) over a 100-year lifespan. Using longitudinal data on leukocyte telomere shortening in adults, we further estimate that HSCs divide about 0.97 times yearly (95% CI: 0.80 - 1.13) after age 20. These findings provide a quantitative framework for understanding TL-dependent hematopoiesis, the most proliferative process in the human soma. They also highlight that if telomere shortening affects age-related health and longevity, it acts primarily through its impact on hematopoiesis. Our results refine hematopoietic stem cell replicative history estimates and might guide treatments involving hematopoietic cell expansion, such as hematopoietic cell transplantation and immunotherapies.