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

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. Significance StatementWhen human somatic cells divide, their telomeres shorten. This process drives age-related shortening of leukocyte telomeres and reflects hematopoietic stem cell (HSC) division at the top of the hematopoietic hierarchy. The magnitude of telomere shortening per somatic cell division in vivo (MTSIV) is a critical yet previously unquantified parameter essential for providing insights into the pace of HSC division in humans. This study estimates that the MTSIV is about 28 base pairs. Using the MTSIV and leukocyte telomere length data from newborns and centenarians, we calculated that HSCs divide approximately 156 times over a 100-year lifespan. This knowledge improves our understanding of HSC replication dynamics and their implications for human health and longevity.