The study investigates the replicative senescence of mouse embryonic fibroblasts (MEFs) and human fibroblasts under standard culture conditions, which include 20% oxygen. MEFs do not senesce in physiological (3%) oxygen levels but undergo a spontaneous event that allows indefinite proliferation in 20% oxygen. DNA repair-deficient MEFs accumulate more DNA damage in 20% oxygen compared to 3% oxygen, suggesting that DNA damage limits MEF proliferation in high oxygen levels. The findings indicate that oxygen sensitivity is a critical difference between mouse and human cells, explaining their proliferative differences in culture and possibly their different rates of cancer and aging. The study also suggests that the superior ability of human cells to prevent or repair oxidative DNA damage contributes to the major differences in cancer incidence and aging between mice and humans.The study investigates the replicative senescence of mouse embryonic fibroblasts (MEFs) and human fibroblasts under standard culture conditions, which include 20% oxygen. MEFs do not senesce in physiological (3%) oxygen levels but undergo a spontaneous event that allows indefinite proliferation in 20% oxygen. DNA repair-deficient MEFs accumulate more DNA damage in 20% oxygen compared to 3% oxygen, suggesting that DNA damage limits MEF proliferation in high oxygen levels. The findings indicate that oxygen sensitivity is a critical difference between mouse and human cells, explaining their proliferative differences in culture and possibly their different rates of cancer and aging. The study also suggests that the superior ability of human cells to prevent or repair oxidative DNA damage contributes to the major differences in cancer incidence and aging between mice and humans.