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Physiological liver cell replacement is central to maintaining the organ's high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective radiocarbon (C-14) birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, allowing the liver to remain a young organ (average age

Physiological liver cell replacement is central to maintaining the organ's high metabolic activity, although its characteristics are difficult to study in humans. Using retrospective 14 C birth dating of cells, we report that human hepatocytes show continuous and lifelong turnover, maintaining the liver a young organ (average age < 3 years ). Hepatocyte renewal is highly dependent on the ploidy level. Diploid hepatocytes show an seven-fold higher annual exchange rate than polyploid hepatocytes. These observations support the view that physiological liver cell renewal in humans is mainly dependent on diploid hepatocytes, whereas polyploid cells are compromised in their ability to divide. Moreover, cellular transitions between these two subpopulations are limited, with minimal contribution to the respective other ploidy class under homeostatic conditions. With these findings, we present a new integrated model of liver cell generation in humans that provides fundamental insights into liver cell turnover dynamics.