39 More intrahepatic lymphocytes were detected than expected in normal liver and may represent the response to handling of see more the liver during harvesting and implantation. The reason behind the reduction in sinusoidal cell telomere length with age (in Kupffer cells and hepatic stellate cells) was beyond the scope of this study. Sinusoidal cells have a different origin, namely bone marrow,40, 41 and are subject to constant immune stimulation through contact with portal blood. Others have demonstrated that hepatocyte telomeres shorten in cirrhotic liver

but that hepatic stellate cells and lymphocytes in regions of liver fibrosis have longer telomeres.24 These studies have only looked at small numbers of each hepatic cell lineage and may not be representative, particularly given the heterogeneity seen in liver tissue. They may also reflect the recruitment

of cells with longer telomeres to the injured liver from bone marrow. In chimeric mice, hepatic stellate cells originate from hematopoetic bone marrow stem cells, particularly following hepatic injury.42 Finally, progestogen antagonist telomere shortening in sinusoidal cells may reflect a reduction in hepatic blood flow, which is especially marked after the age of 50.43, 44 It has been suggested that reduced hepatic flow alone could explain delayed hepatic regeneration after injury.45 Kupffer cells populating the liver originate from bone marrow in both mice and humans after bone marrow transplant46 and constitute a large intrahepatic population. Quantitative study of monocyte production in bone marrow and transit through the circulation showed that in the normal steady state, over 50% of monocytes leaving the circulation

become Kupffer cells. Considering the Kupffer cells as kinetically homogeneous, gives a mean turnover time of the total population of Kupffer cells of 21 days.47 Further studies in normal rat liver revealed an age-related decline in antigen presentation ability by Kupffer cells,48 and Liothyronine Sodium these cells in mice have been shown to have a stimulatory role in liver regeneration.49 In conclusion, we developed a robust, high-volume Q-FISH method for analysis of telomeres in different hepatic cell lineages that highlighted the pitfall of using liver homogenates in the study of aging and senescence. Furthermore, we demonstrated very long telomeres in cholangiocytes in normal liver over a wide age range and age-related telomere attrition restricted to sinusoidal cells. Understanding the normal process of aging in the liver is important in many aspects of hepatology from pharmacology to selection of older donors, and the findings encourage careful selection of older liver donors. Additional Supporting Information may be found in the online version of this article.