The CSX molecular clock across different human tissues. a. Comparisons of CSX tag methylation between human hair (green or red), small intestines (blue) and colon (black). Intestinal data [3, 5, 21] include additional unpublished individuals. Plotted are average values from each individual. In contrast to hair, the intestines show an age-related increase in methylation. Regression analysis of intestinal data were consistent with positive slopes (F1,25 = 21.58, P < 0.0001 for the colon, and F1,10 = 21.03, P = 0.001 for the small intestines), but not with hair data after two years of age (F1,21 = 0.0009, P = 0.98). b. Hair and intestinal genealogies can be divided into three phases (neogenesis (green), stem cell (red) and differentiation (blue)). Anagen cycles allow for episodic changes in hair mitotic ages due to lower follicle divisions, but average mitotic age remains constant with chronological age because bulge stem cell divisions are infrequent. Differentiated intestinal cells divide only a few times and survive about a week, and therefore the age-related increase in mitotic age represents crypt stem cell divisions. Crypt stem cells appear to divide more often than bulge stem cells. c. Hair has two distinct mitotic compartments (lower follicle and bulge, indicated in yellow) whereas the intestines have a single mitotic compartment at the crypt base. The lower follicle physically disappears at telogen and previously mitotic lineages become extinct. This telogen bottleneck allows infrequently dividing bulge stem cells to become common ancestors because their progeny repopulate the new lower follicle. The telogen bottleneck effectively resets the mitotic age of the follicle. A similar bottleneck does not occur in intestinal crypts and therefore a cell must divide frequently to become a common ancestor. Without a bottleneck, crypt mitotic age increases with age. A quiescent crypt cell may have stem cell potential, but is not the common ancestor for present day differentiated cells.