What are the underlying mechanisms of these striking telomere-associated degenerative phenotypes? For highly proliferative organs that rely on resident tissue stem cells for organ renewal and homeostasis, there is clear evidence that reserves of stem and progenitor cells across various tissue types of the late-generation Terc−/− mice are depleted and/or functionally compromised through various processes such as increased apoptosis, senescence and impaired differentiation. For example, the degree of intestinal atrophy in aged, late-generation Terc−/− mice parallels high levels of p53-dependent apoptosis in the stem-cell-rich and progenitor-cell-rich crypt compartment26. Additionally, late-generation Terc−/− HSCs have been shown to be severely disadvantaged in competitive transplantation experiments and show pronounced differentiation towards the myeloid lineage, a profile similar to that in aged humans64,65. In the skin, late-generation Terc−/− epidermal stem cells are also impaired in their proliferative capacity and ability to move out of the hair follicle, defects that may underlie delayed wound healing, hair greying and hair loss in these mice66. Even the brain, an organ of relatively low proliferative activity, shows a compromise of NSC renewal and differentiation capacity in late-generation Terc−/−
