Aging of mammalian intestinal stem cells

Abstract

The intestinal epithelium forms the internal barrier towards all components of nutriment and a multitude of bacteria. Itis the most rapidly renewing tissue in mammals and keeps up basic homeostatic functionover most of the organism’s lifespan. Its stress capacitance is lowered with progressive age, though. This remarkably high capacity of regeneration requires the maintenance of functional stem cells. DNA damage accumulation has been implicated in limiting organ maintenance; thus, checkpoint and repair mechanisms have been devoted to keep up genomic integrity of stem and progenitor cells. Checkpoints engaged include p53, as well as upstream regulators (Exo1, ATM, ATR, Chk1) and downstream targets (p21, PUMA). Repair or clearance of damaged cells blocks cancer development but may dampen organ maintenance thus speeding up aging. Depending on the context, modulation of checkpoint responses allows accelerating or slowing down aging and age-related malignancies. The result depends on the cells affected, the level and kind of DNA damage accumulation and the clearance of damaged cells.