P16INK4a and Stem Cell Ageing A Telomere Independent Process

Norman E. Sharpless

Abstract Long-lived mammals replace lost or consumed cells at a tremendous pace: an adult human replaces ~1% of their many trillion red blood cells every day through de novo synthesis. Similarly, cell division at various rates is at work throughout life to continuously replace lost cells in many epithelial tissues such as the gut, skin, breast, and lung. Moreover, several tissues (e.g., memory T-lymphocytes, pancreatic P-cells) possess a potential for "facultative growth" in the adult; that is, under certain circumstances (e.g., infection, pregnancy), these usually quiescent cells re-enter the cell cycle en masse to increase the mass of a given tissue through controlled proliferation. These forms of tissue replacement and repair require that many adult mammalian tissues contain reservoirs of stem cells capable of generating terminally differentiated effector cell types. The unique cellular property that enables stem cells to maintain such function throughout life is the ability to produce large numbers of differentiated cell types while also self-renewing themselves so that their reserves do not become depleted. In this chapter, I will review some of the evidence to support the notion that certain aspects of mammalian ageing result from an age-dependent decline in the function of self-renewing stem cells, and discuss the relationship of p16INK4a and telomeres with regard to stem cell ageing.

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