Emerging models and paradigms for stem cell ageing

Abstract

Ageing is accompanied by a progressive decline in stem cell function, resulting in less effective tissue homeostasis and repair. Here we discuss emerging invertebrate models that provide insights into molecular pathways of age-related stem cell dysfunction in mammals, and we present various paradigms of how stem cell functionality changes with age, including impaired self-renewal and aberrant differentiation potential.

Figure 1

Emerging paradigms for stem cell ageing. (a) A generic model of normal stem cell function. A quiescent stem cell is activated, divides asymmetrically to give rise to a new stem cell (self-renewal) and another daughter that will undergo proliferative expansion and differentiation. (b) Paradigms of abnormal function of aged stem cells. (A) Failure of self-renewal. Both daughters differentiate, leading to a gradual depletion of the stem cell pool. (B) Impaired stem cell response can arise from a decline of extrinsic signals, a decline of stem cell responsiveness or both. (C) Aberrant differentiation. Multiple and different cases of this defect have been observed and two examples are illustrated. In one case, the normal distribution of progeny among potential fates is abnormally skewed towards one fate. In the other case, some daughters acquire abnormal fates that are not part of the normal repertoire. In the case of the Drosophila ISCs, as described in the text, this occurs without proceeding through a proliferative phase. (d) Senescence or apoptosis. Direct senescence and apoptosis of the quiescent stem cell are shown, but this could also occur among the progeny following activation.