Impact of genomic damage and ageing on stem cell function

Abstract

Impairment of stem cell function contributes to the progressive deterioration of tissue maintenance and repair with ageing. Evidence is mounting that age-dependent accumulation of DNA damage in both stem cells and cells that comprise the stem cell microenvironment are partly responsible for stem cell dysfunction with ageing. Here, we review the impact of the various types of DNA damage that accumulate with ageing on stem cell functionality, as well as the development of cancer. We discuss DNA-damage-induced cell intrinsic and extrinsic alterations that influence these processes, and review recent advances in understanding systemic adjustments to DNA damage and how they affect stem cells.

Figure 1

Cell-autonomous and systemic responses to DNA damage. Various sources of genotoxic stress induce DNA damage that can be removed by specialized DNA repair systems. Cell-autonomous DNA damage checkpoints halt the cell cycle to allow time for repair or, amid severe genome damage, trigger programmed cell death or cellular senescence. Although DNA damage checkpoint mechanisms protect against cancer, the associated removal of cells can contribute to ageing through declining regenerative stem cell pools (grey). Systemic DNA damage responses include attenuation of the somatic growth axis and triggering of innate immune responses, which might support longevity assurance (blue) by enhancing maintenance of tissue functionality and removal of damaged cells, but also contribute to ageing (grey) by damaging tissues and impairing regeneration.

Figure 2

Impact of DNA damage on the stem cell environment. The accumulation of DNA damage and senescent cells during ageing leads to alterations in the stem cell niche and the systemic circulatory environment. Both processes can interfere with signalling pathways (such as Notch, Wnt and Sprouty1) that are required for the maintenance of stem cell quiescence, self-renewal and differentiation. Disturbances in these basic stem cell parameters lead to alterations in the epigenetic landscape of the DNA of ageing stem cells, further aggravating alterations in stem cell quiescence, self-renewal and differentiation.

Figure 3

Consequences of DNA damage on clonal selection in tissue stem cells during ageing. Stem cells in an organ consist of different subpopulations. Ageing-associated accumulation of DNA damage activates checkpoints that remove damaged stem cells by inducing apoptosis, cell cycle arrest or differentiation. This can lead to clonal drifts or imbalances in the pool of remaining stem cells. Checkpoint activation (top) in a growing number of stem cells in ageing tissues impairs the proliferative capacity of these stem cells, which will in turn increase the selective pressure for the outgrowth of mutant cell clones. This process is further accelerated by aberrant growth signals originating from compensatory feedback loops to maintain tissue homeostasis, the accumulation of senescent cells exhibiting a secretory phenotype (SASP), or inflammation as a consequence of immune reactions targeting damaged cells. It is also possible that some stem cells will escape the induction of checkpoints in response to DNA damage (bottom). Checkpoint-deficient stem cells have an increased risk of acquiring mutations that will lead to a selective growth advantage in the context of damage accumulation, checkpoint induction and growth inhibition in the pool of ageing stem cells (top).