Do haematopoietic stem cells age?

Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in lymphopoiesis and skewing towards the myeloid lineage. This HSC-centric view is based largely on studies showing that HSCs from aged mice exhibit these lineage biases following transplantation into irradiated young recipient mice. In this Opinion article, we make the case that the reliance on this approach has led to inaccurate conclusions regarding the effects of ageing on blood-forming stem cells; we suggest instead that changes in the environment contribute to haematopoietic system ageing. We propose that a complete understanding of how ageing affects haematopoiesis depends on the analysis of blood cell production in unperturbed mice. We describe how this can be achieved using in situ fate mapping. This approach indicates that changes in downstream progenitors, in addition to any HSC defects, may explain the reduced lymphopoiesis and sustained myelopoiesis that occur during ageing. As we age, haematopoiesis becomes skewed towards myelopoiesis. Studies of haematopoietic stem cells (HSCs) transplanted into irradiated recipient mice imply that HSC defects are responsible for this ageing effect. Here, the authors urge caution when using irradiated mice to study haematopoiesis ageing, and propose instead that age-related changes in the bone marrow environment and in downstream progenitors, not just HSCs, may also be responsible for myeloid skewing.