Prolonged fasting activates a metabolic switch to lipid- and ketone-based catabolism and decreases circulating insulin-like growth factor-1 (IGF-1), which has been shown to reduce chemotoxicity, although the reasons behind this effect are unclear. Myelosuppression is a side effect of chemotherapy, and Longo and colleagues have now discovered that the positive effects of prolonged fasting can partly be attributed to improved haematopoietic stem cell (HSC) function (Cell Stem Cell 6, 810–823; 2014).

The authors initially found that reduction of circulating IGF-1 levels in the blood was accompanied by a reduction in protein kinase A (PKA) signalling activity in several cell types associated with blood function. They observed that cycles of prolonged fasting followed by challenges with the chemotherapy agent cyclophosphamide reduced the mortality and apoptosis of long- and short-term HSCs as well as multipotent progenitors in the bone marrow. In addition, multi-lineage differentiation was improved in these animals compared with fed mice, in vitro and in transplantation experiments. This was also observed in cancer patients adopting prolonged fasting within a phase I clinical trial. These positive effects of prolonged fasting were independent of the chemotherapy treatment, as they were also present in aged animals, which naturally exhibit a reduction in HSC function and multi-lineage potential. The effects of prolonged fasting could be reproduced in mice lacking the growth hormone receptor, which also have low levels of IGF-1. Transplantation experiments showed that low levels of IFG-1 in animals led to a reduction in IGF-1-mediated PKA signalling, both in haematopoietic cells and in associated stromal cells. Strikingly, the researchers could restore haematopoietic function by reducing the levels of either IGF-R1 or the PKA catalytic subunit by siRNA. Conversely, the benefits were abolished if exogenous IGF-1 was added. It will be fascinating to see if the positive effects of fasting described here can be translated to a clinical setting.