Hypothalamic stem cells control ageing speed partly through exosomal miRNAs

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs. Ablation of hypothalamic stem/progenitor cells in mice leads to ageing-related decreases in physiological parameters and lifespan, and the speed of ageing is partially controlled by these cells through the release of exosomal miRNAs. Dongsheng Cai and colleagues previously showed that the hypothalamus has a critical role in systemic ageing. Here they observe a substantial loss of hypothalamic stem cells in middle-aged mice. They show in several mouse models that ablation of these cells results in ageing-like physiological changes and a shortened lifespan. Conversely, ageing could be slowed and lifespan extended by transplantation of healthy hypothalamic stem cells into middle aged mice. Hypothalamic stem cells secrete exosomal miRNAs, contributing to a pool of circulating miRNAs in the cerebrospinal fluid that declines with age. These secreted exosomes contribute, at least in part, to a deceleration of ageing. The authors conclude that the speed of ageing is partially controlled by hypothalamic stem cells and their exosomal miRNAs in the cerebrospinal fluid.