Hypothalamic stem cells control ageing speed partly through exosomal miRNAs

Nature. 2017 Aug 3;548(7665):52-57. doi: 10.1038/nature23282. Epub 2017 Jul 26.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / cerebrospinal fluid
  • Aging / genetics*
  • Aging / pathology
  • Aging / physiology*
  • Animals
  • Cellular Microenvironment
  • Exosomes / genetics*
  • Exosomes / metabolism
  • Hypothalamus / cytology*
  • Hypothalamus / pathology
  • Hypothalamus / physiology*
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Inflammation
  • Longevity / genetics
  • Longevity / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / cerebrospinal fluid
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / physiology*
  • Neural Stem Cells / transplantation
  • Polycomb Repressive Complex 1 / deficiency
  • Proto-Oncogene Proteins / deficiency
  • SOXB1 Transcription Factors / deficiency
  • Time Factors


  • Bmi1 protein, mouse
  • I kappa B beta protein
  • I-kappa B Proteins
  • MicroRNAs
  • Proto-Oncogene Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Polycomb Repressive Complex 1