Vascular and Neurogenic Rejuvenation in Aging Mice by Modulation of ASM

Neuron. 2018 Oct 10;100(1):167-182.e9. doi: 10.1016/j.neuron.2018.09.010. Epub 2018 Sep 27.


Although many reports have revealed dysfunction of endothelial cells in aging, resulting in blood-brain barrier (BBB) breakdown, the underlying mechanism or mechanisms remain to be explored. Here, we find that acid sphingomyelinase (ASM) is a critical factor for regulating brain endothelial barrier integrity. ASM is increased in brain endothelium and/or plasma of aged humans and aged mice, leading to BBB disruption by increasing caveolae-mediated transcytosis. Genetic inhibition and endothelial-specific knockdown of ASM in mice ameliorated BBB breakdown and neurocognitive impairment during aging. Using primary mouse brain endothelial cells, we found that ASM regulated the caveolae-cytoskeleton interaction through protein phosphatase 1-mediated ezrin/radixin/moesin (ERM) dephosphorylation and apoptosis. Moreover, mice with conditional ASM overexpression in brain endothelium accelerated significant BBB impairment and neurodegenerative change. Overall, these results reveal a novel role for ASM in the control of neurovascular function in aging, suggesting that ASM may represent a new therapeutic target for anti-aging.

Keywords: acid sphingomyelinase; aging; blood-brain barrier; caveolae; neural function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism*
  • Animals
  • Blood-Brain Barrier / enzymology*
  • Blood-Brain Barrier / pathology*
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Rejuvenation / physiology*
  • Sphingomyelin Phosphodiesterase / metabolism*
  • Young Adult


  • Sphingomyelin Phosphodiesterase