Reducing Hypothalamic Stem Cell Senescence Protects against Aging-Associated Physiological Decline

Cell Metab. 2020 Mar 3;31(3):534-548.e5. doi: 10.1016/j.cmet.2020.01.002. Epub 2020 Jan 30.


Age-dependent loss of hypothalamic neural stem cells (htNSCs) is important for the pathological consequences of aging; however, it is unclear what drives the senescence of htNSCs. Here, we report that a long non-coding RNA, Hnscr, is abundantly expressed in the htNSCs of young mice but decreases markedly in middle-aged mice. We show that depletion of Hnscr is sufficient to drive the senescence of htNSCs and aging-like phenotypes in mice. Mechanistically, Hnscr binds to Y-box protein 1 (YB-1) to prevent its degradation and thus the attenuation of transcription of the senescence marker gene p16INK4A. Through molecular docking, we discovered that a naturally occurring small compound, theaflavin 3-gallate, can mimic the activity of Hnscr. Treatment of middle-aged mice with theaflavin 3-gallate reduced the senescence of htNSCs while improving aging-associated pathology. These results point to a mediator of the aging process and one that can be pharmacologically targeted to improve aging-related outcomes.

Keywords: YB-1; aging; htNSC; hypothalamus; neural stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Biflavonoids / chemistry
  • Biflavonoids / pharmacology
  • Catechin / chemistry
  • Catechin / pharmacology
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gallic Acid / analogs & derivatives
  • Gallic Acid / chemistry
  • Gallic Acid / pharmacology
  • HEK293 Cells
  • Humans
  • Hypothalamus / cytology*
  • Mice, Inbred C57BL
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Phenotype
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Y-Box-Binding Protein 1 / metabolism


  • Biflavonoids
  • Cyclin-Dependent Kinase Inhibitor p16
  • RNA, Long Noncoding
  • Y-Box-Binding Protein 1
  • theaflavine gallate
  • Gallic Acid
  • Catechin