Repression of the Antioxidant NRF2 Pathway in Premature Aging

Cell. 2016 Jun 2;165(6):1361-1374. doi: 10.1016/j.cell.2016.05.017.


Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading, through unknown mechanisms, to diverse morphological, epigenetic, and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen, we identify the NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate HGPS aging defects, whereas reactivation of NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores in vivo viability of MSCs in an animal model. These findings identify repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype.

Keywords: HGPS; NRF2; aging; oxidative stress; progerin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging, Premature / genetics
  • Aging, Premature / metabolism*
  • Antioxidants / metabolism*
  • Cell Line
  • Cell Survival
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Progeria / genetics
  • Progeria / metabolism*
  • RNA, Small Interfering
  • Transcription Factors / metabolism
  • Transcription, Genetic


  • Antioxidants
  • CAND1 protein, human
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Small Interfering
  • Transcription Factors