Repression of the Antioxidant NRF2 Pathway in Premature Aging.
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.
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nard
N
Kubben
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.
Weiqi
W
Zhang
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Lixia
L
Wang
High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ty C
TC
Voss
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Jiping
J
Yang
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Jing
J
Qu
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China; Beijing Institute for Brain Disorders, Beijing 100069, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: ghliu@ibp.ac.cn.
Guang-Hui
GH
Liu
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.
Tom
T
Misteli
D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism*; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011371:Progeria / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000975:Antioxidants; C486317:CAND1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors
HGPS; NRF2; aging; oxidative stress; progerin