Repression of the antioxidant NRF2 pathway in premature aging

Authors

• N Kubben
• T Voss
• T Misteli

Abstract

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 extensive morphological, epigenetic and genomic damage and to mesenchymal stem cell (MSC) attrition invivo. We set out to identify primary HGPS disease mechanisms underlying these defects. Using a high-throughput high-content imaging-based siRNA screen we identify the longevity-promoting NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2-mediated transcriptional activation of antioxidants and consequently chronic oxidative stress. Suppressed NRF2 activity or increased oxidative stress are sufficient to recapitulate HGPS aging defects and re-activation of NRF2 activity in HGPS patient cells restores normal function. These findings establish repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype, and suggest NRF2 activating compounds as a promising novel therapeutic strategy in HGPS and aging diseases.

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