Significance: Werner syndrome (WS) is a rare autosomal recessive malady typified by a pro-oxidant/proinflammatory status, genetic instability, and by the early onset of numerous age-associated illnesses. The protein malfunctioning in WS individuals (WRN) is a helicase/exonuclease implicated in transcription, DNA replication/repair, and telomere maintenance. Recent Advances: In the last two decades, a series of important biological systems were created to comprehend at the molecular level the effect of a defective WRN protein. Such biological tools include mouse and worm (Caenorhabditis elegans) with a mutation in the Wrn helicase ortholog as well as human WS-induced pluripotent stem cells that can ultimately be differentiated into most cell lineages. Such WS models have identified anomalies related to the hallmarks of aging. Most importantly, vitamin C counteracts these age-related cellular phenotypes in these systems. Critical Issues: Vitamin C is the only antioxidant agent capable of reversing the cellular aging-related phenotypes in those biological systems. Since vitamin C is a cofactor for many hydroxylases and mono- or dioxygenase, it adds another level of complexity in deciphering the exact molecular pathways affected by this vitamin. Moreover, it is still unclear whether a short- or long-term vitamin C supplementation in human WS patients who already display aging-related phenotypes will have a beneficial impact. Future Directions: The discovery of new molecular markers specific to the modified biological pathways in WS that can be used for novel imaging techniques or as blood markers will be necessary to assess the favorable effect of vitamin C supplementation in WS. Antioxid. Redox Signal. 34, 856-874.
Keywords: Werner syndrome; aging; mouse; stem cells; vitamin C; worm.