Werner syndrome (WS) is a
premature aging disorder caused by mutations in a RecQ-family
DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter mean life span. In contrast, mice lacking the entire Wrn
protein (i.e. Wrn null mice) do not exhibit a
premature aging phenotype. In this study, we used a targeted mass spectrometry-based metabolomic approach to identify serum metabolites that are differentially altered in young Wrn helicase mutant and Wrn null mice. An antibody-based quantification of 43 serum
cytokines and markers of
cardiovascular disease risk complemented this study. We found that Wrn helicase mutants exhibited elevated and decreased levels, respectively, of the anti-inflammatory
cytokine IL-10 and the pro-inflammatory
cytokine IL-18. Wrn helicase mutants also exhibited an increase in serum
hydroxyproline and
plasminogen activator inhibitor-1, markers of extracellular matrix remodeling of the vascular system and
inflammation in aging. We also observed an abnormal increase in the ratio of very long chain to short chain
lysophosphatidylcholines in the Wrn helicase mutants underlying a peroxisome perturbation in these mice. Remarkably, the Wrn mutant helicase
protein was mislocalized to the endoplasmic reticulum and the peroxisomal fractions in liver tissues. Additional analyses with mouse embryonic fibroblasts indicated a severe defect of the autophagy flux in cells derived from Wrn helicase mutants compared to wild type and Wrn null animals. These results indicate that the deleterious effects of the helicase-deficient Wrn
protein are mediated by the dysfunction of several cellular organelles.