| Summary: | As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in <i>WRN</i>, a gene involved in DNA replication and repair. Recent research has shown that <i>WRN</i> mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS (<i>WRNexo<sup>Δ</sup></i>) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young <i>WRNexo<sup>Δ</sup></i> adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. <i>WRNexo<sup>Δ</sup></i> adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged <i>WRNexo<sup>Δ</sup></i> adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in <i>WRNexo<sup>Δ</sup></i> is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate <i>WRNexo<sup>Δ</sup></i> flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases.
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