Abstract
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 WRN, a gene involved in DNA replication and repair. Recent research has shown that WRN 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 (WRNexoΔ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexoΔ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexoΔ 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 WRNexoΔ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexoΔ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexoΔ 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.
Highlights
Aging is the culmination of a complex network of physiological and genetic processes resulting in cellular decline
One unifying concept in identifying causes of aging is a balance between stressors and stress responses [3] in that aging can be promoted by stress levels that exceed the capacity of stress response mechanisms
We chose three exogenous stressors: oxidative stress, elevated ambient temperature, and starvation, which are well supported in the literature as eliciting a stress response in flies [9,10,11,12,13,14,15]
Summary
Aging is the culmination of a complex network of physiological and genetic processes resulting in cellular decline. In 2013, Lopez-Ortin et al categorized common aging processes into the nine hallmarks of aging, a hierarchical framework of causes of cellular damage (e.g., genomic instability, and telomere attrition), damage responses (i.e., dysregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence), and phenotypic manifestations of unrepaired damage (i.e., stem cell exhaustion and altered intercellular communication) [1]. Kennedy et al, contributed a similar list to the aging field, the seven pillars of aging, which drew upon broader categories of decline in cellular processes (proteostasis, metabolism, stem cells and regeneration, macromolecule damage, epigenetics, inflammation, and adaptation to stress) to focus on the extension of human “healthspan” [2]. Cells are routinely exposed to aging-promoting stressors (e.g., 4.0/)
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