Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance <i>via</i> the mitochondrial unfolded protein response.

Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPR^mt) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from <i>Stevia rebaudiana</i>, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of <i>Caenorhabditis elegans</i> was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan(definition) in <i>C. elegans via</i> activation of the ATFS-1-mediated UPR^mt pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in <i>C. elegans via</i> the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in <i>C. elegans</i> required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.