High-glycemic-index diets, as well as a sedentary lifestyle are considered as determinant factors for the development of obesity, type 2 diabetes, and cardiovascular diseases in humans. These diets have been shown to shorten the life span of C. elegans in a manner that is dependent on insulin signaling, but the participation of other signaling pathways have not been addressed. In this study, we have determined that worms fed with high-glucose diets show alterations in glucose content and uptake, triglyceride content, body size, number of eggs laid, egg-laying defects, and signs of oxidative stress and accelerated aging. Additionally, we analyzed the participation of different key regulators of carbohydrate and lipid metabolism, oxidative stress and longevity such as SKN-1/NRF2, HIF-1/HIF1α, SBP-1/SREBP, CRH-1/CREB, CEP-1/p53, and DAF-16/FOXO, in the reduction of lifespan in glucose-fed worms.