Glycogen controls Caenorhabditis elegans lifespan and resistance to oxidative stress

Abstract

A high-sugar diet has been associated with reduced lifespan in organisms ranging from worms to mammals. However, the mechanisms underlying the harmful effects of glucose are poorly understood. Here we establish a causative relationship between endogenous glucose storage in the form of glycogen, resistance to oxidative stress and organismal aging in Caenorhabditis elegans. We find that glycogen accumulated on high dietary glucose limits C. elegans longevity. Glucose released from glycogen and used for NADPH/glutathione reduction renders nematodes and human hepatocytes more resistant against oxidative stress. Exposure to low levels of oxidants or genetic inhibition of glycogen synthase depletes glycogen stores and extends the lifespan of animals fed a high glucose diet in an AMPK-dependent manner. Moreover, glycogen interferes with low insulin signalling and accelerates aging of long-lived daf-2 worms fed a high glucose diet. Considering its extensive evolutionary conservation, our results suggest that glycogen metabolism might also have a role in mammalian aging.

Glycogen at the Crossroad of Stress Resistance, Energy Maintenance, and Pathophysiology of Aging

“…Consumption of a high sugar diet induces metabolic changes in C. elegans similar to those in other animals. [12] Intermediate glucose and amino acid metabolism is also upregulated. [32][33][34][35] They also increase their glycogen stores.…”

“…Notably, deletion of genes required for FA synthesis dramatically increases glucose toxicity. [12] 4. Re-routing carbohydrate metabolism upon glucose excess, oxidative stress, or uncoupling mitochondrial respiration.…”

“…[49] Taken together, these observations suggest that overconsumption of glucose does not immediately induce oxidative stress. [12,50] Remodeling of the carbohydrate utilization pathways might explain such paradoxical resistance. [14,22] Despite the downregulation of the expression of SOD-3, glucose-fed worms are more resistant to exogenous oxidants.…”

“…[10,11] In light of recent findings in Caenorhabditis elegans, [12,13] we aim here to elucidate the surprising connections between glucose toxicity, glycogen accumulation, oxidative stress, and aging. [10,11] In light of recent findings in Caenorhabditis elegans, [12,13] we aim here to elucidate the surprising connections between glucose toxicity, glycogen accumulation, oxidative stress, and aging.…”

The Study of Aging in Caenorhabditis elegans

“…Other studies have looked at the effect of diet on longevity. Recent research with C. elegans shows that diets high in glycogen decrease lifespan and accelerates the aging of the daf-2 worms that normally have an extended lifespan [7].…”