Metabolic shift from glycogen to trehalose promotes lifespan and healthspan in Caenorhabditis elegans

Abstract

As Western diets continue to include an ever-increasing amount of sugar, there has been a rise in obesity and type 2 diabetes. To avoid metabolic diseases, the body must maintain proper metabolism, even on a high-sugar diet. In both humans and , excess sugar (glucose) is stored as glycogen. Here, we find that animals increased stored glycogen as they aged, whereas even young adult animals had increased stored glycogen on a high-sugar diet. Decreasing the amount of glycogen storage by modulating the glycogen synthase, , a key enzyme in glycogen synthesis, can extend lifespan, prolong healthspan, and limit the detrimental effects of a high-sugar diet. Importantly, limiting glycogen storage leads to a metabolic shift whereby glucose is now stored as trehalose. Two additional means to increase trehalose show similar longevity extension. Increased trehalose is entirely dependent on a functional FOXO transcription factor DAF-16 and autophagy to promote lifespan and healthspan extension. Our results reveal that when glucose is stored as glycogen, it is detrimental, whereas, when stored as trehalose, animals live a longer, healthier life if DAF-16 is functional. Taken together, these results demonstrate that trehalose modulation may be an avenue for combatting high-sugar-diet pathology.

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

“…As less G-6-P enters glycolysis, the ETC efficiently decreases the NADH/ NAD þ ratio. As lowering the GSH/GSSG ratio by gsr-1 or gspd-1 knockdown does not extend lifespan irrespective of the diet, [12,13] it is glycogen that causes glucose toxicity. [12] Thus, either a high GSH/GSSG ratio or a high glycogen content shortens lifespan on a high glucose diet.…”

“…[13] The effect of glycogen is independent of insulin signaling, as pyg-1 RNAi dramatically increases glucose toxicity in daf-2 worms, while gsy-1 knockdown rescues glucose toxicity in both daf-2 and daf-16 worms. It is independent of trehalose biosynthesis, because the gsy-1 deletion extends the lifespan of wt and trehalose-deficient worms equally well.…”

“…[12] Thus, either a high GSH/GSSG ratio or a high glycogen content shortens lifespan on a high glucose diet. As lowering the GSH/GSSG ratio by gsr-1 or gspd-1 knockdown does not extend lifespan irrespective of the diet, [12,13] it is glycogen that causes glucose toxicity. Indeed, worms lacking glycogen phosphorylase (pyg-1), the enzyme that catalyzes glucose release from glycogen, accumulate glycogen at a high level and die early when fed a high glucose diet.…”

“…[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.…”

“…Originally viewed as merely inert storage, glycogen has been shown to be associated with numerous proteins that modulate glucose metabolism. [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.…”