Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension.

Author summary It is known that high levels of dietary sugar can negatively impact human health, but the mechanisms underlying this remain unclear. Here we use the facileCaenorhabditis elegansgenetic model to extend understanding of the impact of glucose and glucose metabolism on health and aging. We show that the two opposing glucose metabolism pathways-glycolysis and gluconeogenesis-have dramatically opposite effects on health: glycolytic activity responsible for sugar catabolism is detrimental, but driving gluconeogenesis promotes healthy aging. The powerful longevity regulator DAF-16 is required for the healthspan effects of gluconeogenesis. Our data highlight the intriguing possibility that driving the biosynthetic gluconeogenesis pathway could be a novel strategy for healthspan promotion. Indeed, we find that increasing levels of the core gluconeogenic enzyme PEPCK (PCK-2) in just a few intestinal cells can increase overall health in a DAF-16-dependent manner. Dietary restriction, which can promote health and longevity across species, increases PCK-2 levels in the intestine via DAF-16, and PCK-2 is required for the health benefits seen when calories are limited. Our results define gluconeogenic metabolism as a key component of healthy aging, and suggest that interventions that promote gluconeogenesis may help combat the onset of age-related diseases, including diabetes. High glucose diets are unhealthy, although the mechanisms by which ikelevated glucose is harmful to whole animal physiology are not well understood. InCaenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic genepck-2(encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promotepck-2expression in specific intestinal cells. Dietary restriction also features DAF-16-dependentpck-2expression in the intestine, and the healthspan benefits conferred by dietary restriction requirepck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.