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

Abstract

High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis 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 gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-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.

A glucose-supplemented diet enhances gut barrier integrity in Drosophila

“…Interestingly, high glucose (2% or 111 mM) treatment in young worms (1–3 days old) reduces lifespan, but beginning glucose treatment after worms are at a post-reproductive age (7 days old) extends lifespan ( Lei et al, 2018 preprint). A recent study found a direct effect of glucose metabolism on aging in worms, where glycolysis is detrimental to, and gluconeogenesis is beneficial to healthy aging, though not maximal longevity ( Onken et al, 2020 ). As glucose metabolism is evolutionarily conserved, it will be of interest to explore the role of glycolysis and gluconeogenesis in GSF-dependent lifespan extension in flies and vertebrate models.…”

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

“…[46] In C. elegans, increased activity of PEPCK and another gluconeogenic enzyme, fructose-1,6-bisphosphatase, are each required for the longevity effects of CR. [47] This consumption of oxaloacetate to produce glucose should drive the AST reaction in the reverse direction, depleting aspartate (Reverse AST: AKG + Aspartate → Glutamate + Oxaloacetate).…”

“…[ 46 ] In C. elegans , increased activity of PEPCK and another gluconeogenic enzyme, fructose‐1,6‐bisphosphatase, are each required for the longevity effects of CR. [ 47 ]…”

Effects of High Dietary Carbohydrate and Lipid Intake on the Lifespan of C. elegans

“…To increase the knowledge about the cellular damage induced by these conditions, high-carbohydrate intake studies in C. elegans have been conducted in high-glucose diets that mimic the high-carbohydrate diets consumed by humans. One of the most intriguing results is the reduction of its lifespan and changes in several metabolic regulators that contribute to it exerting deleterious effects by which glucose decreases lifespan [ 21 ].…”

“…After glucose uptake, glycolysis is active in breaking down glucose and extracting energy or storing it in glycogen form. An analysis to determine whether glycolytic genes are associated with lifespan in C. elegans showed that of the three major irreversible regulatory enzymes of glycolysis, hexokinase (HXs), phosphofructokinase (PFK), and pyruvate kinase (PYK-1,2)-, both PFK and PYK knockdown extended the lifespan of C. elegans [ 21 , 30 , 31 ]; a similar effect was seen for glucose phosphate isomerase (GPI) and phosphoglycerate mutase (PGAM), which are also glycolytic enzymes ( Figure 2 ) [ 32 , 33 ]. This effect was probably due to the blockade of glucose metabolism, which likely altered the metabolic flux, reducing mitochondrial respiration or ATP synthesis, thereby increasing the lifespan, similarly to caloric restriction, although we cannot disregard that other pathways may be implicated in increasing lifespan.…”