D-glyceric acid enhances the maintenance of glycerophospholipid membranes in 50-60-year-old healthy humans

Background Already 4-day D-glyceric acid (DGA) regimen causes strong positive metabolic effects in older humans that persist even after 2-week follow-up period. Moreover, the effects resemble exercise regimen and especially membrane integrity seems to be enhanced. Purpose We aim to further elucidate both the exercise and membrane enhancement effects of exogenous DGA. Methods We investigate the responses in underlying metabolic flows indirectly. We use nonacute measurements of blood metabolites and intracellular mRNA expressions, which cover all essential metabolic steps in studied underlying pathway. Strictly irreversible enzyme reactions, their nonacute mRNA changes and associations are the gears. There were altogether 5 different observation points with control in the study. During the first week, the control was the division of participants into high and lower aerobic capacity subgroups with perceived placebo group. Thereafter, the control was genuine placebo group. Results De novo synthesis of DGA seems to be mostly from glycerol. DGA regimen causes GLYCTK activation which coincides with increased use of lipids. Lipids are mostly obtained from TGs lipase reactions that simultaneously liberate glycerol. Endogenous DGA from glycerol prolongs the effect of exogenous DGA. Phosphorylated DGA (2PG) is used as a carbon backbone in glycerophospholipid (GPL) synthesis via glyceroneogenesis. Moreover, we showed that de novo synthesis of GPL was increased during the DGA regimen, which furthermore led to the significant reduction in systemic inflammation. Additionally, our results suggest that lactate and ATP are acutely generated after each dose of the DGA via increased use of glycogen. Conclusions Endogenous DGA generation from glycerol after physical exercise likely explains the strong exercise-like effects of exogenous DGA. Now elucidated DGA-GPL-pathway further underlines the potential of the DGA regimen as an effective medicine for age-associated degeneration diseases with unmet medical need such as neurodegeneration. Trial registration number (14 ^th of Jan 2021), ClinicalTrials.gov Identifier: NCT04713319