A Metabolic Brake on Aging: G3PP Activity Promotes Longevity

Possik E, Schmitt C, Al-Mass A, Bai Y, Côté L, Morin J, Erb H, Oppong A, Kahloan W, Parker JA, Madiraju SRM, Prentki M. Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans. Nat Commun 2022;13(1):177. doi: 10.1038/s41467-021-27803-6.

Background: Glycerol-3-phosphate phosphatase (G3PP) regulates glucose and lipid metabolism by hydrolyzing glycerol-3-phosphate (Gro3P) to glycerol. In mammals, G3PP protects against metabolic stress, but its in vivo physiological roles are incompletely understood. Because glycerol production in Caenorhabditis elegans is essential for osmotic adaptation and metabolic regulation, this nematode was used to explore the functions of G3PP homologs in stress responses and aging.

Hypothesis: This study hypothesized that G3PP homologs in C. elegans act as glycerol-3-phosphate phosphatases that protect against glucose and osmotic stress, regulate fat metabolism and promote healthy aging by limiting Gro3P-driven lipogenesis.

Methods: The authors identified three C. elegans G3PP homologs (pgph-1, pgph-2, pgph-3) and generated deletion and overexpression strains using CRISPR-Cas9 and transgenesis. Worm behaviors, lifespan, fat accumulation, stress resistance and glycerol metabolism were quantified. Locomotion and pumping rates were measured with WormLab to assess neuromuscular and feeding functions.

Results: Triple pgph mutants displayed reduced glycerol and increased Gro3P and fat deposition due to enhanced lipogenesis. pgph-2 emerged as the main isozyme required for glycerol synthesis and resistance to hyperosmotic and glucose-induced stress. Loss of PGPH enzymes shortened lifespan and healthspan, accelerated locomotor decline and heightened stress sensitivity. Conversely, pgph-2 overexpression decreased fat content, preserved motility and extended lifespan, especially under high-glucose conditions.

Conclusions: PGPH enzymes function as in vivo G3PPs that modulate metabolism and stress tolerance. By reducing lipogenesis and mimicking calorie restriction without altering food intake or fertility, PGPH activation promotes healthy aging in C. elegans.