Glycerol‐3‐Phosphate Phosphatase/ <i>PGP:</i> A Novel Dietary Restriction Mimetic Enzyme that Protects from Glucotoxicity and Prolongs Healthspan in <i>C. elegans</i>
Bibliographic record
Abstract
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age‐associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we studied the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol 3‐phosphate phosphatase (G3PP) (gene name Pgp ) that hydrolyzes glucose‐derived glycerol‐3‐phosphate (Gro3P) to glycerol. Gro3P is a key metabolite that regulates flux of various metabolic pathways and particularly, the glycerolipid/fatty acid (GL/FA) cycle associated with obesity, type‐2‐diabetes, and cardiometabolic disorders. We identify three Pgp homologues in C. elegans ( pgph1, pgph‐2, and pgph‐3 ) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis and contributes to stress responses and healthy aging. Hyperosmotic and high glucose stresses induce pgph transcripts, glycerol production, and salt stress adaptation in a PGPH ‐dependent manner. Using targeted metabolomics, we find that Gro3P accumulates in pgph mutant animals in basal conditions and more prominently following salt and glucose stresses, while most intermediary metabolites are rarely altered by PGPH loss. Using an unbiased transcription factors RNAi screen, we further identify transcriptional regulators of pgph‐2 and pgph‐3 salt‐mediated expression. Loss of PGPH increases fat deposition, exacerbates glucotoxicity, decreases resistance to various stresses, shortens median lifespan and decreases healthspan parameters. Importantly, pgph‐2 overexpression reduces fat deposition with age at basal and glucose excess conditions without restricting animal feeding or decreasing reproduction. Overexpression of pgph‐2 improves healthspan and protects from glucotoxicity retarding age‐related locomotor decline in normal and high glucose conditions. Strikingly, our data suggest that the overexpression of pgph‐2 partly mimics the beneficial effects of dietary restriction. Overall, the results demonstrate that G3PP/PGP is a novel evolutionary conserved regulator of glucose and fat metabolism that protects against nutrient and environmental stresses and is involved in glucose detoxification and healthy aging.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".