An enzyme involved in handling glucose-derived metabolites helped laboratory worms remain more mobile as they aged and live longer under excess-glucose conditions. The work centres on PGPH-2, a worm counterpart of glycerol-3-phosphate phosphatase, or G3PP, and suggests how changing the flow of metabolism can influence cellular maintenance.
The study by Elite Possik and colleagues, published in Nature Communications in August 2023, used the nematode Caenorhabditis elegans. It investigated a biological mechanism, not an anti-ageing treatment tested in people.
What G3PP does
G3PP removes a phosphate group from glycerol-3-phosphate to produce glycerol. This reaction forms part of a metabolic route known as the glycerol shunt. Glycerol-3-phosphate sits at a junction between carbohydrate and fat metabolism, so changing how it is processed can affect more than one cellular pathway.
To study this in worms, the researchers created stable transgenic lines that produced more PGPH-2. They compared these animals with controls under normal laboratory conditions and on growth plates supplemented with 2% glucose. The glucose concentration describes an experimental growth medium, not a recommendation for human food intake or a measure of human blood sugar.
Better movement, with an important lifespan distinction
The engineered worms accumulated less fat and fewer age-associated yolk deposits. They also retained better movement with age, measured through body bends. These observations supported an improvement in aspects of healthspan: how well an animal functions as it gets older.
Lifespan gave a more conditional result. The increase was statistically significant under excess-glucose conditions. Under normal growth conditions, the lifespan difference was not statistically significant, even though movement improved. The experiment therefore does not show that increasing this enzyme reliably extends life in every setting.
The benefits were not accompanied by reduced pharyngeal pumping, the feeding-related movement the researchers used as an indicator of food intake. That finding matters because simply feeding less can change ageing in worms. However, pumping is a proxy; it is not a direct measurement of calories absorbed.
Connecting metabolism to cellular recycling
The team traced a pathway from PGPH-2 to changes in glycogen, a stored form of glucose. Lower glycogen levels were associated with activation of AMPK, a regulator that helps coordinate cellular metabolism.
This promoted movement of HLH-30 into the cell nucleus. HLH-30 is the worm counterpart of the mammalian transcription factor TFEB, which helps control genes involved in cellular recycling. The resulting response increased autophagy, a process through which cells break down and reuse their own components.
The researchers tested this proposed connection through genetic interventions. Disrupting parts of the pathway weakened or removed the protective effects. For example, loss of HLH-30 abolished the movement and lifespan benefits under glucose stress. These experiments support a functional link between the metabolic change and the maintenance response, beyond a simple correlation between enzyme levels and survival.
A partial parallel with calorie restriction
Some results resembled benefits associated with calorie restriction, including lower fat accumulation and better function with age. The authors described this as a partial mimicry, rather than showing that raising PGPH-2 is equivalent to eating less.
There was also a trade-off: the stable PGPH-2-overexpressing worms produced slightly fewer offspring, a statistically significant reduction under both normal and excess-glucose conditions. That result rules out describing the intervention as benefit-only or free of reproductive effects.
The study makes G3PP-related metabolism a useful subject for further research. It does not establish whether increasing G3PP in people would reproduce the worm results, which tissues would need to be targeted, or whether an intervention would be safe. Those questions require evidence beyond this experiment.
Related reading
For a different approach to ageing research, see our coverage of molecular changes associated with human muscle ageing.
Reference
- Possik, E. et al. (2023). Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans. Nature Communications, 14, 5214. Research paper and supplementary material.
Update note: Revised on 1 October 2026 to identify the worm model and journal correctly, distinguish healthspan from condition-dependent lifespan results, and include the reproductive trade-off and limits of human translation. The illustration shows a separately studied mouse homolog, as identified in its caption. The original publication date is retained.
