gpd-2
C. elegans
Glyceraldehyde-3-phosphate dehydrogenase 2
What the model saw
Gene: gpd-2 Organism: Caenorhabditis elegans Known functions: Glyceraldehyde-3-phosphate dehydrogenase 2. NAD binding. NADP binding. glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity. oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor.
View unredacted entry
Glyceraldehyde-3-phosphate dehydrogenase 2. NAD binding. NADP binding. glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity. oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor.
Solver output
GPD-2 is a glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a central glycolytic enzyme that catalyzes the oxidative phosphorylation of glyceraldehyde-3-phosphate using NAD+ as a cofactor, producing NADH and 1,3-bisphosphoglycerate. Elevated glycolytic flux through GAPDH promotes glucose catabolism and energy production via fermentation-like pathways, which in C. elegans is associated with reduced lifespan compared to organisms that rely more on mitochondrial oxidative phosphorylation. In C. elegans, increased glycolysis (as opposed to oxidative metabolism) is linked to shortened lifespan, while interventions that reduce glycolytic activity or shift metabolism toward oxidative phosphorylation tend to extend lifespan. The NAD+/NADH ratio modulated by GAPDH activity also feeds into sirtuin (SIR-2.1) and other NAD+-dependent longevity pathways; high GAPDH activity consumes NAD+, potentially reducing sirtuin activity. Thus, the normal pro-glycolytic function of gpd-2 is expected to oppose longevity by promoting glucose-driven metabolism over the mitochondrial and stress-resistance programs associated with extended lifespan in C. elegans.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model correctly predicted anti_longevity for gpd-2. However, the mechanistic reasoning is speculative and not well-grounded in specific experimental evidence. The model constructs a plausible-sounding but generic argument about glycolysis vs. oxidative phosphorylation and NAD+/NADH ratios affecting sirtuins. The actual mechanism by which gpd-2 loss extends lifespan in C. elegans is more specifically tied to mitochondrial function and metabolic reprogramming (e.g., reducing glycolytic flux forces reliance on mitochondrial metabolism, activating stress responses). The model's reasoning about "high GAPDH activity consuming NAD+" reducing sirtuin activity is particularly questionable - GAPDH actually produces NADH from NAD+, which would reduce NAD+ availability, but the causal chain to longevity is oversimplified. The confidence of 0.62 is reasonable given the uncertainty. The mechanism_class of "deregulated_nutrient_sensing" is a loose fit at best.
Raw API responses
solver
{
"reasoning": "GPD-2 is a glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a central glycolytic enzyme that catalyzes the oxidative phosphorylation of glyceraldehyde-3-phosphate using NAD+ as a cofactor, producing NADH and 1,3-bisphosphoglycerate. Elevated glycolytic flux through GAPDH promotes glucose catabolism and energy production via fermentation-like pathways, which in C. elegans is associated with reduced lifespan compared to organisms that rely more on mitochondrial oxidative phosphorylation. In C. elegans, increased glycolysis (as opposed to oxidative metabolism) is linked to shortened lifespan, while interventions that reduce glycolytic activity or shift metabolism toward oxidative phosphorylation tend to extend lifespan. The NAD+/NADH ratio modulated by GAPDH activity also feeds into sirtuin (SIR-2.1) and other NAD+-dependent longevity pathways; high GAPDH activity consumes NAD+, potentially reducing sirtuin activity. Thus, the normal pro-glycolytic function of gpd-2 is expected to oppose longevity by promoting glucose-driven metabolism over the mitochondrial and stress-resistance programs associated with extended lifespan in C. elegans.",
"confidence": 0.62,
"key_pathways": [
"glycolysis / glucose catabolism",
"NAD+/NADH redox balance and sirtuin signaling",
"nutrient sensing and metabolic rate regulation"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for gpd-2. However, the mechanistic reasoning is speculative and not well-grounded in specific experimental evidence. The model constructs a plausible-sounding but generic argument about glycolysis vs. oxidative phosphorylation and NAD+/NADH ratios affecting sirtuins. The actual mechanism by which gpd-2 loss extends lifespan in C. elegans is more specifically tied to mitochondrial function and metabolic reprogramming (e.g., reducing glycolytic flux forces reliance on mitochondrial metabolism, activating stress responses). The model's reasoning about \"high GAPDH activity consuming NAD+\" reducing sirtuin activity is particularly questionable - GAPDH actually produces NADH from NAD+, which would reduce NAD+ availability, but the causal chain to longevity is oversimplified. The confidence of 0.62 is reasonable given the uncertainty. The mechanism_class of \"deregulated_nutrient_sensing\" is a loose fit at best.",
"failure_mode": "right_answer_wrong_reasoning",
"answer_correct": true,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}