idha-1
C. elegans
putative isocitrate dehydrogenase
What the model saw
Gene: idha-1 Organism: Caenorhabditis elegans Known functions: putative isocitrate dehydrogenase. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
View unredacted entry
putative isocitrate dehydrogenase. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
Solver output
idha-1 encodes a mitochondrial NAD+-dependent isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the TCA cycle, generating NADH and CO2. This reaction is a critical node in mitochondrial energy metabolism and also produces alpha-ketoglutarate (αKG), a key metabolite that serves as a cofactor for numerous dioxygenases including histone and DNA demethylases. Robust TCA cycle flux through IDH supports mitochondrial membrane potential, efficient oxidative phosphorylation, and ATP production, all of which are hallmarks of healthy mitochondrial function associated with longevity. In C. elegans, αKG supplementation has been shown to extend lifespan by inhibiting ATP synthase and activating AMPK, suggesting that IDH activity promoting αKG availability is pro-longevity. Additionally, NAD+ regeneration capacity and TCA cycle integrity are tightly linked to mitochondrial health and stress resistance in aging models.
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 predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning is plausible on the surface — IDH activity supports TCA cycle flux and αKG production — but it reaches the wrong conclusion. In C. elegans, idha-1 is anti-longevity, meaning its loss or reduction likely extends lifespan. This is consistent with the broader finding that reducing mitochondrial respiration/TCA cycle activity (e.g., through reduced electron transport chain function) can extend lifespan in C. elegans via mechanisms like reduced ROS production or activation of mitohormesis. The model's reasoning about αKG supplementation extending lifespan is actually somewhat contradictory to its conclusion: if exogenous αKG extends lifespan by inhibiting ATP synthase, that doesn't necessarily mean endogenous IDH activity (which feeds into oxidative phosphorylation) is pro-longevity. The model was moderately confident (0.72) in the wrong direction. The reasoning quality is moderate — it shows relevant biological knowledge but misapplies it to reach the wrong conclusion.
Raw API responses
solver
{
"reasoning": "idha-1 encodes a mitochondrial NAD+-dependent isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the TCA cycle, generating NADH and CO2. This reaction is a critical node in mitochondrial energy metabolism and also produces alpha-ketoglutarate (αKG), a key metabolite that serves as a cofactor for numerous dioxygenases including histone and DNA demethylases. Robust TCA cycle flux through IDH supports mitochondrial membrane potential, efficient oxidative phosphorylation, and ATP production, all of which are hallmarks of healthy mitochondrial function associated with longevity. In C. elegans, αKG supplementation has been shown to extend lifespan by inhibiting ATP synthase and activating AMPK, suggesting that IDH activity promoting αKG availability is pro-longevity. Additionally, NAD+ regeneration capacity and TCA cycle integrity are tightly linked to mitochondrial health and stress resistance in aging models.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / mitochondrial oxidative metabolism",
"alpha-ketoglutarate signaling and epigenetic regulation",
"NAD+/NADH redox balance"
],
"mechanism_class": "mitochondrial_dysfunction",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning is plausible on the surface — IDH activity supports TCA cycle flux and αKG production — but it reaches the wrong conclusion. In C. elegans, idha-1 is anti-longevity, meaning its loss or reduction likely extends lifespan. This is consistent with the broader finding that reducing mitochondrial respiration/TCA cycle activity (e.g., through reduced electron transport chain function) can extend lifespan in C. elegans via mechanisms like reduced ROS production or activation of mitohormesis. The model's reasoning about αKG supplementation extending lifespan is actually somewhat contradictory to its conclusion: if exogenous αKG extends lifespan by inhibiting ATP synthase, that doesn't necessarily mean endogenous IDH activity (which feeds into oxidative phosphorylation) is pro-longevity. The model was moderately confident (0.72) in the wrong direction. The reasoning quality is moderate — it shows relevant biological knowledge but misapplies it to reach the wrong conclusion.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}