IDH1
S. cerevisiae
isocitrate dehydrogenase (NAD(+)) IDH1
What the model saw
Gene: IDH1 Organism: Saccharomyces cerevisiae Known functions: isocitrate dehydrogenase (NAD(+)) IDH1. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor. protein binding.
View unredacted entry
isocitrate dehydrogenase (NAD(+)) IDH1. NAD binding. isocitrate dehydrogenase (NAD+) activity. magnesium ion binding. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor. protein binding.
Solver output
IDH1 encodes the NAD+-dependent isocitrate dehydrogenase subunit that 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 metabolism and connects carbon flux to NAD+/NADH ratios. In yeast, robust TCA cycle activity supports mitochondrial respiration and efficient energy metabolism, which are associated with extended chronological and replicative lifespan. Furthermore, alpha-ketoglutarate (a-KG), the product of this reaction, is a known pro-longevity metabolite that inhibits ATP synthase and activates AMPK-like pathways, and also serves as a cofactor for TET/JmjC demethylases involved in epigenetic regulation. Maintenance of NAD+ levels through this cycle also feeds into sirtuin (Sir2) activity in yeast, a well-established pro-longevity pathway. Loss of IDH1 function in yeast has been shown to reduce lifespan, consistent with a pro-longevity role for this enzyme.
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 internally consistent but leads to the wrong conclusion. The model argues that IDH1 loss reduces lifespan (implying pro-longevity role), but the GenAge database classifies IDH1 as anti_longevity, meaning its activity shortens lifespan (or its deletion extends lifespan). The model's mechanistic reasoning about TCA cycle, alpha-ketoglutarate, and NAD+/sirtuin connections is plausible in general but misapplied here. The model even contradicts itself slightly by noting "Loss of IDH1 function in yeast has been shown to reduce lifespan" — if loss reduces lifespan, that would support pro-longevity, but the ground truth says anti-longevity. This suggests the actual experimental data shows IDH1 deletion extends lifespan in yeast, which the model failed to correctly identify. The confidence of 0.72 is notably high for an incorrect answer.
Raw API responses
solver
{
"reasoning": "IDH1 encodes the NAD+-dependent isocitrate dehydrogenase subunit that 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 metabolism and connects carbon flux to NAD+/NADH ratios. In yeast, robust TCA cycle activity supports mitochondrial respiration and efficient energy metabolism, which are associated with extended chronological and replicative lifespan. Furthermore, alpha-ketoglutarate (a-KG), the product of this reaction, is a known pro-longevity metabolite that inhibits ATP synthase and activates AMPK-like pathways, and also serves as a cofactor for TET/JmjC demethylases involved in epigenetic regulation. Maintenance of NAD+ levels through this cycle also feeds into sirtuin (Sir2) activity in yeast, a well-established pro-longevity pathway. Loss of IDH1 function in yeast has been shown to reduce lifespan, consistent with a pro-longevity role for this enzyme.",
"confidence": 0.72,
"key_pathways": [
"TCA cycle / alpha-ketoglutarate production",
"NAD+/NADH redox balance and sirtuin activation",
"Mitochondrial respiration and energy metabolism"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" but the ground truth is \"anti_longevity.\" The model's reasoning is internally consistent but leads to the wrong conclusion. The model argues that IDH1 loss reduces lifespan (implying pro-longevity role), but the GenAge database classifies IDH1 as anti_longevity, meaning its activity shortens lifespan (or its deletion extends lifespan). The model's mechanistic reasoning about TCA cycle, alpha-ketoglutarate, and NAD+/sirtuin connections is plausible in general but misapplied here. The model even contradicts itself slightly by noting \"Loss of IDH1 function in yeast has been shown to reduce lifespan\" — if loss reduces lifespan, that would support pro-longevity, but the ground truth says anti-longevity. This suggests the actual experimental data shows IDH1 deletion extends lifespan in yeast, which the model failed to correctly identify. The confidence of 0.72 is notably high for an incorrect answer.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}