mdh-1
C. elegans
Malate dehydrogenase, cytoplasmic
What the model saw
Gene: mdh-1 Organism: Caenorhabditis elegans Known functions: Malate dehydrogenase, cytoplasmic. L-malate dehydrogenase (NAD+) activity. catalytic activity. malate dehydrogenase activity. oxidoreductase activity. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
View unredacted entry
Malate dehydrogenase, cytoplasmic. L-malate dehydrogenase (NAD+) activity. catalytic activity. malate dehydrogenase activity. oxidoreductase activity. oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor.
Solver output
MDH-1 is the cytoplasmic malate dehydrogenase that catalyzes the interconversion of malate and oxaloacetate using NAD+/NADH as cofactors. This reaction is a central node in the malate-aspartate shuttle and the TCA cycle, directly regulating cytoplasmic NAD+/NADH ratios. Maintaining a high NAD+/NADH ratio in the cytoplasm supports sirtuin (SIR-2.1 in C. elegans) activity, which is a well-established pro-longevity pathway. Additionally, cytoplasmic MDH activity feeds into gluconeogenesis and amino acid metabolism, supporting metabolic homeostasis under nutrient stress conditions that are associated with longevity (e.g., dietary restriction). Loss of cytoplasmic malate dehydrogenase activity has been shown to impair metabolic flexibility and reduce lifespan in C. elegans, consistent with a pro-longevity role for its normal function.
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 with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning is plausible-sounding but ultimately incorrect. It assumed that because MDH-1 supports NAD+/NADH balance and metabolic homeostasis, it must be pro-longevity. However, in C. elegans, mdh-1 is actually anti-longevity, meaning its loss or reduction extends lifespan. The model even fabricated a claim that "loss of cytoplasmic malate dehydrogenase activity has been shown to impair metabolic flexibility and reduce lifespan in C. elegans," which is the opposite of what the GenAge database records. The mechanistic reasoning about sirtuins and NAD+ is speculative and not supported by the actual experimental evidence for this gene. The model was confidently wrong in both the direction of effect and the mechanism.
Raw API responses
solver
{
"reasoning": "MDH-1 is the cytoplasmic malate dehydrogenase that catalyzes the interconversion of malate and oxaloacetate using NAD+/NADH as cofactors. This reaction is a central node in the malate-aspartate shuttle and the TCA cycle, directly regulating cytoplasmic NAD+/NADH ratios. Maintaining a high NAD+/NADH ratio in the cytoplasm supports sirtuin (SIR-2.1 in C. elegans) activity, which is a well-established pro-longevity pathway. Additionally, cytoplasmic MDH activity feeds into gluconeogenesis and amino acid metabolism, supporting metabolic homeostasis under nutrient stress conditions that are associated with longevity (e.g., dietary restriction). Loss of cytoplasmic malate dehydrogenase activity has been shown to impair metabolic flexibility and reduce lifespan in C. elegans, consistent with a pro-longevity role for its normal function.",
"confidence": 0.72,
"key_pathways": [
"NAD+/NADH redox balance and sirtuin activation",
"TCA cycle and malate-aspartate shuttle",
"dietary restriction metabolic adaptation"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity with 0.72 confidence, but the ground truth is anti_longevity. The model's reasoning is plausible-sounding but ultimately incorrect. It assumed that because MDH-1 supports NAD+/NADH balance and metabolic homeostasis, it must be pro-longevity. However, in C. elegans, mdh-1 is actually anti-longevity, meaning its loss or reduction extends lifespan. The model even fabricated a claim that \"loss of cytoplasmic malate dehydrogenase activity has been shown to impair metabolic flexibility and reduce lifespan in C. elegans,\" which is the opposite of what the GenAge database records. The mechanistic reasoning about sirtuins and NAD+ is speculative and not supported by the actual experimental evidence for this gene. The model was confidently wrong in both the direction of effect and the mechanism.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}