nuo-2
C. elegans
NADH dehydrogenase
What the model saw
Gene: nuo-2 Organism: Caenorhabditis elegans Known functions: NADH dehydrogenase. NADH dehydrogenase (ubiquinone) activity. oxidoreductase activity, acting on NAD(P)H.
View unredacted entry
NADH dehydrogenase. NADH dehydrogenase (ubiquinone) activity. oxidoreductase activity, acting on NAD(P)H.
Solver output
nuo-2 encodes a subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), the first and largest enzyme of the mitochondrial electron transport chain. In C. elegans, partial loss-of-function of Complex I subunits (e.g., nuo-1, gas-1) is well-documented to extend lifespan through mild mitochondrial stress signaling (mitohormesis), activating the mitochondrial unfolded protein response (UPRmt) and reducing electron flow that would otherwise generate damaging reactive oxygen species. However, the normal function of nuo-2 is to support efficient NADH oxidation and ATP production; complete loss is lethal, indicating the gene's baseline activity is essential. The pro-longevity prediction reflects that the gene's normal, intact function maintains mitochondrial homeostasis and prevents the chronic mitochondrial dysfunction and ROS overproduction associated with aging, placing it in the pro-longevity category under physiological conditions. The key tension is that mild reduction of Complex I activity can extend life via hormesis, but the gene's normal molecular role is to sustain oxidative phosphorylation efficiency, which is itself a hallmark of healthy aging.
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 contradictory and ultimately lands on the wrong answer. It correctly identifies that partial loss-of-function of Complex I subunits in C. elegans (like nuo-1, gas-1) extends lifespan via mitohormesis, which would make nuo-2 an anti-longevity gene (since reducing its function extends life). However, the model then pivots to argue that the gene's "normal function" maintains mitochondrial homeostasis and thus classifies it as pro_longevity. This reasoning conflates the gene's molecular role with its longevity influence classification. In GenAge, anti_longevity means that the gene's activity works against longevity (i.e., reducing it extends lifespan), which is exactly what the mitohormesis evidence the model cites would support. The model essentially had the right mechanistic evidence but drew the wrong conclusion from it, and the confidence of 0.62 is not appropriately low given the acknowledged tension in the reasoning.
Raw API responses
solver
{
"reasoning": "nuo-2 encodes a subunit of mitochondrial Complex I (NADH:ubiquinone oxidoreductase), the first and largest enzyme of the mitochondrial electron transport chain. In C. elegans, partial loss-of-function of Complex I subunits (e.g., nuo-1, gas-1) is well-documented to extend lifespan through mild mitochondrial stress signaling (mitohormesis), activating the mitochondrial unfolded protein response (UPRmt) and reducing electron flow that would otherwise generate damaging reactive oxygen species. However, the normal function of nuo-2 is to support efficient NADH oxidation and ATP production; complete loss is lethal, indicating the gene's baseline activity is essential. The pro-longevity prediction reflects that the gene's normal, intact function maintains mitochondrial homeostasis and prevents the chronic mitochondrial dysfunction and ROS overproduction associated with aging, placing it in the pro-longevity category under physiological conditions. The key tension is that mild reduction of Complex I activity can extend life via hormesis, but the gene's normal molecular role is to sustain oxidative phosphorylation efficiency, which is itself a hallmark of healthy aging.",
"confidence": 0.62,
"key_pathways": [
"mitochondrial electron transport chain (Complex I)",
"NADH oxidation / oxidative phosphorylation",
"mitohormesis / UPRmt signaling"
],
"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 internally contradictory and ultimately lands on the wrong answer. It correctly identifies that partial loss-of-function of Complex I subunits in C. elegans (like nuo-1, gas-1) extends lifespan via mitohormesis, which would make nuo-2 an anti-longevity gene (since reducing its function extends life). However, the model then pivots to argue that the gene's \"normal function\" maintains mitochondrial homeostasis and thus classifies it as pro_longevity. This reasoning conflates the gene's molecular role with its longevity influence classification. In GenAge, anti_longevity means that the gene's activity works against longevity (i.e., reducing it extends lifespan), which is exactly what the mitohormesis evidence the model cites would support. The model essentially had the right mechanistic evidence but drew the wrong conclusion from it, and the confidence of 0.62 is not appropriately low given the acknowledged tension in the reasoning.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}