nac-2
C. elegans
Sodium-dependent high-affinity dicarboxylate transporter 2
What the model saw
Gene: nac-2 Organism: Caenorhabditis elegans Known functions: Sodium-dependent high-affinity dicarboxylate transporter 2. citrate transmembrane transporter activity. succinate transmembrane transporter activity. transmembrane transporter activity.
View unredacted entry
Sodium-dependent high-affinity dicarboxylate transporter 2. citrate transmembrane transporter activity. succinate transmembrane transporter activity. transmembrane transporter activity.
Solver output
nac-2 encodes a sodium-dependent high-affinity dicarboxylate transporter responsible for importing TCA cycle intermediates—specifically citrate and succinate—across membranes. Citrate is a key allosteric activator of fatty acid synthesis and an inhibitor of glycolysis (via phosphofructokinase inhibition), while succinate can act as a signaling metabolite that stabilizes HIF-1α and drives pro-growth, pro-inflammatory metabolic states. Elevated import of these dicarboxylates would fuel anabolic metabolism and suppress catabolic/stress-response pathways that are associated with longevity in C. elegans (e.g., reduced insulin/IGF-1 signaling, mitochondrial hormesis). Loss of nac-2 function would be expected to reduce intracellular citrate/succinate availability, potentially mimicking dietary restriction-like metabolic states that extend lifespan. This places nac-2 in the deregulated nutrient-sensing hallmark, as dicarboxylate transport directly modulates the availability of TCA intermediates that feed into TORC1 and lipid anabolic signaling.
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 nac-2. However, the mechanistic reasoning is largely speculative and not well-supported by established literature. The model constructs a plausible-sounding but unverified chain of logic: nac-2 imports citrate/succinate → fuels anabolic metabolism → suppresses longevity pathways → loss of nac-2 extends lifespan. While this reasoning is internally consistent, it relies heavily on extrapolation from mammalian/general biochemistry rather than established C. elegans nac-2 biology. The HIF-1α stabilization by succinate argument is particularly speculative in this context. The classification as "deregulated_nutrient_sensing" is reasonable but not definitively established. The confidence of 0.65 is appropriate given the uncertainty. The correct answer appears to have been reached through plausible but unverified mechanistic speculation rather than solid evidence-based reasoning.
Raw API responses
solver
{
"reasoning": "nac-2 encodes a sodium-dependent high-affinity dicarboxylate transporter responsible for importing TCA cycle intermediates—specifically citrate and succinate—across membranes. Citrate is a key allosteric activator of fatty acid synthesis and an inhibitor of glycolysis (via phosphofructokinase inhibition), while succinate can act as a signaling metabolite that stabilizes HIF-1α and drives pro-growth, pro-inflammatory metabolic states. Elevated import of these dicarboxylates would fuel anabolic metabolism and suppress catabolic/stress-response pathways that are associated with longevity in C. elegans (e.g., reduced insulin/IGF-1 signaling, mitochondrial hormesis). Loss of nac-2 function would be expected to reduce intracellular citrate/succinate availability, potentially mimicking dietary restriction-like metabolic states that extend lifespan. This places nac-2 in the deregulated nutrient-sensing hallmark, as dicarboxylate transport directly modulates the availability of TCA intermediates that feed into TORC1 and lipid anabolic signaling.",
"confidence": 0.65,
"key_pathways": [
"TCA cycle intermediate transport (citrate/succinate)",
"Nutrient/anabolic sensing via citrate-driven lipid synthesis",
"HIF-1α stabilization by succinate signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for nac-2. However, the mechanistic reasoning is largely speculative and not well-supported by established literature. The model constructs a plausible-sounding but unverified chain of logic: nac-2 imports citrate/succinate → fuels anabolic metabolism → suppresses longevity pathways → loss of nac-2 extends lifespan. While this reasoning is internally consistent, it relies heavily on extrapolation from mammalian/general biochemistry rather than established C. elegans nac-2 biology. The HIF-1α stabilization by succinate argument is particularly speculative in this context. The classification as \"deregulated_nutrient_sensing\" is reasonable but not definitively established. The confidence of 0.65 is appropriate given the uncertainty. The correct answer appears to have been reached through plausible but unverified mechanistic speculation rather than solid evidence-based reasoning.",
"failure_mode": "right_answer_wrong_reasoning",
"answer_correct": true,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}