lars-2
C. elegans
leucine--tRNA ligase
What the model saw
Gene: lars-2 Organism: Caenorhabditis elegans Known functions: leucine--tRNA ligase. ATP binding. aminoacyl-tRNA ligase activity. leucine-tRNA ligase activity. nucleotide binding.
View unredacted entry
leucine--tRNA ligase. ATP binding. aminoacyl-tRNA ligase activity. leucine-tRNA ligase activity. nucleotide binding.
Solver output
lars-2 encodes the mitochondrial leucine-tRNA ligase in C. elegans, responsible for charging leucine onto its cognate tRNA to support mitochondrial translation. Critically, leucyl-tRNA synthetase (LRS/LARS) acts as a direct intracellular leucine sensor that activates TORC1 (mTORC1) by recruiting it to the lysosome/vacuole via the RagGTPase pathway. Partial loss-of-function of lars-2 reduces leucine-sensing capacity, thereby attenuating TORC1 signaling, which mimics dietary restriction and extends lifespan in C. elegans. This places lars-2 in the deregulated nutrient-sensing hallmark, where reduced TORC1 activity through impaired leucine sensing is a well-established pro-longevity mechanism. Additionally, mild mitochondrial translation impairment from reduced lars-2 activity can trigger the mitochondrial unfolded protein response (UPRmt), which has also been linked to lifespan extension in C. elegans.
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 constructed a plausible-sounding mechanistic argument (reduced TORC1 signaling via impaired leucine sensing, UPRmt activation) that would support pro_longevity, but this is incorrect for lars-2 in C. elegans. lars-2 is actually anti_longevity, meaning its loss or reduction shortens lifespan rather than extending it. The model's reasoning about cytoplasmic LRS acting as a leucine sensor for TORC1 may be conflating the cytoplasmic leucyl-tRNA synthetase (lars-1) with the mitochondrial form (lars-2). The mitochondrial lars-2 is primarily involved in mitochondrial translation, and its loss likely impairs mitochondrial function in a way that is detrimental to lifespan. The model showed moderate confidence (0.72) in the wrong direction. The reasoning quality is moderate - it is internally coherent but based on incorrect premises about lars-2's role.
Raw API responses
solver
{
"reasoning": "lars-2 encodes the mitochondrial leucine-tRNA ligase in C. elegans, responsible for charging leucine onto its cognate tRNA to support mitochondrial translation. Critically, leucyl-tRNA synthetase (LRS/LARS) acts as a direct intracellular leucine sensor that activates TORC1 (mTORC1) by recruiting it to the lysosome/vacuole via the RagGTPase pathway. Partial loss-of-function of lars-2 reduces leucine-sensing capacity, thereby attenuating TORC1 signaling, which mimics dietary restriction and extends lifespan in C. elegans. This places lars-2 in the deregulated nutrient-sensing hallmark, where reduced TORC1 activity through impaired leucine sensing is a well-established pro-longevity mechanism. Additionally, mild mitochondrial translation impairment from reduced lars-2 activity can trigger the mitochondrial unfolded protein response (UPRmt), which has also been linked to lifespan extension in C. elegans.",
"confidence": 0.72,
"key_pathways": [
"TORC1/mTOR nutrient sensing via leucine-LRS axis",
"mitochondrial translation and UPRmt",
"aminoacyl-tRNA synthesis and proteostasis"
],
"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 constructed a plausible-sounding mechanistic argument (reduced TORC1 signaling via impaired leucine sensing, UPRmt activation) that would support pro_longevity, but this is incorrect for lars-2 in C. elegans. lars-2 is actually anti_longevity, meaning its loss or reduction shortens lifespan rather than extending it. The model's reasoning about cytoplasmic LRS acting as a leucine sensor for TORC1 may be conflating the cytoplasmic leucyl-tRNA synthetase (lars-1) with the mitochondrial form (lars-2). The mitochondrial lars-2 is primarily involved in mitochondrial translation, and its loss likely impairs mitochondrial function in a way that is detrimental to lifespan. The model showed moderate confidence (0.72) in the wrong direction. The reasoning quality is moderate - it is internally coherent but based on incorrect premises about lars-2's role.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}