vha-6
C. elegans
V-type proton ATPase 116 kDa subunit a 3
What the model saw
Gene: vha-6 Organism: Caenorhabditis elegans Known functions: V-type proton ATPase 116 kDa subunit a 3. ATPase binding. proton-transporting ATPase activity, rotational mechanism.
View unredacted entry
V-type proton ATPase 116 kDa subunit a 3. ATPase binding. proton-transporting ATPase activity, rotational mechanism.
Solver output
vha-6 encodes the 116 kDa 'a' subunit (subunit a3/Vph1-like) of the vacuolar-type H⁺-ATPase (V-ATPase), which acidifies the lysosomal lumen via rotational proton pumping. Proper lysosomal acidification is an absolute prerequisite for lysosomal hydrolase activity and the completion of autophagy flux, including the degradation of autophagic cargo. In C. elegans, V-ATPase activity on lysosomes is also required for TORC1 regulation and nutrient sensing via the Ragulator/TORC1 axis on the lysosomal surface. Loss of vha-6 function impairs lysosomal acidification, blocks autophagic degradation, and disrupts proteostasis, all of which accelerate aging. Thus, the normal function of vha-6 supports lysosomal integrity and autophagy, promoting longevity.
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 focused on the idea that vha-6 supports lysosomal acidification and autophagy, and therefore its normal function promotes longevity. However, the GenAge database classifies vha-6 as anti_longevity, meaning that the gene's activity actually shortens lifespan (i.e., loss or reduction of vha-6 extends lifespan). The model's mechanistic reasoning about V-ATPase function in lysosomal acidification is generally correct in terms of biology, but the model incorrectly inferred the direction of the longevity effect. In C. elegans, reduction of V-ATPase subunits like vha-6 has been shown to extend lifespan, possibly through reduced TORC1 signaling or other mechanisms. The model was fairly confident (0.72) in the wrong direction.
Raw API responses
solver
{
"reasoning": "vha-6 encodes the 116 kDa 'a' subunit (subunit a3/Vph1-like) of the vacuolar-type H⁺-ATPase (V-ATPase), which acidifies the lysosomal lumen via rotational proton pumping. Proper lysosomal acidification is an absolute prerequisite for lysosomal hydrolase activity and the completion of autophagy flux, including the degradation of autophagic cargo. In C. elegans, V-ATPase activity on lysosomes is also required for TORC1 regulation and nutrient sensing via the Ragulator/TORC1 axis on the lysosomal surface. Loss of vha-6 function impairs lysosomal acidification, blocks autophagic degradation, and disrupts proteostasis, all of which accelerate aging. Thus, the normal function of vha-6 supports lysosomal integrity and autophagy, promoting longevity.",
"confidence": 0.72,
"key_pathways": [
"lysosomal acidification via V-ATPase",
"macroautophagy/lysosomal degradation",
"TORC1 nutrient sensing on lysosomal membrane"
],
"mechanism_class": "disabled_macroautophagy",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. The model's reasoning focused on the idea that vha-6 supports lysosomal acidification and autophagy, and therefore its normal function promotes longevity. However, the GenAge database classifies vha-6 as anti_longevity, meaning that the gene's activity actually shortens lifespan (i.e., loss or reduction of vha-6 extends lifespan). The model's mechanistic reasoning about V-ATPase function in lysosomal acidification is generally correct in terms of biology, but the model incorrectly inferred the direction of the longevity effect. In C. elegans, reduction of V-ATPase subunits like vha-6 has been shown to extend lifespan, possibly through reduced TORC1 signaling or other mechanisms. The model was fairly confident (0.72) in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}