unc-32
C. elegans
V-type proton ATPase 116 kDa subunit a 1
What the model saw
Gene: unc-32 Organism: Caenorhabditis elegans Known functions: V-type proton ATPase 116 kDa subunit a 1. ATPase binding. proton-transporting ATPase activity, rotational mechanism.
View unredacted entry
V-type proton ATPase 116 kDa subunit a 1. ATPase binding. proton-transporting ATPase activity, rotational mechanism.
Solver output
unc-32 encodes the 116 kDa 'a' subunit (subunit a1) of the vacuolar-type H⁺-ATPase (V-ATPase), which acidifies lysosomes and other endomembrane compartments via a rotational proton-pumping mechanism. Proper lysosomal acidification is essential for autophagosome-lysosome fusion and cargo degradation, making V-ATPase activity a prerequisite for functional macroautophagy and proteostasis. In C. elegans, lysosomal V-ATPase activity also activates TORC1 on the lysosomal surface (the Ragulator/v-ATPase axis), linking nutrient sensing to growth and longevity pathways; paradoxically, reduced TORC1 extends lifespan, but loss of V-ATPase also cripples autophagy and lysosomal degradation, which shortens lifespan. The dominant evidence in C. elegans is that intact lysosomal acidification (via unc-32/V-ATPase) is required for autophagy-dependent longevity programs (e.g., those downstream of daf-2/IIS and dietary restriction), placing normal unc-32 function on the pro-longevity side by enabling autophagic flux and proteostasis maintenance.
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 acknowledges the paradox (reduced TORC1 extends lifespan, but loss of V-ATPase also cripples autophagy) but then incorrectly resolves it by concluding unc-32 is pro_longevity. In C. elegans, unc-32/V-ATPase is anti_longevity, likely because it activates TORC1 signaling on the lysosomal surface — meaning normal unc-32 function promotes aging by keeping TORC1 active. The model's mechanistic framing around autophagy enabling longevity programs is plausible in isolation but leads to the wrong conclusion. The model was moderately confident (0.62) in the wrong direction.
Raw API responses
solver
{
"reasoning": "unc-32 encodes the 116 kDa 'a' subunit (subunit a1) of the vacuolar-type H⁺-ATPase (V-ATPase), which acidifies lysosomes and other endomembrane compartments via a rotational proton-pumping mechanism. Proper lysosomal acidification is essential for autophagosome-lysosome fusion and cargo degradation, making V-ATPase activity a prerequisite for functional macroautophagy and proteostasis. In C. elegans, lysosomal V-ATPase activity also activates TORC1 on the lysosomal surface (the Ragulator/v-ATPase axis), linking nutrient sensing to growth and longevity pathways; paradoxically, reduced TORC1 extends lifespan, but loss of V-ATPase also cripples autophagy and lysosomal degradation, which shortens lifespan. The dominant evidence in C. elegans is that intact lysosomal acidification (via unc-32/V-ATPase) is required for autophagy-dependent longevity programs (e.g., those downstream of daf-2/IIS and dietary restriction), placing normal unc-32 function on the pro-longevity side by enabling autophagic flux and proteostasis maintenance.",
"confidence": 0.62,
"key_pathways": [
"lysosomal acidification / V-ATPase proton pumping",
"macroautophagy / autophagic flux",
"TORC1 lysosomal nutrient sensing (Ragulator-V-ATPase axis)"
],
"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 acknowledges the paradox (reduced TORC1 extends lifespan, but loss of V-ATPase also cripples autophagy) but then incorrectly resolves it by concluding unc-32 is pro_longevity. In C. elegans, unc-32/V-ATPase is anti_longevity, likely because it activates TORC1 signaling on the lysosomal surface — meaning normal unc-32 function promotes aging by keeping TORC1 active. The model's mechanistic framing around autophagy enabling longevity programs is plausible in isolation but leads to the wrong conclusion. The model was moderately confident (0.62) in the wrong direction.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}