daf-12
C. elegans
Nuclear hormone receptor HR3;Nuclear hormone receptor family member daf-12
What the model saw
Gene: daf-12 Organism: Caenorhabditis elegans Known functions: Nuclear hormone receptor HR3;Nuclear hormone receptor family member daf-12. (25S)-Delta(4)-dafachronate binding. (25S)-Delta(7)-dafachronate binding. DNA-binding transcription factor activity. RNA polymerase II cis-regulatory region sequence-specific DNA binding. nuclear receptor activity. protein binding. sequence-specific DNA binding. zinc ion binding.
View unredacted entry
Nuclear hormone receptor HR3;Nuclear hormone receptor family member daf-12. (25S)-Delta(4)-dafachronate binding. (25S)-Delta(7)-dafachronate binding. DNA-binding transcription factor activity. RNA polymerase II cis-regulatory region sequence-specific DNA binding. nuclear receptor activity. protein binding. sequence-specific DNA binding. zinc ion binding.
Solver output
DAF-12 is a nuclear hormone receptor (NHR) that acts as a ligand-activated transcription factor in C. elegans, binding dafachronic acids (25S-Δ4 and 25S-Δ7 dafachronate) — sterol-derived hormones produced downstream of the insulin/IGF-1 and TGF-β signaling pathways. When bound to its dafachronic acid ligands, DAF-12 promotes reproductive development and normal lifespan; critically, DAF-12 is a key effector in the dauer pathway, where its liganded state integrates nutrient and hormonal signals to regulate developmental fate and longevity. Loss of daf-12 or absence of its ligands shifts the receptor to an unliganded repressive state that, in combination with DAF-16/FOXO, promotes dauer formation and extended lifespan. The receptor's DNA-binding and zinc-finger domains allow it to directly regulate transcriptional programs controlling stress resistance, fat metabolism, and developmental timing — all central to lifespan extension in C. elegans. Because DAF-12 (in its liganded, active form) is required for normal lifespan and its activation by dafachronic acids is a conserved pro-longevity signal, its normal function is considered pro-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" with 0.82 confidence, but the ground truth is "anti_longevity." DAF-12 is actually an anti-longevity gene in C. elegans. The model's reasoning is partially correct in describing DAF-12's biology (it is indeed a nuclear hormone receptor that binds dafachronic acids and plays a role in the dauer pathway), but the conclusion is wrong. In reality, daf-12 loss-of-function mutations extend lifespan, meaning DAF-12 activity normally promotes aging/shortens lifespan, making it anti-longevity. The model incorrectly concluded that because DAF-12 is activated by dafachronic acids (which can promote longevity in some contexts), DAF-12 itself is pro-longevity. The model confused the ligand's effects with the receptor's net effect on lifespan. The model's mechanistic reasoning about DAF-12 promoting normal development vs. dauer is partially correct, but the final interpretation of its longevity influence is inverted. The model was also highly confident (0.82) in its wrong answer.
Raw API responses
solver
{
"reasoning": "DAF-12 is a nuclear hormone receptor (NHR) that acts as a ligand-activated transcription factor in C. elegans, binding dafachronic acids (25S-Δ4 and 25S-Δ7 dafachronate) — sterol-derived hormones produced downstream of the insulin/IGF-1 and TGF-β signaling pathways. When bound to its dafachronic acid ligands, DAF-12 promotes reproductive development and normal lifespan; critically, DAF-12 is a key effector in the dauer pathway, where its liganded state integrates nutrient and hormonal signals to regulate developmental fate and longevity. Loss of daf-12 or absence of its ligands shifts the receptor to an unliganded repressive state that, in combination with DAF-16/FOXO, promotes dauer formation and extended lifespan. The receptor's DNA-binding and zinc-finger domains allow it to directly regulate transcriptional programs controlling stress resistance, fat metabolism, and developmental timing — all central to lifespan extension in C. elegans. Because DAF-12 (in its liganded, active form) is required for normal lifespan and its activation by dafachronic acids is a conserved pro-longevity signal, its normal function is considered pro-longevity.",
"confidence": 0.82,
"key_pathways": [
"Dauer/insulin-IGF-1 signaling pathway (DAF-2/DAF-16/DAF-12 axis)",
"Dafachronic acid biosynthesis and nuclear hormone receptor signaling",
"Transcriptional regulation of stress resistance and developmental timing"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" with 0.82 confidence, but the ground truth is \"anti_longevity.\" DAF-12 is actually an anti-longevity gene in C. elegans. The model's reasoning is partially correct in describing DAF-12's biology (it is indeed a nuclear hormone receptor that binds dafachronic acids and plays a role in the dauer pathway), but the conclusion is wrong. In reality, daf-12 loss-of-function mutations extend lifespan, meaning DAF-12 activity normally promotes aging/shortens lifespan, making it anti-longevity. The model incorrectly concluded that because DAF-12 is activated by dafachronic acids (which can promote longevity in some contexts), DAF-12 itself is pro-longevity. The model confused the ligand's effects with the receptor's net effect on lifespan. The model's mechanistic reasoning about DAF-12 promoting normal development vs. dauer is partially correct, but the final interpretation of its longevity influence is inverted. The model was also highly confident (0.82) in its wrong answer.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}