daf-28
C. elegans
uncharacterized protein
What the model saw
Gene: daf-28 Organism: Caenorhabditis elegans Known functions: uncharacterized protein. hormone activity. insulin receptor binding.
View unredacted entry
uncharacterized protein. hormone activity. insulin receptor binding.
Solver output
DAF-28 is an insulin-like peptide (ILP) in C. elegans that binds the insulin receptor DAF-2 and acts as an agonist ligand. Activation of DAF-2 by ILPs like DAF-28 triggers the canonical PI3K/AGE-1/PDK-1/AKT signaling cascade, which phosphorylates and cytoplasmic-sequesters the FOXO transcription factor DAF-16. Nuclear DAF-16 is the master regulator of stress resistance, metabolic reprogramming, and longevity genes; its inhibition by DAF-28/DAF-2 signaling therefore suppresses the pro-longevity transcriptional program. Loss-of-function in daf-28 (or daf-2) extends lifespan in a daf-16-dependent manner, confirming that normal DAF-28 activity opposes longevity. This places DAF-28 squarely within the insulin/IGF-1 signaling (IIS) axis, the archetypal nutrient-sensing pathway governing aging across metazoans.
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's mechanistic reasoning is largely correct - DAF-28 is indeed an insulin-like peptide that acts as a DAF-2 agonist and activates the IIS pathway, which suppresses DAF-16/FOXO and opposes longevity. However, the model predicted "anti_longevity" while the ground truth is "pro_longevity." This is a surprising discrepancy. In GenAge, daf-28 is classified as pro_longevity, which likely reflects that loss-of-function of daf-28 extends lifespan (meaning the gene itself promotes longevity when active, or alternatively the database classifies it based on the direction of the mutation that affects lifespan). The model's reasoning that DAF-28 acts as an anti-longevity factor (because it activates DAF-2 and suppresses DAF-16) is mechanistically sound from a biological standpoint, but the GenAge classification disagrees. This may reflect a nuance in how GenAge assigns pro_longevity vs anti_longevity - if loss-of-function extends lifespan, the gene could be classified as anti_longevity, but GenAge says pro_longevity here. This is a genuinely confusing case, but the model's answer does not match the ground truth. The model was highly confident (0.82) in the wrong answer.
Raw API responses
solver
{
"reasoning": "DAF-28 is an insulin-like peptide (ILP) in C. elegans that binds the insulin receptor DAF-2 and acts as an agonist ligand. Activation of DAF-2 by ILPs like DAF-28 triggers the canonical PI3K/AGE-1/PDK-1/AKT signaling cascade, which phosphorylates and cytoplasmic-sequesters the FOXO transcription factor DAF-16. Nuclear DAF-16 is the master regulator of stress resistance, metabolic reprogramming, and longevity genes; its inhibition by DAF-28/DAF-2 signaling therefore suppresses the pro-longevity transcriptional program. Loss-of-function in daf-28 (or daf-2) extends lifespan in a daf-16-dependent manner, confirming that normal DAF-28 activity opposes longevity. This places DAF-28 squarely within the insulin/IGF-1 signaling (IIS) axis, the archetypal nutrient-sensing pathway governing aging across metazoans.",
"confidence": 0.82,
"key_pathways": [
"insulin/IGF-1 signaling (IIS) / DAF-2 pathway",
"DAF-16/FOXO transcription factor regulation",
"PI3K/AGE-1/AKT nutrient-sensing cascade"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model's mechanistic reasoning is largely correct - DAF-28 is indeed an insulin-like peptide that acts as a DAF-2 agonist and activates the IIS pathway, which suppresses DAF-16/FOXO and opposes longevity. However, the model predicted \"anti_longevity\" while the ground truth is \"pro_longevity.\" This is a surprising discrepancy. In GenAge, daf-28 is classified as pro_longevity, which likely reflects that loss-of-function of daf-28 extends lifespan (meaning the gene itself promotes longevity when active, or alternatively the database classifies it based on the direction of the mutation that affects lifespan). The model's reasoning that DAF-28 acts as an anti-longevity factor (because it activates DAF-2 and suppresses DAF-16) is mechanistically sound from a biological standpoint, but the GenAge classification disagrees. This may reflect a nuance in how GenAge assigns pro_longevity vs anti_longevity - if loss-of-function extends lifespan, the gene could be classified as anti_longevity, but GenAge says pro_longevity here. This is a genuinely confusing case, but the model's answer does not match the ground truth. The model was highly confident (0.82) in the wrong answer.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": true
}