hlh-30
C. elegans
Helix-loop-helix protein 30
What the model saw
Gene: hlh-30 Organism: Caenorhabditis elegans Known functions: Helix-loop-helix protein 30. DNA-binding transcription factor activity, RNA polymerase II-specific. RNA polymerase II cis-regulatory region sequence-specific DNA binding. protein dimerization activity.
View unredacted entry
Helix-loop-helix protein 30. DNA-binding transcription factor activity, RNA polymerase II-specific. RNA polymerase II cis-regulatory region sequence-specific DNA binding. protein dimerization activity.
Solver output
hlh-30 is the C. elegans ortholog of mammalian TFEB (Transcription Factor EB), a master transcriptional regulator of autophagy and lysosomal biogenesis. As a helix-loop-helix transcription factor with RNA Pol II-specific DNA-binding activity and protein dimerization capacity, HLH-30 binds CLEAR (Coordinated Lysosomal Expression and Regulation) elements in promoters of autophagy and lysosomal genes to drive their expression. Activation of HLH-30/TFEB is a key downstream effector of multiple longevity pathways in C. elegans, including reduced insulin/IGF-1 signaling (daf-2 mutants), dietary restriction, and mTOR inhibition, all of which promote nuclear translocation of HLH-30. Loss of hlh-30 shortens lifespan and blunts the longevity benefits of these interventions, while overexpression of hlh-30 extends lifespan, confirming its pro-longevity role through upregulation of autophagic flux and lysosomal degradation capacity.
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 correctly identified hlh-30 as pro_longevity with high confidence (0.85). The mechanistic reasoning is excellent and accurate: hlh-30 is indeed the C. elegans ortholog of mammalian TFEB, it does regulate autophagy and lysosomal biogenesis via CLEAR elements, it is downstream of insulin/IGF-1 and mTOR pathways, and loss-of-function shortens lifespan while overexpression extends it. The mechanism class "disabled_macroautophagy" is a reasonable label (though slightly awkward phrasing - it refers to the pathway being regulated rather than being disabled). The key pathways listed are all correct and well-supported by the literature. This is a comprehensive and accurate prediction.
Raw API responses
solver
{
"reasoning": "hlh-30 is the C. elegans ortholog of mammalian TFEB (Transcription Factor EB), a master transcriptional regulator of autophagy and lysosomal biogenesis. As a helix-loop-helix transcription factor with RNA Pol II-specific DNA-binding activity and protein dimerization capacity, HLH-30 binds CLEAR (Coordinated Lysosomal Expression and Regulation) elements in promoters of autophagy and lysosomal genes to drive their expression. Activation of HLH-30/TFEB is a key downstream effector of multiple longevity pathways in C. elegans, including reduced insulin/IGF-1 signaling (daf-2 mutants), dietary restriction, and mTOR inhibition, all of which promote nuclear translocation of HLH-30. Loss of hlh-30 shortens lifespan and blunts the longevity benefits of these interventions, while overexpression of hlh-30 extends lifespan, confirming its pro-longevity role through upregulation of autophagic flux and lysosomal degradation capacity.",
"confidence": 0.85,
"key_pathways": [
"autophagy/lysosomal biogenesis (TFEB/CLEAR pathway)",
"insulin/IGF-1 signaling (daf-2/daf-16 axis)",
"mTOR nutrient sensing pathway"
],
"mechanism_class": "disabled_macroautophagy",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly identified hlh-30 as pro_longevity with high confidence (0.85). The mechanistic reasoning is excellent and accurate: hlh-30 is indeed the C. elegans ortholog of mammalian TFEB, it does regulate autophagy and lysosomal biogenesis via CLEAR elements, it is downstream of insulin/IGF-1 and mTOR pathways, and loss-of-function shortens lifespan while overexpression extends it. The mechanism class \"disabled_macroautophagy\" is a reasonable label (though slightly awkward phrasing - it refers to the pathway being regulated rather than being disabled). The key pathways listed are all correct and well-supported by the literature. This is a comprehensive and accurate prediction.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}