sinh-1
C. elegans
Stress-activated map kinase-interacting protein 1 homolog
What the model saw
Gene: sinh-1 Organism: Caenorhabditis elegans Known functions: Stress-activated map kinase-interacting protein 1 homolog. phosphatidylinositol-4,5-bisphosphate binding.
View unredacted entry
Stress-activated map kinase-interacting protein 1 homolog. phosphatidylinositol-4,5-bisphosphate binding.
Solver output
sinh-1 is the C. elegans homolog of SIN1 (MAPKAP1), a core and essential component of the mTORC2 complex. mTORC2 phosphorylates and activates AKT (PKB), which in turn phosphorylates and inhibits the FOXO transcription factor DAF-16 — a key pro-longevity effector downstream of the insulin/IGF-1 signaling pathway. The phosphatidylinositol-4,5-bisphosphate (PIP2) binding activity of sinh-1/SIN1 is critical for mTORC2 membrane recruitment and substrate recognition. By promoting mTORC2-AKT signaling, sinh-1 suppresses DAF-16/FOXO nuclear activity, thereby opposing the transcriptional program that extends lifespan. Loss-of-function of mTORC2 components, including SIN1, has been shown to extend lifespan in C. elegans through derepression of DAF-16.
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 predicted anti_longevity for sinh-1. The mechanistic reasoning is excellent and well-grounded: sinh-1 is indeed the C. elegans SIN1/MAPKAP1 homolog, a core component of mTORC2. The model correctly identifies the mTORC2→AKT→DAF-16/FOXO axis as the key pathway, explains the PIP2 binding role in mTORC2 membrane recruitment, and correctly concludes that loss of sinh-1 would extend lifespan by derepressing DAF-16. The confidence level of 0.72 is appropriate given the indirect nature of the evidence (mTORC2 component rather than a directly studied longevity gene). All aspects of the prediction are accurate.
Raw API responses
solver
{
"reasoning": "sinh-1 is the C. elegans homolog of SIN1 (MAPKAP1), a core and essential component of the mTORC2 complex. mTORC2 phosphorylates and activates AKT (PKB), which in turn phosphorylates and inhibits the FOXO transcription factor DAF-16 — a key pro-longevity effector downstream of the insulin/IGF-1 signaling pathway. The phosphatidylinositol-4,5-bisphosphate (PIP2) binding activity of sinh-1/SIN1 is critical for mTORC2 membrane recruitment and substrate recognition. By promoting mTORC2-AKT signaling, sinh-1 suppresses DAF-16/FOXO nuclear activity, thereby opposing the transcriptional program that extends lifespan. Loss-of-function of mTORC2 components, including SIN1, has been shown to extend lifespan in C. elegans through derepression of DAF-16.",
"confidence": 0.72,
"key_pathways": [
"mTORC2-AKT signaling",
"insulin/IGF-1 signaling (DAF-2/AGE-1/DAF-16 axis)",
"PI(4,5)P2-dependent mTORC2 membrane recruitment"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for sinh-1. The mechanistic reasoning is excellent and well-grounded: sinh-1 is indeed the C. elegans SIN1/MAPKAP1 homolog, a core component of mTORC2. The model correctly identifies the mTORC2→AKT→DAF-16/FOXO axis as the key pathway, explains the PIP2 binding role in mTORC2 membrane recruitment, and correctly concludes that loss of sinh-1 would extend lifespan by derepressing DAF-16. The confidence level of 0.72 is appropriate given the indirect nature of the evidence (mTORC2 component rather than a directly studied longevity gene). All aspects of the prediction are accurate.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}