Irs1
M. musculus
insulin receptor substrate 1
What the model saw
Gene: Irs1 Organism: Mus musculus Known functions: insulin receptor substrate 1. SH2 domain binding. insulin receptor binding. insulin-like growth factor receptor binding. phosphatidylinositol 3-kinase activator activity. phosphatidylinositol 3-kinase binding. phosphotyrosine residue binding. protein binding. protein domain specific binding. protein kinase C binding. protein kinase binding. protein-containing complex binding. protein-macromolecule adaptor activity. signaling adaptor activity. signaling receptor complex adaptor activity. transmembrane receptor protein tyrosine kinase adaptor activity.
View unredacted entry
insulin receptor substrate 1. SH2 domain binding. insulin receptor binding. insulin-like growth factor receptor binding. phosphatidylinositol 3-kinase activator activity. phosphatidylinositol 3-kinase binding. phosphotyrosine residue binding. protein binding. protein domain specific binding. protein kinase C binding. protein kinase binding. protein-containing complex binding. protein-macromolecule adaptor activity. signaling adaptor activity. signaling receptor complex adaptor activity. transmembrane receptor protein tyrosine kinase adaptor activity.
Solver output
IRS1 is the primary adaptor protein downstream of the insulin and IGF-1 receptors, directly activating PI3K/AKT/mTOR signaling upon ligand binding. This insulin/IGF-1 signaling (IIS) axis is one of the most conserved pro-aging pathways across model organisms; its attenuation consistently extends lifespan. IRS1 activates PI3K by binding phosphotyrosine residues on the insulin/IGF-1 receptor and recruiting the p85 regulatory subunit of PI3K, thereby amplifying downstream mTORC1 and FOXO-inhibitory signaling. Reduced IRS1 activity (as seen in Irs1 knockout mice) leads to improved insulin sensitivity in some tissues, suppressed mTOR activity, and nuclear retention of FOXO transcription factors, all of which promote longevity. Irs1 knockout mice are indeed long-lived, confirming that the normal pro-growth, pro-anabolic function of IRS1 opposes 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 correctly predicted anti_longevity for Irs1 in Mus musculus with high confidence (0.88). The mechanistic reasoning is excellent: IRS1 is correctly identified as a key adaptor in the insulin/IGF-1 signaling pathway, activating PI3K/AKT/mTOR signaling. The model correctly notes that Irs1 knockout mice are long-lived, confirming the anti-longevity classification. The reasoning about FOXO transcription factor regulation, mTOR suppression, and the conserved pro-aging nature of the IIS pathway is all accurate and well-articulated.
Raw API responses
solver
{
"reasoning": "IRS1 is the primary adaptor protein downstream of the insulin and IGF-1 receptors, directly activating PI3K/AKT/mTOR signaling upon ligand binding. This insulin/IGF-1 signaling (IIS) axis is one of the most conserved pro-aging pathways across model organisms; its attenuation consistently extends lifespan. IRS1 activates PI3K by binding phosphotyrosine residues on the insulin/IGF-1 receptor and recruiting the p85 regulatory subunit of PI3K, thereby amplifying downstream mTORC1 and FOXO-inhibitory signaling. Reduced IRS1 activity (as seen in Irs1 knockout mice) leads to improved insulin sensitivity in some tissues, suppressed mTOR activity, and nuclear retention of FOXO transcription factors, all of which promote longevity. Irs1 knockout mice are indeed long-lived, confirming that the normal pro-growth, pro-anabolic function of IRS1 opposes longevity.",
"confidence": 0.88,
"key_pathways": [
"Insulin/IGF-1 signaling (IIS) pathway",
"PI3K/AKT/mTOR axis",
"FOXO transcription factor regulation"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model correctly predicted anti_longevity for Irs1 in Mus musculus with high confidence (0.88). The mechanistic reasoning is excellent: IRS1 is correctly identified as a key adaptor in the insulin/IGF-1 signaling pathway, activating PI3K/AKT/mTOR signaling. The model correctly notes that Irs1 knockout mice are long-lived, confirming the anti-longevity classification. The reasoning about FOXO transcription factor regulation, mTOR suppression, and the conserved pro-aging nature of the IIS pathway is all accurate and well-articulated.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}