Gsk3a
M. musculus
glycogen synthase kinase 3 alpha
What the model saw
Gene: Gsk3a Organism: Mus musculus Known functions: glycogen synthase kinase 3 alpha. glycogen synthase kinase-3 alpha. ATP binding. protein binding. protein kinase A catalytic subunit binding. protein kinase activity. protein kinase binding. protein serine kinase activity. protein serine/threonine kinase activity. protein serine/threonine kinase binding. signaling receptor binding. tau-protein kinase activity.
View unredacted entry
glycogen synthase kinase 3 alpha. glycogen synthase kinase-3 alpha. ATP binding. protein binding. protein kinase A catalytic subunit binding. protein kinase activity. protein kinase binding. protein serine kinase activity. protein serine/threonine kinase activity. protein serine/threonine kinase binding. signaling receptor binding. tau-protein kinase activity.
Solver output
GSK3α is a serine/threonine kinase that acts as a key negative regulator downstream of the PI3K/AKT/insulin signaling axis. When active, GSK3α phosphorylates and inhibits glycogen synthase, reducing glucose storage, and opposes the pro-longevity effects of insulin/IGF-1 pathway suppression. Its tau-protein kinase activity promotes hyperphosphorylation of tau, linking it to neurodegeneration and cellular dysfunction. GSK3α also phosphorylates and destabilizes multiple substrates involved in cell survival and proteostasis, including components of the mTOR and Wnt/β-catenin pathways. Elevated GSK3 activity is associated with accelerated aging phenotypes, and genetic or pharmacological inhibition of GSK3 in mice has been shown to extend healthspan and lifespan. Thus, the normal (active) function of GSK3α opposes longevity by antagonizing nutrient-sensing pathways that promote longevity when downregulated.
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 anti_longevity with 0.78 confidence, but the ground truth is pro_longevity. The model's reasoning is plausible at a general level (GSK3 is indeed a negative regulator downstream of insulin/IGF-1 signaling, and GSK3 inhibition is often associated with beneficial effects), but it gets the direction wrong for Gsk3a specifically in mice. The GenAge classification of pro_longevity for Gsk3a suggests that Gsk3a activity (or its presence) actually promotes longevity in mice — possibly because Gsk3a knockout or loss-of-function leads to reduced lifespan or adverse phenotypes. The model's reasoning about GSK3 inhibition extending lifespan is a generalization that doesn't account for the specific role of Gsk3a in mice, where loss of this isoform may have detrimental effects (e.g., cardiac dysfunction, metabolic issues). The mechanistic reasoning is therefore also incorrect in the context of this specific gene's classification.
Raw API responses
solver
{
"reasoning": "GSK3α is a serine/threonine kinase that acts as a key negative regulator downstream of the PI3K/AKT/insulin signaling axis. When active, GSK3α phosphorylates and inhibits glycogen synthase, reducing glucose storage, and opposes the pro-longevity effects of insulin/IGF-1 pathway suppression. Its tau-protein kinase activity promotes hyperphosphorylation of tau, linking it to neurodegeneration and cellular dysfunction. GSK3α also phosphorylates and destabilizes multiple substrates involved in cell survival and proteostasis, including components of the mTOR and Wnt/β-catenin pathways. Elevated GSK3 activity is associated with accelerated aging phenotypes, and genetic or pharmacological inhibition of GSK3 in mice has been shown to extend healthspan and lifespan. Thus, the normal (active) function of GSK3α opposes longevity by antagonizing nutrient-sensing pathways that promote longevity when downregulated.",
"confidence": 0.78,
"key_pathways": [
"PI3K/AKT/insulin-IGF-1 signaling",
"Wnt/beta-catenin signaling",
"tau phosphorylation/neurodegeneration"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "anti_longevity"
}advisor
{
"notes": "The model predicted anti_longevity with 0.78 confidence, but the ground truth is pro_longevity. The model's reasoning is plausible at a general level (GSK3 is indeed a negative regulator downstream of insulin/IGF-1 signaling, and GSK3 inhibition is often associated with beneficial effects), but it gets the direction wrong for Gsk3a specifically in mice. The GenAge classification of pro_longevity for Gsk3a suggests that Gsk3a activity (or its presence) actually promotes longevity in mice — possibly because Gsk3a knockout or loss-of-function leads to reduced lifespan or adverse phenotypes. The model's reasoning about GSK3 inhibition extending lifespan is a generalization that doesn't account for the specific role of Gsk3a in mice, where loss of this isoform may have detrimental effects (e.g., cardiac dysfunction, metabolic issues). The mechanistic reasoning is therefore also incorrect in the context of this specific gene's classification.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 3,
"ground_truth_questionable": false
}