HES1
S. cerevisiae
oxysterol-binding protein related protein HES1
What the model saw
Gene: HES1 Organism: Saccharomyces cerevisiae Known functions: oxysterol-binding protein related protein HES1. lipid binding. oxysterol binding. sterol transfer activity.
View unredacted entry
oxysterol-binding protein related protein HES1. lipid binding. oxysterol binding. sterol transfer activity.
Solver output
HES1 in S. cerevisiae encodes an oxysterol-binding protein (OSBP) homolog involved in lipid binding, oxysterol binding, and sterol transfer activity. OSBP-related proteins mediate non-vesicular sterol transport between organelle membranes (e.g., ER to plasma membrane), which is critical for maintaining lipid homeostasis and membrane integrity. Proper sterol distribution is tightly linked to nutrient sensing pathways, particularly TORC2-mediated signaling and sphingolipid metabolism, which regulate cellular aging. Loss of sterol transfer activity can disrupt membrane lipid composition, impairing organelle function and accelerating aging-associated phenotypes. OSBP homologs in yeast (e.g., Kes1/Osh4) have been shown to modulate phosphoinositide and sterol balance, and their activity generally supports cellular homeostasis, suggesting a pro-longevity role for normal HES1 function.
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 pro_longevity but the ground truth is anti_longevity. HES1 in S. cerevisiae is an oxysterol-binding protein homolog, and its deletion (loss of function) appears to extend lifespan, making it anti-longevity. The model's reasoning incorrectly assumed that because HES1 supports lipid/sterol homeostasis, it must be pro-longevity. However, the model failed to consider that some OSBP homologs in yeast (like Kes1/Osh4) can actually inhibit longevity pathways - for example, by competing with or modulating TOR signaling or phosphoinositide metabolism in ways that limit lifespan extension. The model's mechanistic reasoning about sterol transport supporting cellular homeostasis is plausible in general but leads to the wrong conclusion here. The confidence of 0.55 is relatively low, which is appropriate given the uncertainty, but the prediction is still wrong.
Raw API responses
solver
{
"reasoning": "HES1 in S. cerevisiae encodes an oxysterol-binding protein (OSBP) homolog involved in lipid binding, oxysterol binding, and sterol transfer activity. OSBP-related proteins mediate non-vesicular sterol transport between organelle membranes (e.g., ER to plasma membrane), which is critical for maintaining lipid homeostasis and membrane integrity. Proper sterol distribution is tightly linked to nutrient sensing pathways, particularly TORC2-mediated signaling and sphingolipid metabolism, which regulate cellular aging. Loss of sterol transfer activity can disrupt membrane lipid composition, impairing organelle function and accelerating aging-associated phenotypes. OSBP homologs in yeast (e.g., Kes1/Osh4) have been shown to modulate phosphoinositide and sterol balance, and their activity generally supports cellular homeostasis, suggesting a pro-longevity role for normal HES1 function.",
"confidence": 0.55,
"key_pathways": [
"non-vesicular sterol transport",
"lipid/membrane homeostasis",
"TORC2-sphingolipid signaling"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted pro_longevity but the ground truth is anti_longevity. HES1 in S. cerevisiae is an oxysterol-binding protein homolog, and its deletion (loss of function) appears to extend lifespan, making it anti-longevity. The model's reasoning incorrectly assumed that because HES1 supports lipid/sterol homeostasis, it must be pro-longevity. However, the model failed to consider that some OSBP homologs in yeast (like Kes1/Osh4) can actually inhibit longevity pathways - for example, by competing with or modulating TOR signaling or phosphoinositide metabolism in ways that limit lifespan extension. The model's mechanistic reasoning about sterol transport supporting cellular homeostasis is plausible in general but leads to the wrong conclusion here. The confidence of 0.55 is relatively low, which is appropriate given the uncertainty, but the prediction is still wrong.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}