Sirt6
D. melanogaster
Sirtuin 6
What the model saw
Gene: Sirt6 Organism: Drosophila melanogaster Known functions: Sirtuin 6. sirtuin 6. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H3K deacetylase activity. histone H3K9 deacetylase activity, NAD-dependent. histone deacetylase activity. histone deacetylase activity, NAD-dependent. transcription corepressor activity.
View unredacted entry
Sirtuin 6. sirtuin 6. NAD+ binding. NAD-dependent protein lysine deacetylase activity. histone H3K deacetylase activity. histone H3K9 deacetylase activity, NAD-dependent. histone deacetylase activity. histone deacetylase activity, NAD-dependent. transcription corepressor activity.
Solver output
Sirt6 is an NAD+-dependent histone deacetylase that specifically targets H3K9 acetylation marks, a well-characterized epigenetic modification associated with chromatin compaction and transcriptional silencing. By maintaining proper H3K9 deacetylation, Sirt6 preserves heterochromatin integrity and suppresses aberrant transcription, counteracting the age-associated loss of epigenetic information. In mammals, SIRT6 is a well-established longevity factor that suppresses genomic instability, regulates NF-κB-driven inflammatory gene expression via its transcription corepressor activity, and modulates IGF1/insulin signaling — all pro-longevity functions. Its NAD+ dependency directly links it to the deregulated nutrient-sensing axis, but its primary molecular role is epigenetic (H3K9ac erasure). Drosophila Sirt6 is expected to fulfill analogous chromatin-maintenance and transcriptional repression roles, supporting lifespan extension.
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 pro_longevity for Drosophila Sirt6 with high confidence (0.85). The mechanistic reasoning is well-grounded: it correctly identifies Sirt6 as an NAD+-dependent H3K9 deacetylase involved in heterochromatin maintenance and transcriptional repression, and draws reasonable parallels to mammalian SIRT6 longevity functions. The model appropriately notes that Drosophila Sirt6 is "expected" to fulfill analogous roles, showing appropriate epistemic humility about the cross-species inference. The mechanism class (epigenetic_alterations) is appropriate. Minor deduction: the reasoning leans heavily on mammalian data and extrapolates to Drosophila, which is reasonable but slightly speculative.
Raw API responses
solver
{
"reasoning": "Sirt6 is an NAD+-dependent histone deacetylase that specifically targets H3K9 acetylation marks, a well-characterized epigenetic modification associated with chromatin compaction and transcriptional silencing. By maintaining proper H3K9 deacetylation, Sirt6 preserves heterochromatin integrity and suppresses aberrant transcription, counteracting the age-associated loss of epigenetic information. In mammals, SIRT6 is a well-established longevity factor that suppresses genomic instability, regulates NF-κB-driven inflammatory gene expression via its transcription corepressor activity, and modulates IGF1/insulin signaling — all pro-longevity functions. Its NAD+ dependency directly links it to the deregulated nutrient-sensing axis, but its primary molecular role is epigenetic (H3K9ac erasure). Drosophila Sirt6 is expected to fulfill analogous chromatin-maintenance and transcriptional repression roles, supporting lifespan extension.",
"confidence": 0.85,
"key_pathways": [
"H3K9 deacetylation and heterochromatin maintenance",
"NAD+-dependent sirtuin signaling",
"transcriptional corepression of pro-aging gene programs"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity for Drosophila Sirt6 with high confidence (0.85). The mechanistic reasoning is well-grounded: it correctly identifies Sirt6 as an NAD+-dependent H3K9 deacetylase involved in heterochromatin maintenance and transcriptional repression, and draws reasonable parallels to mammalian SIRT6 longevity functions. The model appropriately notes that Drosophila Sirt6 is \"expected\" to fulfill analogous roles, showing appropriate epistemic humility about the cross-species inference. The mechanism class (epigenetic_alterations) is appropriate. Minor deduction: the reasoning leans heavily on mammalian data and extrapolates to Drosophila, which is reasonable but slightly speculative.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 4,
"ground_truth_questionable": false
}