Sirt6
M. musculus
sirtuin 6
What the model saw
Gene: Sirt6 Organism: Mus musculus Known functions: sirtuin 6. NAD-dependent protein deacylase sirtuin-6. DNA binding. DNA damage sensor activity. NAD+ binding. NAD+-protein mono-ADP-ribosyltransferase activity. NAD+-protein-arginine ADP-ribosyltransferase activity. NAD+-protein-lysine ADP-ribosyltransferase activity. NAD-dependent protein demyristoylase activity. NAD-dependent protein depalmitoylase activity. NAD-dependent protein lysine deacetylase activity. TORC2 complex binding. chromatin DNA binding. chromatin binding. damaged DNA binding. enzyme regulator activity. histone H3K18 deacetylase activity, NAD-dependent. histone H3K56 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, hydrolytic mechanism. histone deacetylase activity, NAD-dependent. histone deacetylase regulator activity. lncRNA binding. nucleosome binding. protein homodimerization activity. protein lysine deacetylase activity. transcription corepressor activity. zinc ion binding.
View unredacted entry
sirtuin 6. NAD-dependent protein deacylase sirtuin-6. DNA binding. DNA damage sensor activity. NAD+ binding. NAD+-protein mono-ADP-ribosyltransferase activity. NAD+-protein-arginine ADP-ribosyltransferase activity. NAD+-protein-lysine ADP-ribosyltransferase activity. NAD-dependent protein demyristoylase activity. NAD-dependent protein depalmitoylase activity. NAD-dependent protein lysine deacetylase activity. TORC2 complex binding. chromatin DNA binding. chromatin binding. damaged DNA binding. enzyme regulator activity. histone H3K18 deacetylase activity, NAD-dependent. histone H3K56 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, hydrolytic mechanism. histone deacetylase activity, NAD-dependent. histone deacetylase regulator activity. lncRNA binding. nucleosome binding. protein homodimerization activity. protein lysine deacetylase activity. transcription corepressor activity. zinc ion binding.
Solver output
SIRT6 is a NAD+-dependent histone deacetylase that deacetylates H3K9ac, H3K18ac, and H3K56ac at chromatin, promoting genome stability by facilitating DNA double-strand break repair and suppressing retrotransposon activity. Its DNA damage sensor activity and damaged DNA binding function place it directly at sites of genomic insults, where it recruits repair factors. SIRT6 also represses HIF-1α-driven glycolytic gene expression and IGF/mTOR signaling as a transcription corepressor, linking it to deregulated nutrient sensing suppression. Sirt6 knockout mice display a severe premature aging phenotype with genomic instability, metabolic defects, and shortened lifespan, while Sirt6 overexpression extends lifespan in male mice, firmly establishing its pro-longevity role. The NAD+ dependency connects SIRT6 activity to the broader NAD+ decline observed in aging, making it a central node in multiple longevity-promoting pathways.
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 with very high confidence (0.95). The mechanistic reasoning is accurate and detailed: SIRT6 knockout mice show premature aging and shortened lifespan, while overexpression extends lifespan in male mice. The model correctly identifies the key mechanisms including H3K9ac/H3K56ac deacetylation for genome stability, DNA damage repair, HIF-1α/IGF/mTOR signaling repression, and NAD+ dependency. All stated facts are well-established in the literature. The reasoning is comprehensive and well-grounded.
Raw API responses
solver
{
"reasoning": "SIRT6 is a NAD+-dependent histone deacetylase that deacetylates H3K9ac, H3K18ac, and H3K56ac at chromatin, promoting genome stability by facilitating DNA double-strand break repair and suppressing retrotransposon activity. Its DNA damage sensor activity and damaged DNA binding function place it directly at sites of genomic insults, where it recruits repair factors. SIRT6 also represses HIF-1α-driven glycolytic gene expression and IGF/mTOR signaling as a transcription corepressor, linking it to deregulated nutrient sensing suppression. Sirt6 knockout mice display a severe premature aging phenotype with genomic instability, metabolic defects, and shortened lifespan, while Sirt6 overexpression extends lifespan in male mice, firmly establishing its pro-longevity role. The NAD+ dependency connects SIRT6 activity to the broader NAD+ decline observed in aging, making it a central node in multiple longevity-promoting pathways.",
"confidence": 0.95,
"key_pathways": [
"DNA double-strand break repair / H3K9ac and H3K56ac deacetylation",
"IGF1/mTOR signaling repression via transcription corepressor activity",
"NAD+-dependent chromatin regulation and retrotransposon silencing"
],
"mechanism_class": "genomic_instability",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted pro_longevity with very high confidence (0.95). The mechanistic reasoning is accurate and detailed: SIRT6 knockout mice show premature aging and shortened lifespan, while overexpression extends lifespan in male mice. The model correctly identifies the key mechanisms including H3K9ac/H3K56ac deacetylation for genome stability, DNA damage repair, HIF-1α/IGF/mTOR signaling repression, and NAD+ dependency. All stated facts are well-established in the literature. The reasoning is comprehensive and well-grounded.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}