Sirt1
M. musculus
sirtuin 1
What the model saw
Gene: Sirt1 Organism: Mus musculus Known functions: sirtuin 1. NAD-dependent protein deacetylase sirtuin-1. DNA-binding transcription factor binding. HLH domain binding. NAD+ binding. NAD-dependent protein decrotonylase activity. NAD-dependent protein lysine deacetylase activity. NAD-dependent protein lysine delactylase activity. NAD-dependent protein-lysine depropionylase activity. RNA polymerase II cis-regulatory region sequence-specific DNA binding. bHLH transcription factor binding. deacetylase activity. enzyme activator activity. enzyme binding. enzyme inhibitor activity. histone H3K deacetylase activity. histone H3K14 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H4K12 deacetylase activity, hydrolytic mechanism. histone H4K16 deacetylase activity, NAD-dependent. histone binding. histone deacetylase activity. histone deacetylase activity, NAD-dependent. histone decrotonylase activity, NAD-dependent. identical protein binding. keratin filament binding. mitogen-activated protein kinase binding. nuclear receptor binding. p53 binding. promoter-specific chromatin binding. protein binding. protein domain specific binding. protein kinase B binding. protein lysine deacetylase activity. transcription coactivator activity. transcription corepressor activity. transcription regulator inhibitor activity.
View unredacted entry
sirtuin 1. NAD-dependent protein deacetylase sirtuin-1. DNA-binding transcription factor binding. HLH domain binding. NAD+ binding. NAD-dependent protein decrotonylase activity. NAD-dependent protein lysine deacetylase activity. NAD-dependent protein lysine delactylase activity. NAD-dependent protein-lysine depropionylase activity. RNA polymerase II cis-regulatory region sequence-specific DNA binding. bHLH transcription factor binding. deacetylase activity. enzyme activator activity. enzyme binding. enzyme inhibitor activity. histone H3K deacetylase activity. histone H3K14 deacetylase activity, NAD-dependent. histone H3K9 deacetylase activity, NAD-dependent. histone H4K12 deacetylase activity, hydrolytic mechanism. histone H4K16 deacetylase activity, NAD-dependent. histone binding. histone deacetylase activity. histone deacetylase activity, NAD-dependent. histone decrotonylase activity, NAD-dependent. identical protein binding. keratin filament binding. mitogen-activated protein kinase binding. nuclear receptor binding. p53 binding. promoter-specific chromatin binding. protein binding. protein domain specific binding. protein kinase B binding. protein lysine deacetylase activity. transcription coactivator activity. transcription corepressor activity. transcription regulator inhibitor activity.
Solver output
SIRT1 is a NAD+-dependent class III histone deacetylase that deacetylates histones H3K9, H3K14, H4K16, and H4K12, maintaining repressive chromatin states and genomic stability. It also deacetylates p53, suppressing p53-mediated apoptosis and senescence, and acts as a transcription corepressor/coactivator modulating key longevity-associated transcription factors including FOXO, NF-κB, and PGC-1α. SIRT1 activity is tightly coupled to NAD+ levels, linking it directly to the deregulated nutrient-sensing hallmark via the AMPK/mTOR axis and caloric restriction pathways. Overexpression of SIRT1 in mice extends healthspan and lifespan, while its loss accelerates aging phenotypes, consistent with a pro-longevity role. Its broad epigenetic regulatory function—counteracting age-associated hypoacetylation drift and maintaining transcriptional fidelity—places it squarely within the epigenetic alterations hallmark of aging.
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 SIRT1 as pro_longevity with very high confidence (0.95). The mechanistic reasoning is excellent and accurate: SIRT1 is indeed a NAD+-dependent deacetylase that deacetylates histones and p53, links to caloric restriction pathways, and overexpression studies in mice support pro-longevity effects. The model correctly identifies the epigenetic alterations mechanism class and accurately describes the key pathways involved. All aspects of the prediction are well-supported by the scientific literature.
Raw API responses
solver
{
"reasoning": "SIRT1 is a NAD+-dependent class III histone deacetylase that deacetylates histones H3K9, H3K14, H4K16, and H4K12, maintaining repressive chromatin states and genomic stability. It also deacetylates p53, suppressing p53-mediated apoptosis and senescence, and acts as a transcription corepressor/coactivator modulating key longevity-associated transcription factors including FOXO, NF-κB, and PGC-1α. SIRT1 activity is tightly coupled to NAD+ levels, linking it directly to the deregulated nutrient-sensing hallmark via the AMPK/mTOR axis and caloric restriction pathways. Overexpression of SIRT1 in mice extends healthspan and lifespan, while its loss accelerates aging phenotypes, consistent with a pro-longevity role. Its broad epigenetic regulatory function—counteracting age-associated hypoacetylation drift and maintaining transcriptional fidelity—places it squarely within the epigenetic alterations hallmark of aging.",
"confidence": 0.95,
"key_pathways": [
"NAD+/SIRT1 deacetylase axis and caloric restriction signaling",
"p53 deacetylation and cellular senescence suppression",
"Histone H3/H4 deacetylation and chromatin integrity maintenance"
],
"mechanism_class": "epigenetic_alterations",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model correctly predicted SIRT1 as pro_longevity with very high confidence (0.95). The mechanistic reasoning is excellent and accurate: SIRT1 is indeed a NAD+-dependent deacetylase that deacetylates histones and p53, links to caloric restriction pathways, and overexpression studies in mice support pro-longevity effects. The model correctly identifies the epigenetic alterations mechanism class and accurately describes the key pathways involved. All aspects of the prediction are well-supported by the scientific literature.",
"failure_mode": "correct",
"answer_correct": true,
"mechanism_correct": true,
"reasoning_quality": 5,
"ground_truth_questionable": false
}