A systematic evaluation of SIRT6 as transcriptomic biomarker of aging

Abstract

SIRT6 is a NAD+-dependent sirtuin that plays central roles in chromatin regulation, DNA repair, telomere maintenance, metabolic homeostasis, and inflammatory control. Although SIRT6 have long been implicated in aging because of its association with several hallmarks of aging, the available evidence remains largely context-dependent and mechanistic, limiting the interpretation of SIRT6 as a robust and evolutionarily conserved biomarker of aging. To comprehensively investigate the role of SIRT6 as an aging biomarker, we established SIRT6.db, a multi-species transcriptomic resource that integrates SIRT6-targeted perturbation experiments across diverse biological systems and organisms form all available SIRT6-related publications collected via a large-scale textual analysis of the SIRT6 literature using topic modeling. Based on this database, we identified both species-specific and evolutionarily conserved transcriptional and functional signatures associated with SIRT6 perturbation and established their relevance to hallmarks of aging. We showed that SIRT6 expression is generally stable during normal aging, but becomes dysregulated in Alzheimer's disease in cell type and stage-specific manner, highlighting the context dependence of its potential as a transcriptomic biomarker of aging.