Aging in Fast-Forward: An Inducible SIRT6 Deficiency model as a Lens on Brain Aging and Neurodegeneration

Abstract

Aging and neurodegeneration occur gradually, making in vitro modeling challenging and costly. We generated a time-resolved, reversible neuron-like aging model by gradually depleting SIRT6. Within three weeks, their transcriptomes recapitulated brain-aging signatures and hallmarks. RNA-seq revealed clusters of nonlinear changes and predicted oscillatory DNA-damage and apoptotic programs, allowing stress response and adaptation. SIRT6 loss led to nuclear envelope breakdown and micronuclei accumulation, resembling accelerated-aging phenotypes. Some defects could be rescued by re-expressing SIRT6. As a tool for discovery, we uncovered disrupted nucleocytoplasmic transport as an aging pathway shared with neurodegenerative disorders. When SIRT6 depletion reached 30 days, transcriptional changes correlated with those in Alzheimers patients, but reversed after SIRT6 re-expression. Pathways associated with shSIRT6 and healthy aging became anticorrelated with AD, pointing to critical signatures. Our affordable and easy-to-use model captures key molecular features of aging, distinguishes physiological from disease-linked changes, and accelerates mechanistic discovery in a controllable, neuron-based system.