Proposed experiment from debate on Epigenetic clocks and biological aging in neurodegeneration

SUMMARY

# Proposed experiment from debate on Epigenetic clocks and biological aging in neurodegeneration ## Background and Rationale This longitudinal study examines whether TET2 overexpression can counteract age-related cognitive decline and epigenetic drift in neurodegeneration. TET2 is a key DNA demethylase that maintains genomic stability and proper gene expression patterns, potentially serving as an intervention target for age-related neurodegeneration. The experiment uses transgenic mice with indu

METHODOLOGY NOTES

**Phase 1: Animal Preparation and Baseline Assessment (Weeks 1-4)** • Obtain 120 C57BL/6J mice (8-10 weeks old, equal male/female distribution) • Randomize into 3 groups: TET2 overexpression (n=40), vector control (n=40), wild-type control (n=40) • Perform baseline cognitive testing using Morris water maze, novel object recognition, and Y-maze • Collect baseline blood samples for methylation analysis and biomarker assessment • Establish housing in controlled environment (12h light/dark cycle, ad libitum feeding) **Phase 2: Viral Vector Administration (Week 5)** • Stereotaxically inject AAV9-TET2 or AAV9-empty vector into hippocampus (bilateral, 2μL per site) • Use coordinates: AP -2.0mm, ML ±1.5mm, DV -1.8mm from bregma • Monitor post-surgical recovery for 2 weeks with daily health assessments • Confirm transgene expression via qPCR at 3 weeks post-injection (n=6 per group) **Phase 3: Longitudinal Cognitive Assessment (Months 2-24)** • Conduct comprehensive cognitive battery every 3