Neurodegeneration and the roles of DNA damage and nutrition

This thesis investigates the accumulation of DNA damage, particularly of
transcription-blocking lesions, as a driver of aging and neurodegeneration.
We furthermore examine interventions to enhance genomic stability and
extend neuronal health and lifespan in DNA repair-deficient mouse
models. While 30% dietary restriction (DR) significantly extends health and
lifespan, our results show that Rapamycin, an mTOR inhibitor and a alleged
DR mimetic, is ineffective in these mice. Various anti-aging compounds
also showed no effect, except for NAD+ precursors, likely due to NAD's role
in DNA repair. Next, we show that DR likely impacts the brain, at least in
wild type mice, by increasing DNA repair and reducing neuronal signaling.
Using a Purkinje-specific DNA repair-deficient models, we demonstrate
DR’s cell-autononmous neuroprotective effects in preventing
neurodegeneration and motor decline. Our findings confirm DR's efficacy
in reducing DNA damage in repair-deficient mice and support these
models for discovering interventions to maintain genomic health and
extending neuronal health and lifespan.