PhD defence M.B. (María) Birkisdóttir

Brief summary:

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.