We are investigating the impact of DNA damage on mammalian physiology during aging and its causative role in the premature onset of age-related diseases, including cancer. We are using a series of genetically engineered mouse models that carry inborn defects in Nucleotide Excision Repair and/or transcription as well as mice that carry tagged versions of proteins involved in DNA repair and/or transcription. This approach allows us to understand how mammalian cells exploit their natural defense strategies to counteract DNA damage-driven pathologies and prolong healthspan.