Jan Hoeijmakers his personal motivation in science is to try to find rational-based solutions for ubiquitously occurring, devastating diseases such as cancer and aging-related pathologies, which represent the dominant healthcare problems world-wide. To find ways to promote healthy aging, I focused on the most important molecule in cells, the DNA, carrying all instructions for life, reasoning that persisting damage to this biomolecule must have lasting deleterious effects on cell function and properties, and hence may contribute to compromised health. Therefore I joined the Department of Genetics of the Erasmus University in Rotterdam in 1981 to work on DNA repair processes in mammals, which preserve the integrity of our genome, despite continuous attack by a plethora of DNA-damaging agents. From the beginning we have consistently made major contributions towards identifying human DNA repair genes, which provided the basis for understanding mechanisms of DNA repair in vitro as well as in live cells and intact mice by developing GFP-tagging and dynamic innovative photobleaching techniques, for generating valid mouse models and for delineating their biological and clinical importance for cancer and aging. In this way we recently pioneered the link between DNA damage, repair and aging and succeeded in getting aging in mice to a significant extent under control. We also identified DNA damage-driven transcriptional stress as major cause of aging explaining the basis of proteinopathies and discovered a surprising effect of nutritional interventions, with implications for repair syndromes, dementia’s, chemotherapy and ischemia reperfusion injury in surgery and organ transplantation.