Conflict with Arius and Arianism as well as successive Roman emperors shaped Athanasius's career. In 325, at the age of 27, Athanasius began his leading role against the Arians as his bishop's assistant during the First Council of Nicaea. Roman emperor Constantine the Great had convened the council in May–August 325 to address the Arian position that the Son of God, Jesus of Nazareth, is of a distinct substance from the Father. Three years after that council, Athanasius succeeded his mentor as archbishop of Alexandria. In addition to the conflict with the Arians (including powerful and influential Arian churchmen led by Eusebius of Nicomedia), he struggled against the Emperors Constantine, Constantius II, Julian the Apostate and Valens. He was known as "Athanasius Contra Mundum" (Latin for Athanasius Against the World).

Athanasius began his leading role at what age?