Ruling various empires involved Charles V in constant warfare. This, along with his failing health, is the most likely reason for Charles to have abdicated the throne.
Charles V abdicated his empire slowly. His first abdication were the kingdoms of Sicily and Naples in 1554. The final one was the abdication of the throne of the Holy Roman Empire in 1556. Moreover, he suffered crippling gout, along with epilepsy and a deformity of the jaw.