It was soloitis... he soloed so many and his health got progressively worse the more he soloed, which is why he told kisame to back off from konoha jounins cause if itachi soloed he wouldn't be able to make it to part 2 sasuke fight even with his drugs... this is why he is second best uchiha behind jiraiya who is an distant Uchiha, Madara got long white hair when he was old. Jiraiya has white hair too, the red markings in his eye are the Sharingans melted away