Something I've recently noticed is that there's been a lot of mentioning about how rough Luffy is being on his body. When he unleashed Gear Second to fight Rob Lucci, Lucci mentioned that by strengthening himself with this method he was shortening his "life itself". When fighting Moria in his giant shadow-fueled form Luffy earned complaints from his crew that he was being to hard on his body by going into both Gear Second and Third simultaneously. After that he lost 10 years of his life to survive Magellans poison. I'm guessing that by the end of One Piece this will have all built up to the point where Luffy knows he will die soon.
The Straw Hats will be disbanded by Luffy and there will be a bunch of emotional drama. Then I'm guessing he'll end up repeating history and like the late Pirate King, Gol D. Roger, he will turn himself into the marines, be executed, and thus One Piece will end.
Thoughts? To me this seems pretty likely since Luffy's battles and injuries in the New World can only get more intense and more demanding of his body.