The most powerful sign is that your work no longer enchants you - it's not deep, delightful, and mutually satisfying. When this happens, it may be time to look for new challenges.
For a long time I used to think this a silly, straw-splitting distinction: how could you hate what a man did and not hate the man? But years later it occurred to me that there was one man to whom I had been doing this all my life - namely myself.