How do you know when it's time to let go of a story?

I'm so intrigued by your answers, but surprised that so many of us seem to let go only when the game makes us. Having just said goodbye myself to a two year old save, partly because it was so heavy to play with all the bugs, I can't imagine how you keep your saves going for 5, 6 or 10 years. Granted, I do use a lot of mods so maybe that's my own fault.