I've had an idea like this since I was little boy. I wanted to see a game where you start out completely healthy and normal, and then your character is struck with a horrible disease. In the struggle to find the cure, the game's enemies and obstacles remain the same difficulty, but the disease hinders your abilities further and further, gradually increasing the challenge. I'm surprised no one has done it yet.
One game that had a interesting mechanic was Maximo: Ghosts to Glory. Maximo begins the game with three slots which he can "lock" special powers in. He can gain more than three powers, but if he dies, he only respawns with the "locked" powers. The player gathers many different powers, but they must decide which powers are the most important to keep, because failure results in losing most of those powers. As each boss is defeated, Maximo is gioven and extra slot to "lock" an additional power. So you still grow stronger like a classic RPG and can amass an impressive arsenal of powers, but in a time of crisis, you can easily lose some of those powers, keeping the difficulty at a good challenge at all times.