Have replied to the first part of this in another thread.
I guess this is mostly a matter of opinion, but I consider that if you fight your enemy to the point of destruction, it is more or less your own fault (except perhaps in a multi-player game) and you're simply getting your just deserts. This game after all simulates the Hellenistic age, and this was not the way of the world then. If there is one thing I would like to get right in this game, then it is that players bringing modern and "gamey" ideas like total wars to the death into the game, will learn a bit of historical reality and get slaughtered.

The game system is not vindictive (at least not as currently designed), and it will always be possible to buy off the enemy with tribute, gifts, and submission. Bow the neck become a vassal, and
behave like one and one's chances of survival should be good. A novel departure from most strategy games, where surrender is hardly ever considered an option (e.g., Europa Universalis). We shall see whether this works out as intended.
The Roman senate will usually be prepared to accept vassalage from civilized states, rather than direct conquest (no second chances though). The Carthaginian senate is not interested in conquest as such. The various Successor states may attempt to destroy each other, but there will always be the option of going into exile with a neighbor, and then attempting to return at a latter time.
In game terms, the historical destructions of Carthage and Macedon would be avoidable by strict devotion to their vassalage, Syria by not plunging into civil wars, Egypt by backing the right side in the final civil war.
I don't know whether you should loose all your points (likely there will be a high-score table, after all), but I don't see how the player can be acclaimed as the winner if he is wiped out. After all, if you get destroyed in 200 BC, very few are going to want the computer to play the next 180 years just in order to see whether the AI scores more points. This is more interesting only in the case of a multi-player game.
Piracy is not a direct major political threat, btw - in that they cannot go in and seize a kingdom. It can cause dangerous unrest, though.
Also, on never-ending story, why not? I am not suggesting no fixed end point, I am suggesting the capability to play on beyond the end-point, just for the joy of the game.
But at the cost of historicity. I think 250-300 years is going to the upper limits of what one can handle in a historical system, while still keeping the game historical. The game system setup wouldn't handle many of the issues that would start popping up as we enter the first AD; e.g., the spread of Christianity, the homogenization of the Empire, the Persian resurgence, and the German pressure on the borders. However, if one really wanted to continue, I imagine it would be rather easy to modify the savegame to allow this.