My biggest save has 214 sims marked played and about twenty permanent townies, the rest I cull manually after each session. The game is not allowed to cull sims or relationships and relationship decay is set to 10% to ensure that the only changes that occur come from actual gameplay. Aging is off, I move the timeline along when it feels appropriate.
The story in this save revolves around the detective career sims and their extended families, to the point that whenever world-shattering events occur (like werewolves getting discovered, magic coming to the world or the first contact with Sixam), those events somehow are centered on the Detroit municipal police, central station. It's totally unrealistic, but that's just how things are.
Supporting characters fade in and out of the spotlight. I play a household intensely and then have them stay in the background for rl months. Sometimes I think I do not really play my sims, but the overall story of my city. I decide what event will happen next, and then I pick a family that fits this theme best.