I enjoy this vein of thought. It would feel more satisfying if escalation in difficulty (e.g. "Deity" level) added mechanical complexity and trade offs rather than just giving opponents artificial advantages.
- Tile focus can damage the output of surrounding tiles
- Mines might temporarily/permanently reduce nearby food production or appeal
- Longterm tile focus can outright destroy the resource - Overfishing, Strip mining, Soil depletion
- Bring back or re-emphasize some of the old mechanics - Population explosions also increase civil unrest
- Corruption quickly eats away economic output
- Opponent choices can cause cumulative/permanent damage to your cities if they are nearby, downstream, or downwind.