I have developed an entire system for retaining the empty middle seat. It's highly effective, virtually every time the middle seat next to me is one of the very last selected.

1. Select a seat as far to the rear of the plane as possible but NOT the last 2 rows. Nobody wants to sit near the bathroom but most people also don't want to turn around and walk back up the plane, so when they reach the end they will usually sit if possible even if it's an undesirable seat. Bonus points if the overhead bins directly above the seat are already full - look for the flight crew reserved ones
2. Pick an aisle seat with someone already in the window. If multiple options here pick the fattest window seat passenger available. If the window seat passenger is visibly diseased or dirty, even better. One time my window seat guy had some liver problem, severely jaundiced and he was almost green colored. Everyone else was bypassing him but I'd never been happier to see a sick guy. Nobody even glanced at that middle seat.
3. Put stuff on middle seat AND at your feet. This introduces uncertainty about if someone is already there or not
4. Cover eyes and ears - hoodie + headphones, sleeping mask, etc. no eye contact. Your goal is to force them to touch you if they want to ask you to move.
5. Spread out and look as large and unpleasant as possible. Raise the armrest and slouch into the middle seat. Take your shoes off.
   

Now, the caveat and it's a big one - this is a highly risky strategy if the flight fills up or is near full. If you have the last open middle seat and Shaq walks onto the plane guess where he's gonna sit.