At least for live action, is the fact that they aren't immortal.
This pretty obviously stands to reason but I thought it was worth exploring the implications of it as well. I started thinking about it as a result of watching this show Lucifer.
A long running urban fantasy show called Supernatural has protagonists that are human. The characters around them can run the gamut from human to supernatural themselves, but the main characters are plain mortal. Another show, Angel, didn't run as long but it's widely accepted as being great and influential. A lot of the side characters are mortal but the main character is a vampire.
Angel got cancelled by its parent channel after five great seasons, but even if the showrunner, writers, and actors wanted to go back and capture some of that magic, even if they had the support and funding, they couldn't write around the fact that the main star has gotten many, many years older.
In animation, you don't see this. The voice doesn't change as much as skin does over the years so you can have a protagonist pretend immortality pretty well. Look at the Simpsons; they're ageless and have been for 20 years.
But in live action, people get older. Or they change in other ways; get pregnant, get scars, get ill, all things which can visibly impact their character on a show in which they should be functionally changeless.
I've held for a while now that animation is the future because of this. You don't face the same problems that TV does with actors who may want to do other roles, or who may quit acting altogether. For better or worse it's easier to find a voice stand in then a face stand in, so a show can continue running even if the voice actors for the major characters have to change.
This might change with Deepfake technology, if it can overlay a youthful appearance over an actor's face. I suppose time will tell.