This is just an idea I had after the season 3 finale aired, and before Meagan Mcarthy banished the idea that Twilight would outlive her friends.
100 years after finding her destiny and ascending to the Princess of Magic, Twilight is faced will the most dire and tragic of foes: Time. Twilight is immortal and will linger on, but her friends can't stay with her forever.
How would she have handled their passing?
And is Celestia to blame?