I don't fly in the 121 world yet (and I may never), but I have been a professional in a field known to have fatigue problems with rest requirements that are supposed to solve the problems of fatigue. One thing I learned from that is that no bureaucrat can look at a group of people and say, "You know, every one of you is going to need X amount of rest, and all fatigue will go away."
I don't know the solution exactly because I haven't studied it enough. But I know that you can change the rest rules all you want to, but the fact that different people are different means that you're always going to have fatigue problems in aviation, medicine, trucking, etc.