honestly, i don't think you'll notice much in the way of mileage, the resistance would be comperable to a headwind... though i DO believe on a new engine the wear would be considerable... on a worn engine, the one with 295,000 you couldn't do anything better than run 20-50 in it!
if you were to take a motor designed to run on 5-20, and put 20-50 into it, it would essentially wear it to the point where 20-50 would be the correct oil for the clearances that it has, it will take a while for it to happen, but it will be significantly accelerated... say for instance, (random numbers, don't quote me on this) if your 5-20 engine was stepped up slowly from 5-20, to 5-30 to 10-30 to 15-40 to 20-50 as the engine wears, your motor would be "ready" for 20 50 at... 100,000 miles, and you went straight from 5-20 to 20-50 at 10 miles on the truck at say 10,000 miles, your truck would show 100,000 miles of wear...
if you want the motor to last as long as possible, you should be stepping the thickness of the oil up slowly as the engine wears... at what time you change the oil weight is largely debatable, and really anyone who claims they know is full of crap, the only person who i would really trust (other than myself and my gut) to ACTUALLY know what it the perfect oil weight is, would be an engineer who has taken apart my motor and measured EVERY bearing and oil galley with a micrometer and where applicable, plastigauge