What does the phrase “I’m down with” mean?

If you are down with something it means that you have knowledge of something or are in agreement with it. I’m down with science means “I am familiar with science” or “science is a good thing.” To be down with something is a slang phrase, and not terribly common in formal speech or writing.

You could also speak of having a disease, sometimes preceded by the verb to come if the sickness hasn’t yet fully taken hold. eg. I am coming down with a cold. or She is down with the flu.

To be up with something is only used in the imperitive, eg. up with the king! — meaning hey, that king is pretty great. Or: up with ice cream! (Yay! Ice Cream!) You would never say I am up with something. That wouldn’t be proper english. Although you could say I am up to something, you sneaky little devil, you. (In case it’s not clear, “I am up to something” means “I have an ulterior motive I don’t wish to reveal.”)

If you are addressing someone directly who is presently seated, you could use a command: up with you! (stand up.)