I get it. My eyes are red and puffy. I am a walking bag of bones. And while your statement is probably meant to show that you care, it doesn't really stimulate discourse. Try these instead.
  1. "Want to get a cup a coffee?"
    V active!! Physically helps! See also: cafe work sessions, if you know they are on a deadline.
  2. "Who got kicked off of Dancing with the Stars?"
    Call upon a passion of this person. It might be work or every day stresses that make them tired. Remind them of things that they love to get *happily* worked up about...and let them nerd out for a minute.
  3. "What do you need?"
    Much better than the toss-away "how are you," this is more likely to pinpoint the origin of stress. An answer might take form of a lame joke (i.e. "to rob a bank") but at least you move a bit closer to what is *really* on the other person's mind.
  4. "What cool theories are you working with in your dissertation right now?"
    (Or *insert major project*) Maybe the person has a big project they're working on and it feels endless. Give them an outlet so they feel that their daily work matters. Remember: asking a broad question like, "How's your dissertation coming along" will only lead to vague answers like, "Oh, it's okay."