What entries that should not be remove every time we use a registry cleaner?

I use several registry cleaners in keeping up my registry clean, and have no problem using them, removing only those safe to remove entries. But when I tried to search for an older programs that was already uninstalled for a long time, I found them but I doubt if these entries are very safe to remove coz I’m not pretty sure if this was use or connected or still use by other functional programs in my pc. What can you suggest on this?