I do agree that Apple needs to get better at I/O scheduling – even with an SSD the experience is less responsive than BeOS was on 90s PC hardware — but the animation loop has typically been a reliable diagnostic cue in my experience for distinguishing between swapping / disk failure and other issues.
This is exactly what I've seen. If I catch it early enough and can get the UI to respond to me tabbing to the terminal, I can kill Safari's web content processes or whatever it is that's leaking memory and it goes away.
I think what's happened is that every single developer at Apple has SSDs on their work and home computers so they get wasteful with memory. When iPhoto needs 150% memory to update an index you're not even going to notice that with an SSD, but with an HDD the system can freeze up.
This will eventually resolve itself once every computer has a SSD, but in the meantime the existing Macs with HDDs will be a mess.
I would start by checking the logs to see whether there's anything obviously failing, running the hardware diagnostics (reboot while holding down the D key – https://support.apple.com/en-us/HT201257), and then uninstalling all of the apps which you mentioned that require privileged access since at least Karabiner and Little Snitch are kernel extensions and third-party kexts are notorious sources of bugs for months after a new OS X release.