Let's assume some things:

• Back-ups do run every X minutes, yet the things I save should be permanent.

• There's a firewall and virus scanner in place, yet there happens to be a zero day attack on me.

• I am using Windows. (Although feel free to append Linux / OS X parts to your answer)

Here is the problem

• Any software can change anything inside my user folder.

• Tampering with the files could cost me my life, whether it's accessing / modifying or wiping them.

So, what I want to ask is:

• Is there a permission-based way to disallow programs from accessing my files in any way by default?

• Extending on the previous question, can I ensure certain programs can only access certain folders?

• Are there other less obtrusive ways than using Comodo? Or can I make Comodo less obtrusive?

For example, the solution should be proof against (DO NOT RUN):

del /F /S /Q %USERPROFILE%