It seems pretty clear that Knuth was not talking about instruction-level optimization, but about those activities/features that came to be known as metaprogramm

It seems pretty clear that Knuth was not talking about instruction-level optimization, but about those activities/features that came to be known as metaprogramming, reflection, refactoring etc. I imagine he was thinking about human-directed program transformations that are almost language and machine-independent, implicitly high-level, whole-program stuff, rather than aimed at writing "idiomatic" fast machine code. So I guess not the kind of optimization you have in mind. What sounds more applicable for your use case would be profile-directed optimization, maybe based on mutating an initial fragment of assembler in ways that preserve its semantics but might improve performance. Like https://en.wikipedia.org/wiki/Superoptimization https://en.wikipedia.org/wiki/Superoptimization. But unless you wanted to create an instruction set that included reflection as a feature, this would most conveniently be written in another language. Edit: I should clarify, obviously self-modifying code written in assembler is in some sense reflective, but it's hard work.