Very interesting!

Speaking of misfolded proteins and neurodegeneration, those of us not descended from hyperthermophyle archaea have to deal with cleaning them up in neurons. I'm sure we have the same issue in all our other cells, but those are replaced over time. Neurons are mostly not (although stimulating BDNF may eventually make that untrue).

So we’ve for some junk to clean up. Our cells do this a couple of ways, autophagy and the ubiquitin-proteasome proteolytic pathway.

What stimulates autophagy? Typically some kind of cellular stress, usually lack of food. BTW: there's been some in vitro work indicating that at least one of the heat shock proteins can also do this*.

There’s some work showing that antioxidants can interfere with autophagy. I’ve read a couple of papers indicating that mitochondria use reactive oxygen species (ROS) as a signaling channel with the containing cell. My guess is that antioxidants interfering here is the issue (but the actual mechanics of autophagy initiation don’t seem to be well understood). I am reconsidering my antioxidant use — particularly during any fast as promoting autophagy in neurons is pretty much the only reason I do this. Also sulforaphane, as this creates glutathione (a very strong antioxidant).

I’m not clear we have any control over the ubiquitin-proteasome proteolytic pathway — other than in a negative way (e.g. limiting ubiquitin availability, either through depleting it or otherwise limiting precursors). But this is an area I haven’t been looking at.

*possibly related: there has been some clinical work showing that significantly raising body temperature (more than possible in a sauna/banya) has a therapeutic effect on depression.