Fascinating. Looking forward to sitting down with it.
I spent some thoroughly enjoyable time with your paper. As you would expect, I have questions the answers to which might rest on my lack of understanding. Also keep in mind that I took organic 40 years ago – when in my 40s – and then only for fun and curiosity. I was definitely the oldest guy in the class. I’ll parse my questions out over time, hopefully to integrate your response.
Focusing on the broad gero thesis (setting aside specific elements such as renal protection) your case focuses on the pH of the mitochondrial matrix and the nucleus (much detail here, I’ll try to pick up later) but employs urinary pH as a dependent variable. It seems to me that we are considering three physically distinct compartments with three different regulatory systems with a strategy that treats them as one dial to be turned? Oral citrate does not set mitochondrial matrix pH, and it does not set nuclear pH. Blood pH is precisely regulated at 7.35–7.45 by respiratory and renal compensation no matter how much citrate one takes. Intracellular pH is mostly regulated by sodium and hydrogen exchangers and bicarbonate transporters. It seems to me (I could easily be wrong here) that a citrate load moves urine pH (which is likely geroprotective in some circumstances) but tells us little about the pH of the matrix or nucleus where the acetylation mechanism is supposed to operate. The measured DV is causally downstream and disconnected from the proposed mechanism. I’ll stop here for now. You may have a different DV in mind to assess optimization of the matrix and/or nucleus.
Urinary pH is massively influenced by food (including exogenous citrate). Serum pH maybe worth worrying about, but urinary pH is a big issue for avoiding gout. I have not looked at the nuclear pH which I assume is maintained in the physiological range (7.2-7.4)