I think the correlations MF has found between F1F0 ATP hydrolysis rate and both species lifespan and damage to various biomolecules are very interesting. One major problem is he just doesn’t present much other data that IF1 regulates aging one way or the other, especially given the similar correlations he’s shown between metabolic rate and species lifespan.
His “evidence” that increased IF1 activity slows a biomarker of aging in mice is that it reduces ROS. The result he cites is a paper showing that increased IF1 activity increases ROS, data which MF claims was wrongly interpreted. That aside, while ROS is almost certainly involved in the aging process, it’s absolutely not a reliable biomarker, and there’s many lines of data that support this. This “evidence” is about as good as no evidence at all.
Additionally, his entire theory is based upon the “fact” that IF1 inhibits only the reverse mode of ATP synthase, acting by a ratchet and pawl mechanism. Perhaps that is the current consensus of the field, but just digging into it a bit I found a 2015 paper in Cell Reports that contradicts this. They found that the phosphorylation status of IF1 regulates its activity, and that unphosphorylated IF1 can inhibit both the forward (ATP synthesis) and reverse (ATP hydrolysis) modes of ATP synthase, which as they acknowledge, challenges the traditional view of IF1 as a unidirectional inhibitor.
MF cites other papers by these authors but makes no mention of this paper (presumably because it strongly challenges his theory), which I find is a major issue.
The paper I linked also shows that beta-adrenergic stimulation regulates IF1 phosphorylation/activation in vivo, with the beta-adrenergic antagonist propranolol acting to dephosphorylate and activate IF1, which as they demonstrate, acts to inhibit both the forward and reverse modes of ATP synthase.
Additionally worth mentioning is a result in Nature Communications, which found that beta-adrenergic inhibition (with nebivolol) also acts to increase the expression of IF1 protein in vivo.
These last couple results I mention because nebivolol has been tested in the ITP and failed. Obviously we really have no idea what the effect of chronic nebivolol in mice is with respect to pIF1/IF1 expression. Maybe it has little effect in most tissues. That said, it still is evidence against MF’s theory and he should address it, as I’m sure he’s aware of these results.
Hopefully MF can find a way to gather more in vivo data with respect to his lead compound, as I’m sure funding is an issue. I’d also like to see biochemical data that unambiguously demonstrates the unidirectional ATP synthase inhibitor claim.