Turns out the future does have flying cars

Why would you aim for bare minimum?

POV: You’re 25 miles into the Chicago Marathon and on your way to a 2:34 PR. Here’s what the final mile looks like from inside the race.

I think that in nature (read: with no carbohydrate intake during exercise), the rate of fat oxidation at a given exercise intensity is a key determinant of durability. Why? Simply because it allows the body to spare its limited carbohydrate stores. However, we are no longer hunting for food. Indeed, we now consume carbohydrates while "hunting". Perhaps the increasingly high carbohydrate intakes during exercise introduced in recent years have changed the scenario. Maintaining high carbohydrate availability is becoming easier, making carbohydrate depletion less of a limiting factor. As a consequence, the physiological determinants of durability may have shifted, at least in part, beyond carbohydrate availability alone. Possible mechanisms? Central fatigue, muscle damage, and systemic inflammation, among others. While these mechanisms are also influenced, at least in part, by carbohydrate availability, they can develop independently of carbohydrate availability and, consequently, fat oxidation rates. This could explain why fat oxidation rates are associated with durability when no carbohydrates are ingested during exercise, but this association disappears when high amounts of carbohydrates are consumed during exercise.

"Ketone Confusion" - A seemingly esoteric question about exogenous ketones that matters... A LOT! The question is: Does the ketone precursor 1,3-butanediol damage the liver? For context: 1,3-butanediol is included in a number of exogenous ketone products, including @ketone (Ketone IQ) @Kenetik etc., and is one half of the ketone ester originally developed through work at the NIH and Oxford funded with a $10M grant from DARPA. So, let’s unpack it together, for the uber nerds and nuance ninjas among you. Some animal experiments have raised concerns that the ketone precursor 1,3-butanediol could cause liver injury. I’ve previously expressed concern myself, even though the evidence at present is largely from mouse models. But I think I’m changing my tune because there is a major wrinkle hiding in the mouse model. And if you understand it, you’ll see why this might be a much bigger problem that affects how we interpret all ketogenic diet and ketone-related research. Our little story centers on an enzyme called Nicotinamide nucleotide transhydrogenase (NNT). NNT lives in the inner mitochondrial membrane and plays an important role in managing cellular “redox chemistry.” Ahh! Scary jargon. The short of it is that energy generation pathways in cells require the transfer of electrons. When electrons are passed to something that thing becomes “reduced” because its charge goes down (electrons have negative charge). When electrons are removed from something it becomes “oxidized.” Red-uce + Ox-idize = Redox. Main point: This passing of electrons impacts all things energy generation, oxidative stress, and metabolism in the cell. So, if you screw with a key enzyme in this process (NNT), things are at risk of getting wonky. But why does that really matter? Well… and this is what I didn’t realize until now: one of the most widely used laboratory mouse strains, C57BL/6J, carries a spontaneous mutation in the Nnt gene that results in defective NNT function (PMIDs: 15729571; 16804088). 👉And it’s specifically in this NNT-defective strain of inbred mice we see some signal of 1,3-butanediol causing harm to the liver. 👉Interestingly, other closely related substrains, where NNT has been added back (e.g. the NIH strain, C57BL/6N) don’t show this same phenomenon. But I don’t want to leave you deficient in mechanism so let’s dig deeper and show why loss of NNT causes issues, and then I’ll summarize the important parts. 👉The liver metabolizes 1,3-butanediol through two steps toward BHB. In the process electrons are passed to NAD⁺, generating NADH. Normally, NADH isn’t a bad thing. It’s fundamental to metabolism. 👉But dump enough reducing equivalents into a system and you can push the NADH/NAD⁺ ratio upward, creating an unusually “reduced” cellular environment. 👉That can constrain NAD⁺-dependent reactions, alter mitochondrial fuel metabolism and even increase oxidative stress. (There are a few ways, but basically if electrons pile up at the front door of mitochondria, Complex I, they can end up creating a traffic jam and backflow creating reactive oxygen species.) This is where NNT enters the story. NNT transfers electrons from NADH to NADP⁺: So... NADH → [NNT] → NADPH Those molecules sound almost identical, but they play very different roles. NADPH is critical for maintaining antioxidant defenses (this “P” for Protect), including the glutathione and thioredoxin systems. So an NNT-deficient animal potentially faces a one-two punch when challenged with a large 1,3-BD load: 1. NADH overflow: 1,3-butanediol metabolism generates NADH, and the natural pressure valve on NADH buildup is broken, meaning you can easily tip the cells redox state too far to the NADH side, leading to altered energy metabolism and oxidative stress. 2. Antioxidant pressure: NNT can no longer efficiently make NADPH for mitochondrial antioxidant defenses. An analogy: Imagine 1,3-butanediol metabolism as throwing sparks as part of normal metabolic processes. A normal liver has wet grass and a sprinkler system. No problem. An NNT-deficient liver is like dry kindling without a water source. Okay, but why does this seemingly esoteric bit of biochemistry matter? Because when we get conflicting animal data on ketones, metabolism, and overall function (with people inevitably gravitating toward the data that serve their purposes) we’re going to continue talking past each other unless we identify the basis of the discrepancies in the literature. Why this matters is because all humans have NNT. It is clearly important to overall metabolic health and metabolism. Unpublished data from my friend and colleage, Dr. @AKoutnik, going back over a half decade shows the signal why. Quote, shared with permission: “Back in graduate score I ran direct comparison research between mice with NNT knocked in and knocked out. When I administered exogenous ketones into animals with NNT, they would rapidly get sick and demonstrate signals of liver toxicity. They also were not able to fully metabolize the ketone bodies. However, animals with NNT fully functional, observed no toxicity and completely normal metabolic response to ketones. This presented a major problem. The overwhelming majority or research on animal models, often exploring their role in health and disease have come from C57/BL6J models where NNT is not functional and deleted. Since all humans have NNT, mice deficient in NNT are not able to demonstrate appropriate metabolism of these molecules, particularly molecules that require liver metabolism (like 1,3 Butanediol). This is often when we may see problems in animals in molecules that millions of humans have consumed without any reports of liver related issues. The overwhelming majority of researchers in this field have no idea, even researchers who focus on animal models and diet. I have only met one who was aware (Dr. Peter Crawford).” It’s also worth emphasizing that millions of doses have been consumed by the general public, without any major reported side effects. That doesn’t unequivocally rule out any possible harm in anyone ever under all circumstances. But I find it reassuring. At the end of the day, my number one preference is to get into ketosis through a low-carb diet and/or fasting. But for those circumstances where topping off your ketones is desirable, I don’t think 1,3-butanediol is something we need to be particularly worried about based on the evidence I’ve seen. More broadly, though, I think this gives us an excellent case study in the sneaky ways different research groups can get seemingly contradictory results, not necessarily because one is wrong, but because of some obscure (but important) variable hiding beneath the surface. And that leaves me with a bigger question: What else might we be missing? P.S. Huge credit to @AKoutnik for pointing me down this fascinating rabbit hole. I hope we can explore this more deeply together in future.