Greetings!
Welcome to the Physiology Friday newsletter.
Details about the sponsors of this newsletter and deals on products I love, including Wild Roman skincare, Ketone-IQ, Equip Foods, and ProBio Nutrition can be found at the end of the post.
Most weeks, I use this newsletter to take one study and pull it apart. This week, I wanted to do something a bit different.
I spend a good amount of time reading papers and arguing about physiology on X (née Twitter). Occasionally, a study or discussion sends me down a rabbit hole (sometimes practical, sometimes speculative) and occasionally lights enough of a fire under me to warrant a (usually snarky) reply on social media or, in cases where it’s something I’m passionate or knowledgeable about, a full-on post.
That’s what you’re getting today.
Could you transfuse the benefits of exercise?
I came across a study recently that made me stop and then sent me down a slightly science-fiction rabbit hole. I ended up posting about it on X.
Researchers took plasma from exercise-trained rats and transferred it into rats genetically engineered to model Alzheimer’s disease. In the animals treated early in the disease process, exercise-trained plasma increased mitochondrial respiration in the hippocampus, the brain region central to learning and memory. It was a tiny proof-of-concept experiment—only three animals per treatment group—so this isn’t remotely ready for translation to humans. But the idea itself fascinates me.
We generally think about exercise adaptation as something that happens to the person exercising. I train, so my mitochondria improve, my cardiovascular system adapts, and my muscles become better at producing and using energy.
But exercise also radically changes what’s circulating in the blood. Muscle releases myokines, in addition to the hundreds to thousands of other hormones, metabolites, and signaling molecules that spike during and after a workout.
What if some portion of the “exercise phenotype” is transferable?
This isn’t completely hypothetical. In 2021, researchers collected what they called “runner plasma” from voluntarily exercising mice and infused it into sedentary mice. The plasma reduced neuroinflammatory gene expression, and the researchers identified a protein known as clusterin as one potential mediator of those effects.
And the broader idea that circulating factors can transfer biological effects has an even longer history.
One of the stranger experiments in aging research is heterochronic parabiosis, in which researchers surgically connect the circulatory systems of a young and an old animal. A classic 2014 study found that exposure to young circulation increased dendritic spine density and synaptic plasticity in the hippocampus of old mice. More importantly, simply administering young plasma to old mice improved spatial learning and other measures of cognitive function. In a later experiment, researchers maintained old and young mice in heterochronic parabiosis for three months and found reductions in epigenetic age in the blood and liver of the old animals. Some of those molecular changes were still evident two months after the animals were separated.
So maybe there really is such a thing as biologically “better” blood.
Which naturally made me wonder: If I’ve been marathon training for months, is my plasma somehow more valuable than it was before the training block?
Could you someday take the circulating factors produced by someone with exceptional cardiovascular fitness and use them therapeutically in someone with mitochondrial dysfunction, neurodegeneration, or age-related physiological decline?
And then you can push this into even weirder territory.
Could we identify and manufacture the specific circulating factors responsible? Could we transplant healthy mitochondria themselves to mimic a portion of the physiological signal normally created by exercise?
That last idea isn’t entirely science fiction either. Researchers have already experimented with mitochondrial transplantation, including human work in patients with severe heart injury. But this remains an extremely experimental field. We’re several enormous scientific leaps away from me selling my post-marathon mitochondria to the highest bidder. But I love the conceptual question.
It also creates an interesting ethical line.
If you give something like this to someone with a mitochondrial disease, that’s therapy. If you give it to a healthy athlete before the Olympics, is that doping?
For now, this is mostly an entertaining thought experiment built around some very preliminary animal data. But I’ll admit… the idea of premium, marathon-trained plasma is much more interesting than another recovery peptide.
Creatine protocols, misinterpreted (again)
The second rabbit hole started with a post from Dr. Ben Bikman. He was traveling, sleep-deprived, and mentioned taking creatine because of research suggesting that creatine can protect cognitive performance during sleep deprivation.
I pushed back on X—not because I don’t think creatine works, but because I think the study he was referring to is often interpreted as testing something slightly different from what it actually tested.
The experiment was a randomized, double-blind crossover study in 15 healthy adults. Participants consumed a single massive dose of creatine: 0.35 grams per kilogram of body weight. For a 75-kilogram person, that’s roughly 26 grams of creatine at once (do it at your own risk).
They took it at about 8:30 p.m., at the beginning of a planned overnight period of sleep deprivation, and researchers then assessed brain energetics and cognition repeatedly over the following hours while participants remained awake.
Creatine altered several markers of brain energy metabolism, attenuated some of the sleep-deprivation-induced deterioration in cognition, and reduced subjective fatigue. That’s genuinely fascinating. But there’s a difference between knowing you’re about to spend the night awake and taking ~25 grams of creatine as you enter the “energetic stress,” and taking a normal or megadose of creatine after a night where you only slept 4 hours.
Those aren’t the same intervention. Creatine isn’t caffeine! Creatine primarily acts through the creatine-phosphocreatine system, which functions as an intracellular energy buffer and helps regenerate ATP when energetic demand increases.
And the researchers had a particularly interesting hypothesis for why such a large acute dose might work in this situation.
Getting exogenous creatine into the brain is normally difficult. Measurable increases in cerebral creatine generally require repeated supplementation. The authors proposed that combining very high circulating creatine concentrations with the increased energetic demands of sleep deprivation might temporarily increase cerebral creatine uptake.
In other words, sleep deprivation itself may have created part of the physiological environment that allowed the acute creatine dose to work.
That hypothesis has since received some additional support. A 2026 follow-up from the same group gave 29 participants a smaller acute dose of 0.2 g/kg during sleep deprivation. Creatine again attenuated deterioration in several cognitive tasks, although the effects were smaller than those observed with 0.35 g/kg.
So my pushback here isn’t that the creatine result is overhyped. It’s that the protocol matters.
Maybe taking creatine the morning after a terrible night of sleep helps. That’s a perfectly reasonable question. But these experiments don’t demonstrate that. They show that a large acute dose administered during a planned period of sleep deprivation can attenuate some of the metabolic and cognitive deterioration that occurs as wakefulness continues. So to me, when someone claims to “feel more alert” after taking creatine in the morning, that’s the placebo effect at work.
Building muscle to burn fat (?)
Finally, I saw Tim Ferriss post a version of a very persistent fitness argument: resistance training is superior to cardio for fat loss because adding muscle raises your metabolism and allows you to burn more calories throughout the day.
I responded because I think the underlying physiology is often exaggerated.
The basic story usually goes something like this:
Lift weights → gain muscle → dramatically increase metabolism → burn substantially more calories 24 hours a day.
Meanwhile, cardio only burns calories while you’re actually doing it (which isn’t even true, due to something called excess post-exercise oxygen consumption, or EPOC).
It’s a great story, but the math is considerably less exciting.
Skeletal muscle is metabolically active tissue, but at rest it isn’t particularly metabolically expensive. Skeletal muscle’s estimated resting metabolic rate is roughly 13 calories per kilogram per day, or about 6 calories per pound per day. That’s dramatically lower than organs such as the brain, liver, heart, and kidneys.
Let’s be extremely generous and say you add 10 pounds of actual skeletal muscle (which, by the way, is freaking HARD). That’s an excellent outcome from a dedicated resistance-training program. Based purely on the tissue-specific metabolic cost of muscle, those 10 pounds would account for roughly 60 additional calories per day at rest.
That’s not zero, but you have not transformed yourself into a metabolic furnace.
Intervention studies tell a similar story.
In one study, participants completed 96 resistance-training sessions over approximately nine months. Resting metabolic rate increased from an average of 1,653 to 1,726 calories/day—about 73 additional calories per day.
A broader systematic review and meta-analysis similarly concluded that resistance training can increase resting metabolic rate, with an average effect on the order of roughly 100 calories/day compared with controls—not the hundreds upon hundreds of calories sometimes implied by the “muscle turns you into a furnace” narrative.
Now compare that with actually doing cardio.
Depending on your body size, intensity, and duration, 30–60 minutes of running, cycling, rowing, or another form of aerobic exercise can expend several hundred calories that day. A longer endurance session can push that much higher (funny aside—someone on X responded that this means you have to do cardio every singe day to achieve that benefit. I replied, slightly tongue in cheek, “that’s the entire point!”)
So the claim that cardio is somehow metabolically irrelevant because its calories are primarily expended while you’re doing it is irrelevant itself. The same goes for weight lifting! You don’t just work hard to build muscle and then get to sit idly while it burns calories for you, no maintenance required. Though wouldn’t it be nice?
None of this is an argument against lifting.
But if we’re specifically comparing the energetic cost of having several additional pounds of muscle with the energetic cost of repeatedly performing aerobic exercise, the latter can be substantially larger.
And to be clear, resistance training doesn’t need an imaginary metabolic effect to be worthwhile. Lift because muscle and strength are enormously important, and do cardio because cardiovascular fitness and aerobic capacity are enormously important.
And if fat loss is the goal, combining the two probably makes a lot more sense than turning them into opposing teams.
Ultimately, I agree with Tim’s claim in the same post that “abs are made in the kitchen.” So we agree on something there.
Thanks for reading. See you next Friday.
~Brady~
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I completely agree that muscle burns less calories than people think. HOWEVER, to be fair, you need to include the calories burned while BUILDING the muscle, ie the training, just like you do for the cardio training.
Brady, one of the best, most informative posts on Substack. Full stop.
Thank you, your takes are insightful and I entirely agree with how studies are presented vs. interpreted in real life.