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~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Wild Roman is an all-natural skincare brand for men who want a simple, effective routine designed to strengthen skin with modern formulas and wild-sourced ingredients. The company was started by my friend Sahil Bloom, and it’s the only skincare brand I’ve enjoyed using. Their biggest seller is the complete face routine, and I’m partial to the bar soap (seriously… it’s incredible stuff).

Shop through my link to get the $99 Face Routine, free Bar Soap, and free shipping, plus 15% off regularly priced items.

Greetings!

Welcome to the Physiology Friday newsletter.

Quick promo for a new partner of this newsletter: Wild Roman. They’re an all-natural skincare brand for men who want a simple, effective routine designed to strengthen skin with modern formulas and wild-sourced ingredients. The company was started by my friend Sahil Bloom, and it’s the only skincare brand I’ve enjoyed using. Their biggest seller is the complete face routine, and I’m partial to the bar soap (seriously… it’s incredible stuff). Get it for yourself, or gift it to a guy who needs it!

Shop through my link to get the $99 Face Routine, free Bar Soap, and free shipping, plus 15% off regularly priced items.

(Details about the other sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.)

Cold exposure and sauna are usually treated as a punctuation mark at the end of a workout.

But they’re used for different reasons.

When it comes to cold, the basic idea is recovery—cool the body, reduce soreness and inflammation, and perhaps feel a little more prepared to train again tomorrow. That mechanism is fairly well-established, and athletes have been using ice baths in this regard for decades.

For heat—sauna or hot water immersion being the most common forms—the goal is usually enhancing the cardiovascular adaptations to exercise by providing an additional stimulus. Heat promotes blood flow, sweating, and cardiac output, essentially mimicking low-intensity cardiovascular exercise. Combining 20–30 minutes of sauna after a run has become one of my favorite training techniques.

But what if, instead of viewing these thermal stressors as “add-ons” to a productive workout, we moved them to the beginning? At that point, they become no longer just a recovery tool, but a primer—a short, deliberate stressor intended to alter the physiological state in which you begin exercising.

A new study tested exactly that idea. And I think the findings will redefine how we think of a “warmup.”1

The study included 20 healthy, active adults: 12 men and eight women, with an average age of 24. Each participant completed three experimental conditions in a randomized order:

• Cold-water immersion: 10 minutes immersed to the base of the neck in 50°F (10°C) water (respectfully, I’ll pass).

• Contrast therapy: alternating two minutes in the same cold water with two minutes in a 180°F (82°C) sauna for 10 minutes total, beginning and ending in the cold.

• Control: 10 minutes seated in a thermoneutral room at 75°F (24°C).

Immediately after each condition, the participants completed a 90-second test of their reaction time (a measure of cognitive performance). They then sat for 20 minutes while the researchers measured oxygen consumption and carbon dioxide production, which allowed them to estimate fat oxidation at rest. Then, they completed an 18-minute cycling test that progressed from 20% to 70% of their maximal cycling power. Each stage lasted three minutes. Heart rate, perceived exertion, and fat oxidation were recorded along the way, followed by one final reaction-time test.

Five minutes after the exposures ended, fat oxidation was highest after continuous cold-water immersion (0.17 grams per minute) and nearly double the fat-oxidation rate measured in the control condition (0.09 grams per minute) at that time point. Fat oxidation was 0.11 grams per minute at that time point following contrast therapy.

The effect was brief. By 20 minutes after exposure, fat oxidation after continuous cold was no longer significantly different from control. However, fat oxidation was now higher in the contrast condition at 20 minutes—0.12 grams per minute versus 0.08 grams per minute after the control. These metabolic effects of contrast therapy carried into exercise.

• At 20% of maximal cycling power, fat oxidation averaged 0.45 grams per minute after contrast therapy and 0.30 grams per minute after control.

• At 30% of maximal power, the corresponding rates were 0.33 and 0.20 grams per minute.

• Above those two lowest workloads, the differences disappeared.

Heart rate followed a similar intensity-dependent pattern. After contrast therapy, it was approximately 9 to 13 beats per minute lower than control during the 20%, 30%, and 40% stages. Yet perceived exertion was the same, and heart rate no longer differed significantly at the higher intensities.

It’s tempting to interpret the lower heart rate as evidence that the same workload had become easier. I don’t think we can say that. Heart rate is only one part of the cardiovascular equation during exercise. A lower heart rate at a fixed workload could reflect a larger stroke volume, a change in autonomic nervous system tone, or some other blood flow adjustment. The study measured none of those variables. Perceived effort also did not improve. So the most we can say is that the contrast condition changed the cardiovascular response to gentle cycling. Whether it improved efficiency or performance remains unanswered.

Did the cold plunge sharpen the brain?

Immediately after exposure, reaction time was significantly faster after cold than after contrast therapy (654 versus 692 milliseconds), but it was not significantly faster than the control condition. The cold condition also improved significantly from its own baseline to the final test.

So the data hint at an alerting effect of brief cold exposure, even if they don’t establish that cold exposure reliably improves cognition compared with doing nothing, at least within the limits of this particular study.

Anyone who has stepped into very cold water knows that sleepiness is not the immediate problem. In fact, this is probably one of the most reliable effects of acute cold exposure. It turns you ON!

Something I found interesting (even a bit odd) was that some outcomes on the cognitive function test were worse after contrast therapy. Maybe the energetic and cognitive load of switching from extreme cold to extreme heat multiple times imposes too much stress on the brain. I think that’s reasonable—it takes a lot of energy to heat up and cool down the body.

Would I do this before training? Maybe.

This study makes pre-exercise thermal exposure scientifically interesting. Whether it’s practically convincing is another story.

Ten minutes of neck-deep immersion in extremely cold water is a substantial cold stress. The contrast condition also required moving every two minutes between very cold water and a very hot sauna. And participants did not begin cycling immediately afterward; they first completed cognitive testing and a 20-minute seated recovery. That is a substantial (and time-consuming) pre-workout routine, and it’s not something many of us will (or can) do before every workout. We probably don’t need to. Though I think there’s a case for strategic use of it.

Continuous cold and contrast therapy can acutely change the state in which exercise begins. Continuous cold may create a brief arousal response. So if your goal is to enhance alertness before a workout—or even before a meeting, presentation, or other cognitively demanding task—it’s an effective tool. On the other hand, alternating cold and sauna may shift fuel selection and lower heart rate during easy exercise. So if your goal is optimizing metabolic responses to or adaptations from a lower-intensity cardiovascular workout, contrast therapy may be an effective pre-workout strategy.

What we do not know is whether either response helps you train harder, perform better, adapt more, or lose more fat. Those are the outcomes that would make the extra suffering (and the elaborate pre-workout choreography) worth it, in my opinion.

I think there are certainly ways that we can scale down the protocol used in this study into a more “bite-sized” priming routine for a workout. Maybe that means completing a few rounds of alternating cold and hot water in a shower before you get dressed for a workout. Maybe you do have access to a cold plunge or sauna that you can utilize for a few minutes before completing a “real” warm-up involving dynamic stretching and some plyometrics.

My conclusion is not that everyone should cold plunge before exercising. Instead, I think the broader theme here is that temperature is not merely recovery scenery. It is a physiological input that belongs in the larger architecture of our workout. My interest is certainly piqued… even though you probably won’t catch me dunking my head under freezing cold water any time soon.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

Exercise makes the heart a little larger and more compliant (think “stretchier”). A larger, more compliant heart fills with more blood, meaning more blood leaves with each beat, and maximal oxygen uptake—or VO2 max—goes up.

This is one reason endurance athletes tend to have large, compliant hearts and high VO2 max values.

The relationship also works in the other direction.

Sedentary aging is associated with a smaller, stiffer left ventricle (the heart’s largest chamber). Maximal heart rate falls, the arteries stiffen, the heart fills with less blood, stroke volume drops, and VO2 max declines. Some of that decline occurs even in people who remain active (but inactivity accelerates it).

Exercise can push back against this process at almost any age. But the cardiovascular system does not appear to retain the same plasticity forever.

Middle age, then, may be a particularly important window—not because the heart becomes untrainable afterward, but because some adaptations become harder to recover.

Sex adds another layer. Women generally have smaller left ventricles than men. They also tend to have less fat-free mass and lower hemoglobin concentrations, which reduces the amount of oxygen that can be carried in a given volume of blood. None of these differences is inherently pathological. But together, they help explain why women generally have lower absolute cardiac outputs and VO2 max values than men. They may also influence how the cardiovascular system adapts to training.

Several longitudinal studies have reported smaller increases in VO2 max, stroke volume, or cardiac output in women than men following the same endurance program. The difference seems to become more pronounced with age: young women can show robust cardiovascular adaptations, while older women show… less robust ones.

Why?

One possibility is that a smaller heart is also a less trainable heart. A small ventricle may have less filling capacity, greater relative stiffness, and more constraint during maximal exercise. If that means less capacity to remodel, it could place a ceiling on the improvement in stroke volume and VO2 max—especially as the heart ages.

But there is another possibility: heart size and heart trainability are not the same thing. A smaller heart could have just as much capacity to remodel, or perhaps even more room to change. And sex differences in VO2 max could emerge even when the resting heart adapts similarly, because VO2 max depends on far more than cardiac factors!

That is the physiological puzzle behind a new study in The Journal of Physiology.1

The researchers put previously sedentary, middle-aged men and women through two full years of structured endurance training to ask so questions:

1. Do women experience smaller fitness gains because their hearts remodel less?

2. Does beginning with a smaller heart limit how much cardiac remodeling is possible?

They got one answer they expected—and one that they didn’t.

The study included 28 healthy but sedentary adults: 13 men and 15 women, with an average age of about 54.

The first 10 months were progressive. Participants began with three 30-minute base sessions per week. The researchers then gradually added training sessions near the ventilatory threshold (right around the top of an “zone 2” intensity) and 4 × 4-minute intervals performed at about 95% of their peak heart rate. By month six, the participants were training roughly five to six hours per week and completing two interval sessions. They also performed two strength sessions each week.

After month 10, the program shifted into a 14-month maintenance phase. Total training load was kept relatively stable, but one weekly interval session was replaced with more lower-intensity exercise.

VO2 max increased in both men and women, mostly during the first 10 months of progressive training.

In absolute terms:

• The men increased VO2 max by 0.53 liters per minute.

• The women increased by 0.27 liters per minute—about half as much.

When VO2 max was expressed relative to body mass, the difference narrowed.

• Men improved by 6.5 milliliters per kilogram per minute, compared with 4.2 in women.

• Across the full two years, that amounted to an average increase of 20.1% in men and 16.6% in women.

Interestingly, when changes were expressed relative to fat-free mass, the sex difference mostly disappeared!

Were the men just training harder? Not apparently. The women actually accumulated a higher training load during the first 10 months and at least as much across the entire study. So a smaller response in the women could not easily be dismissed as less training.

Instead, the differences appeared to come not from cardiac adaptations at rest, but when the heart was pushed to its limit.

VO2 max is governed by the Fick equation. In plain language, maximal oxygen use depends on how much blood the heart can pump (heart rate x stroke volume) and how much oxygen the tissues can remove from that blood.

Peak heart rate barely changed in either group. The major sex difference was in how much blood the heart ejected with each beat.

In men, peak stroke volume increased from 98 to 120 milliliters. In women, it increased from 72 to 81 milliliters. Peak cardiac output rose from 16.8 to 20.8 liters per minute in men, compared with 12.4 to 14.0 liters per minute in women.

So the women’s smaller gain in absolute VO2 max was explained largely by a smaller increase in peak stroke volume and cardiac output. That makes it sound as if the women’s hearts simply failed to remodel as much. But they didn’t! The amount of blood the heart could fill with increased during the first 10 months by a similar magnitude in men and women, and heart chamber stiffness also fell (improved) in both groups.

The women still had smaller and stiffer hearts on average at the end of the study, but their hearts were not less capable of structural remodeling. They enlarged and became more compliant, even though their improvement in peak pumping capacity was smaller.

The smallest hearts did not have the smallest response

The researchers expected participants with the smallest hearts at baseline to show the least remodeling. But the opposite happened.

Within each sex, a smaller starting left ventricular volume was associated with a larger increase after training.

One plausible explanation here is that the smallest hearts had more room to move toward the “trained” phenotype. Which makes sense—we’d expect a smaller (and perhaps a stiffer or less compliant) heart to respond more to the stress of endurance exercise than a larger heart that’s already compliant. Especially in a group of people who are more or less “naive” to exercise.

Central and peripheral adaptations moved on different time courses

There was one more result buried in the two-year design that I found especially interesting.

During the progressive phase—when participants were doing two interval sessions per week—the amount of oxygen extracted from the blood at maximal exercise increased in both sexes. During the maintenance phase—when researchers removed one interval session and replaced it with more lower-intensity work while keeping the calculated training load similar—oxygen extraction then returned to approximately baseline. Meanwhile, peak stroke volume and cardiac output continued to rise, and VO2 max stayed essentially flat.

So the peripheral and central sides of the Fick equation changed in opposite directions and canceled each other out at the level of VO2 max, which suggests that exercise intensity and volume may preferentially support different adaptations: high-intensity favors improvements in your ability to take up and use oxygen, while lower-intensity favors oxygen delivery.

This is not evidence that dropping exactly one interval session reverses peripheral adaptations, but it does show that an unchanged VO2 max can conceal a lot of physiological movement underneath it.

The big takeaway here isn’t earth-shattering. An aggressive exercise training stimulus will cause the heart to adapt, and that’s true regardless of whether you’re male or female, old or young, or have a smaller or larger heart.

Middle age is not too late for meaningful cardiac remodeling. The research group who published this study has several other papers showing the same thing. The heart can adapt at any age and fitness level, provided you work out hard enough! These participants were in their early-to-mid 50s, had been sedentary, and still enlarged and made their left ventricle “stretchier” over the first 10 months of training.

The study also adds to the ongoing conversation about whether men and women respond similarly to exercise. Yes, sex influenced the response, but not in one simple, universal way. Men had larger gains in absolute VO2 max, peak stroke volume, and cardiac output. Yet men and women showed similar remodeling at rest, and the difference in VO2 max improvement disappeared when scaled to fat-free mass. “Trainability” depends partly on which adaptation we choose to call the response, in this case. And it would be foolish to conclude “men responded more” or “women responded less.”

Women should not expect disappointing gains, nor do they (or people with small hearts) need a special endurance training protocol.

We often talk about “the training response” as though it were one thing. It isn’t. VO2 max is an integrated outcome. Heart size, compliance, stroke volume, cardiac output, hemoglobin, blood flow distribution, muscle oxygen extraction, and body composition all contribute—and they do not necessarily adapt at the same rate. Changes in these factors can also “mask” themselves underneath a flattened VO2 max response, which is why I often tell people not to worry if their training progresses but their (smartwatch-estimated) VO2 max does not.

If this study shows is anything, it’s that we should be quick to question blanket statements like “women don’t respond to training like men” or “smaller hearts may be less adaptable.” Physiologically speaking, it’s never that black and white.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

A few days ago, Max Lugavere posted that walking is “the most underrated form of cardio there is.”

Read more

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

One of the few nearly indisputable principles of exercise physiology is that you get out what you put in.

It’s a cliché. But, physiologically speaking, it’s mostly true.

The harder you work (and the more consistently you do it), the more your body is forced to adapt. I suppose that’s as true in life as it is in exercise, but nowhere does it seem more obvious than with exercise intensity.

That helps explain the rise of high-intensity interval training over the past decade or so (although zone 2 is currently making a strong attempt to reclaim the crown). High-intensity training gained traction because research showed that it could produce meaningful benefits in far less time than traditional endurance exercise. And I mean FAR less. In some foundational studies, interval sessions lasting roughly 10–15 minutes produced improvements in aerobic fitness and cardiometabolic health comparable to 45–60 minutes of moderate, continuous exercise.

That’s pretty freaking remarkable.

Does this mean we should perform all our exercise at a high intensity? Of course not (that’s a discussion for another day).

But it does reinforce a broader idea that many of the benefits of exercise appear to be intensity dependent. And if that’s true, the obvious question is…why?

What happens inside the body during a few minutes of very hard exercise that makes it such a potent stimulus?

The usual explanations are that high-intensity exercise raises your heart rate more, burns more calories per minute, and places greater stress on your cardiovascular system. All of that is true. But, to me, those explanations are a little too surface-level. They describe how hard the body is working. They don’t fully explain the “biological message” that the workout sends. That message appears to be carried, at least partly, by molecules collectively called exerkines.

The complete collection of factors secreted in response to exercise is broadly referred to as the exercise secretome (researchers in this field love their “omes”). Together, these contain thousands upon thousands of molecules that we’re only beginning to characterize.

So, if we want to understand why high-intensity exercise can produce outsized benefits relative to the time invested, it makes sense to study the secretome.

Does harder exercise simply release more signals? Does it release different signals? Do those molecules come from different organs, target different tissues, or relate differently to long-term health?

A new study attempted to answer all of those questions. And in doing so, they also raised another one: if we can identify exactly how high-intensity exercise reshapes this secretome—and which molecules produce which downstream effects—could we eventually, in effect, design “exercise in a pill?”

I won’t get too far ahead of myself. First, let’s look at what the researchers actually found.1

This was less a single experiment than a series of connected experiments designed to follow exercise signals from the bloodstream to their possible source, their potential target tissues, and, eventually, their relationship with long-term health. The latter aspect is perhaps the most applicable part of this whole study.

The primary experiment included 19 healthy, active men with an average age of 26. They were assigned to one of two cycling protocols:

Sprint-interval exercise (SIE) involved six 30-second all-out efforts against a resistance based on body mass, separated by four minutes of recovery. That’s only three minutes of maximal-effort exercise.

Moderate-intensity exercise (MIE) involved 90 minutes of continuous cycling at approximately 90–100% of the first lactate threshold—the point at which blood lactate begins rising above resting levels.

Blood was collected before exercise, immediately afterward, and again three hours later. A subset of the participants then completed eight weeks of either sprint-interval training or moderate-intensity training, with three to four sessions per week. The researchers repeated the same acute exercise and blood-sampling protocol after the training period to determine whether the molecular response was unique to the pre-training state or persisted after participants became better trained.

• Immediately after the sprint session, 714 proteins changed significantly. That was nearly one-quarter of all the proteins the researchers detected, and more than 98% increased. These included proteins involved in vascular function, inflammation, fuel metabolism, and hormonal signaling. Three hours later, however, the number of altered proteins had fallen nearly 20-fold. The sprint session created a very large but very short-lived spike in circulating proteins.

• The moderate-intensity session produced almost the opposite pattern. Only seven proteins changed immediately after 90 minutes of cycling, but that number increased to 19 three hours later.

When the researchers directly compared the responses to the two protocols, 280 proteins differed immediately after exercise. Three hours later, only two differed: follistatin and insulin-like growth factor-binding protein 1 (both of which were higher after moderate exercise).

The eight-week training period did not eliminate these responses! The same general pattern remained when the acute exercise tests were repeated: an immediate increase after sprint exercise and a delayed increase after moderate exercise. Several individual proteins also responded similarly before and after training, which suggests that sprint response wasn’t just a shock produced by giving untrained participants an unfamiliar workload. At least some of these intensity-dependent signals remained after repeated training.

The metabolites behaved similarly.

• Sprint exercise changed 203 metabolites immediately after exercise. These included lactate, pyruvate, succinate, and malate—molecules that reflect rapid glucose breakdown, mitochondrial energy production, and accelerated ATP turnover (all of which are increased during exercise in an intensity-dependent manner). Three hours after the sprint session, 199 metabolites remained altered, but the profile had shifted. Rather than being dominated by products of rapid carbohydrate metabolism, it now included several circulating fatty acids.

• Moderate exercise again produced the more delayed response. Only 31 metabolites changed immediately after cycling, compared with 203 after sprinting. Three hours later, however, 183 metabolites had changed. Most were fatty acids or other molecules associated with lipid metabolism. So, once again, sprint exercise produced the large immediate signal, while moderate exercise generated a slower metabolic one. Several of these metabolite responses also persisted after the eight-week training intervention.

Where were these signals coming from?

The predicted sources included immune cells, skeletal muscle, adipose tissue, the liver, pancreas, pituitary, intestine, brain, and several other organs—not just working skeletal muscle.

Next question. Where were they going?

To find out, the researchers performed what was essentially a plasma-swap experiment. Human fat cells were exposed for three hours to blood collected either before or immediately after exercise. Blood collected after sprint exercise increased the expression of 1,128 genes and decreased the expression of another 549. Plasma collected after moderate exercise produced a much smaller response: only 14 genes increased, and 11 decreased.

This is a wild finding, because the cells were not contracting, producing force, or experiencing the exercise session themselves. They were simply exposed to blood collected from someone who had just exercised! Something about the post-sprint environment dramatically altered the genetic program in fat cells.

You might be asking yourself—so what? Who cares about the “secretome” unless it’s having a relevant impact on some health or performance outcome?

That leads to the final aspect of the study.

Did these proteins relate to long-term health?

The researchers used a UK Biobank resource containing plasma-protein measurements from 53,026 people and data covering 1,066 diseases. They searched for health associations involving the 741 proteins altered by either sprint or moderate exercise.

Across those proteins, they identified 46,993 protein-disease associations. Counterintuitively, most were associated with higher rather than lower disease risk, which may reflect the fact that acute exercise temporarily activates inflammatory and cellular stress signals (protein rising briefly after a workout can be part of a beneficial adaptive response even if chronically elevated levels are associated with disease).

So the authors then narrowed their analysis to proteins associated with lower disease risk. This left 143 proteins spanning 14 broad disease categories, most of which had been altered exclusively by sprint exercise. When they focused specifically on obesity, type 2 diabetes, and other metabolic disorders, they identified 33 exercise-responsive proteins associated with lower risk. Thirty-two of the 33 were altered after sprint exercise, while only three were altered after moderate exercise. And more than one-quarter of these 33 proteins were also inversely associated with chronological age (higher levels were associated with a lower, or younger, chronological age).

The tl;dr: sprint exercise acutely altered a larger number of circulating proteins, and many of those same proteins were associated with better cardiometabolic outcomes in a large observational dataset. What we can’t say is that any one of these proteins (or sprint/moderate-intensity exercise itself) causes better health outcomes. Although there’s plenty of other strong evidence to suggest that’s true.

Do these findings solve the “zone 2 versus high-intensity” debate? Of course not. There is no solution (or correct answer as to which one is “better”).

But they are a strong… and I mean very strong… argument in support of the idea that high(er) intensity exercise is a more potent, and therefore a more beneficial, stimulus. It sends the body a stronger signal, and that signal (probably) shapes long-term health outcomes. If we look at the epidemiological data linking vigorous exercise (performed in short bouts or even “randomly” throughout the day) to disease risk, the argument becomes even stronger.

To wrap up, I want to return to a radical idea I surfaced at the beginning of this email.

The idea of “exercise in a pill” is usually dismissed outright, occupying the same sci-fi realm as the fountain of youth. I’m the first one to admit that the idea of replicating the full spectrum of benefits exercise gives us seems insane. So bear with me for a moment.

This study was able to identify the entire suite of proteins, metabolites, and signaling molecules released during a single session of exercise. We are now able to characterize precisely what happens—and to what magnitude it happens—when we break a sweat. Knowing this, it doesn’t seem too far-fetched that some pill (or more likely injection) could simulate this response in someone without them even stepping foot in a gym.

But to simplify exercise into its component parts is insulting. It disregards the social aspects of exercise, the physical movement going on during exercise, and the psychological benefits that come along with it.

We can (probably) replicate the exercise secretome, but we (almost certainly) can’t replicate the social, physical, and psychological landscape in which exercise is performed.

And truly, who would want to?

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Most athletes are accustomed to tracking heart rate, pace, power, and maybe lactate. Tymewear approaches training from a different direction by measuring breathing directly. Its VitalPro chest strap (which I’ve been using in my own training for several months) measures breathing rate, tidal volume, and minute ventilation, allowing athletes to track how much air they’re moving during exercise and use changes in ventilation to identify physiological thresholds (zones) and training intensity.

Arnar and I get into the physiology behind these measurements, why ventilation has traditionally been largely confined to exercise physiology labs, and what becomes possible when athletes can measure it during normal training.

What I like most about the device is that it gives me a physiological signal that complements the metrics I’m already looking at. I can see how my breathing responds as intensity increases and where those responses begin to change.

I’ve found this particularly interesting for Zone 2 and threshold training, where relatively small changes in intensity can move you into a very different physiological domain. It’s also useful when heart rate becomes harder to interpret—for example, during longer sessions or training in the heat.

I think the value of ventilation is in adding another layer of physiological context to the measures I’m already using—and, for someone who enjoys understanding why a workout feels the way it does, it’s a pretty compelling metric.

Episode topics

• Why I wanted to discuss ventilation and the VitalPro

• Arnar Larusson’s background in engineering, prosthetics, and exosuits

• Why breathing is a direct measure of internal workload

• Why heart rate is confounded by heat and dehydration

• Heat stress, core temperature, and why heart rate drifts

• My Zone 2 problem in the Texas heat

• Breathing rate, tidal volume, and minute ventilation

• Breathing rate as a signal of perceived exertion and fatigue

• VT1, VT2, and how they relate to lactate thresholds

• Why VT1 and VT2 define training zones

• What athletes gain when they train by ventilation instead of heart rate

• What changes at the ventilatory thresholds

• Why fitter athletes produce less CO₂ at the same workload

• Why breathing rate alone is not enough

• Whether breathing patterns reveal anything about fatigue

• Durability and why prolonged exercise causes physiological drift

• Why a rising heart rate is not always a problem

• Why ventilation simplifies the durability picture

• Why heart rate, pace, and lactate are all proxies

• Why lactate can be a noisy marker compared with CO₂-driven ventilation

• How professional cycling teams use ventilation in training

• Why running needs a better effort metric than pace or heart rate

• Can ventilation improve calorie-burn estimates?

• What the threshold test actually tells you

• How beginners should start using the device

• How the VitalPro measures ventilation through chest expansion

• Where to find Tymewear and follow the company

  ---

If you’re interested in experimenting with Tymewear yourself, I have a listener offer for the Tymewear Training Membership:

Get 67% off your first subscription order for either:

• Tymewear Training Membership — 1 Year

• Tymewear Training Membership — 2 Year

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Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

I’m often ravenous after finishing a long run. Even more so if I haven’t had breakfast beforehand or fueled aggressively during.

This lines up with a nice physiological story: I burned through a lot of carbs (glycogen), so now my body wants me to replace it!

(I’ve told myself some version of this story many times… usually while standing in front of the fridge).

The logic makes sense.

This idea is sometimes called the glucostatic theory of appetite. The basic premise is that carbohydrate availability helps regulate how much we eat. So for athletes burning through a lot of carbs, it seems intuitive that post-workout appetite would ramp up. But we also burn fat during exercise, with how much depending on the intensity and duration of that exercise. So the question becomes whether the type of fuel we burn during exercise has any influence on what, or how much, we eat after. Seems like an easy question to study, right?

The obvious way to make someone burn more carbohydrate (and hence less fat) during exercise is to give them carbohydrate. But that also changes calorie intake, insulin, gut hormones, and fuel availability.

So, is it the carbohydrate being burned that matters—or the carbohydrate being eaten?

A new study used a slightly unusual tool to pull those two factors apart: niacin.1

Niacin is vitamin B3. At high doses, niacin activates a receptor called GPR109A in adipose tissue and suppresses lipolysis—the release of fatty acids from stored body fat. With fewer fatty acids available to burn, the body is pushed toward greater carbohydrate oxidation even when no carbohydrate has been consumed.

Niacin allowed the researchers to change the fuel mix without adding fuel.

This was a really neat study with some surprising findings. Let’s dive in.

Fifteen healthy, recreationally active adults—10 men and five women, with an average age of 29—completed three trials:

• FAST: Exercise after an overnight fast, with placebo drinks and tablets.

• CARB: Carbohydrate before and during exercise (1.6 grams per kilogram of bodyweight given 1 hour before exercise followed by 0.2 grams per kilogram every 15 minutes during, which works out to 2.4 grams per kilogram total, or about 175 grams of carbohydrate for the average participants in the study).

• NIACIN: Niacin before and during exercise, with a calorie-free placebo drink.

The participants cycled for 60 minutes at 95% of their first lactate threshold, an easy-to-moderate aerobic intensity chosen because fat oxidation should be relatively high at this intensity. The researchers calculated fat and carbohydrate oxidation, collected blood throughout the trial, and then—two hours after exercise—gave participants a large rice-and-cheese meal and told them to eat until they were comfortably full (sign me up).

The important comparison here was between CARB and NIACIN. Both were expected to suppress fatty-acid availability and increase carbohydrate oxidation, but only one supplied carbohydrate and calories.

The interventions worked almost exactly as intended.

• During the fasted trial, participants oxidized an average of 21 grams of fat during the hour of cycling.

• Fat oxidation fell to 11 grams with carbohydrate and 13 grams with niacin… so about half as much.

Carbohydrate oxidation moved in the opposite direction. Participants oxidized:

• 75 grams of carbs during the fasted exercise.

• 97 grams during exercise with carbs.

• 94 grams during exercise with niacin.

That’s not a subtle metabolic nudge. Niacin increased carbohydrate oxidation nearly as much as actually consuming carbohydrate, despite providing no carbohydrate and producing no comparable rise in insulin. Both carbohydrate and niacin lowered circulating non-esterified fatty acids. But insulin and glucose rose most clearly with carbohydrate. Branched-chain amino acids fell with carbohydrate but not niacin, while ketones were highest after fasted exercise, lower with niacin, and lowest with carbohydrate.

If greater carbohydrate oxidation creates a carbohydrate debt that rapidly drives us to eat, the niacin condition should have produced the largest post-workout meal, because the participants burned considerably more carbohydrate than they did while fasted, but they had not consumed any carbohydrate to offset it.

That did not happen.

Two hours after exercise, average energy intake was:

• 833 calories in the fasted condition.

• 786 calories in the carbohydrate condition.

• 780 calories in the niacin condition.

There was no difference among conditions. If anything, the numerical direction was opposite the researchers’ hypothesis: participants ate about 53 fewer calories after niacin than after fasted exercise.

The carbohydrate trial is interesting for a second reason. The average participant consumed roughly 700 calories of carbohydrate before and during exercise, yet ate only about 47 fewer calories at the later meal than in the fasted condition! Within the few hours captured by this experiment, people did not automatically compensate for the calories they drank during exercise by eating less afterward.

Glucagon-like peptide-1 (GLP-1), a gut-derived appetite hormone involved in satiety and glucose regulation (and the target of the ultra-popular GLP-1 agonist drugs being used for weight loss), was highest with carbohydrate, intermediate with niacin, and lowest in the fasted trial—both immediately after exercise and two hours later. Yet meal intake was still essentially the same.

This is one of those studies that might seem counterintuitive to your own personal experience.

I certainly “feel” a difference in my appetite depending on whether I’ve worked out fasted or fueled with carbohydrates. Do I necessarily eat more because of that change in appetite? Perhaps not. That would line up with what this study found, and I think it supports the broader idea that how much/what we eat is likely influenced more by our own habits, eating preferences, and what we “think” we need to do versus what our body is “telling us” via appetite. We are creatures of habit, after all, and I’m going to eat my post-workout bowl of yogurt and granola no matter what.

The first thing this study emphasizes is that acute fuel use and longer-term energy balance are not the same thing.

The second is that calories consumed during training may not be automatically “eaten back” in reverse.

What was a pretty substantial carbohydrate intake during exercise (about ~700 calories worth in the carbohydrate trial) did not produce a meaningful reduction in the subsequent meal. For an athlete using carbohydrate to preserve performance, increase training quality, or accelerate recovery, that is not inherently a problem—the calories are serving a purpose. But it is worth remembering that appetite does not always perform exact calorie accounting on our behalf. And for those exercising for the purpose of weight or fat loss, it’s an important practical point. You need to be aware of energy intake because the body isn’t going to do it for you.

Finally, I think this study is a nice example of how physiology resists single-signal explanations. Carbohydrate oxidation changed. Fatty-acid availability changed. GLP-1 changed. Ketones and lipoproteins changed. But the amount of food people ate did not. It’s a friendly reminder that the body is, in fact, not a simple ledger keeping track of inputs and outputs. That seems to be a running theme among many of the studies I choose to write about in this newsletter.

Physiology often starts with a clean story. In this case: use more carbohydrate, create a carbohydrate debt, get hungrier.

The more realistic story is that appetite integrates many imperfect signals over time, and the fuel mixture used during one workout is not a single instruction to eat.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Greetings!

Today’s Q&A is basically four versions of the same question:

What do you eat before really early runs?

What about when you train in the afternoon?

What do you eat during your runs?

And what do you eat afterward?

So, really, this is just a post about how I think about fueling before, during, and after exercise.

I like talking about this stuff because…

Read more

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

One of the funniest (and, come to think of it, most preposterous) arguments I’ve ever heard against running or other forms of aerobic exercise is that it will “use up all your heartbeats.”

(This isn’t exactly a common argument. But trust me, I’ve heard it).

The basic idea is that the heart can produce only a finite number of beats over a lifetime. Once you use them all up… well, that’s it. By this logic, anything that increases your heart rate spends those beats faster and moves you closer to the finish line of life.

There are many problems with this idea, beginning with the fact that the heart does not come equipped with a predetermined lifetime allotment of beats. But even if we accept the premise for a moment, the math still doesn’t work. Bear with me as we go through a little arithmetic.

Let’s say I exercise for two hours every day from age 20 until age 80. During those two hours, my heart rate averages 130 beats per minute. As a result of all that chronic aerobic training, we’ll assume my heart rate averages 40 beats per minute during the other 22 hours of the day.

During exercise, my heart would beat:

130 beats per minute × 120 minutes = 15,600 times.

During the remaining 22 hours:

40 beats per minute × 1,320 minutes = 52,800 times.

That gives us 68,400 heartbeats per day—or approximately 1.50 billion heartbeats over 60 years.

Now consider someone who performs no exercise at all. They avoid those two hours of elevated heart rate, but their heart averages 70 beats per minute throughout the day.

Seventy beats per minute × 1,440 minutes gives us 100,800 heartbeats per day—or approximately 2.21 billion heartbeats over the same 60 years.

Despite exercising for two hours every single day, the trained person accumulates roughly 710 million fewer heartbeats. That’s about 32% fewer beats over 60 years.

OK… this is a deliberately simplified thought experiment. But it illustrates an important point that we spend far more of our lives not exercising than exercising. A lower heart rate during the other 22 hours of the day can easily outweigh the temporary increase produced during a workout.

So, if the heart really did have a limited number of beats, aerobic exercise might be one of the best ways to conserve them.

Thankfully, the heart is not a punch card. And exercise doesn’t merely slow it down at rest—it changes how the entire oxygen cascade functions.

Endurance training produces structural and functional changes in the heart. In trained athletes, stroke volume (the amount of blood pumped with each contraction) increases. Because every beat moves more blood, the heart can maintain a given cardiac output with fewer beats at rest and during submaximal exercise.

This also helps explain why endurance-trained people tend to have a higher maximal oxygen uptake, or VO₂ max. More blood delivered means more blood available to use for energy production.

But it’s not the entire explanation. The relationship is described by the Fick equation:

Oxygen consumption (VO₂) = cardiac output × arteriovenous oxygen difference

Cardiac output describes how much blood the heart pumps per minute, and it’s equal to heart rate × stroke volume.

The arteriovenous oxygen difference (or a-vO₂ difference) describes how much oxygen the working muscles extract from that blood. It is the difference between the oxygen content of arterial blood leaving the heart and venous blood returning to it.

These are often described as the central and peripheral components of VO₂ max, and they refer to how much oxygen the cardiovascular system can deliver and how much oxygen the muscles can extract and use, respectively.

When we think about why an endurance-trained person has a higher VO₂ max, we tend to emphasize the first half of this equation. The trained heart can pump more blood, deliver more oxygen, and support a higher rate of aerobic energy production. And in many highly trained endurance athletes, that is true. But the Fick equation gives us another possibility. If the muscles extract substantially more oxygen from every unit of blood, oxygen consumption can increase without a corresponding increase in cardiac output.

Someone could consume more oxygen while their heart pumps the same amount of blood—or even less.

A new study supports that premise. And not only does it give some great insight into what determines aerobic capacity in trained versus untrained people, but it also explains why endurance exercise might be so good for the heart.1

Researchers recruited 85 healthy men. Forty-four were recreational long-distance runners who participated in half-marathons or marathons. The other 41 were healthy but untrained controls. The runners were an average of 33 years old, while the controls averaged 29. The groups were similar in body weight, height, body mass index, and body surface area.

Everyone completed a maximal exercise test on a stationary bike, and throughout the test, the researchers measured oxygen consumption, cardiac output, and two especially important variables.

• The first was cardiac power output, which combines cardiac output with mean arterial blood pressure. Cardiac output tells us how much blood the heart pumps, blood pressure reflects the force against which it must pump, and putting them together provides an integrated estimate of the heart’s pumping performance.

• The second was the arteriovenous oxygen difference, or a-vO₂ difference (which I described above).

Obviously, the runners were much fitter. Their VO₂ max averaged 53.2 ml/kg/min, compared with 38.7 ml/kg/min in the untrained controls. That is a difference of approximately 37%. They reached a peak workload of 276 watts, compared with 231 watts in the controls. And they also reached a slightly higher maximal heart rate (174 versus 166 beats per minute) and a higher peak systolic blood pressure during exercise (205 versus 192 mmHg).

If we stopped there, we might reasonably assume that the runners achieved their higher VO₂ max by driving the heart harder. But that’s not what happened!

• At maximal exercise, the runners’ cardiac output averaged only 18.7 liters per minute. In the untrained controls, it reached 22.6 liters per minute. The fitter runners were pumping nearly four fewer liters of blood per minute.

• Their maximal stroke volume was also lower (109 versus 126 milliliters of blood per beat).

• Cardiac power output (our measure of the heart’s pumping performance) followed the same pattern. It reached 5.01 watts in the runners and 5.64 watts in the controls—about 11% lower in the runners.

So, compared with the untrained participants, the runners reached a higher exercise workload and consumed considerably more oxygen despite a lower cardiac output, lower stroke volume, and lower cardiac power output.

To explain how, we need to look at the other side of the Fick equation.

• The runners’ a-vO₂ difference reached 21.6 milliliters of oxygen per 100 milliliters of blood.

• In the controls, it reached only 15.9 milliliters.

That represents roughly 36% greater oxygen extraction in the runners—their muscles removed substantially more oxygen from every unit of blood delivered to them, so they didn’t need their hearts to pump as much blood because they were making better use of the oxygen contained within that blood.

This is the central (no pun intended) finding of the study.

Interestingly, the runners did not display the stereotypical resting cardiovascular profile we might expect from an endurance-trained group. Their resting heart rate was actually higher than that of the controls (70 versus 62 beats per minute) and their resting systolic and diastolic blood pressures were also higher, as was their absolute cardiac output.

This finding was odd to me. But these were recreational runners, not elite athletes, and the paper did not report enough detail about their training volume, training history, or recent exercise to determine why their resting measurements looked this way.

I published my book on VO₂ max a few years ago. Since then, I’ve continued to learn so much about aerobic fitness—what determines it, how it changes with age, and how it responds to training—that, at some point, an updated edition will be necessary! Today’s study updates my thinking in a few important ways.

Traditionally, I (and much of the field) have viewed the heart’s pumping capacity as the primary limiter of VO₂ max. This is known as a “central limitation,” and it appears to be especially important among highly trained endurance athletes. But newer evidence suggests that aging and inactivity may shift the bottleneck toward the periphery. The problem may not be how much oxygen the cardiovascular system can deliver, but how much of that oxygen the working muscles can actually extract and use.

This study reinforces the idea that aerobic fitness depends as much on oxygen utilization as oxygen delivery. Utilization is influenced by the amount of active muscle we have, the quantity and quality of its mitochondria, and its network of capillaries (the tiny blood vessels where oxygen moves from the circulation into the working tissues). If one or more of these components decline with aging or inactivity, aerobic capacity can fall even when the heart retains the ability to pump more blood.

But these findings may extend beyond simply explaining a lower VO₂ max. The poorer peripheral oxygen extraction in the untrained men required their cardiovascular systems to move more blood to meet a lower metabolic demand.

I don’t think this study proves that such compensation damages the heart over time. But if we look at rates of cardiovascular disease among chronic exercisers versus non-exercisers, the picture becomes quite clear. There are implications to this.

When the muscles become less capable of extracting and using oxygen, the heart may have to work harder. Our hearts may not contain a finite supply of beats. But that doesn’t mean the efficiency of each beat is irrelevant.

Exercise asks more of the heart during training so the entire body can, literally, accomplish more with each beat. Efficiency, it seems, may be the stuff of life. That’s true in sports and elsewhere.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

One of the questions I got recently was:

“On a scale of 1 to 10, how would you rate running twice a day for recreational runners?”

Read more

“The plural of anecdote is not data.”

You hear this constantly in science, medicine, nutrition, and increasingly, in the world of peptides and supplements.

Someone says that they tried a peptide and their shoulder stopped hurting. Or they started taking a supplement and their sleep improved.

The standard response from the “critics” is that none of this cou…

Read more

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

Heat is, well, a hot topic right now—for lack of a better word.

And I mean that in a couple of different ways.

The first is an area near and dear to my heart. Athletes, myself included, are talking about (and increasingly embracing) deliberate heat training as a way to improve their performance.

That can take the form of passive heat exposure, such as using a sauna or soaking in a hot bath after training. Or it can be more active, such as deliberately exercising in the heat, wearing extra layers, or turning off the fan during an indoor workout (a decision that always sounds better before the workout begins).

The research coming out on heat training is fascinating. It’s the closest thing we have to altitude training. I think more athletes are realizing that heat doesn’t always have to be a stressor we avoid. When used deliberately, it can also be a training stimulus, so long as we don’t overdo it.

But heat is being discussed in another, much less voluntary context.

Without turning this into a discussion about climate change, the basic reality is that temperatures are extremely high in many parts of the world, including, currently, across large parts of the United States. That becomes an especially serious problem in places where homes and buildings aren’t equipped with air conditioning, or where people don’t have reliable access to cooling.

Whenever a heat wave arrives, the news coverage is filled with warnings about the dangers of excessive heat. One group is almost always singled out… older adults. They’re told to avoid the heat, stay hydrated, seek air conditioning, and use various cooling strategies to reduce their risk of heat exhaustion, heat stroke, and other forms of heat-related illness.

Some of the reasons are already well known. Aging can alter the sweating response, reduce the body’s ability to move heat toward the skin, and narrow the overall margin available for coping with thermal stress.

What is less clear is when this decline actually begins. Is there a particular age at which we suddenly become less heat tolerant? (Almost certainly not.) Or does our ability to handle heat gradually decline across the adult lifespan?

Understanding when heat tolerance begins to deteriorate could help us identify risk earlier and develop better strategies for preserving that capacity as we age.

Because thermoregulation isn’t completely fixed. Our ability to handle heat can be trained. Repeated heat exposure produces adaptations that help the body dissipate heat more effectively, and aerobic fitness influences many of the same systems involved in that response.

That brings us to a separate but related question.

Could better cardiorespiratory fitness—or simply engaging in more physical activity—help preserve our ability to regulate temperature as we get older? Or does aging eventually win regardless?

A new study examined exactly these questions by exposing adults ranging from 20 to 79 years old to (a brutal!) six hours of extreme heat. The experiment gave the researchers a way to test whether staying fit and physically active could offset some of that age-related decline.1

The answer appears to be yes… but only partly.

The researchers recruited 61 healthy adults—27 women and 34 men—ranging from 20 to 79 years old. The sample included 25 younger adults, 16 middle-aged adults, and 20 older adults.

• First, everyone completed a treadmill test to measure peak oxygen uptake, or VO₂ peak.

• Participants wore an accelerometer for seven days to estimate their usual moderate-to-vigorous physical activity.

• Then each participant spent six hours in an environmental chamber set to 109°F (43°C) and 25% relative humidity. Every hour consisted of 50 minutes of seated rest followed by 10 minutes of treadmill walking at three metabolic equivalents, roughly the intensity of light housework. In other words, they spent the hottest six hours of the day in a brutally hot room while occasionally getting up to do something. This was the researchers’ attempt to enhance something known as ecological validity (how well a study predicts real-world behavior and everyday life settings).

The researchers continuously measured rectal temperature (not glamorous, but very useful), skin temperature, and heart rate. They also measured whole-body sweat loss and local sweating at the back and forearm. Participants completed several cognitive tests before the exposure and again during the final 30 minutes, received 4 milliliters of water per kilogram of body mass every hour, with more available on request, and ate a meal.

Average core temperature was 98.4°F (36.9°C) after the first hour and 99.7°F (37.6°C) after six hours. By the end, it had risen by an average of about 2°F or 0.91°C. But individual responses ranged from only 0.60°F (0.33°C) to as much as ~3°F (1.62°C).

Age explained part of that difference. The older the participants were, the less they sweated.

• Whole-body sweat rate declined by 6 grams per square meter of body surface area per hour with every additional decade of age.

• For every additional decade of age, the rise in core temperature increased by 0.14°F (0.08°C). That sounds small. But across the study’s roughly six-decade span, that adds up to nearly one degree Fahrenheit or half a degree Celsius of additional core-temperature rise!

Another result I found interesting was that older adults did not show a larger heart rate increase during the exposure.

Their absolute heart rate was actually lower—by about 3 beats per minute per decade at rest and 4 beats per minute per decade at the end of the exposure. But the change in heart rate across the six hours was similar regardless of age.

As for fitness, it helped—but not quite how I expected.

• For every 10 mL/kg/min increase in VO₂ peak, whole-body sweat rate was 11 grams per square meter per hour greater.

• Resting heart rate was about 5 beats per minute lower, and heart rate at the end of the heat exposure was about 4 beats per minute lower for the same increase in cardiorespiratory fitness.

So we might assume that the fitter participants kept their core temperature lower.

Nope.

A 10 mL/kg/min difference in VO₂ peak was associated with essentially no difference in the rise in core temperature. The researchers also found no evidence that greater fitness changed the age-related temperature trajectory over the six hours.

Fitness improved parts of the cooling machinery, but those advantages did not translate into a measurably smaller rise in core temperature. Weekly physical activity was even less predictive.

An additional 60 minutes of moderate-to-vigorous activity per week was not associated with core temperature, heart rate, or whole-body sweat rate.

I find this result less convincing as evidence of what physical activity can and cannot do. This was a remarkably active group—only six people fell below the activity guidelines for their age—so there may not have been enough inactive people to reveal a meaningful contrast. Not to mention that a seven-day activity snapshot is unlikely to tell us as much as a person’s cardiorespiratory fitness.

Did the heat make people worse at thinking?

Older age was associated with lower performance across all four cognitive domains, both before and after the heat exposure. But the six hours of heat did not worsen memory or visual reasoning. Attention and processing-speed scores actually improved.

No, I don’t think sitting in a 109°F room is a clever new brain-training strategy.

Because heat did not clearly impair cognition, the researchers could not really test whether fitness or activity offered protection. Both were associated with better processing speed, but not with broad advantages across the other tests. (If you’re fitter, you appear to have a sharper brain. No breaking news there.)

Thus, I would consider cognition mostly a null finding, although an informative one. These healthy, hydrated adults maintained performance on the tests used here. I think that’s good news for us all.

This study does not recreate the full public-health problem of extreme heat.

But I do think it reveals something useful about the underlying physiology. Heat vulnerability appears to accumulate gradually across adulthood. It does not suddenly switch on when someone enters the “older adult” category.

If we take the results at face value, the age-related decline in thermoregulation looked gradual rather than catastrophic. That may partly reflect how active the participants were. The active sample is certainly a limitation for generalizability, but I also see it as a reminder that maintaining fitness and activity may preserve some physiological reserve.

Higher cardiorespiratory fitness appeared to provide some additional physiological reserve against the heat—especially as we get older. Cooling strategies still matter, but we should also be emphasizing that heat tolerance is trainable. I think exercise and deliberate heat exposure, including sauna use, could become useful tools in efforts to reduce heat-related illness. What would happen if every household had a sauna (I’m unaware of any heat illness statistics in sauna-using countries like Finland versus the U.S., but it would be interesting to compare!)

Fitness often works by widening our margin for error. It rarely makes the stressor disappear. I’m not immune to the heat because my VO₂max is in the mid-70s. But I sure as hell tolerate it better. This “reserve” concept extends far beyond heat, too.

Fitness cannot negotiate with thermodynamics. But if we can embrace the heat, it seems we can also become more resilient to it. Something about “what doesn’t kill you…”

You know the rest.

P.S.—If you’re interested in this topic, I highly recommend “Hotwired” by Bill Gifford. I just finished it, and it’s a wildly fun exploration of how to harness heat to live and perform better.

Thanks for reading. See you next Friday.

~Brady~

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Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

Exercise burns energy. Food replaces it. And if too little energy remains after training, the body starts cutting costs. And when athletes under-fuel, we tend to treat the problem as a simple “calorie shortage.”

That basic idea is captured by a concept known as energy availability. It is the energy you consume minus the energy you expend during exercise, divided by your fat-free mass:

Energy availability = (energy intake − exercise energy expenditure) ÷ fat-free mass

Imagine a runner with 60 kilograms of fat-free mass who eats 2,500 calories and burns 1,000 calories during training. That leaves an energy availability of 25 calories per kilogram of fat-free mass per day. That’s a level low enough to trigger physiological changes within a matter of days.

What does that look like? Well, the body responds to this shortage by becoming more selective about where it spends energy. Processes essential to immediate survival take priority. Processes related to growth, reproduction, bone remodeling, and other longer-term investments may receive less. This is the physiology underlying low energy availability, the Female Athlete Triad, and Relative Energy Deficiency in Sport, also known as REDs.

But there is one huge complication…

That creates a difficult question: how much of the body’s response is caused by the energy shortage itself, and how much is caused by having too little carbohydrate available? Because they are not necessarily the same thing!

Two athletes can have identical energy availability while finishing the day with very different amounts of carbohydrate left after training. Researchers call this carbohydrate availability:

Carbohydrate availability = carbohydrate intake − carbohydrate oxidized during exercise

One athlete might replace most of the carbohydrate burned during a long workout. Another might consume the same number of calories but replace those calories largely with fat or protein. Their energy budgets are identical. Their carbohydrate budgets are not. And carbs are much more than just fuel. They influence IGF-1 (a hormone important for growth and tissue repair), testosterone, thyroid hormones, appetite hormones, and more.

Many of these reliably fall during short periods of low energy availability. So the question is whether some of that decline reflects low carbohydrate availability layered on top of the calorie deficit.

A new randomized crossover study tried to separate the two.1

Researchers recruited 16 young, recreationally active adults—nine women and seven men—and put each participant through two four-day periods of low energy availability.

That brings up an important point. Low energy availability does not always mean someone is eating very little. A high training load can create the same shortage even when food intake looks substantial on paper. In fact, I think there’s good reason to assume that a calorie deficit achieved via eating less is NOT the same as the same deficit achieved by exercising more. But I digress…

The two conditions differed in how their calories were distributed:

• During the low-carbohydrate-availability condition, participants consumed 4.2 grams of carbohydrate per kilogram of body mass per day. After subtracting the carbohydrate used during exercise, their carbohydrate availability was about 1.4 grams per kilogram per day.

• During the high-carbohydrate-availability condition, participants consumed 6.7 grams per kilogram per day, leaving about 3.7 grams per kilogram per day available after exercise, or roughly twice that of the low-carbohydrate group.

Even the “low” condition included what might look like a respectable daily carbohydrate intake. It became low only in the context of nearly two hours of cycling every day.

Energy intake and protein intake were nearly identical between conditions. To make room for more carbohydrate without adding calories, the researchers reduced fat. Carbohydrate supplied 46% of calories in the low condition and 73% in the high condition; fat supplied 37% and 11%, respectively; protein was matched at 15% of total daily calories.

Before and after each condition, the researchers measured body composition, resting metabolism, fasting hormones, fuel use at rest and during exercise, blood lactate, peak oxygen uptake, and maximal cycling power.

What happened?

Both conditions produced almost identical weight loss: about 2.2 pounds or roughly 1 kilogram in four days. Resting metabolic rate did not change. So the calorie deficit was doing what calorie deficits do, regardless of where the calories came from.

The hormonal response was a bit more interesting.

IGF-1 fell in both conditions, but the decline was roughly cut in half when carbohydrate availability was high.

IGF-1 declined by 20.2% during low carbohydrate availability and by 9.4% during high carbohydrate availability.

The higher-carbohydrate diet did not prevent endocrine suppression. But it meaningfully attenuated one of its clearest signals.

Insulin and testosterone both declined significantly during low carbohydrate availability but not during high carbohydrate availability. Leptin (sometimes referred to as the “hunger hormone” also appeared to fall less in women when more carbohydrate was available.

But this is where the statistics matter. When the researchers tested that difference directly, changes in insulin, testosterone, leptin, and T3 were not significant. In other words, they didn’t change. IGF-1 was the only measured hormone for which the evidence clearly showed a different response between the two diets.

Now onto the exercise data.

Maximal blood lactate during the max exercise test fell by 1.2 mmol/L after the low-carbohydrate condition and was essentially unchanged after the high-carbohydrate condition. The lactate curve also shifted to the right only when carbohydrate availability was low.

Odd, right? A given lactate concentration at a higher percentage of peak oxygen uptake might look like an improved lactate threshold. But after four days of under-fueling, that is probably not what happened. Rather, the decline in maximal lactate suggests that low carbohydrate availability reduced the ability to rapidly break down carbohydrate and produce lactate during hard exercise!

Keeping carbohydrate availability high appeared to preserve more of that glycolytic capacity.

That did not translate into a measurable performance difference. Peak oxygen uptake and maximal cycling power were unchanged in both conditions.

At rest and during exercise, low energy availability shifted the participants toward greater fat use, but higher carbohydrate availability did not clearly prevent that shift. Men generally showed larger increases in maximal fat oxidation and larger decreases in carbohydrate oxidation during submaximal exercise.

In other words, the calorie deficit still shifted resting and exercise metabolism in a meaningful way, even when carbohydrate intake was high.

So, is low energy availability partly a carbohydrate problem?

It appears to be—at least for some acute responses.

This study makes a strong case that the macronutrients inside a calorie deficit are not interchangeable. Two diets can produce the same energy availability while creating different hormonal and energy-use signals. Preserving carbohydrate availability cut the short-term IGF-1 decline roughly in half and prevented the reduction in maximal blood lactate. But otherwise, all else looked mostly the same after this four-day intervention.

Carbohydrate softened part of the response but did not make under-fueling physiologically harmless.

I think that this study cannot tell us a lot of things, but that doesn’t mean it isn’t practical. It doesn’t tell us that a change in fasting IGF-1 over four days leads to a noticeable health or performance outcome, nor does it tell us whether more carbohydrate prevents the long-term outcomes associated with REDs such as menstrual disturbances, impaired bone health, recurrent injury, or declining performance. Those questions require longer studies in athletes.

Here’s the use case.

If you’re temporarily entering an energy deficit, knowingly or unknowingly, such as might happen during a high-volume training block, a weight-making phase, or simply a few days when food intake isn’t keeping pace with your training… protect your carbohydrate intake!

In practice, that may mean really focusing on carbohydrate across high-demand training days and, at the micro level, optimizing the timing of carb intake around workouts (though this study did not test nutrient timing).

Eat enough to support the work you’re doing. Carbohydrates aren’t a shield against chronic under-fueling. But if you can’t restore a deficit immediately, the type of calories you preserve probably matter. The body appears to respond not only to how much energy remains, but also to which fuel remains available.

The best solution to low energy availability is still to restore energy availability.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Last week, I appeared on The Neuro Experience podcast with Louisa Nicola, a neuroscientist and one of my absolute favorite people in the health and wellness space right now.

We talked about some of the latest science on what running a marathon does to your brain, the best types of training to improve VO₂ max, exercise non-responders, and much m…

Read more

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

Exercise is generally accepted as a great way to lose weight, maintain weight, or prevent weight regain.

And that’s because we tend to view metabolism as a math equation.

The number of calories we burn in a day—our total energy expenditure, or TEE—is ultimately determined by three things:

• Resting energy expenditure (REE), which reflects how many calories your body uses to support normal physiological processes.

• Activity energy expenditure (AEE), which reflects how many calories you burn through exercise and other physical activity.

• Diet-induced thermogenesis (DIT), which reflects the energy required to digest and process food… think “meat sweats.”

Researchers call this the additive model of energy expenditure. It assumes resting and activity energy expenditure are independent: one does not meaningfully reduce the other.

Over the past decade or so, the additive model has been challenged by another theory known as the constrained model.

Researchers observed that among highly active people, activity energy expenditure tended to be high, but total daily energy expenditure was not always much greater than it was in less-active people. In some studies, when people undertook huge amounts of exercise, their total daily energy expenditure rose less than their activity level would predict—or sometimes not at all.

This discrepancy was attributed to something called metabolic compensation. It’s the idea that doing more activity somehow causes the body to reduce energy allocation elsewhere, lowering resting energy expenditure and keeping total daily energy expenditure relatively constant. I go on that same 10-mile run, burn 800 calories, but my body “offsets” that by investing less energy in other stuff my body has to do.

That compensation might come from lower hormone production, fewer resources devoted to reproduction, or what researchers call behavioral compensation, where people simply engage in less non-exercise activity, such as fidgeting, pacing, or spontaneous movement throughout the day. I’ll admit that I spend a bit more time on the couch after a long run… that’s behavioral compensation in action.

The constrained model is often used to explain why exercise is not a particularly powerful tool for weight loss: the body “adapts,” and eventually calorie burn becomes something like a zero-sum game.

It’s a highly controversial idea—and according to a new study, this particular version of it is not well supported by the evidence.1

• • •

To test whether energy expenditure is truly additive or constrained, researchers used two complementary approaches.

First, they conducted a tightly controlled experiment in 12 adults. Each person completed two separate 10-day periods—a high-activity and a low-activity period—separated by a washout period:

• During the high-activity period, participants added 135 MET-minutes of physical activity per day. A MET is a unit of activity intensity: 1 MET is the rate of energy expenditure at rest. 35 MET-minutes is roughly equivalent to 30–45 minutes of moderate-intensity activity or a few hours of brisk walking. Not elite-athlete levels, but well above their usual baseline.

• During the low-activity period, they were essentially told to be “as lazy as possible” (my wording, not theirs).

During the high-activity phase, activity energy expenditure rose by about 28%, or roughly 250 calories per day.

What happened to total energy expenditure?

It rose by about 272 calories per day—a 10% increase—while resting energy expenditure, adjusted for body size and composition, did not fall (neither body weight nor body composition changed meaningfully in either group during each 10-day period).

In other words, the extra activity these participants were doing added almost one-for-one to their total energy expenditure, without measurable compensation through a suppressed resting metabolism—exactly what the additive model predicts.

Case closed, right?

Somewhat.

This was a short-term study, and one argument for the constrained model is that there may be a time lag between increases in activity and metabolic compensation. Ten days might not be enough for that compensation to emerge.

So the researchers complemented the experiment with observational data from 268 adults living under normal, free-living conditions.

If long-term physical activity really causes resting metabolism to drop, you would expect to see that relationship across a diverse group ranging from sedentary to highly active.

As a final sanity check, the researchers also compared the human data with metabolic scaling patterns across other mammals. The same basic relationship held: resting and activity energy expenditure behaved independently. Their findings in the large group of adults did not appear to be some unique quirk of human biology.

• • •

Most of us do not exercise simply to burn calories. Nor are the benefits of exercise limited to losing or maintaining weight.

But it is nice to know that, within the range of activity most people are likely to perform, our energy budget appears to be more additive than constrained. The more you exercise, the more energy you burn.

That does not mean you should take the calorie number on your fitness tracker literally. This study supports the direction of the equation, not the precision of a wrist-worn estimate.

The body is not a perfectly predictable math equation. Energy expenditure on any given day fluctuates with activity, body composition, diet, sleep, and a host of other factors we cannot fully account for.

I also don’t think this study proves once and for all that the constrained model of energy expenditure has been debunked. I’m not even sure science can ever do that with a single model. But I think anecdotal experience alone is enough to convince most of us that the additive model makes intuitive sense.

Anybody who has done a block of intense exercise training—preparing for a marathon or triathlon, for example, or simply increasing activity for the fun of it—has probably noticed that unless they stay on top of their eating, weight tends to drop. When I run more, I lose weight. If I eat more to offset that running, my weight stays stable.

On the opposite end of the spectrum, there is even some evidence that energy expenditure may remain elevated after strenuous exercise through a phenomenon known as excess post-exercise oxygen consumption, or EPOC.

I’ll end with one final nuance that I don’t think much of this research has fully addressed. Even the high-activity condition in today’s study involved a fairly moderate amount of daily exercise. There is still a chance that some metabolic compensation occurs at the extreme upper end of exercise—what you might see in Tour de France cyclists, Ironman triathletes, or ultramarathon runners.

I’m open to the possibility that there is some kind of cap on sustained human energy expenditure (in fact, it’s an idea that has been proposed in the literature). Once you approach that cap—which very few people ever do—the body may begin diverting resources away from physiological maintenance. That is probably part of what we see in athletes who lose their menstrual cycle when high training loads are combined with inadequate energy intake.

Whether metabolism is constrained probably does not change how you or I are going to train. Regardless of which model is ultimately closest to the truth, it probably shouldn’t.

But I’m curious: would it change anything for you?

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

"Those who think they have not time for bodily exercise will sooner or later have to find time for illness." — Edward Stanley, 19th century British Politician

In science and medicine, exercise is usually treated as the intervention—the unusual thing we add to someone’s life to see whether it improves their health.

But physical activity is not the intervention. It is the biological norm. Being inactive is the intervention, at least in modern times.

Our physiology evolved under conditions of regular movement (exercise, by contrast, is a relatively modern invention… and quite weird if you think about it).

As the authors of a new paper (the subject of today’s newsletter) put it, physical activity is a “canonical characteristic” of humans. Yet we’ve normalized its absence so completely that we now view exercise as a special behavior.

You can see this play out in medical and exercise research, where “healthy sedentary” people are often used as the control group. But Inigo San-Millan and his colleagues argue that the concept of a healthy sedentary person may be biologically inconsistent. Sedentarism may not represent a neutral baseline at all, but rather, an early stage of “bioenergetic dysfunction”—a state in which the machinery responsible for producing energy has already begun to downshift, even before someone develops a disease.

And if we know anything, it is that mitochondrial dysfunction is the root of all evil (I am only slightly being tongue-in-cheek here).

This new study by Dr. San-Millan’s group asked whether the way someone burns fuel—and the point at which lactate begins to rise during exercise—may serve as a window into what is happening inside their mitochondria.1

The answer appears to be yes. In sedentary people, what looked like “low fitness” from the outside was accompanied by a distinct bioenergetic phenotype underneath it.

You’re going to want to sit down (or perhaps, stand up and run around) for this one…

The study included 19 otherwise healthy men who were around 42 years old on average. Nine did no regular exercise (ever!), while ten performed at least 150 minutes of aerobic exercise per week for six months or longer. These are referred to as the “sedentary/inactive” and “active” groups, respectively.

One thing to keep in mind is that these groups were not perfectly matched. The sedentary participants had a higher average BMI (28.3 versus 23.8 in the active group), which could have contributed to some of the metabolic differences. They also had a VO₂ max that was nearly 40% lower than the active group.

The first big difference was that the muscles of the sedentary people had a smaller aerobic engine.

Compared with the active participants, the sedentary group had 26–36% lower capacity to produce energy across the entire mitochondrial electron transport chain (this is the “battery” that turns electron flow into ATP inside the mitochondria). For every milligram of muscle tested, the sedentary participants had roughly one-third less capacity to use oxygen and produce energy through their mitochondria.

The biggest difference involved a protein called mitochondrial pyruvate carrier 1, or MPC1.

When we break down glucose, we produce pyruvate. That pyruvate then has two main options: it can enter the mitochondria and be oxidized for energy, or it can be converted into lactate. MPC1 is part of the transport system that moves pyruvate into the mitochondrial matrix. You can think of it as one of the doorways connecting the breakdown of glucose outside the mitochondria (glycolysis) to aerobic energy production inside the mitochondria.

In the sedentary participants, MPC1 abundance was 49% lower! This was the largest difference among the major proteins measured in the study, and it was accompanied by a 37% reduction in the muscle’s ability to use pyruvate to produce energy.

Interestingly, the groups had similar amounts of GLUT4, the transporter that helps move glucose into skeletal muscle cells, and similar amounts of two proteins involved in converting pyruvate and lactate back and forth. So it doesn’t appear that the groups differed in their ability to bring glucose into the muscle cell—the difference was downstream at the step where pyruvate (from glucose breakdown) enters the mitochondria.

(I get that some of this stuff sounds complex. But it’s so cool! So bear with me).

A simple way to think about this is that glucose could still reach the muscle, but the doorway into the mitochondria appeared to be narrower. This was confirmed by showing that two breakdown products of lactate (citrate and malate) were also less capable of making their way into the mitochondria in sedentary muscle compared to active muscle (about a 35–40% reduction).

Every result we’ve just talked about relates to glucose (carbohydrate) metabolism. So sedentary people might just be worse “carb burners” and make up for it by being better “fat burners.” Wrong.

In sedentary people, activity of CPT1—the enzyme that helps move fatty acids into the mitochondria—was 51% lower, and fatty-acid oxidation inside the mitochondria was 32–25% lower.

Sedentary people had a generalized reduction in the amount of oxidative machinery available within the muscle. They were worse at transporting/burning carbs and fat for energy.

And their mitochondrial membranes looked different too.

The researchers also measured reactive oxygen species, or ROS.

At first glance, the active participants actually produced more ROS in absolute terms. But they also had more metabolic activity, and when this was accounted for, the sedentary participants generated more ROS relative to how much oxygen they were consuming—which could mean less efficient energy production or even worse antioxidant capacity.

Another big difference is what we’ll refer to as a “metabolic traffic jam” upstream of the mitochondria. Sedentary muscle appeared to accumulate more breakdown products of carbohydrates while having less capacity to move those fuels into and through the mitochondria.

Meanwhile, the active profile was more consistent with greater use of fatty acids and more activity within the energy-producing systems in the mitochondria.

What happened when they exercised?

All of the differences the researchers observed between the muscles of active and sedentary participants were reflected during exercise.

The active participants had:

• 31% higher absolute VO₂ max

• 38% higher VO₂ max relative to body mass

• 35% higher maximal power output

• 42% higher power output relative to body mass

None of that should be particularly surprising. The more interesting result was how the two groups produced energy as exercise intensity increased.

• In the active group, fat oxidation rose throughout low-to-moderate exercise and peaked at around 0.35 to 0.40 grams per minute near 150 watts.

• Lactate remained below approximately 1 mM across much of this range, and only as the workload became harder did fat oxidation begin to decline while carbohydrate use and blood lactate rose.

• At easier workloads, the active participants could rely heavily on fat. As exercise became more demanding, they gradually shifted toward greater carbohydrate use.

This is metabolic flexibility in action, and it’s the “classic” response to increasing exercise intensity (and it’s quite beautiful, if you ask me).

The sedentary group followed a very different pattern.

• Their fat oxidation peaked at only around 0.15 to 0.20 grams per minute, roughly half of what was observed in the active group. It also began falling much earlier as workload increased.

• At the same time, carbohydrate use became dominant earlier and lactate began rising from the first few stages of exercise (in addition to being higher at rest, before they even started pedaling the bike).

• At 125 and 150 watts, blood lactate was more than 60% higher in the sedentary participants. They reached the limits of their oxidative metabolism (“fat burning”) much earlier. They had to rely more heavily on glycolysis, resulting in earlier and greater lactate accumulation.

Now let’s get to what I think is the most practically useful part of the study.

The researchers did not just find differences between the two groups. They also found that the measurements taken from resting muscle were strongly related to what happened during exercise.

People whose muscle had a greater capacity to use fat at rest also burned more fat on the bike.

Blood lactate showed the opposite pattern. People with lower mitochondrial capacity at rest tended to accumulate more lactate during exercise. And participants with more MPC1 (the pyruvate transporter we talked about earlier) tended to burn more fat and accumulate less lactate during exercise.

Having a higher VO₂ max was also associated with better mitochondrial energy production.

All of this suggests that the lactate and fat-oxidation responses observed during an exercise test may provide some insight into what is happening inside the muscle.

The authors even propose that measuring fat oxidation and lactate during a submaximal exercise test could provide a noninvasive window into mitochondrial health.

They specifically suggest that the combination of:

• Blood lactate above 2.5 millimoles per liter

• Fat oxidation below 0.4 grams per minute

During exercise at approximately 50% to 60% of VO₂ max may “

“... define a noninvasive physiological signature of mitochondrial function, directly linking systemic exercise responses to underlying cellular bioenergetics.”

I would treat that threshold as a hypothesis, not a diagnostic rule. The study did not show that people who crossed this threshold went on to develop diabetes, cardiovascular disease, or any other clinical outcome. But I see this as potentially being the next thing these researchers investigate to validate their thresholds, and the broader concept is intriguing.

Rather than using VO₂ max alone, an exercise test could potentially assess how much fat someone burns, how quickly lactate rises, and where the body shifts toward greater carbohydrate reliance, which could provide a more detailed picture of metabolic flexibility than VO₂ max by itself.

For nearly all of human history, regular movement was built into daily life. Sedentarism is the newer experiment. And if this study tells us anything, it’s that skeletal muscle appears to build—and maintain—only as much capacity as it is regularly asked to use. It’s literally “use it or lose it” in action.

In that sense, the lower mitochondrial capacity in sedentary people is less a mysterious malfunction and more of a predictable adaptation to an environment that no longer requires much physical work. And it explains why it’s estimated that only about 12% of people are “metabolically healthy.”

How I think we should think about this is that exercise is not some optional “health intervention” layered on top of normal human biology. To quote the authors:

That flips the usual framing not only for personal health philosophy, but for how we think about exercise science and medicine. We often assume that a person who does not exercise is starting from a neutral baseline and that training pushes physiology above normal. This paper suggests the opposite may be true—regular physical activity maintains the metabolic machinery our bodies expect to need, while inactivity allows that machinery to gradually atrophy.

The sedentary men in this study were not sick. Yet their muscles already show signs of metabolic dysfunction, which may be some of the earliest detectable steps on the path from inactivity to metabolic disease, long before a diagnosis ever appears.

None of this is to moralize exercise or physical activity. That happens too often on social media. But we can’t deny the major reality of biology.

Movement is not something we do to improve our physiology. It’s our default state.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).

Believe it or not, one of the most frequently asked questions I get about running isn’t even about running. It’s about how I use cycling to run better.

Indeed, cycling has become a huge part of my overall training in recent years, partly out of necessity and partly out of utility. I wanted to find a way to train more without putting myself at risk of inj…

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Almost every time I read a new scientific study, and especially every time I sit down to write about one, I find myself returning to the same basic question: 

What the heck can I actually do with this?

In the world of exercise science, nutrition science, and medical science, much of the work is ultimately pointed toward application. We study the body beca…

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Greetings!

Welcome to the Physiology Friday newsletter.

Details about the sponsors of this newsletter and deals on products I love, including Ketone-IQ, Create creatine, Equip Foods, and ProBio Nutrition can be found at the end of the post.

“It’s tough to make predictions. Especially about the future.” – Yogi Berra

Most of us take our workouts for granted.

When we embark on a marathon training plan or progressive overload regimen in the gym, we expect that it’ll lead to the desired result—a faster time or bigger, stronger muscles.

That’s especially true if we’ve performed the same training before with reasonable success. We responded well the first time, so we should respond in a similar way the next, right?

Let’s refer to this idea as “reproducibility of training adaptation.” The basic idea is that if I put you through 12 weeks of high-intensity intervals, tempo runs, and a hefty amount of zone 2 training, you might improve your VO₂ max by 5–10%.

If I let you take some time off to eat some ice cream and enjoy a few drinks by the beach (the more scientific word for this is “detraining”), and then put you through the exact same training again, we’d expect your VO₂ max to improve by that same 5–10%, assuming you started at the same baseline.

Once a responder, always a responder.

A new study suggests our assumptions about this are wrong.

Exercise science might have a reproducibility problem.

The study—aptly titled “Limited reproducibility of individual physiological adaptations to repeated endurance exercise training”—used a design that is surprisingly rare in exercise science: the same people completed the same endurance training program… twice.1

Rather than comparing one group of people to another, the researchers essentially asked what happens if we put the same individuals through the same training stimulus, under carefully controlled conditions. Do they adapt the same way both times?

The study was built to directly test the idea that people have somewhat consistent “trainability”—someone who improves a lot from one endurance block should also improve a lot when exposed to a similar block again.

Participants completed two separate eight-week endurance training periods, with an eight-week detraining period between them. Each training block included 24 supervised cycling interval sessions, lasting 45 minutes each, performed at intensities ranging from moderate to maximal effort. Every session was supervised, the workouts were prescribed, and the same individuals repeated the same training program twice.

Before and after each eight-week training period, participants completed two submaximal cycling tests, a VO₂ max test to exhaustion, and a 15-minute maximal performance test.

This gave the researchers several layers of information:

1. How participants responded at lower fixed workloads.

2. How their maximal oxygen uptake changed.

3. How their actual cycling performance changed in a sustained maximal effort.

They even had participants perform a familiarization session one week before the first baseline testing period to reduce learning effects, and a rest day was scheduled before each testing block so fatigue from recent exercise would be less likely to distort the results.

The study also went well beyond performance testing to include whole-body DXA scans to assess body composition, leg muscle biopsies, blood samples, total hemoglobin mass measurements, and questionnaires. If it’s relevant to performance, they measured it.

When the researchers zoomed out and looked at the average response (what’s typical in exercise science research), the endurance training intervention was effective and remarkably reproducible.

But when they zoomed in and asked whether the same person responded the same way to the same training program, the answer was mostly no.

That distinction is the entire study.

First, the basics: participants actually did the training. Adherence was nearly perfect, and participants entered the two training periods in a highly comparable state. Baseline VO₂ max, 15-minute cycling power, maximal power, hemoglobin mass, blood volume, body mass, and lean mass were all very reproducible before the first and second training blocks. That means the eight-week detraining period was largely successful, and people were not simply carrying the adaptations from the first block into the second. The study had essentially “reset the clock” well enough to ask the main question.

Here’s what happened at the group level:

• The first eight-week training block increased 15-minute maximal power output from 137 to 154 watts, a gain of 17 watts or about a 15% improvement. The second block increased it from 142 to 164 watts, a gain of 22 watts or about a 16% improvement.

• VO₂ max increased by 3.3 mL/kg/min in the first block and 3.4 mL/kg/min in the second (a 9.4% vs. a 9.8% increase).

• Maximal power output during the final minute of the VO₂ max test increased by 24 watts in the first block and 30 watts in the second.

But then we look at the individual data…

The researchers asked whether the people who improved the most in the first training period were also the people who improved the most in the second. If “trainability” were a stable personal trait, you would expect a fairly strong relationship. That is not what happened.

Individual changes in VO₂ max showed poor reproducibility between the two training periods. The same was true for 15-minute cycling performance, maximal power, submaximal performance, hemoglobin mass, blood volume, red blood cell volume, plasma volume, muscle fiber size, mitochondrial enzyme activity, and capillarization outcomes. Almost everything that mattered physiologically showed weak within-person agreement from one training block to the next.

This is the key result: the group average was stable, but the individual rankings were not.

A person could gain a lot of VO₂ max in the first block and much less in the second. Another person could look like a modest responder the first time and then adapt more strongly the second time (if you look at the right panel in the figure below, which depicts individual responses, this is clear to see).

We see the same story when we look at the muscle level.

• Citrate synthase activity, a marker of mitochondrial oxidative capacity, increased in both training periods: by about 47.7% in the first block and 38.4% in the second.

• Another enzyme involved in fat metabolism increased more in the second training period than in the first.

• Capillary density increased more in the first training period than in the second, and the number of capillaries per muscle fiber (a marker of capillary density) showed a larger numerical increase in the first block as well.

• Hemoglobin mass, blood volume, red blood cell volume, and plasma volume increased more in the first training period than in the second, while hemoglobin concentration changed more in the second. But many of these differences were small (close to the expected measurement error for some blood-volume assessments).

The broader point is not simply whether capillaries or hemoglobin mass increased more in one block than the other.

Because VO₂ max is driven by improvements in oxygen delivery and extraction (i.e., hemoglobin mass, mitochondrial function, and capillarization), we might expect variability in these measures to explain a large portion of the variability in VO₂ max or performance. But they didn’t.

Hemoglobin mass variability explained only a small portion of the maximal power changes. Capillary density explained a modest portion of 15-minute performance and VO₂ max changes. But most of the tested relationships were weak—there was no single obvious mechanism that explained why someone responded differently the second time.

In other words, the “instability” of training response was not simply because hemoglobin or mitochondria changed differently. The adaptive response appeared to be distributed across systems, and the variability probably emerges from the interaction of many moving parts… and maybe even some random biological noise!

The researchers also found no clear evidence that the relationship between the first and second training response differed by sex or age.

Why might the same training program produce different responses in the same person?

I don’t think “noise” fully captures what is happening here.

To me, two explanations stand out. The first is that the body remembers. The second is that life is never the same twice.

Let’s start with muscle memory, or, more broadly, biological memory. The researchers did an impressive job trying to reset participants before the second training period. But “returning to baseline” on a few measurable outcomes does not mean the body has returned to the exact same biological state.

In that case, the second training block may have been applied to a subtly different biological organism, one that had already experienced eight weeks of structured endurance training. This is especially true since these participants were initially “untrained” and had never really performed formal exercise training. That point should be underscored.

“Muscle memory” probably isn’t one clean mechanism, though. It may be a collection of partially retained adaptations—structural, metabolic, vascular, neural, and molecular—that influence the starting state for the next block of training.

The second explanation is one that we’re all familiar with—lifestyle variables are never the same.

Even in a tightly controlled study, people are not lab animals. We sleep differently from week to week. We eat differently. We experience stress, illness, travel, family obligations, work demands, mood changes, changes in motivation, subtle changes in daily activity, and countless other fluctuations that are hard to measure and impossible to fully control.

Training adaptation is a result of the workout interacting with the body’s current state. A 45-minute interval session performed after a good night of sleep, adequate carbohydrate intake, low stress, and a normal week of activity is not the same biological stimulus as the same interval session performed after poor sleep, under-fueling, elevated stress, or the tail end of a mild illness.

That context includes stable factors like genetics, sex, age, and baseline fitness, but it also includes ever-changing factors like recovery, sleep, energy availability, stress, inflammation, illness, glycogen stores, and prior training history. Some of these variables may shift enough that they never show up in a standard baseline test, yet still meaningfully influence the adaptive response.

So if we really think about it, the “messiness” of the study might actually be its most realistic feature. The researchers controlled everything they could, yet individual responses still varied widely. It makes the findings reflective of real life. None of us ever repeats the same training block under identical conditions.

Here’s the question we should all be asking when starting any training program (or even a workout): “What state am I in right now, and what does my body need in order to respond?”

When I initially read this paper, it seemed like the nail in the coffin for exercise science research. After all, if we can’t even get reliably consistent results in the same exact person, then everything we know about how to prescribe training is wrong. And what to make of the hundreds, if not thousands, of studies we’ve used to base our training, nutrition, and even sleep recommendations on for decades? Should we just throw them out the window and concede that none of it matters if we can’t predict whether they’ll work or not?

After some reflection, I don’t think we’ve hit crisis mode quite yet. Exercise science doesn’t have a “reproducibility problem.”

Exercise science has a human problem.

We’re all unique. So we should take what we can from training studies, apply it to our unique selves, and adapt and respond accordingly. That’s the real takeaway here.

And I think it’s a real paradigm shift for how we think about exercise.

Thanks for reading. See you next Friday.

~Brady~

Ketone-IQ is high-performance energy in a bottle. I use it for post-exercise recovery along with enhancing focus, mood, and cognition. Take 30% off your order.

Create is the first “modern creatine” brand. They sell a wide range of creatine monohydrate gummies, and just launched a new creatine + electrolyte mix product plus travel-size packets of creatine gummies. They’re giving my audience 20% off their order.

ProBio Nutrition—the all-in-one supplement that I use every single day—is offering 20% off. My preference is the tangy orange flavor, but they also sell an unflavored “smoothie booster” that’s great in a shake, smoothie, or juice.

• Equip Foods makes some of the cleanest, best-tasting protein products around. I am absolutely obsessed with their Prime grass-fed protein bars (the peanut butter ones are to die for, but they also just released a new chocolate peanut butter flavor).