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.

If there’s one topic I keep returning to every time a new study comes out, it’s endurance exercise and heart disease. Part of that is, of course, personal. I’m a lifelong endurance athlete with no plans to stop. But it’s also because the science is complex and continually evolving.

I’ve written about this a lot over the years. Today I want to pull it all into one state-of-the-science review, built from the research I’ve already covered here, with some links back to each original post if you want the details!

Here’s the question running through all of it:

If exercise is one of the best things you can do for your heart, why do so many lifelong endurance athletes have so much coronary plaque? And should those of us who train a lot be worried?

Let’s dig in.

The paradox

Exercise is the real fountain of youth. The biggest drop in risk comes from going from nothing to something, and in my opinion the minimum guideline dose (150 minutes moderate or 75 minutes vigorous per week) is actually a bit too low. The benefits also seem to have a high ceiling.

• A high VO₂ max is one of the most potent predictors of all-cause mortality, and the lowest risk shows up in people with so-called “elite” levels of aerobic fitness.

• Athletes tend to live longer than the general population, with about 30–40% lower all-cause and cardiovascular mortality.

• Long-distance runners and cross-country skiers have lived 2.8–5.7 years longer than reference populations.

(I discuss these data in my post The Latest Evidence on Atherosclerosis in Athletes.)

But for at least a decade, one finding has refused to fit this neat story. People who do extreme volumes of exercise, or who have done high levels of endurance exercise for most of their lives (most of them men), seem to have more markers of cardiovascular disease. In particular, they have higher levels of coronary artery calcium (CAC) and more atherosclerotic plaque.

That’s the paradox: high levels of exercise build the fitness that lowers mortality, yet seem to come with more plaque in the arteries that feed the heart.

Why might very high levels of training be a problem? High-intensity exercise is stressful. Blood pressure and heart rate spike, blood flow becomes turbulent, and the heart and arteries go through high levels of mechanical stress and inflammation. Over years, the hypothesis goes, this might promote vascular remodeling, fibrosis, scarring, and atherosclerosis.¹ Let’s see what the data say.

More calcium, but the stable kind

One of the first and largest studies to show more atherosclerosis in athletes was the Measuring Athletes’ Risk of Cardiovascular Events (MARC) study.²

MARC looked at the lifelong exercise habits of 284 middle-aged amateur male athletes (average age 55), who were recreational or locally competitive. Here’s what it found:

• The athletes with the most lifelong exercise (about 6 hours per week from age 12 onward) were more likely to have a CAC score above zero than the least-active group (about 1.5 hours per week). They also had more plaque of any type.

• Moderate- and vigorous-intensity exercise weren’t linked to CAC or plaque. Very-vigorous-intensity exercise was. The more time spent at very-vigorous intensity each week, the more CAC and plaque.

• But the type of plaque was different. The high-volume exercisers had fewer mixed plaques and more calcified plaques.

That became the comforting explanation. Calcified plaques are thought to be more stable and less likely to rupture than mixed plaques (calcified plus fatty components). So maybe athletes’ extra plaque is the less harmful kind.

Other studies from that period pointed the same way:

• A 2017 study found more CAC and plaque in male masters endurance athletes than in sedentary controls, but mostly calcified plaque. Controls had more mixed plaque.

• A 2020 study found total exercise volume was not related to CAC progression in middle-aged male and female endurance athletes.

• A 2021 study of 25,000+ healthy adults found the most active people were more likely to have CAC and faster progression.

I’ve summed up the consensus this way: athletes, especially those doing high volumes and/or intensities of exercise, may be at higher risk for CAC and plaque, but the type of plaque they have might not put them at higher risk of cardiovascular events.

It was a neat, reassuring story. The next few years made it messier.

The “benign” plaque idea takes a hit

In 2023, the Master@Heart (Masters Athlete’s Heart) study set out to test the athlete plaque paradox directly.³

(I wrote about it in Physiology Friday #155.)

The study included three groups, with an average age of about 56:

• 191 lifelong athletes, who started endurance sport before age 30

• 191 late-onset athletes, who started after age 30

• 176 healthy non-athletes, who exercised less than 3 hours per week

The athletes trained about 11 and 10 hours per week, compared with about 1 hour in the non-athletes, and were much fitter—VO₂ peak was 48 and 46 ml/kg/min in the lifelong and late-onset athletes versus 37 ml/kg/min in the non-athletes. Blood pressure, cholesterol, and family history of heart disease were similar across the groups.

• On average, CAC scores were low to non-existent in all three groups, and the number of plaques per person was similar.

• But the lifelong athletes had higher stenosis severity and segment involvement scores (measures of overall plaque burden) than the non-athlete controls.

• Compared with controls, lifelong exercise was linked to higher odds of having more than one coronary plaque, proximal plaque, calcified plaque, non-calcified plaque, and mixed plaque. The odds were roughly 58% to 180% higher, depending on the plaque type.

• Lifelong athletes were also more likely than late-onset athletes to have a ≥50% narrowing (stenosis) in a coronary segment.

• The one bit of good news was that lifelong athletes had fewer vulnerable plaques, meaning plaques with high-risk features that make them more likely to rupture. Vulnerable plaques were uncommon in every group, though.

This cracked the tidy story. Lifelong athletes were more likely to have calcified and non-calcified/mixed plaques, plus more significant stenosis and proximal plaque, all linked to higher heart disease risk! The overall mix of plaque types was similar across groups. Athletes didn’t have a uniquely “safe” kind of plaque… they just had more of it.

There was also a dose-response pattern in which lifelong athletes looked worse than late-onset athletes, who looked worse than the healthy non-athletes. That undercuts the “they took up running at 40 after years of bad habits” explanation, because the people who had trained the longest had the most plaque.

Two things matter here. The lifelong athletes still had a generally low risk profile overall. And this was an imaging study, not an outcomes study. It tells us what athletes’ arteries look like, not whether they’re having more heart attacks. The authors planned at least two years of follow-up for clinical outcomes, and I’ll come back to that gap at the end.

Does training make plaque progress?

The next question was whether continuing to train hard affects how atherosclerosis changes over time. MARC-2 brought back the original MARC cohort seven years later, at an average age of about 60.⁴

A few things stood out:

• The men were actually exercising more at follow-up, yet CAC prevalence rose from 54% to 71%, plaque from 64% to 83%, and blood pressure from 129/80 to 139/82 mmHg. Some of that is aging, but cardiovascular health declined despite more activity.

• Volume didn’t predict progression. CAC and plaque changed about the same in the men exercising around 8 hours per week as in those exercising around 3 hours per week.

• Intensity was more complicated. A larger share of vigorous-intensity exercise was linked to slower CAC progression. A larger share of very-vigorous-intensity exercise was linked to faster CAC and plaque progression, mostly driven by more calcified plaque rather than non-calcified or mixed plaque.

My summary of MARC 1 and 2 is this: high levels of exercise seem to affect the presence of CAC and plaque, but volume doesn’t seem to drive progression, and a good share of relatively high-intensity work may even slow it. The very top end of intensity may have diminishing returns.

HIIT reduced plaque in people with heart disease

If very hard exercise is bad for coronary arteries, HIIT should be risky for people who already have coronary disease. A randomized trial I covered in Physiology Friday #199 found the opposite.⁵

The CENIT trial randomized 59 adults (average age 58) with stable coronary disease, all recently stented and on lipid-lowering therapy, to HIIT or usual care for 6 months. HIIT meant two supervised sessions per week of 4 × 4-minute intervals at 85–95% of peak heart rate (the classic Norwegian 4 × 4 workout).

• Plaque volume dropped 1.2% with HIIT, with no change in controls, and the arteries’ remodeling index improved.

• VO₂ peak rose by 3.3 ml/kg/min, and BMI and waist circumference fell.

• LDL and ApoB didn’t change.

That 1.2% drop rivals what’s reported for statin therapy (0.9–1.22%). Since LDL and ApoB didn’t move, my best guess is that higher endothelial shear stress (a good thing), which HIIT increases even more than moderate exercise, played a role.

A reader asked how to square this with MARC-2’s very-vigorous finding. That’s a fair question, but the studies measured different things in different people—a 6-month randomized trial of supervised intervals in patients on lipid-lowering drugs (measuring plaque volume) versus self-reported, long-term training habits in healthy older athletes (measuring CAC progression). Together, they suggest some hard work is good for the arteries. Whether years at the very top end is a different story is still open to interpretation.

Traditional risk factors still matter

In late 2024, a new analysis of the MARC-2 cohort asked something we hadn’t really addressed: how much of athletes’ CAC is about training, and how much is about everything else?⁶ (I wrote about this in Lifestyle Risk Factors Predict Coronary Calcification among Male Endurance Athletes.)

In 289 male athletes (average age 60), the usual suspects still applied:

• Family history of coronary artery disease was the strongest predictor of severe CAC.

• Age: each additional decade meant a 92% higher risk of CAC ≥100 and 215% higher risk of CAC ≥400.

• Systolic blood pressure (14% higher risk of CAC ≥100 per 10 mmHg) and smoking history (38–53% higher risk per pack-years) mattered too.

Less traditional factors showed up as well:

• Energy intake: each 1,000 kcal/day less meant a 40% higher risk of CAC ≥100 and 71% higher risk of CAC ≥400.

• Dietary fat: a 10% higher share of energy from fat went with 34–60% lower risk.

• Training load: each 10 MET-hours/week meant 11% higher risk of CAC ≥100, but only 3% for CAC ≥400.

So training load plays a role, but it’s one factor among many, and not the biggest. The diet results surprised me. My (speculative) guess is that athletes this age may have adopted the low-fat, high-refined-carbohydrate diets promoted decades ago. Or maybe adequate dietary fat just isn’t something to fear. And remember that blood pressure rose about 10 mmHg in this same cohort over seven years, suggesting athletes aren’t immune to the risk factors that affect everyone else.

Does post-race troponin tell us who has plaque?

Another theory is that very high amounts of endurance exercise cause repeated cardiac damage that eventually promotes disease. Troponin, the key marker of cardiac injury, rises after heart attacks but also after marathons. Those rises were once considered harmless, but people with abnormally high post-exercise troponin turn out to be at higher risk of cardiovascular events and death.

In Physiology Friday #278, I covered a study asking whether athletes with hidden coronary disease have bigger troponin responses.⁷ Researchers measured troponin before and after walking, cycling, and running events in 1,017 recreational athletes (average age 56), then CT-scanned the 68 highest and 34 lowest responders.

• CAC scores, CAC prevalence (65% vs. 50%), and plaque types didn’t differ between high and low responders.

• Resting troponin T correlated with CAC, but post-exercise troponin and the size of the rise did not.

• Almost 52% had post-exercise troponin T above the upper reference limit (in the “looks like a heart attack” range).

• Atherosclerosis showed up in 62%, in line with the ~60–70% reported in masters athletes.

So big troponin spikes and coronary atherosclerosis are both common in middle-aged recreational athletes, but they don’t seem to be linked. In the authors’ words, most of the variation in exercise-induced troponin rises “is not attributable to occult coronary artery disease [but rather] unknown factors.” A blood test after your next race won’t tell you whether you have plaque.

The athlete’s heart is not the same thing as heart disease

A lot of confusion comes from lumping together how the heart muscle remodels with training and atherosclerosis in the coronary arteries.

“Athlete’s heart” refers to the structural and functional changes that come with long-term endurance training. It isn’t a disease. It’s usually a normal physiological response to repeated high cardiac output demands (I covered this in detail in Physiology Friday #320).

These changes include mild-to-moderate enlargement of the ventricles and heart walls, better left ventricular filling, better heart mechanics (twisting and untwisting with each beat), and enlarged atria.⁸ The adaptations here give the heart a “timing advantage” that optimizes performance during exercise.⁹

None of that has anything to do with plaque. A big, efficient heart doesn’t protect your coronary arteries, and having CAC doesn’t mean your remodeled heart is sick. That said, there are two gray areas:

• Fibrosis (collagen buildup that stiffens the heart) has been reported in veteran endurance athletes.¹⁰

• AFib is the best-established “too much” finding. It’s more common in long-term endurance athletes, especially male masters athletes, likely because of bigger atria, autonomic changes, and years of repeated strain.¹¹ It’s usually manageable and treatable. (This one is personal… I’ve had occasional short bouts of AFib after very intense workouts in hot, humid weather. Cardiologists couldn’t find anything, but it’s scary when it happens.)

The question that matters most is this: are athletes actually having more heart attacks or dying sooner? Everything we have says no:

• The absolute risk of sudden cardiac death during exercise is extremely low: about 1 death per 1.42 million hours of vigorous exercise in one cohort of male physicians, and about 0.9–1.6 deaths per 100,000 marathon finishers. Most exercise-related deaths happen in people with underlying heart disease.

• The fitter you are, the lower your risk of a cardiac event during exercise.

• Runners had 30% lower all-cause mortality and 45% lower cardiovascular mortality than non-runners in one study of more than 55,000 people, and people who had been running longer did even better.¹² Finnish elite skiers lived 2.8–4.3 years longer than other men.

(For a deep dive into this and references, take a look at one of my earliest posts ever, No, Endurance Exercise Won’t Kill You.)

My best explanation hasn’t changed much. Plaque type might be part of it, but more likely, exercise protects athletes against the extra plaque they carry by improving endothelial function, blood pressure, coronary blood flow, and metabolic health.

But being active lessens the risk of a high CAC score. It doesn’t erase it. If two people have the same CAC score, the more active one is at lower risk, but both are at higher risk than someone with a low score.

Physiologically speaking…

Taken together, here’s where I land.

Lifelong endurance athletes, at least middle-aged and older men, really do have more coronary plaque than their healthy peers, and “it’s just the stable kind” is too simple an explanation. Training load plays some role, very-vigorous intensity maybe more, but family history, blood pressure, smoking, age, and perhaps diet matter as much or more.

At the same time, athletes keep living longer and having less cardiovascular disease. The athlete’s heart is an adaptation, not a disease, and the rare bad outcomes seem to depend more on underlying vulnerability than on weekly training volume.

So, physiologically speaking, this means:

• The evidence still strongly favors a long, healthy life for people who like to push the limits now and then.

• Fitness lowers the risk that comes with plaque. It doesn’t make plaque go away.

• Treat blood pressure, lipids, and a high CAC score as seriously as anyone else would (exercise doesn’t protect you from adverse risk factors).

I think it’s best to be aware and cautious, but not alarmist. Even the highest levels of fitness don’t make you immune to disease, and that’s humbling. But in the words of Amby Burfoot, if endurance exercise really were deadly: “Show me the bodies in the street.”

I’ll keep following this research as long as I keep running, which I hope will be a very long time.

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 with the code HOLMER20 at checkout. 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.

References

1. Franklin BA, Thompson PD, Al-Zaiti SS, et al. Exercise-related acute cardiovascular events and potential deleterious adaptations following long-term exercise training: placing the risks into perspective–an update. A scientific statement from the American Heart Association. Circulation. 2020. doi:10.1161/CIRCULATIONAHA.119.044467

2. Aengevaeren VL, Mosterd A, Braber TL, et al. Relationship between lifelong exercise volume and coronary atherosclerosis in athletes. Circulation. 2017;136(2):138–148. doi:10.1161/CIRCULATIONAHA.117.027834

3. De Bosscher R, Dausin C, Claus P, et al. Lifelong endurance exercise and its relation with coronary atherosclerosis. European Heart Journal. 2023;44:2388–2399. doi:10.1093/eurheartj/ehad152

4. Aengevaeren VL, Mosterd A, Bakker EA, et al. Exercise volume versus intensity and the progression of coronary atherosclerosis in middle-aged and older athletes: findings from the MARC-2 study. Circulation. 2023;147(13):993–1003. doi:10.1161/CIRCULATIONAHA.122.061173

5. Vesterbekkmo EK, Aksetøy ILA, Follestad T, et al. High-intensity interval training induces beneficial effects on coronary atheromatous plaques: a randomized trial. European Journal of Preventive Cardiology. 2023;30(5):384–392.

6. Berge K, Janssen SLJE, Velthuis BK, Myhre PL, Mosterd A, Omland T, Eijsvogels TMH, Aengevaeren VL. Predictors of coronary atherosclerosis in middle-aged and older athletes: the MARC-2 study. Eur Heart J Cardiovasc Imaging. 2025;26(3):461–470. doi:10.1093/ehjci/jeae317

7. Janssen SLJE, van Everdingen WM, Saalmink WBJ, et al.; TREAT study collaboration. Relationship between exercise-induced cardiac troponin elevations and occult coronary atherosclerosis in middle-aged athletes. J Am Coll Cardiol. 2025;85(24):2370–2382. doi:10.1016/j.jacc.2025.04.047

8. Eijsvogels TMH, et al. Are there deleterious cardiac effects of acute and chronic endurance exercise? Physiol Rev. 2016;96:99–125.

9. Spencer LW, Flannery MD, Janssens K, et al. A race against time: timing constraints of cardiac filling and athletic performance. Am J Physiol Heart Circ Physiol. 2026;330(5):H1423–H1432. doi:10.1152/ajpheart.00896.2025

10. Lindsay MM, Dunn FG. Biochemical evidence of myocardial fibrosis in veteran endurance athletes. British Journal of Sports Medicine. 2007;41(7):447–452.

11. Javed W, Brown B, Chambers B, et al. The timing and relationship of ventricular arrhythmia with exercise patterns in veteran male endurance athletes. European Journal of Preventive Cardiology. 2026; zwag021. doi:10.1093/eurjpc/zwag021

12. Lee D, Pate RR, Lavie CJ, Sui X, Church TS, Blair SN. Leisure-time running reduces all-cause and cardiovascular mortality risk. JACC. 2014;64(5):472–481.

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.

As an endurance athlete, I find the concept of durability, also known as “physiological resilience,” fascinating.

Durability refers to when, and by how much, your physiological capabilities (e.g., running economy or lactate threshold) deteriorate during prolonged exercise. We spend months, sometimes years, improving our fitness, but we also need to think about what allows us to preserve it as exercise duration increases.

Carbohydrate availability appears to be part of that story. Three recent studies approach the question from different directions, and together they bring some clarity to why (I think) high-carb fueling works its magic.

But the results don’t line up that clearly!

To see why, we need to separate three things that often get treated as interchangeable.

• Carbohydrate intake is what you consume.

• Exogenous carbohydrate oxidation is how much of that incoming carbohydrate you burn for energy.

• Whole-body carbohydrate oxidation includes both incoming fuel and carbohydrate supplied by your body, including its glycogen stores.

Those distinctions sound technical, but they matter, because it means that a larger number on your fueling plan doesn’t automatically tell us how much fuel you’ll burn, how much glycogen you’ll spare, or even how well you’ll perform.

The first study, led by Ed Maunder and colleagues, began with the carbohydrate already inside the body. What happens to durability if you make athletes burn through that supply faster?

Eleven trained cyclists—eight men and three women—completed exercise tests when fresh and after two hours of cycling. They repeated those conditions with an unusual intervention: niacin combined with mild heating of their thighs. Niacin suppresses the release of fat from adipose tissue, reducing its availability as fuel for the body. Warming the muscles can accelerate glycogen breakdown. Together, the interventions increased estimated endogenous carbohydrate oxidation during the ride by about 19%.

The cyclists rode at the same intensity in both exercise conditions: 90% of their power at the first ventilatory threshold, or VT1. This is a breathing-based marker used to identify the transition from moderate to heavy exercise. They ate a carbohydrate-containing meal beforehand but drank only water during the rides.

After ordinary cycling, power at their ventilatory threshold fell by approximately 7%. When carbohydrate use was accelerated, it fell a further 7% relative to the ordinary exercise condition—roughly 13% below the fresh condition overall! Burning through more of their own carbohydrate roughly doubled the deterioration in this measure of durability.

The difference was attributed to a change in metabolic efficiency— how effectively the cyclists converted the energy they expended into power at the pedals. After ordinary cycling, efficiency improved, partly offsetting the reduction in threshold power. That improvement was absent when carbohydrate use was accelerated.

The authors proposed that greater glycogen depletion in slow-twitch muscle fibers might have forced the cyclists to recruit more of their less-efficient fast-twitch fibers.

On the other hand, critical power, the higher boundary between heavy and severe exercise, didn’t differ significantly between conditions. Here, it was estimated using a three-minute all-out test performed before and after the 2-hour ride. So the effect depended on which physiological capability the researchers examined (durability isn’t one single quality that every test captures equally well).

This experiment is useful because it tells us that accelerating the use of internal carbohydrates made one important physiological boundary less durable. What it doesn’t tell us is whether eating carbs would prevent that decline—or how much athletes need to eat.

For that, the next study gets closer to a decision…

Oscar Brogaard Mazza and colleagues studied 15 trained male cyclists and triathletes consuming either 60 or 100 grams of carbohydrate per hour during four hours of cycling with high-intensity intervals. They also ate a carbohydrate-rich diet for the preceding 24 hours—a “mini carb load,” if you will.

After the four-hour ride, participants completed a 15-minute time trial. The researchers compared that performance with a time trial completed when fresh.

Average power declined by 9.3% with 60 grams per hour and 6.4% with 100 grams per hour. The higher intake preserved an additional 9 watts, on average. So both conditions still produced a decline. More carbohydrate reduced the performance loss, but it didn’t eliminate it.

The more interesting result came from the muscle biopsies. Muscle glycogen declined substantially during both rides, with no detectable difference between the two intake conditions. The athletes performed better with more carbohydrate, but this wasn’t due to the fact that eating more carbs “spared” muscle glycogen.

Meanwhile, whole-body carbohydrate oxidation was better maintained with the higher intake, and blood glucose remained stable in both conditions.

That doesn’t make glycogen unimportant. But this study should make us more careful about the explanations we attach to a particular performance result. To say that “more carbs preserved more muscle glycogen” goes beyond what these data show.

There’s still one practical question that’s unanswered. This study compared 60 with 100 grams per hour. It didn’t establish whether 80 or 90 would have produced the same benefit, or whether pushing intake even higher would help even more.

The third study takes on that last question.

Henry Martyn and colleagues studied eight trained men using a protocol of three hours of cycling followed by an exercise-capacity test at 150% of their lactate threshold. That final test involved riding at a demanding fixed workload for as long as possible.

The first visit used 10 grams of carbohydrate per hour as familiarization. The subsequent trials tested 90, 120, and 150 grams per hour (that’s a LOT of carbs).

As intake increased from 90 to 120 to 150 grams per hour, average exogenous carbohydrate oxidation rose from 1.23 to 1.48 to 1.62 grams per minute. The athletes were burning more of the carbohydrate they consumed. Yet whole-body carbohydrate oxidation was identical at 120 and 150 grams per hour, and exercise capacity didn’t differ significantly among the three higher intakes.

The researchers estimated an optimal intake of 107 grams per hour. Use that information for what you will!

(I’ll plan to do a deeper dive into this study in a future newsletter… so stay tuned!)

In a discussion I had several months ago on a podcast, I mentioned how I currently think about carbs and performance—they won’t allow someone to run or ride faster than they are capable of (they’re not a “performance-enhancing drug”), but they will allow someone to realize their full potential.

In other words, adequate fueling lets you use the fitness you have built. It makes you more durable.

It pains me sometimes to think about all of the fitness I left on the table by not fueling (or hydrating) adequately. I’d reach the end of a long run or workout having not taken in any source of fuel the entire time. And while not completely ravaged, I certainly wasn’t performing as well (or as durably) as I could have. The more I’ve embraced fueling, the better and more enjoyable my training and racing have become.

I do think that high-carb fueling is the reason we are seeing athletes push the limits of performance across the board in the endurance sports world. And the crazy thing is… we don’t entirely know how. The familiar explanations such as sparing muscle glycogen and “burning more carbs” are incomplete. The studies I discussed today illustrate that idea clearly. So what’s going on?

There’s certainly a role of the brain and nervous system that we don’t yet fully understand. And I believe that this “central” component likely ties into the concept of durability. When the body senses that there’s adequate fuel available, it allows us to push our bodies for longer at a higher intensity.

So maybe everything just comes down to resilience.

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 with the code HOLMER20 at checkout. 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.

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.

Read more

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.

When I wake up and check my sleep score or overnight resting heart rate, it’s mostly out of curiosity. I don’t (usually) use it to inform how I’ll train, act, or feel today.

And I certainly don’t think an unusual change in any number is a reason to proactively visit the emergency room.

That’s likely true for most people who use a wearable device. It’s a dense source of information, not a diagnostic tool. Of course, there are some who obsess over the numbers to a fault (a term I’ve heard referred to as ‘orthometria’), treating high sleep scores as a badge of honor and low ones as a reason to avoid anything strenuous during the day.

A lot of this is due to the fact that currently, most of us just don’t know how to act on the data, or whether doing so improves our health or performance beyond a number on the screen. It has many questioning the utility of these devices, and others ditching them altogether and “going analog.”

I don’t think that’s the correct approach—there’s a lot of valuable information to be gleaned from the watches, rings, and bands some of us wear daily. Maybe it’s not information you or I can directly interpret and act upon, but it’s something that AI algorithms increasingly can. And for one man—the subject of today’s newsletter—the data told a meaningful (and unfortunately fatal) story.1

At 7:46 p.m. on March 21, 2025, the 76-year-old man finished a hard, 30-minute indoor cycling workout—his 530th recorded Peloton ride.

Three minutes later, his Apple Watch detected a fall.

His wife, who was a physician, heard the impact from another room. She found him unresponsive and without a pulse, began CPR, and used his watch to call for help. Despite 39 minutes of advanced cardiac life support and multiple defibrillation attempts, he died.

It’s a tragic story. But what makes the case scientifically intriguing is what happened before that evening.

His heart rate variability (HRV) fell by more than half, his resting and overnight heart rate increased, his deep sleep was cut by more than half, and an estimate of six-minute walking distance fell by 50 meters.

Most of these changes clustered four to six months before his death.

This was a retrospective case study involving one person, so it doesn’t show that wearables can predict sudden cardiac death. The authors explicitly say they cannot make that claim. But it does raise a fascinating question about whether the most useful information from a wearable isn’t a single “abnormal” number, but a body (and biometrics) that is gradually—and coherently—becoming different from its normal self.

After reading this one, you’ll either want to throw out your wearable device or invest in a second one. I’ll let you decide which.

Some important context—this wasn’t an otherwise healthy older man whose wearable data suddenly went haywire, and this wasn’t “death by Peloton.” He had a long history of heart problems, including an enlarged left ventricle, abnormal heart rhythms, valve disease, and evidence of an earlier heart attack.

He even had a cardiology appointment scheduled…

It would have occurred 11 days after his death.

So the wearable changes weren’t emerging from a healthy baseline. They were unfolding in a heart that was already vulnerable—which is essential context for everything that follows.

After his death, researchers integrated four unusually rich sources of long-term data, including approximately:

• seven years of medical records.

• seven years and 530 workouts from a Peloton bike.

• five years of Apple Watch data.

• two years of nightly Oura Ring data.

The densest overlapping period began in October 2023, when both the watch and ring were collecting continual data.

Of 39 wearable-derived signals, 30 showed a significant change point—a moment when the values shifted away from their previous pattern. But those changes didn’t occur randomly. Rather, they formed two distinct clusters.

The first appeared between April and July 2024, around the man’s hernia operation and six-week recovery. It primarily involved walking, physical activity, and sleep duration.

The second cluster looked different.

Beginning in late September and continuing through early December, signals spanning autonomic function, heart rate, sleep, respiration, and walking capacity shifted within a relatively narrow window. The researchers described it as an “abrupt, synchronized shift.” And unlike the post-surgery changes, several of these metrics never returned to their earlier baseline!

The clearest changes appeared in heart rate variability, or HRV, which measures the variation in the time between heartbeats. It’s influenced by the autonomic nervous system—the network that continually adjusts heart rate in response to sleep, stress, exercise, recovery, breathing, and disease.

(Side note: A single HRV reading isn’t especially informative. People have very different normal values, and even within one person, HRV can bounce around considerably from day to day, which is why I recommend most people don’t overthink this one.)

This guy’s pattern was harder to dismiss. Both of his devices recorded a large decline relative to his own baseline.

• Daytime HRV measured by the Apple Watch fell from 179 to 91 milliseconds.

• Nocturnal HRV measured by the Oura Ring fell from 180 to 63 milliseconds.

At roughly the same time, his resting heart rate increased from 44 to 49 beats per minute, and his average overnight heart rate rose from 50 to 53 beats per minute and continued climbing, averaging 55 beats per minute during the final 30 days of his life. So his heart was beating faster at rest but showing less beat-to-beat variation. That tells me something in his autonomic nervous system had shifted.

His sleep and physical function changed too.

• Estimated deep sleep fell from 39 to 18 minutes per night (a reduction of more than 50%).

• His Apple-Watch-estimated six-minute walk distance declined from 465 to 415 meters, along with a decline in “walking steadiness.”

• Overnight respiratory rate decreased from 15.4 to 14.7 breaths per minute, and blood oxygen saturation increased from 95.4% to 96.6% (the researchers acknowledged that neither of these changes has a straightforward interpretation as physiological deterioration).

While these signals were changing, the man dramatically increased his cycling.

During the final 79 days of his life, he completed 69 indoor cycling workouts, which was 20 more than the 59 he had completed during all of 2024. That included a 24-day streak with few rest days. Thirteen of those final rides ranked in the top 25% of all of his “hardest” workouts, and eight ranked in the top 10%! The final workout (the one that killed him) also ranked in his top 10% for intensity. It followed a moderate-intensity ride the previous day, which had itself followed an outdoor ride two days earlier.

Across those sessions, his typical heart-rate trajectory approached—and during longer rides exceeded—his age-based upper target of 128 beats per minute, and during several of his hardest workouts, his heart rate surpassed 140 beats per minute and even approached 150 beats per minute during his final ride. (For those keeping track, his predicted max heart rate would be ~144 based on his age of 76.) If true, these workouts were “near maximal” for him.

Pair an older man with heart disease and declining functional markers with an abrupt increase in training frequency and intensity, and the context of all of this seems to make sense, physiologically speaking. That final “nail in the coffin” workout may have acted as a trigger on top of an already vulnerable situation. Or maybe the timing was coincidental.

If your or my resting heart rate increases by 5 beats per minute from one day to the next, it probably doesn’t mean much.

But that isn’t what happened here.

The authors argue that the relevant question isn’t whether one HRV value falls inside a universal “normal” range. It’s whether someone’s physiology has “stepped away from its own baseline, coherently and durably.”

I think that may be the most important idea in the entire paper.

Wearables are particularly good at establishing personal baselines. Your normal resting heart rate may be different from mine. Your HRV may be dramatically different from mine. Comparing the two tells us very little. But if several of your metrics depart from their established ranges at the same time—and remain there—that may contain valuable information.

This is where the applications come in.

If I know my newsletter audience well enough, I think it’s safe to say that you have a wearable device (maybe several) that’s constantly tracking your biometric data.

Technology is at the point where it’s easy for these devices or AI to spot trends, departures from normal patterns, and extreme outliers in our data that warrant investigation. That’s especially true if you have years and years of data (sometimes, more is better).

This idea is similar to the “biological passport” used in elite athletics to detect doping or the use of performance-enhancing substances. If an athlete produces a result that falls way outside their baseline—whether that be a performance or a measure of their red blood cell count or testosterone level—it’s a red flag. It’s comparing apples (you) to apples (you)—not apples to oranges (me).

Most of us are wearing “biological passports” on our fingers and wrists.

While it’s tempting to read this paper as evidence that an Apple Watch and Oura Ring saw a cardiac death coming, they didn’t. The analysis was performed postmortem, after the outcome was known. Researchers could examine hundreds of days of data with the benefit of hindsight and identify where the most important changes occurred. There was no prospectively defined “alert.” No clinician was receiving these trajectories in real time, and no validated algorithm indicated that a dangerous event was approaching. Nor do we know if acting on the wearable data would have changed the outcome.

These data shouldn’t be treated as a do-it-yourself diagnostic system.

The paper’s authors call these continuously generated data “among the largest untapped inputs in cardiovascular medicine.” I think that’s right. But unlocking their value will require more than increasingly polished readiness scores. It will require systems that can identify sustained deviations from personal baselines, combine signals across physiological domains, incorporate symptoms and medical history, and present that information to clinicians in a usable form.

We’re getting close to this reality. In fact, my Oura ring’s “symptom radar” feature is precisely designed for that—identifying when things like my breathing rate, HRV, or body temperature deviate from my averages.

A single wearable value is easy to dismiss… and often should be! But if your sleep, resting heart rate, symptoms, and exercise response all begin telling the same story, the noise could start to become a signal.

Wearables are a double-edged sword. Harmful when they create anxiety, are treated as a diagnosis, or become your primary source of gauging how you feel (versus, you know, your own feelings).

But they’re an incredibly useful tool when used correctly. I think we’re still learning what “used correctly” means, but we’re getting 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 with the code HOLMER20 at checkout. 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!

I recently joined John Gay on The Shakeout Podcast to talk about performance supplements. Before long, we found ourselves revisiting a familiar villain known as lactate.

For decades, lactate was blamed for burning legs and muscle fatigue. Now the pendulum has swung in the other direction (as things tend to do in this space). Lactate is a fuel, …

Read more

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.

I studied exercise physiology for more than 10 years. During that time, I learned all about how the human body responds and adapts to activity.

But one area I found most fascinating was inactivity physiology—how the body responds when it doesn't get an appropriate stimulus, or when modern-day conditions make vigorous movement no longer a requisite part of day-to-day life for most people.

My favorite example of inactivity physiology in action is a classic experiment known as the Dallas Bedrest study.1

Researchers took five healthy men in their early 20s, measured their cardiovascular fitness in detail, then confined them to bed for 20 days before putting them through an endurance-training program. In less than three weeks of inactivity, VO₂ max fell by about 27%. That’s a remarkable loss of aerobic capacity over an extraordinarily short period.

The study became even more valuable when researchers brought the same men back decades later: after 30 years of aging, their absolute VO₂ max had declined by only about 11–12%, meaning the three weeks of bed rest had impaired aerobic capacity more than three decades of normal aging! Six months of endurance training at age 50 restored their VO₂ max to roughly their untrained level at age 20, although not to their youthful trained peak. By age 60, VO₂ max had fallen to about the same level observed immediately after the original bed-rest period.

This highlights both how rapidly disuse can erode fitness and how much of that capacity remains responsive to exercise even later in life.

What also stands out about this study is that the participants were healthy young men! Aging changes physiology in ways that make the body more susceptible to periods of inactivity, which is why illness, injury, and even extended periods without training can be devastating for an older adult (some scientists refer to these as “catabolic crises”—periods when muscle mass or aerobic fitness drop so precipitously that they never fully recover).

Thanks to the Dallas Bedrest study and other research spanning several decades, we have a good idea of how disuse affects muscle function and physical capacity, but we know less about how extreme inactivity affects mitochondria, the energy-producing “powerhouses” of the body.

What better way to do that than to use the most extreme form of inactivity—complete bed rest.

That’s what a new study did. I don’t envy the participants, but the results are eye-opening.2

The study included 10 healthy older men with an average age of 68.5 years and no major cardiovascular, metabolic, neuromuscular, or inflammatory conditions.

For 10 days, the men remained in bed, horizontal, and avoided activity involving muscle contraction. You heard that right… 10 full days in bed with zero activity. Sounds like my worst nightmare. All 10 men completed the study without reported adverse effects. Measurements previously collected from the same cohort confirmed meaningful disuse across the study period—quadriceps muscle volume decreased by 6.2%, vastus lateralis (a muscle in the thigh) thickness dropped by 7.4%, and muscle strength declined by 13.3%.

Ten days was enough to produce measurable muscle loss and functional impairments.

So what happened at the cellular level?

The first surprise was what didn’t happen.

The mitochondria consumed the same amount of oxygen while idling, while actively producing ATP, and when pushed to their maximum capacity. In other words, “mitochondrial function” was unchanged after 10 days of bed rest.

But there appeared to be fewer engines overall. Citrate synthase activity, a commonly used marker of mitochondrial content, decreased. Mitochondrial volume density also fell, meaning mitochondria occupied less space within the muscle fibers after bed rest.

When the researchers divided ATP-producing capacity by mitochondrial content, mitochondrial respiration actually appeared to increase relative to the estimated number of mitochondria. The remaining mitochondria seemed to be maintaining the workload of the larger population of mitochondria before bed rest!

But mitochondria do more than produce ATP. They also generate reactive oxygen species as a byproduct of moving electrons through the respiratory chain. In small amounts, these molecules act as useful signals. In excess, they can contribute to oxidative stress and damage cells, tissues, and even DNA.

After bed rest, the mitochondria released more reactive oxygen species. But the effect depended on the metabolic conditions. The problem appeared mainly when they were idling. When energy demand arrived, their normal ability to produce ATP—and avoid reactive oxygen species production—was preserved.

One obvious explanation for impaired mitochondrial function would be damage to the energy-producing machinery itself. The researchers didn’t find that.

The quantities of the protein machinery that moves electrons and produces ATP remained unchanged. So even though the mitochondrial population had become smaller, the measured energy-producing machinery within them had not yet noticeably deteriorated.

Mitochondria also constantly divide, fuse, and remodel themselves. After bed rest, the mitochondria appeared to become more permissive to a process known as fission (when one mitochondrion divides into two), but when researchers manually assessed more than 11,000 individual mitochondria, they found no change in the visible shape of the mitochondria (which they refer to as elongation, branching, or structural complexity). Other proteins involved in mitochondrial fission, fusion, and quality control also remained unchanged.

Some of the largest changes appeared at the level of gene expression.

After only 10 days, 3,217 genes were expressed differently than before bed rest. Seventy-six were strongly upregulated, 113 were strongly downregulated, and the rest changed more moderately.

Many genes involved in aerobic respiration, the electron transport chain, ATP production, mitochondrial protein assembly, fuel transport, and the citric-acid cycle (aka the Krebs cycle) were dialed down. Genes associated with glycolysis (sugar-burning) and cellular stress were among those dialed up.

What does all of this mean?

After just 10 days of bed rest, the muscle was already reducing the genetic instructions used to build and maintain mitochondria. But the respiratory proteins manufactured before bed rest were still present, and mitochondria were still functioning normally, for the most part. That’s a pretty strong indication that the brief—albeit extreme—period of inactivity put these men into what we can consider a “transition state” before the mitochondria have officially begun to shut down. These signals were the canary in the coal mine, so to speak, for the larger process of deconditioning that was yet to come (had they stayed in bed any longer).

I think this study underscores two important lessons about (extreme) inactivity.

The first is that changes happen fast. Anyone who has ever taken even a brief period away from their usual exercise or training schedule has probably felt this. Getting out of shape is much easier than getting into (or back into) it. It’s a cruel reality of physiology. A bed rest study is the most extreme example of an off-season, but it’s a vivid reminder that, physiologically speaking, “use it or lose it” is very, very real.

The second lesson is the more promising one—the human body is incredibly resilient and adaptable. One result of the Dallas Bedrest study that I omitted was that, after the initial 3 weeks of bed rest, the participants completed eight weeks of intensive endurance training, during which their average VO₂ max rose by about 45% from the post-bed-rest value and roughly 18% above their original baseline! The deconditioning they experienced during bed rest was entirely reversible.

The current study illustrates this adaptability—the mitochondria appeared to become more efficient in some ways during bed rest, even in the context of some broader, adverse changes. It seems to me that over a short enough time, even extreme inactivity isn’t enough to cause irreparable damage or dysfunction, at least at the fundamental level of the body’s energy-producing factories.

Now for the practical part.

Of course, the obvious lesson here is to avoid a situation that requires you to lie in a bed for a week or more. But life happens—we get sick, we undergo a major surgery, or we’re injured in a way that prohibits us from weight-bearing activity (I’ve been there). Should we panic when this happens? No. But we should be aware of the consequences and think about the before and after, should such a scenario occur.

It’s a great argument for “prehab”—keeping your fitness and muscle mass as high as possible going into any extended period of inactivity as a “buffer” against deconditioning. This is easy if the inactivity is planned, harder if it’s not. So yes—I am saying you should just stay in good shape year-round.

It’s also a reason to have a post-inactivity strategy for regaining fitness. An intensive 6–8 weeks of resistance or aerobic training is probably enough to reverse any damage done during extended downtime. Emphasis on intensive.

If I ever encounter a situation where I’m confined to a bed for 10 days, please pray for me and those around me.

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.

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.

Energy balance is central to almost everything.

For most athletes trying to perform optimally, the goal is generally to be around energy balance, or perhaps even in a slight energy surplus during periods of heavy training, or “bulking… the phase I’m currently in. ;)

The basic idea is simple—you want enough energy coming in to maintain your body weight, preserve strength, support recovery, and, quite literally, have enough energy to train.

This is actually a pretty personal topic for me because energy intake is something I’ve thought about for most of my athletic career, and something I struggled with, especially when I was younger.

About a decade ago, I went through a period of chronic injury that included multiple bone stress injuries. After two or three of these in the span of just a few years, I decided I needed to figure out what was going on.

The pattern was frustratingly consistent. I would recover, gradually start running again, build my training back up, and then sustain another bone stress injury. Eventually, I had blood work done and got a DEXA scan to assess my bone mineral density. Without going into all of the results, they weren’t particularly encouraging. For someone my age and sex, my bone mineral density was quite low.

Of course, I had never had a DEXA scan before, so I had no baseline for comparison. Maybe my bone density had always been relatively low. But it forced me to think much more seriously about how I had been fueling (or, more accurately, underfueling).

A few years earlier, an injury had forced me to take roughly four to six months away from running. During that period, I ate poorly in the sense that I simply wasn’t eating enough, and I also wasn’t doing much resistance training. Looking back, I think that period may have been a major turning point. I likely lost muscle, strength, and potentially bone mass at the same time. When I eventually returned to running, I was probably starting from a somewhat vulnerable place. And I think that chronic underfueling was probably part of the problem.

Importantly, that underfueling wasn’t even occurring during a period of massive training volume. It was happening while I was injured!

Fortunately, this is something I’ve gotten much better at managing over the years through smarter training progression, better control of overall training load, more resistance training, and, quite simply, eating more and eating better.

But I’m certainly not the only endurance athlete who has struggled with this.

In sports science, chronic underfueling is often discussed within the framework of relative energy deficiency in sport, or RED-S. It’s the idea that an athlete’s energy intake is insufficient relative to the energy required to support both exercise and normal physiological function.

But over the past several years, an interesting question has emerged within endurance sports:

Is underfueling purely an energy problem—or can it also be a carbohydrate problem?

Those two things obviously overlap, but carbohydrates have received particular attention because their role extends well beyond simply providing fuel for hard exercise. Carbohydrate availability can influence training quality, glycogen stores, endocrine signaling, immune function, and the cellular response to exercise. And something I’ve become especially interested in over the past few years is the relationship between carbohydrate availability and bone metabolism.

So, what happens if an athlete is technically eating enough calories to maintain energy balance, but carbohydrate availability is still very low?

Could carbohydrate restriction alone—independent of an overall calorie deficit—alter hormones, bone remodeling, or the physiological adaptations to endurance training? Mechanistically, that idea isn’t particularly far-fetched. Carbohydrate availability is one of the signals the body uses to sense the energetic demands of exercise and regulate the response to training.

And a new study set out to test exactly this question.1

The researchers separated energy availability from carbohydrate availability, asking whether restricting carbohydrate could produce some of the physiological consequences we normally associate with underfueling, even when total energy intake was adequate.

The results have some important practical implications for endurance athletes.

So let’s dig in.

The researchers recruited eight healthy, endurance-trained men. They were 27 years old, on average, exercised at least three times per week, and had an average VO₂ max of 54. Fit, but not elite.

Every participant completed two dietary conditions lasting 4 days each:

• A normal-carbohydrate diet containing 62% carbohydrate, 19% fat, and 19% protein

• A low-carbohydrate, high-fat diet containing 12% carbohydrate, 69% fat, and 19% protein

The diets were matched for total calories and protein. Participants consumed approximately 3,925 calories and 186 grams of protein per day in both conditions. That means the difference was almost entirely a swap between carbohydrate and fat: carbohydrate intake fell from 607 to 117 grams per day, while fat increased from 84 to 301 grams per day in the low-carbohydrate condition.

The researchers also controlled exercise energy expenditure. Every morning, the men completed a cycling session at approximately 63% of VO₂max until they had expended 15 calories per kilogram of fat-free mass—about 983 calories per session, which took 87–89 minutes. Combined with an energy intake of 60 calories per kilogram of fat-free mass, this maintained energy availability at 45 calories per kilogram of fat-free mass per day. That design was the point. The researchers created a substantial carbohydrate shortage without simultaneously imposing low energy availability.

During the normal-carbohydrate condition, daily carbohydrate availability—the amount consumed minus the amount estimated to have been burned during exercise—remained between 433 and 446 grams per day. During the low-carbohydrate condition, it began at −52 grams per day and increased to only 15 grams per day by day 3. A negative value doesn’t mean the athletes had “negative carbohydrates” in their bodies (that’s not physiologically possible), but it means they burned more carbohydrate during exercise than they consumed that day and had to draw on stored glycogen to make up the difference.

• By day 2, participants burned an estimated 172 fewer grams of carbohydrate and 67 more grams of fat per day at rest during the low-carb condition compared with the normal condition, and on day 4, they were still burning 133 fewer grams of carbohydrate and 54 more grams of fat each day. So we know that metabolism shifted in the expected direction.

• That happened at rest, but also during exercise, where blood glucose and lactate were lower in the low-carb condition, while perceived effort was higher at every workload above 50 watts.

• Furthermore, cycling efficiency improved across the normal-carbohydrate condition but not the low-carbohydrate condition.

In just 4 days, low-carb essentially made exercise “harder.” (This isn’t breaking news. Anyone familiar with this space is probably aware of the dismal data on the keto diet for exercise performance).

Despite this large metabolic shift, the broad endocrine disruption typically associated with low energy availability didn’t appear. Insulin, testosterone, triiodothyronine (T3, or active thyroid), leptin, hepcidin (a marker of iron homeostasis), and erythropoietin (EPO) were not altered by the low-carbohydrate diet. Resting metabolic rate was also unchanged.

On the other hand, IGF-1 (a marker of anabolic or growth signaling) tended to drop during the low-carb condition while rising during the normal condition.

The bone markers told a more selective story. And here is where I think the study provides some especially valuable information.

A marker of bone formation known as procollagen type 1 N-terminal propeptide (or P1NP) was unchanged in both conditions, but beta-CTX, a marker released during bone resorption or bone breakdown, increased during low-carb availability.

Let me be clear: this does not mean that the athletes lost measurable bone in four days. Beta-CTX is a circulating marker of bone breakdown, not a scan of bone density. But it suggests that bone resorption responds rapidly to carbohydrate restriction even when calories remain adequate and the broader endocrine environment looks relatively stable. What that looks like over several weeks to months is another question entirely. But it’s enough to warrant our attention.

Lastly, the researchers analyzed the muscle proteome, essentially taking an inventory of which proteins became more or less abundant. A total of 57 responded differently between the two diets. Thirty proteins increased during low-carb availability and decreased during the normal diet. These were concentrated in pathways related to fatty-acid uptake, lipid-droplet handling, cellular transport, calcium signaling, and several components of mitochondrial energy production. The remaining 27 moved in the opposite direction. Many were proteins involved in translating genetic instructions into new proteins. Others were associated with the muscle’s contractile machinery and extracellular matrix.

Simply put, the muscle appeared to reorganize itself around greater fat handling while reducing parts of the machinery involved in protein production and muscle structure. But this wasn’t the sweeping increase in mitochondrial proteins the researchers expected. In fact, their initial hypothesis was that carbohydrate restriction would cause a drastic increase in the body’s oxidative (i.e., “fat-burning”) machinery. But that didn’t happen, and their reasoning is that this type of training response might, in fact, require an energy deficit, not just a carbohydrate deficit.

So, does low carbohydrate availability produce the same physiological state as low energy availability?

Not exactly.

Adequate energy availability appears to protect against many of the classic endocrine responses to underfueling. In this study—albeit over a very short time frame—the body didn’t enter the broad state of “hormonal conservation” we often associate with RED-S or low-energy availability. But the two diets still weren’t physiologically interchangeable, as we saw through the negative impact of low carbohydrate availability on bone breakdown markers and IGF-1.

Adequate calories may have kept the lights on, but they didn’t prevent every tissue from sensing that something was… missing.

To me, that’s the most interesting finding.

There are some important reasons not to take these results too far. They don’t prove that every low-carbohydrate training session is harmful. Nor does it tell us that athletes need to be “carbmaxxing” every hour of every day.

What it does show is that calories alone don’t tell us whether an athlete is optimally fueled for the work they’re doing.

There may still be situations in which temporarily training with lower glycogen availability is useful. The idea behind “train low” is that exposing muscle to exercise while carbohydrate availability is reduced may amplify certain cellular signals involved in endurance adaptation. Evidence supports its effectiveness when used strategically.

This study complicates that argument a bit, because (as the authors suggest), low glycogen alone may not be enough to produce the full adaptive response observed when athletes train with both low carbohydrate availability and an acute energy deficit.

That being said, intentionally adding an energy deficit brings its own obvious trade-offs—especially if repeated frequently. That makes carbohydrate periodization a much better framework than chronic carbohydrate restriction. The idea behind this strategy is that carbohydrate intake can rise and fall with training demand—more around long sessions, high-intensity workouts, races, and heavy training blocks, and potentially less when the workload and need for rapid recovery are lower.

But if you have a history of bone stress injuries (like me), low bone mineral density, or chronic underfueling risk, I’d be especially reluctant to treat carbohydrate restriction as a harmless shortcut to greater fat oxidation. Increasing fat burning is easy to measure. Whether the tradeoff is worthwhile is a much bigger question, and one I constantly wrestle with myself.

Looking back at my own history, I still think inadequate total energy intake was probably the biggest nutritional problem. But this study adds another layer to how I think about fueling.

Eating enough total energy is the foundation, without which every system involved in health, recovery, and performance can begin to suffer.

But “enough calories” and “adequately fueled” aren’t always synonymous.

I can consume sufficient energy on paper while still providing too little carbohydrate for the volume and intensity of training I’m asking my body to absorb. The consequences may not immediately appear in body weight, resting metabolism, or the hormones commonly measured in blood work. They may begin more quietly in things like bone turnover, glycogen availability, and the molecular signals governing how muscle repairs and adapts.

A study in just 8 young men might not be a strong enough data point to alter your dietary or fueling practices. But these early, interesting signals are, I think, the starting point for informing better protocols for health and performance.

I hope that it didn’t take you too much energy to finish this article. If it did, maybe it’s time to replenish those glycogen stores.

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.

Timing is an aspect of health I’ve been thinking about for a while. And it’s probably the area of my life where I’ve “experimented” the most in regard to performance, sleep, and day-to-day productivity.

We spend a lot of time debating what to eat, how much to exercise, and how many hours to sleep. These are important questions. But the more I read and wr…

Read more

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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