I’m incredibly excited to share this video with you for this week’s edition of the newsletter.

I sat down with Dr. Latt Mansor of Ketone-IQ to dive deep into a brand-new study in cyclists showing that taking ketones after exercise enhances beneficial blood vessel responses and increases EPO production during recovery.1 I’ve provided the study abstract and summary below, but we get into all the details in the video.

What excites me so much about this study is that they used Ketone-IQ (rather than ketone esters, which have dominated the research to date). It’s the ketone supplement I’ve been using for my own training, so seeing these effects validated in the research is huge.

Full disclosure… I’m part of the science advisory board at Ketone-IQ, and I’m an affiliate for their products, but it’s for a good reason. They have become the brand I trust, and their team is dedicated to advancing the science of ketones.

Try some for yourself: Unlock sharper focus and support long-term brain health and exercise recovery with Ketone-IQ — Get 30% off your subscription.

My training is built around consistency. Most days, that means running. But the equipment in this garage lets me add low-impact aerobic work, strength training, uphill treadmill sessions, easy spins, warm-ups, and recovery workouts without needing to leave the house.

A few of the main pieces I cover in this video include:

• FEIERDUN DB1 adjustable dumbbells

• YOSUDA EM1 long-stride magnetic elliptical

• Feier TM1 fully folding treadmill

• Concept2 RowErg

• Zwift Ride Smart Frame paired with a Wahoo KICKR CORE trainer

Huge shoutout to Jason Rodriguez for filming this content and creating an incredible video. You can find Jason on Instagram @ctxsmedia.

Equipment featured

FEIERDUN DB1 Quick Adjustable Dumbbells

Find them here: https://www.fedfitness.com/products/quick-adjustable-dumbbell-52-5lbs

These have probably been my favorite addition to the gym. As a distance runner, upper-body strength is something I can easily neglect, and having adjustable dumbbells makes it much easier to get in quick, consistent strength work.

The DB1 dumbbells go up to 52.5 pounds each and adjust in 2.5-pound increments, which gives me plenty of flexibility for curls, presses, push-ups, accessory work, and short strength sessions throughout the day. The big advantage is convenience: instead of needing a full rack of dumbbells, I can quickly adjust the weight and move from one exercise to the next.

YOSUDA EM1 Long-Stride Magnetic Elliptical

Find it here: https://www.fedfitness.com/products/long-stride-magnetic-elliptical-machine

I’ve never been a huge elliptical person, but this one has become a useful tool for low-impact cardio days. It’s smooth, compact, and easy to use when I want aerobic work without adding more running impact.

I’ve been using it about once a week, especially when I want something different from the bike. It has multiple resistance levels, Bluetooth/app connectivity, and a compact footprint, which makes it a good fit for a garage gym or smaller home gym setup.

Feier TM1 Fully Folding Treadmill

Find it here: https://www.fedfitness.com/products/fully-folding-treadmill

The treadmill has become a daily-use tool for me. I use it for uphill strides, controlled intervals, easy runs, shakeout runs, and bad-weather training days.

It goes up to 11.2 mph and 12% incline, which gives it a wide enough range for many of the treadmill sessions I like to do. One of my favorite uses is putting on a weighted vest, cranking up the incline, and doing uphill walking when I want a harder low-impact session. I’ve also been impressed by the softness of the ride, the traction of the belt, and the fact that it folds up when not in use.

Concept2 RowErg

The Concept2 rower is one of my daily warm-up tools. I often use it for 90 seconds to three minutes before a run to get the upper body, lower body, and cardiovascular system moving before I head out the door.

It’s simple, durable, and effective, and for me, it’s less about doing long rowing workouts and more about using it as a quick full-body primer before training.

Zwift Ride Smart Frame + Wahoo KICKR CORE

Get it here: https://us.zwift.com/products/zwift-ride-kickr-core-2

The Zwift setup is probably the biggest overall game-changer for my training as a runner. I use it almost every day, sometimes twice per day, mostly for easy aerobic riding and additional low-impact training volume.

Cross-training has become a major part of how I build fitness while staying healthy. The bike lets me add five to ten extra hours of aerobic work per week without the impact of running. Most of my rides are easy spins, but I’ll also use it for intervals about once a week.

The electronic shifting, Zwift integration, and TV setup make the experience much more enjoyable. I’m not just staring at a wall—I can ride Zwift, watch something, listen to a podcast, or use it as an easy way to loosen up after a hard run.

Why I built a home gym

The biggest reason I built this setup is convenience. I’m using something in this gym almost every day. Some days it’s the treadmill. Some days it’s the bike. Some days it’s the dumbbells. Some days it’s just a short row before a run.

I think the key pieces for anyone are equipment that supports what you already do: strength training, low-impact aerobic work, controlled treadmill running, and recovery-friendly movement. You don’t need everything at once, but it helps to think about what would let you train consistently even when the weather is bad, life is busy, or you don’t feel like driving to the gym.

For me, the essentials are:

• A way to strength train

• A treadmill for controlled running

• A low-impact cross-training option

• A space that feels enjoyable enough to actually use every day

The next step for this garage gym is making it feel a little more homey, and eventually, I’d love to add a sauna. But for now, this setup gives me almost everything I need for marathon training, strength, longevity, and general fitness.

Disclosure: FED Fitness sent me several of the products featured in this video to test and review.

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.

If you want to perform well in any endurance sport (whether you run, ride, swim, row, ski, hike, race triathlons… or simply train for health and longevity), you need a big aerobic engine, the ability to hold a high fraction of that engine, and the efficiency to turn oxygen into forward motion.

These are more commonly referred to as VO2 max, fractional utilization, and movement economy. And for a long time, they’ve made up the “holy trinity” of endurance sports.

But this classic endurance model isn’t perfect.

Two athletes can have similar lab values and look nearly identical early in a workout or race. Then, somewhere after an hour or so of hard effort, repeated surges, heat, hills, fueling mistakes, muscle damage, or plain old accumulated fatigue start to separate them. One athlete keeps rolling. The other starts fading (in physiology, morale, or both).

That difference is what sports scientists are increasingly trying to describe with a new set of terms: durability, fatigability, repeatability, and resilience.

They sound similar, but they’re not, and this week’s study by Benedikt Meixner, Michael Joyner, and Billy Sperlich does a great job at defining them and laying out what they mean for endurance sports (I’ll try to do the same as it applies to everyday athletes, too).1

It’s not a traditional experiment. It’s a viewpoint article, which means the authors are not testing a new training intervention or reporting a new dataset. Instead, they are trying to clean up the language around these emerging concepts. And honestly, it matters a lot. Because a lot of people are using words like durability, fatigue resistance, resilience, and repeatability almost interchangeably. Coaches use them. Researchers use them. Athletes use them. I’ve probably done it too. But these terms do not all mean the same thing. And if we want to measure them, train them, and actually apply them to performance, we need to be more precise.

That is the central idea of this paper. The classic endurance model is still foundational, but it may be incomplete unless we also account for how athletes respond when exercise gets long and unpredictable.

Durability

Durability is probably one of the most important concepts for anyone doing endurance exercise.

A durable athlete does not just have a good lactate threshold in the lab. They still have a strong threshold after 90 or 120 minutes of exercise, their heart rate does not drift wildly upward at the same pace or power, their mechanics do not collapse, and their fuel use does not become inefficient.

Durability captures the idea that your fitness on paper is not always the same as your fitness after you have already done a lot of work (it’s why I often recommend people give some extra thought to their “predicted marathon pace”).

The authors point to several mechanisms that may contribute to durability, including cardiovascular drift, neuromuscular fatigue, metabolic shifts, carbohydrate depletion, and changes in economy or critical power. They also note that durability can be assessed by looking at physiological drift during prolonged exercise or by testing performance markers before and after a long endurance effort.

I think durability is one of the missing links between being fit and being able to execute the event or workout you trained for.

Fatigability

Fatigability is related to durability, but it is not the same.

This concept is especially obvious in cycling, where athletes may need to respond to surges, climbs, attacks, and stochastic power demands. But it applies across endurance sports too, and even Hyrox competition is probably a fantastic example where “fatigability” emerges as an important attribute.

An athlete with high fatigability might look great early but lose output rapidly as the session or race continues. Their power, pace, mechanics, coordination, or perceived effort starts to deteriorate quickly. An athlete with low fatigability can absorb the work and keep producing.

The key difference from durability is that fatigability often involves variable or repeated intensity while recovery is limited. Durability is more about preserving physiological function over prolonged steady or semi-steady exercise. Fatigability is more about how quickly someone cracks as the workload accumulates.

Repeatability

Repeatability is the ability to recover and reproduce high-intensity performance across multiple bouts, stages, heats, or efforts.

An athlete can be durable but not very repeatable. They may grind well for a long, steady effort but struggle when asked to produce repeated surges or high-intensity bouts. Another athlete may have excellent repeatability in short efforts but lack the durability to hold performance deep into a long event.

Repeatability depends on recovery kinetics. That’s how quickly heart rate, lactate, neuromuscular function, metabolic processes, and fuel availability rebound between efforts. The paper notes that this trait appears trainable and may improve with maturation and accumulated training experience. Training consistently over time fixes everything. Well, not everything… but it fixes a lot.

Resilience

Resilience is the broadest and perhaps most slippery concept.

A resilient athlete can adapt when the day gets ugly. They can manage heat, adjust pacing, fuel when the gut is unhappy, and absorb mental fatigue without a total performance collapse.

This trait matters for almost everyone who trains. A hot day, a missed water bottle, poor sleep, travel stress, a chaotic schedule, or an unusually demanding load at work or family life can expose whether fitness is robust or fragile.

This is not just a psychological trait either. Resilience has physiological roots, including our ability to regulate body temperature, hydration, sleep, cognition, and neuromuscular function.

That is important because I think many of us often moralize fatigue. When we fall apart, we assume we were weak or “soft.” Sometimes effort and mindset matter, of course. But often the body is dealing with a complex set of stressors that were not prepared for.

Resilience can be trained, but it requires specificity. Heat acclimation helps with heat. Long sessions help with prolonged fatigue. Fueling practice helps with gut tolerance. Strength training may help protect mechanics and muscular function. Sleep and recovery help preserve the systems that keep you adaptable.

Although I’d like to think there is some “cross-adaptation” that happens, too.

It’s important to note that the paper argues that these constructs should not be treated as interchangeable names for “good at not getting tired.” They are different capacities, with different mechanisms and different relevance depending on the event or goal.

That might be hard to see at first (I had to re-read these definitions several times), but physiologically speaking, the concepts become intuitive when you place them in the context of your own athletic domain. That exercise can also be useful for identifying your weaknesses (we all have one or two) and training them accordingly.

I’ll volunteer mine:

I am extremely durable. I can run forever. And if you tested me before and after a 2-hour run, I could likely produce similar values on a VO2 max or lactate threshold test. I’m also very repeatable—my efforts often get better as a workout goes on (if I get sufficient recovery), not worse.

But I am NOT resilient. Throw a wrench in my plans and introduce an unexpected variable, and I’m likely to psych myself out or crumble a bit under the unpredictability. So that’s something to work on…

None of this means we throw out VO2 max, lactate threshold, or economy. Those are still the foundation of a well-rounded performer.

But I think the next frontier in endurance performance may be understanding not just how high your ceiling is, but how much of that ceiling you can still access when the going gets tough.

That is what durability, fatigability, repeatability, and resilience are trying to describe.

The lesson for us all is simple: don’t just train to be strong when fresh. Train to remain yourself when tired. And that, I think, applies to much more than just athletics!

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.

Here’s my “favorite social post of the week". Maybe it’s the fact that the algorithm is feeding me more of this guy’s content, but Dr. Sean OMara seems to one-up himself every day with a more ridiculous take on health. Here, he claims that “fruit ages you” despite mounds of evidence that it probably does exactly the opposite (it’s loaded with nutrients, fiber, and other stuff that’s beneficial for health).

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.

The world of comparative physiology has always fascinated me. How do humans stack up against other animals when it comes to our ability to function and adapt at the cellular or structural level?

One of my favorite examples is the heart.

A shrew’s heart can beat more than 1,000 times per minute. At that rate, the entire cardiac cycle (the squeeze, the relaxation, the refill, and the next squeeze) happens in about 60 milliseconds.

A blue whale lives at the other end of mammalian physiology. Its heart rate can drop to just 2 to 8 beats per minute, giving each heartbeat somewhere between 7.5 and 30 seconds to unfold.

This incredible contrast reveals one of the most important constraints in cardiovascular physiology: the heart is always racing against time. Let me explain.

Every beat has to accomplish two things. First, the heart has to fill with blood. Then, it has to eject that blood into circulation. When heart rate is low, there is plenty of time for both. When heart rate rises during exercise, the cardiac cycle shortens. The body needs more blood flow, so the heart beats faster. But the faster it beats, the less time it has to fill.

That presents somewhat of a paradox. To exercise harder, our heart has to pump more blood per minute. But to pump more blood per minute, it often has to beat faster. And the faster it beats, the less time it has to fill the ventricles (our heart’s largest chambers) before the next contraction.

This is where the endurance athlete’s heart becomes so interesting.

Elite endurance athletes are often bradycardic, meaning they have unusually low resting heart rates. In my case, my overnight resting heart rate is often around 33 beats per minute, which is deep in the “athlete’s heart” range.

“Athlete’s heart” refers to the structural and functional remodeling that occurs in response to long-term endurance training. It is not a disease. It is usually a physiological adaptation to repeated exposure to high cardiac output demands (e.g., chronic endurance training).

During endurance exercise, cardiac output can increase dramatically. Cardiac output is the amount of blood the heart pumps per minute, and it is determined by two things: heart rate (how often the heart beats) × stroke volume (how much blood the heart ejects per beat).

Most people think about exercise intensity through the lens of heart rate. But endurance performance is not just about beating faster. In fact, endurance athletes often have lower heart rates at rest, lower heart rates at the same absolute workload, and sometimes slightly lower maximal heart rates than non-athletes.

Their major advantage is stroke volume.

With chronic endurance training, the heart adapts to move more blood per beat. The left ventricle often becomes larger and more compliant, meaning it can accommodate more blood. The heart also becomes better at relaxing quickly between beats, a property called lusitropy.

This matters because diastole (the filling phase) is not passive in the simplistic sense. The heart does not just flop open and wait for blood. It actively relaxes. That relaxation creates a pressure gradient that helps pull blood into the ventricle. Then, late in the relaxation phase, the atrium contributes an additional push.

So for an endurance athlete, the heart is not simply bigger. It is better timed. It can fill more and eject more. And during exercise, when the cardiac cycle is getting squeezed into smaller and smaller windows of time, it can preserve performance by moving blood faster through each phase of the heartbeat.

That brings us to the central question of a new study: how do endurance athletes maintain larger stroke volumes during exercise when rising heart rate progressively steals away the time available for the heart to fill with blood?1

The results show us that a low resting heart rate may not just be a marker of fitness. It may represent a built-in timing advantage. A slower heart rate gives the ventricle more time to fill. And in endurance athletes, that extra time is paired with a bigger, more compliant, more powerful pump.

The researchers studied 32 people: 21 endurance athletes and 11 controls.

The athlete group included cyclists and runners primarily, with a few athletes from other endurance or highly trained sporting backgrounds. The control group exercised less than three hours per week and had no long-term history of competitive endurance sport. The groups were similar in age, sex distribution, and resting blood pressure. But as expected, they were very different physiologically. The athletes had a VO₂ peak of 56.2 mL/kg/min compared with 33.1 mL/kg/min in controls. They also produced much higher peak power on the exercise test: 394 watts versus 251 watts. So we’re definitely looking at two “levels” of performers here (important).

Participants exercised on a cycle ergometer at 20%, 40%, and 60% of their peak power output (representing light, moderate, and high-intensity exercise, respectively) while researchers measured heart rate, stroke volume, cardiac output, left ventricular ejection time, diastolic filling time, and something called the systolic-to-diastolic duration ratio.

That last variable is important, so let’s break it down. Systole is the ejection phase, when the left ventricle contracts and sends blood into the aorta. Diastole is the filling phase, when the ventricle relaxes and refills before the next beat.

At low heart rates, diastole takes up most of the cardiac cycle. This is good for filling. But as heart rate rises, diastole shortens much more dramatically than systole. Eventually, the heart starts “running out” of filling time.

The researchers also calculated systolic and diastolic flow rates. Plainly speaking, what we’re looking at here is how fast the athlete’s heart can empty, and how fast it can refill.

At rest, the athletes showed the classic features of athlete’s heart.

• Their resting heart rate was much lower than controls: 44 vs. 68 beats per minute.

• Their left ventricular end-diastolic volume index was much larger: 98 vs. 65 mL/m².

• Their left atrial volume index was also larger: 47 vs. 31 mL/m².

That means the athletes had bigger filling chambers.

But the heart was not just bigger. It also showed signs of enhanced diastolic filling and appeared to “front-load” filling. The ventricle relaxes well, fills efficiently early in diastole, and does not need to depend as heavily on a forceful atrial push at rest. The athletes also had a longer cardiac cycle, a longer diastolic (filling) period, and a longer ejection time compared to controls. In other words, the athlete’s heart had more time for everything. More time to fill. More time to eject. More time to operate.

That is the benefit of a low resting heart rate!

The problem during exercise

In both athletes and controls, exercise dramatically shortened the cardiac cycle. But the athletes handled the timing constraint differently.

At high-intensity exercise, the athletes were working at a much higher absolute workload: 226 watts compared with 145 watts in controls. Despite this, their heart rate was lower: 133 vs. 147 beats per minute.

That lower exercise heart rate gave the athletes slightly more time per beat—they had a longer total cardiac cycle, a longer filling phase, but a similar ejection time. By high-intensity exercise, the difference between athletes and controls was mainly on the filling side. The athletes preserved a little more diastolic time while also moving a much larger stroke volume.

The systolic-to-diastolic (S/D) ratio gives us a way to visualize the shifting balance between ejection time and filling time.

At rest, both groups spent more time in diastole (filling) than systole (ejection). During exercise, the S/D ratio increased in both groups. This is expected. As heart rate rises, diastole shortens disproportionately, so systole occupies a larger fraction of the cardiac cycle. But at high-intensity exercise, the athletes maintained a lower S/D ratio than controls: 0.82 vs. 1.00.

That means the controls had reached a point where systolic time and diastolic time were roughly equal. The athletes, despite doing more mechanical work, still preserved a more favorable balance toward diastolic filling. This may be one reason endurance athletes can sustain high stroke volumes at high heart rates. They are not simply forcing the heart to beat faster. They are preserving enough filling time while also increasing the velocity of filling and ejection.

But the new insight from this study was how athletes maintained those stroke volumes under severe timing constraints.

At rest, systolic and diastolic flow rates were similar between athletes and controls. But during exercise, the athletes pulled away. At high-intensity exercise, systolic flow rate was significantly higher in athletes. Diastolic flow rate was also higher during moderate exercise, though by the highest exercise stage, the groups were closer together. From rest to high-intensity exercise, systolic flow rate increased by 89% in athletes compared with 63% in controls. Diastolic flow rate increased even more dramatically: 400% in athletes and 370% in controls.

That last number is wild. During exercise, the heart has to fill with approximately the same volume it ejects, but it has to do it in a dramatically shorter time window. The only way to make that work is to increase filling velocity. This is where the athlete’s heart appears to excel. It has a larger ventricle, better filling characteristics, and the ability to generate high flow rates to fill the ventricle with more blood before the next ejection phase (don’t you just love physiology?)

Stroke volume and cardiac output

The athletes had higher stroke volume indexes at every stage (rest and low-, moderate-, and high-intensity exercise). That higher stroke volume translated into higher cardiac output during exercise.

At rest, cardiac output was identical between groups: 5.8 L/min in both athletes and controls. This is one of the elegant features of endurance adaptation. The athlete’s resting cardiac output is not necessarily higher because the low heart rate offsets the larger stroke volume. Fewer beats, more blood per beat, similar flow per minute.

But during high-intensity exercise, the athlete advantage became obvious. Cardiac output reached 17.3 L/min in athletes compared with 14.4 L/min in controls. The athletes were pumping more blood per minute, producing more power, and sustaining larger stroke volumes despite having less and less time to fill the heart with each beat.

This is one of the central physiological advantages of endurance training.

Why do athletes have lower maximal heart rates?

One interesting observation was that athletes had a slightly lower maximal heart rate than controls: 171 vs. 179 beats per minute, which is consistent with prior research suggesting endurance training can slightly reduce maximal heart rate.

Why would an endurance athlete benefit from a lower peak heart rate? The answer may be that heart rate is only helpful as long as filling is preserved.

At some point, increasing heart rate further may not increase cardiac output because the ventricle has too little time to fill. For a highly trained endurance athlete with a large ventricle and high stroke volume, the constraint may not be whether the heart can beat faster. The constraint may be whether the heart can fill fast enough. A slightly lower maximal heart rate may preserve diastolic filling time just enough to maintain a large stroke volume. In that model, the athlete’s heart is not underperforming by beating slightly slower. It may actually be optimizing the balance between rate and filling.

Thoughts on overtraining and suppressed heart rate

The most intriguing application for athletes may be overtraining, overreaching, and the sometimes confusing observation that heart rate can become suppressed when an athlete is fatigued.

Many endurance athletes (myself included) have experienced this. You go out for a workout expecting to hit a normal high-end heart rate, but your body will not get there. The usual explanation is autonomic fatigue, altered sympathetic drive, or reduced cardiac responsiveness. Those explanations may still be true. But this study adds another possible layer.

If the fatigued heart has impaired relaxation, it may not be able to fill as quickly. If filling rate is compromised, then pushing heart rate higher could further reduce diastolic filling time and threaten stroke volume. In that situation, a suppressed heart rate response might be “protective.” The system may be limiting heart rate to preserve enough time for the ventricle to fill.

That idea is speculative, but it makes sense, physiologically speaking.

During normal training adaptation, the athlete’s heart becomes better at filling quickly and ejecting powerfully. During excessive fatigue, the opposite may occur temporarily: filling dynamics may be impaired, stroke volume may be harder to maintain, and the heart may avoid higher rates because the time cost is too great.

So, while a low resting heart rate can be a sign of endurance adaptation, a suppressed exercise heart rate during a workout can be a sign of fatigue.

This study paints an awesome picture of how every heartbeat is a negotiation between filling and ejection. Between the need to move more blood and the need to allow enough time for the ventricle to refill.

The athlete’s heart wins that race not by ignoring the clock, but by adapting to it.

Hopefully, you found this exploration interesting, even though the usual “practical applications” aren’t there. When a study like this catches my eye, I can’t help but write about it. Because even if there’s not a clear takeaway, I think that when we learn the physiology of how our bodies work, we can intuit more about our own health and performance. Which is perhaps the biggest practical application of them all.

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.

This week, I wanted to share some of my favorite studies from the endurance sports world that I’ve been excited about. All of these summaries were published in my other newsletter, ‘Run Long, Run Healthy’, where I explore the science of running (mostly) and summarize the latest research in the world of endurance.

I promise you’ll find these studies useful whether you’re a runner or not! Here’s what you’ll learn:

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.

Do Super Shoes Make You Faster While Increasing Injury Risk?

Super shoes have become one of the strangest training decisions in running. On the one hand, they are clearly fast. The combination of highly resilient foam, tall midsoles, and stiff embedded plates can improve running economy and make race pace feel just a little more forgiving. On the other hand, almost every runner now has a story: the friend who started doing workouts in plated shoes and suddenly had calf issues, foot pain, or a bone stress injury that seemed to come out of nowhere.

That does not mean super shoes are dangerous. But it does raise the question of when these shoes do change how we run, where does that stress go?

A new study looked at exactly that question in elite distance runners. The researchers had 23 healthy elite runners, 11 women and 12 men, run in three different shoe conditions: a neutral shoe, a lightweight responsive foam shoe, and an advanced footwear technology shoe with highly cushioned foam and a stiff embedded plate. The runners tested each shoe in randomized order at three self-selected speeds: training effort, tempo effort, and 5K race pace. During each condition, the researchers measured movement and force patterns that have previously been associated with bone stress injuries.

In the advanced footwear condition, runners showed a lower cadence, meaning they took fewer steps per minute. Lower cadence often goes along with longer strides or slight overstriding, which can increase loading demands on the body over time. The researchers also found more inward collapse of the arch/rearfoot compared with the neutral shoe, another mechanical pattern that has been linked with bone stress injury risk. These changes were described as small, but small changes repeated thousands of times per run can matter when an athlete is stacking workouts, long runs, and high weekly mileage.

But there was also a potentially protective signal. In the super shoes, runners pushed off less with their ankles. That suggests the shoe may reduce demand on the ankle plantarflexors, including the calf-Achilles complex, during propulsion.

This is the part that makes the interpretation more complicated. Super shoes may not simply increase or decrease injury risk; they may redistribute load. Less ankle demand could be helpful for some runners, while altered cadence and greater rearfoot motion could shift stress elsewhere, including toward the bones of the foot or lower leg.

What this means

If you race in plated shoes, you probably need some exposure to them in training so race day does not become a brand-new mechanical stimulus. But I would be cautious about making them your everyday trainer, especially during high-volume blocks or when returning from injury.

Rotate shoes, introduce plated models gradually, and pay attention to early warning signs in the foot, shin, calf, and Achilles. The key idea is that super shoes may help you run faster by changing how load is distributed, but your bones, tendons, and muscles still need time to adapt to that new loading pattern.

Female Runners are More Durable than Males

Most runners think about fitness in terms of what they can do when they’re fresh. What’s your VO2 max? What’s your threshold pace? What can you run for a 5K, half-marathon, or uphill time trial when the legs are ready to go?

But racing rarely asks that question. Racing asks a much more interesting one—what can you still do after two or three hours of accumulated fatigue?

That’s the idea behind “durability” (a.k.a “physiological resilience”), one of the more useful concepts in endurance performance right now. It’s not just how strong your engine is at the start. It’s how much of that engine you can keep using after glycogen drops, muscles get beat up, stride mechanics shift, and perceived effort starts climbing. A new study asked whether male and female runners differ in that quality.

Researchers studied 11 highly trained female trail runners and 11 highly trained male trail runners who were matched by performance level using International Trail Running Association rankings. The runners completed three lab visits: a graded exercise test, a fresh 12-minute uphill time trial, and then a 3-hour treadmill run at moderate intensity with another 12-minute uphill time trial inserted every 60 minutes. During the prolonged run, the athletes consumed 90 grams of carbohydrate per hour and drank water as desired, while the researchers measured physiology, biomechanics, perceived exertion, and the strength of muscles in the thigh and surrounding the knee.

The women held up better. After three hours, female runners had only a 1.1% decline in uphill time-trial speed, while male runners slowed by 9.9%. That is a massive difference in durability. This was not because the women were working less hard in the time trials; heart rate, perceived effort, and peak oxygen uptake during the time trials were broadly similar in how they responded across the protocol. Instead, the difference seemed to come from greater metabolic and neuromuscular resilience.

During the 3-hour steady-state run, both groups shifted toward greater fat use over time, but the shift was much larger in men. By three hours, carbohydrate oxidation had dropped by 29% in male runners versus only 9% in female runners. Respiratory exchange ratio also fell more in men, suggesting a bigger move away from carbohydrate metabolism. During the repeated uphill time trials, the same pattern showed up again: men had larger drops in carbohydrate oxidation, larger increases in fat oxidation, and bigger reductions in peak blood lactate.

That lactate finding is important. In a hard uphill effort, peak lactate is partly a sign that the runner can still access high-intensity carbohydrate-driven energy production. By the final time trial, male runners showed a 53% drop in peak lactate, compared with a 27% drop in females. That suggests the men were losing some ability to hit the same high-intensity metabolic gear as fatigue accumulated.

Muscle strength also declined more in men, with males showing an 18% reduction after two hours, while females were essentially unchanged at that time point. Meanwhile, running economy worsened similarly between sexes, and both groups made fatigue-related biomechanical adjustments: longer ground contact time, reduced stride length, and lower leg stiffness. In other words, the durability advantage in women did not seem to come from some radically different stride pattern. It looked more like better preservation of the metabolic and muscular systems that support performance late in a long effort.

There is one big caveat: the study matched runners by duration, not distance. Because the men ran faster, they covered more total distance during the protocol: about 26 miles versus 22 miles for women. They also expended more energy relative to body mass. The researchers tried to account for this statistically, and the findings largely held up, but this still matters. If the study had matched distance instead of time, the gap might have been smaller.

What this means

The practical takeaway is that durability deserves more attention than fresh fitness.

A runner with a great threshold test or fast standalone workout may not be the runner who performs best after two or three hours, especially on hilly terrain. For everyone, one of the best ways to assess durability may be to place short, controlled hard efforts late in long runs and see how much performance, form, and perceived effort deteriorate. The race is not decided by what your physiology looks like when you’re fresh; it’s decided by what’s still available when the easy miles are behind you.

Does a Post-Run Cold Plunge Block Training Benefits?

Ice baths have one of the best reputations in endurance sports and one of the messiest evidence bases. They feel like recovery. They look like recovery. But there’s always been a bigger question of whether they’re actually helping adaptation, or just making you feel like you’re recovering better?

To answer this question, a new study looked at what is happening inside the muscle after five weeks of interval training plus regular cold-water immersion.

The researchers recruited 16 healthy young men and split them into two groups. Both groups completed the same five-week high-intensity interval training (HIIT) program on a treadmill: three sessions per week of 2-minute intervals at 95% of the runner’s speed at VO2 max, progressing from 5 to 8 reps before tapering down at the end. One group did 11 minutes of cold-water immersion at about 52℉/11°C immediately after each session, while the control group just sat passively at room temperature. Before training, after week 4, and again after week 5, the researchers measured VO2 max, maximal aerobic speed, and time to exhaustion in a run at a constant speed. They also took samples of the runners’ muscles to look at satellite cells, markers of mitochondrial growth, and inflammatory markers.

The main finding was that the ice baths did not meaningfully change anything that mattered. Both groups improved over time, and they improved to a similar extent.

• VO2 max went up.

• Speed at VO2 max went up.

• Time to exhaustion improved.

On the muscle side, satellite cell content increased, and a marker of mitochondrial growth known as PGC-1α also rose, which is what you’d hope to see with a solid block of interval training. But none of those changes were different between the cold-water immersion group and the control group. The inflammatory markers in muscle also did not meaningfully shift with cold-water immersion. The training worked, and the post-workout ice baths neither boosted nor blunted the main endurance adaptations they measured.

What this means

If you use cold-water immersion after hard workouts because it helps you feel fresher, less sore, or more mentally ready for the next session, this study suggests that habit probably is not harming your endurance adaptations.

But it also probably is not giving you a secret fitness edge. That makes ice baths more of a recovery management tool than a performance-enhancing one. I would view them as optional, context-dependent, and most useful during heavy training blocks, races with short turnarounds, or periods where soreness is interfering with consistency.

The bigger levers are still the obvious ones: good training, enough easy running, enough fuel, enough sleep, and recovery practices you can actually stick with.

What Elite Ethiopian Runners Can Teach Us About Training Blocks

There’s always something fascinating about studies on elite East African runners, partly because we’re trying to understand athletes who are already operating near the ceiling of human endurance performance.

A new study asked what happens when elite distance runners move through sequential blocks of endurance, strength, and speed training?

Instead of treating these training types as competing philosophies, the researchers looked at how each block contributed to different pieces of performance. Twenty elite Ethiopian male middle- and long-distance runners completed three six-week training blocks in a fixed order: endurance training first, then strength training, then speed training. There were two-week periods of normal mixed training between blocks. Testing was done before and after each phase, including estimated VO₂max, resting heart rate, running economy, blood markers like hemoglobin and hematocrit, 400-meter speed, a 5,.000-meter time trial, and a 12-minute Cooper test. The athletes trained and tested at altitude, roughly 2,400–2,700 meters (which reflects their normal environment).

The endurance block looked like classic aerobic development: high-volume continuous running, progressing toward about 75 miles/120 kilometers per week, mostly at moderate aerobic intensity. This phase produced the biggest aerobic and hematological changes.

• Estimated VO₂max increased by about 6.2 ml/kg/min

• Resting heart rate dropped by nearly 4 beats per minute

• Hematocrit increased by 4.35 percentage points

• Red blood cell count rose

• Hemoglobin increased modestly.

• Performance improved too: the Cooper test increased by 236 meters, and 5,000-meter time improved by about 18 seconds.

The strength block included circuit-style bodyweight strength work and hill sprints, which makes it more specific to running than a generic resistance program.

• This block produced the largest improvement in running economy, with oxygen cost falling by 4.2%.

• It also improved 400-meter speed by 1.21 seconds and shaved another 6 seconds from the 5,000-meter time trial.

• VO₂max and most hematological markers did not change much during this phase, suggesting the main benefit was neuromuscular: better force production, better coordination, and possibly improved stiffness or elastic return.

The speed block used long intervals from 1,000 to 1,600 meters and shorter intervals from 200 to 800 meters, with intensity ranging from about 95% to 110% of estimated VO₂max.

• This phase improved 400-meter speed by another second and 5,000-meter time by 9 seconds, with only a small increase in estimated VO₂max.

What this means for runners

Runners should stop thinking of endurance, strength, and speed as separate camps and start thinking about how they fit together across a training cycle.

For most runners, the sequence makes intuitive sense: use an endurance-focused phase to build aerobic capacity and durability, add strength and hills to improve economy and force production, then layer in faster intervals to sharpen race-specific speed. The biggest mistake would be copying the exact training of 13-minute 5K runners; the better lesson is the structure. Even elite athletes improved when training stress became more targeted and sequential. For recreational and competitive runners, that might mean spending several weeks emphasizing aerobic volume, then keeping the mileage stable while adding strength and hill work, and finally shifting toward faster intervals as race day approaches.

Why “Feelings” Outperform Complex Training Load Metrics

Runners are drowning in load metrics right now. Training load, recovery score, acute load, chronic load, biomechanical stress, heart-rate strain. The promise is that if you track enough of them, you’ll finally understand what your training is really costing you. But a new paper asks whether these metrics even agree with each other in the first place?

Researchers took 12 experienced recreational runners and had them complete three different outdoor runs: a 45-minute steady endurance run, a 5k submaximal effort, and a 5 x 1000-meter interval session with 2 minutes of rest between reps. The runners wore heart-rate monitors and special units that could measure their biomechanics on the pelvis and lower legs, and they also gave a rating of perceived exertion (RPE) after each workout. From that, the researchers calculated three different load measures: session RPE, heart-rate-based training impulse (TRIMP), and a biomechanical load score based on estimated peak ground reaction forces summed across the run. The biomechanical metric was not just counting steps or distance. It was trying to estimate how much cumulative loading the body experienced by weighing higher-impact steps more heavily (no pun intended).

Session RPE clearly separated the workouts in a way that makes intuitive sense. The endurance run felt easier, while the 5k and interval sessions felt harder. Average session RPE was about 112 for the endurance run, 188 for the interval session, and 194 for the 5k effort.

But TRIMP did not significantly distinguish the sessions. Neither did the biomechanical load metric. That is the heart of the paper. The runners felt a clear difference between session types, but the objective metrics did not really reflect that difference, at least not in a clean way. TRIMP averaged about 85 for the endurance run, 95 for intervals, and 94 for the 5k. Weighted cumulative load was also fairly similar across sessions. So, depending on which metric you looked at, these workouts either looked meaningfully different or basically the same.

The correlations tell a similar story. Session RPE and TRIMP had a moderate relationship (heart rate and perceived effort lined up somewhat), but biomechanical load seemed to be capturing something else entirely, or maybe not capturing load very well in this setup.

What this means

You should be very cautious about handing too much authority to any single load number on your watch.

Heart-rate load, biomechanical load, and perceived effort are not the same thing, and this study suggests they may diverge quite a bit depending on the session. I think that is a strong argument for keeping subjective feedback in the loop, even if you love data. How hard the run felt still matters. In practice, the best monitoring system is probably a simple combination of session type, duration, pace, heart rate, and (honest) session RPE, rather than chasing one supposedly all-knowing metric. The body is more complicated than that, and your training log should reflect it.

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.

Endurance performance comes down to three things: VO₂ max, threshold, and economy.

VO₂ max is your aerobic ceiling. Threshold is how much of that ceiling you can use and sustain. Economy is how much oxygen it costs you to produce a given pace or power output.

This framework is often associated with Dr. Michael Joyner’s classic 1991 model of marathon performance, which estimated the limits of human endurance based on these three physiological determinants. Since then, the model has become one of the foundational ways scientists, coaches, and endurance geeks like me think about performance across sports like running, cycling, triathlon, cross-country skiing, and other long-duration events.

The “problem” with the model is that it’s never been used to answer this question: if you take a large group of real endurance athletes, ranging from recreationally trained people to world-class performers, how much does each factor actually matter? What separates “good” from “great”?

A new study in Sports Medicine tried to answer that question with a huge dataset of 888 endurance athletes, including 495 runners and 393 cyclists. The researchers examined how VO₂ max, exercise economy, and fractional utilization of VO₂ max related to endurance performance.1

They wanted to know which physiological traits best explain why some athletes can sustain faster speeds or higher power outputs than others.

The answer? VO₂ max still matters a lot. Economy matters a lot too. But fractional utilization, the percentage of VO₂ max you can sustain at threshold, may not be as useful for separating higher- and lower-performing athletes as we often assume.

The classic endurance model

Dr. Michael Joyner’s model is elegant because it reduces endurance performance to three big pieces (I like to think of them as “pillars” of endurance performance).

First, there is VO₂ max, the maximum amount of oxygen your body can take in, deliver, and use during intense exercise. A bigger aerobic engine gives you more room to work with. This matters not only for performance, but also for health, because VO₂ max reflects the integrated function of the heart, lungs, blood, blood vessels, mitochondria, and working muscles.

Second, there is fractional utilization of VO₂ max. This is the percentage of your VO₂ max you can sustain at a key threshold. Two athletes might both have a VO₂ max of 60 ml/kg/min, but if one can sustain work near threshold at 85% of VO₂ max and the other can only sustain 75%, that changes the performance equation.

Third, there is exercise economy. For running, this is the oxygen cost of running at a given speed. For cycling, it is the oxygen cost of producing a given power output. More broadly, economy is how much energy it costs your body to perform a specific endurance task. A more economical athlete uses less oxygen at the same pace or power (they’re more efficient).

Together, these three factors can be used to estimate the speed or power an athlete can sustain at lactate threshold or lactate turnpoint—an intensity that’s close to “marathon pace.” Lactate threshold was defined in this study as the first rise in blood lactate above baseline, while lactate turnpoint represented a more rapid and sustained increase in lactate. The researchers used speed at these points for runners and power at these points for cyclists as performance proxies.

So this study did not directly test race outcomes, finishing times, or real-world competition results. It tested physiological markers that are strongly related to endurance performance.

The study included 495 runners (105 of whom were female) and 393 cyclists (42 of whom were female). The participants ranged widely in ability, from recreational athletes to world-class performers.

Everyone completed lab-based incremental exercise testing. For runners, the test was performed on a treadmill. They ran in four-minute stages, with short rests for blood lactate sampling, while researchers measured oxygen uptake and ventilation. After the submaximal test, participants rested for 15–20 minutes and then completed a separate test to exhaustion to determine VO₂ max.

For cyclists, the protocol was similar but performed on a smart trainer or cycle ergometer. They completed four-minute stages with increasing power, blood lactate sampling, and gas exchange measurements, followed by a ramp test to exhaustion.

From these tests, the researchers calculated VO₂ max, exercise economy, fractional utilization at lactate threshold and lactate turnpoint, and speed or power at those thresholds.

They then asked two big questions.

First, how strongly does each physiological trait relate to threshold speed or power (our “performance proxy”)?

Second, how much does each trait contribute to the overall prediction of these performance proxies?

VO₂ max is still the heavyweight

VO₂ max was the strongest predictor of performance proxies in both runners and cyclists.

That means when you look across a broad range of endurance athletes, the people with bigger aerobic engines tend to perform better. There are exceptions, of course, and exceptions are often the most interesting cases. But at the population level, VO₂ max remains the physiological variable that most clearly separates lower-performing from higher-performing endurance athletes.

VO₂ max is not destiny, but it is still one of the biggest determinants of endurance potential.

The key nuance is that VO₂ max becomes less useful when you compare athletes who are already very similar. If you take a group of elite endurance athletes with VO₂ max values clustered in a narrow range, economy, durability, fueling, biomechanics, tactics, heat tolerance, and threshold characteristics may explain more of the difference. But if you compare recreational athletes, competitive amateurs, sub-elites, and elites together, VO₂ max is going to do a lot of explanatory work, and that’s exactly what happened here.

The second big contributor was exercise economy.

Lastly, fractional utilization of VO₂ max—the percentage of VO₂ max used at lactate threshold or lactate turnpoint—contributed far less to performance differences than VO₂ max or economy.

That does not mean threshold does not matter. It absolutely does.

But it does suggest that when you look across a broad range of endurance athletes, fractional utilization is not very good at distinguishing who is better. A recreational athlete with a relatively low VO₂ max might operate at a high percentage of that VO₂ max at threshold. Meanwhile, a better-trained athlete with a much higher VO₂ max might have a similar or even lower fractional utilization but still produce a much higher absolute output because the engine is so much larger.

Here’s a simple way to think about it.

Athlete A has a VO₂ max of 45 and can sustain 85% of it.

Athlete B has a VO₂ max of 65 and can sustain 78% of it.

Athlete A may look better if you only focus on fractional utilization. But Athlete B is almost certainly producing more work because 78% of a much larger engine is still a bigger absolute output.

Similar performance can come from different physiological profiles

If we could accurately predict who wins a race by just looking at, say, VO₂ max, then it wouldn’t be much fun, would it?

Not every endurance athlete needs the same physiology. In fact, similar performances can be achieved with very different combinations of VO₂ max, economy, and fractional utilization.

This is one of the reasons endurance performance is so fascinating. There is not one perfect physiological profile. Some athletes are engine monsters. Some are economy freaks. Some have exceptional threshold characteristics. Some are durable and barely fade. Some are biomechanically gifted. Some are unusually efficient in a specific sport. Some are just really, really good at doing the work for a very long time.

The Joyner model gives us the major ingredients, but athletes can combine those ingredients in different ways.

The paper gives a great historical example of this idea using Frank Shorter and Steve Prefontaine (two legendary American distance runners).

On paper, their race performances over 5,000 and 10,000 meters were remarkably similar. Shorter ran 13:26.6 for 5K and 27:45.9 for 10K, while Prefontaine ran 13:21.9 and 27:43.6. That’s essentially the same performance neighborhood. But physiologically, they were not identical athletes. Prefontaine reportedly had a much higher VO₂ max (84.4 ml/kg/min) compared with Shorter’s 71.3 ml/kg/min.

That difference is enormous. If we only looked at VO₂ max, we might assume Prefontaine should have been far superior. But the stopwatch says otherwise. Shorter was able to arrive at almost the same performance outcome with a smaller aerobic engine, which implies that other factors (likely economy, fractional utilization, durability, pacing skill, biomechanics, and race execution) helped close the gap. Pre just had a monster engine.

This is also a useful reminder for everyday athletes. You may never know your exact VO₂ max, economy, or lactate profile, and you probably don’t need to obsess over any single number. It’s better to ask: “What is my current limiter?”

Some athletes need to build the engine. Others need to become more economical. Others need to improve fatigue resistance, fueling, or race execution.

This is an incredibly foundational study, in my opinion. And its biggest strength is the sample size.

A lot of endurance physiology studies include 10, 15, or 20 participants. This study included 888 athletes.

The study also included both runners and cyclists, both males and females, and athletes ranging from recreational to world-class. That makes the findings more useful than studies limited to a tiny group of homogeneous athletes.

The main limitation is that this study did not directly measure race performance. It used speed or power at lactate threshold and lactate turnpoint as performance proxies.

Those are meaningful proxies, but real-world performance is messier. Competition is not just a lab test stretched over a longer time period. Actual endurance performance includes pacing, fueling, heat, terrain, equipment, tactics, muscle damage, psychology, and durability.

Durability may actually be the biggest missing piece here.

The classic Joyner model focuses on VO₂ max, fractional utilization, and economy, but endurance performance is increasingly being understood through a fourth lens: how well these variables hold up under fatigue. An athlete’s economy when fresh is useful. Their economy two, three, or four hours into an event may be more important (for more on durability, see my previous post on it).

Two athletes may have identical VO₂ max, threshold, and economy in the lab, but one may maintain those traits after prolonged work while the other deteriorates. That is performance durability, and it may help explain why some athletes are much better competitors than their lab values suggest. And honestly, I think it’s the variable that still gives much of endurance sports its mystique.

How should we apply this paper to training and health?

Let’s stop treating VO₂ max, threshold, and economy as competing explanations and start seeing them as interacting pieces of the same performance and health puzzle.

If you are newer to endurance training or still developing aerobically, raising VO₂ max and building a bigger aerobic engine probably matters a lot, which means consistent training volume, aerobic development, intervals, long sessions, and long-term exposure are foundational.

As you become more trained, economy, threshold, and durability likely become increasingly important. They are what’s going to move you from “good” to “great” within your current performance capabilities.

The best endurance programs probably touch all three determinants across a season: build the engine, make the engine more efficient, and then teach the body to sustain a high output when fatigue sets in.

This study is a nice reminder that endurance performance is both simple and complicated.

The simple version is that better endurance athletes usually have a bigger aerobic engine and better economy. That was true 35 years ago, and it is still true now. Dr. Joyner’s model still holds up.

The complicated version is that athletes can arrive at similar performances through different physiological routes, and the best athletes often have several of these traits stacked together, but the combination is not identical for everyone.

For anyone interested in improving their endurance performance, the art is figuring out which part of the puzzle needs the most attention right now.

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.

“The best time to exercise is the time that works for you.”

At the most basic level, I agree with this statement. Exercise is good for you, no matter when you do it.

But if we look a little deeper into the biology of it, theoretically, there should be a time of day—one that’s unique to each of us—that produces the most robust response to a workout, and therefore the greatest health, fitness, or performance benefit.

It all has to do with circadian biology.

Much of this is determined by your chronotype—the biological predisposition to be a “morning person” or a “night person.” This isn’t just about when you like to go to bed or wake up. Your chronotype literally influences when you prefer to engage in physical activity, your motivation to do so, and, perhaps more importantly, when you perform your best.

This suggests that personalizing exercise to one’s chronotype could optimize its benefits, whether by improving blood pressure, glucose regulation, or VO₂ max. It also suggests that, unfortunately, “night owls” forced to exercise in the morning (or “early birds” forced into a late-night workout) due to work schedules and society’s structure might be blunting their physiological adaptations.

There is biological plausibility here. The concept is clean and easy to understand. And according to a new study, there may be some genuine merit to the idea that exercise works better when it’s aligned with your internal biological rhythm.1

The study included 134 adults who had at least one cardiovascular risk factor, such as high blood pressure, overweight or obesity, impaired fasting glucose, low physical activity, or a family history of cardiovascular disease. So they were at risk for cardiovascular disease, but didn’t actually have a clinical diagnosis of it.

The participants were classified using a validated questionnaire as either a morning or an evening chronotype. Then they were assigned to one of two groups:

• A chronotype-aligned group that trained at their preferred biological time—morning types trained in the morning, and evening types trained in the evening.

• A chronotype-misaligned group that trained at the opposite time—morning types exercised in the evening, and evening types exercised in the morning.

Everyone performed the same training: 40 minutes of moderate-intensity aerobic exercise, at 60–70% of max heart rate, five times per week for 12 weeks.

Both groups improved, as you would expect, but the participants in the chronotype-aligned exercise group improved more… much more in fact. For most outcomes, the improvements were roughly twice as large in the group that exercised at a time aligned with their chronotype:

• Their systolic and diastolic blood pressure dropped by 11 mmHg and 7 mmHg, respectively, versus drops of about 6 mmHg and 3 mmHg in the misaligned group.

• Their estimated VO₂ peak increased by 4.4 mL/kg/min, versus a 2.3 mL/kg/min improvement in the misaligned group, and they also lasted longer on a treadmill test: +4.3 minutes versus +1.5 minutes.

• Their HRV improved by 12.7 ms, versus a 5.8 ms improvement in the misaligned group.

• Their LDL cholesterol dropped by 13.7 mg/dL, versus a 7.6 mg/dL drop in the misaligned group.

• Their fasting glucose decreased by 6.6 mg/dL, versus a 3.2 mg/dL drop in the misaligned group.

• Their body weight decreased by about 1.6 kg, versus a 0.8-kg drop in the misaligned group.

• Their sleep quality improved by 3.4 points, versus a 1.2-point improvement in the misaligned group.

There was one finding (though exploratory) that I found interesting. All of the participants—regardless of whether they were a morning or evening chronotype—experienced improvements in blood pressure, HRV, aerobic fitness, and other risk factors. However, the magnitude of improvement generally appeared to be larger in morning chronotypes compared to evening chronotypes, regardless of whether they were in the aligned or misaligned group. What that implies, I’m not quite sure.

I have probably read and/or written about dozens of studies at this point investigating whether the time of day at which exercise is performed is important. The results of most of these studies have been pretty unequivocal—it doesn’t matter. Exercising in the morning or evening generally produces similar health and performance outcomes.

But after reading this study, I realize that the research has been asking the wrong question.

It’s not “night vs. day.” It’s biological alignment versus not.

Many of these studies failed to account for chronotype. In other words, they were isolating time of day as a variable without taking into account individual biological variation.

When we do that, it turns out that timing does make a difference.

Does this mean you should reorganize your workout routine to sync with your biological clock?

Most likely, you’re already doing this out of pragmatism. With at least some control over our daily schedules, most of us have chosen to work out when it’s most enjoyable. For some, that means early in the morning before the workday. For others, that means late-afternoon exercise after leaving the office.

The good news from this study is that even when exercise isn’t performed at our biological “sweet spot,” it’s still beneficial.

On the other hand, I think there is a strong case that if you do have the freedom to choose when to exercise, doing so at a time that aligns with your chronotype is smart. Chronotype-aligned exercise produced roughly twice the improvement as misaligned exercise in this study. That meant larger gains in aerobic fitness, larger reductions in blood pressure and other cardiovascular risk factors, and even a greater reduction in body weight. And that was when participants did the exact same exercise. If you told me I could get twice the benefit from my workout just by shifting when I performed it, I’d take that deal.

These findings can also apply more broadly. All of us should probably be thinking about when we schedule our tasks and obligations during the day so that they align with when our alertness, mood, and performance peak. I know myself well enough to never plan on doing deep or creative work after about 4 PM. And if I want to be at my best for a podcast, I know that scheduling it for late morning, immediately after my workout, is when I’m giving the best performance.

Circadian biology has been one of my favorite topics for a while. I think that’s because it takes health and makes it more granular.

It’s not just about what we do, but when we do it. Biology thrives when we’re aligned.

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).

Initially, I figured it would be a good rehab tool and a bridge between walking and returning to run. But now, even though I’m back to running full force, I don’t go a day without walking with either the 20- or 30- lb plate on my back. Why not?

Much of this was inspired by Michael Easter, author of the amazing Substack Two Percent and too many other awesome books to name. So… I decided to pick his brain on whether “rucking” or walking with weight could have benefits for runners and athletes (the answer is yes, but you’ll need to listen to learn why and how).

I really enjoyed this one. You will too.

Newsletter partners you should check out…

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.

I’ve run a few marathons in my life (4 to be exact). One thing that’s consistent after each one is the debilitating muscle soreness that often lingers for up to a week.

Another is that my brain typically feels like mush for a few days. I get the “runner’s high” like anyone else (especially after a personal best), but when it comes to any high-level thinking… consider me useless.

There’s probably a good explanation for that.

A few months ago, I wrote about a study showing temporary reductions in brain myelin content after marathon running. Myelin is the fat-rich insulation around axons in the brain that helps neural signals travel efficiently. So if you hear “myelin reduction,” your mind may immediately go to neurological disease or damage. But the prior study suggested that this reflected a reversible change after extreme endurance exercise, with recovery over time (levels normalized after about a month). What I found most interesting about the study was the mechanism.

During prolonged endurance exercise, the body (and brain) gradually shifts toward greater reliance on fat as carbohydrate availability becomes more constrained. We understand that shift reasonably well in skeletal muscle. We understand it less well in the brain, which is usually thought of as a glucose-hungry organ, but it is not metabolically static. Under certain conditions, it can use alternative fuels, and the support cells around neurons may play an important role in helping neural circuits keep functioning when energy demand is high. The possibility raised by this line of research is that myelin is more metabolically flexible than we used to assume.

When the brain runs low on glucose in the latter stages of a marathon, myelin might provide energy-rich lipids as an “alternative” fuel source. Hence, myelin levels dropped post-race in the group of runners.

Well, the authors of that study just published a follow-up paper that asks (at least I think) a more interesting question: If myelin changes after a marathon, does brain function change too?1

The answer is not as simple as “yes” or “no.” The researchers found that basic neural signal transmission appeared preserved, while some higher-order cognitive functions showed temporary changes after the race. Let’s take a deeper look.

The study focused on two main questions.

First, the researchers wanted to know whether neural signal transmission was preserved after marathon running. Since myelin helps determine how quickly signals travel through the nervous system, the most direct concern would be slower conduction. If a marathon meaningfully disrupted myelin function, you might expect motor, sensory, visual, or auditory pathways to show impairments.

Second, the researchers wanted to know whether cognitive performance changed after the race. They tested specific domains, including processing speed, interference control, visuomotor speed, attention, and executive flexibility.

I like this design because it separates basic neural transmission from higher-order cognition. Those are related, but they are not the same. The nervous system can preserve basic signaling while still showing temporary changes in more demanding cognitive tasks.

It turns out that distinction ends up being central to the study!

The participants were healthy adults divided into a marathon-running group and a non-running control group. The runners were recruited from official marathon or ultramarathon events and regularly engaged in endurance training. The control group came from the same general population, was matched as closely as possible for age and sex, and did not complete endurance events during the study period. Overall, the cognitive testing sample included 43 marathon runners and 29 controls. The neurophysiology portion (measuring conduction speeds) was much smaller, with only three runners, so I would treat that part as preliminary and proof-of-concept rather than definitive.

Participants were tested before the race, within 48 hours after finishing, and again one month later. Controls were tested at similar time intervals. This is important because cognitive testing has practice effects. If you repeat the same test multiple times, you often improve simply because you understand the task better. Having a control group allowed the researchers to compare post-race changes against normal learning effects.

The most reassuring result (if you’re a marathon runner) was that neural signal transmission appeared stable after marathon running. The researchers also looked at response amplitudes, which can reflect the strength or excitability of the brain’s response to stimuli. These were stable as well, with no consistent post-marathon reductions.

This suggests that even if MRI markers of myelin content change after extreme endurance exercise (as shown in the prior study), the basic timing of neural communication may be preserved. The nervous system may have enough redundancy or “buffering capacity” that short-term myelin remodeling does not translate into obvious deficits in neuron signaling.

On the cognitive tests, the pattern was not that runners became broadly impaired after the marathon, but that certain higher-order functions looked temporarily less efficient. In a processing speed test, controls improved across repeated sessions (as you would expect from practice), while runners showed a smaller immediate post-race improvement before catching up by one month. On a test known as the Stroop Test, controls again improved with repetition, but runners showed a temporary increase in interference after the race, suggesting it was briefly harder to suppress an automatic response and stay focused on the correct one. By one month, that effect had normalized, too.

On the other hand, basic visual/motor, attention, and executive tasks were preserved after the marathon. Runners and the control group improved over time on tests of these measures, with runners showing no clear post-race impairment.

To me, this is the key result. The marathon seemed to selectively affect more demanding cognitive processes while sparing more basic mental tasks. They didn’t broadly experience “marathon brain.”

The way I read this paper is that the marathon brain is not damaged. It is metabolically stressed and temporarily adapting. I’ll insert one of my favorite quotes from the paper here:

A marathon places the body in a state of prolonged energetic demand, and we need to think about how that affects the brain as much as it does the muscles, heart, and other organs. The brain has to help regulate movement, effort, pain, motivation, temperature, autonomic function, and decision-making throughout the event. In fact, it would be surprising if the brain looked exactly the same afterward, especially in the first 48 hours.

At the same time, the brain appears to protect its most essential signaling systems, and the authors connect this to other stress states where higher-order cognition is more vulnerable than basic sensory or motor function. Under fatigue, low-oxygen conditions, or acute physiological stress, the brain “sacrifices” higher-order thinking but keeps basic processes online. That’s how evolution wired us, after all.

Most of us can understand this intuitively, even if we have not thought of it as neuroscience. After a major race or hard competition, the body is not the only thing that feels a little off. The brain can feel slightly foggy, and study gives a “why” and a “how” to that experience.

The practical takeaway is not that marathons are dangerous for the brain (maybe just your mental health).

The more useful takeaway is that the brain should be included in how we think about recovery from extreme endurance exercise.

It’s normal for athletes to think about muscle repair, glycogen restoration, hydration, and sleep. But cognitive recovery matters. The day or two after a major endurance event is probably not the best time to schedule your most cognitively demanding work, make major decisions, or expect yourself to be mentally sharp for hours (it’s perhaps ironic that most marathon races occur on a Sunday).

What does that recovery look like? Probably not much different than how we think about bodily recovery. Sleep, adequate carbohydrate intake, enough total energy, hydration, and reducing stress levels. The study did not test recovery strategies, so we cannot say that any one intervention speeds cognitive normalization. But from a physiology perspective, it is reasonable to assume that restoring energy availability and sleep would support brain recovery and are probably the strategies with the biggest return on investment.

Honestly, what makes endurance exercise such a fascinating model for human physiology is that it’s not just a test of the legs or the cardiovascular system. It is a test of the entire human being, including the brain’s ability to maintain function under stress.

The brain after a marathon may not be “worse.” It may be doing exactly what a resilient biological system is supposed to do. It protects what matters most, adjusts what can temporarily be adjusted, and recovers when the stress has passed.

A good metaphor for running… and for life.

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).

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.

This week, I’m sharing the video of my recent appearance on the Down to Health podcast, where I talked about VO2 max, wearables, cardio myths, and other topics related to training, fitness, and longevity.

This was by far one of the most fun podcasts I’ve ever been a part of, and I think you’ll love it. Be sure to give the guys at DTH a subscribe if you enjoy their show!

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.

We like to think of exercise as falling neatly into one of two buckets: aerobic (“with oxygen”) or anaerobic (“without oxygen”).

Sprinting is anaerobic. Endurance exercise is aerobic. Nice and simple.

The problem is that the body is not nearly that tidy… it doesn’t flip from one energy system to another like a switch. It relies on overlapping pathways from the very first seconds of exercise, and what changes is the relative contribution of each pathway as the effort goes on.

I think this is one of those areas where exercise science has suffered a little from its own terminology. The labels “aerobic” and “anaerobic” are useful, but they can also be misleading when they get turned into hard categories instead of broad descriptions. And it’s really affected the way we (incorrectly) talk about exercise.

A background on energy systems

Muscle contraction always runs on ATP. That’s the immediate currency.

But ATP stores inside our muscles are tiny, so the body has to regenerate ATP constantly during exercise. It does that through three main bioenergetic pathways: the phosphagen system, glycolysis, and oxidative phosphorylation.

The key point is that these systems are always interacting. One may predominate, but they are not taking turns.

This is a concept underscored and (updated) in a new review paper.1

There’s a nice bit of historical context in the review.

A lot of this conversation traces back more than a century to the earliest studies measuring oxygen uptake during and after exercise. That work led to the concept of oxygen deficit, which is basically the gap between the oxygen an exercise bout would theoretically require and the oxygen the body has actually consumed. That gap became one of the classic ways to estimate the anaerobic contribution to energy production. In 1965, researchers introduced a concept known as critical power, which gave physiologists another way to think about the relationship between sustainable aerobic power and a finite amount of work that can be done above that threshold. This new review is really an updated attempt to synthesize decades of work built on those ideas.

The authors systematically searched seven databases and ended up including 102 studies, which together provided 311 data points from maximal exercise trials. Most of the data came from cycling and running, though the review also included swimming, kayaking, skiing, rowing, climbing, and arm-crank exercise. The participants were mostly trained adults, mostly male (unfortunately common in exercise physiology research), with an average age of about 24 years. The exercise bouts ranged from 6 seconds to more than 28 minutes. Then the authors modeled how the relative aerobic and anaerobic contributions changed across exercise duration.

One thing I appreciated is that the paper doesn’t pretend this is an easy measurement problem. A quick explanation…

Aerobic contribution is relatively straightforward to estimate because oxygen uptake during exercise can be measured directly (hence why you can get your maximal aerobic capacity measured in a lab). Anaerobic contribution is where things get messy. The review grouped studies into three main categories of how they measured it: oxygen deficit methods, mixed methods, and theoretical models.

All of these are useful, but none of them is perfect. In fact, the authors are very clear that there is still no universally accepted gold standard for quantifying anaerobic energy release during whole-body maximal exercise. Despite all of that methodological messiness, the overall pattern that emerged was pretty consistent. The model estimated that:

A 10-second maximal effort is about 91% anaerobic and 9% aerobic.

At 20 seconds, it’s 82% anaerobic and 18% aerobic.

At 30 seconds, it’s 75% anaerobic and 25% aerobic.

By 60 seconds, the effort is already estimated at 58% anaerobic and 42% aerobic.

Then comes the number that’s the cornerstone of the review. Equal aerobic and anaerobic contribution occurs at about 78.6 seconds. By 90 seconds, the aerobic contribution has already moved ahead, at roughly 54% aerobic and 46% anaerobic. At 2 minutes, the review estimates about 62% aerobic. At 3 minutes, about 72% aerobic. At 5 minutes, about 81% aerobic.

For me, the headline of the paper is that the aerobic system becomes important much earlier than most people assume. And it challenges the lazy version of the aerobic vs. anaerobic story.

We often talk as if short, hard exercise is basically anaerobic until some later point when the aerobic system finally joins the party. But the review makes clear that oxidative metabolism ramps up quickly during intense exercise.

The aerobic system is not a backup generator that kicks in late. It is contributing meaningfully even in very short maximal efforts, and its contribution rises fast. The authors also point out that oxygen uptake kinetics are faster during high-intensity exercise than traditionally appreciated, which helps explain why aerobic contribution is already substantial within the first minute or so.

The paper is careful not to oversell precision, which I think is important. These percentages are modeled estimates built from several different studies with varying exercise modes, protocols, and pacing strategies. So I wouldn’t treat 78.6 seconds as some magical physiological law written in stone. But the general conclusion is pretty persuasive—anaerobic energy supply is finite, aerobic energy supply is ongoing, and the balance between the two shifts earlier and more rapidly than a lot of our conventional thinking suggests.

In short, our old binary framing is too rigid.

The phosphagen, glycolytic, and oxidative energy systems are all involved from the outset of exercise. So the real question is not whether an effort is aerobic or anaerobic. The better question is how much each system is contributing, how quickly that balance changes, and what that means for performance and fatigue. That’s a much better (and much more interesting) way to think about exercise physiology, in my opinion.

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.

One of the oldest questions in exercise science is why some people seem to improve dramatically with training while others improve only modestly or, at least on paper, not at all.

That debate sits at the center of the long-running idea of “non-responders” to exercise. It’s compelling, but also contested.

This concept comes from studies showing that when a group of people completes the same training program, some increase their cardiorespiratory fitness (their VO₂ max improves) while others show little change. In some cases, a few participants even appear to get worse… but that apparent decline is often more likely to reflect measurement error, day-to-day biological variability, or statistical noise than a true drop in fitness.

That’s one reason the whole idea of a true “non-responder” remains hotly debated. And I’m skeptical of it myself.

A lot of research shows that when so-called non-responders are given a larger dose of exercise (more weekly volume, a higher frequency of sessions, or more intensity), they often do respond. Their cardiorespiratory fitness improves. In other words, they may not be biologically incapable of adapting; they may simply need a different stimulus.

Probably one of my favorite exercise science studies ever was one that challenged the whole idea of “non-responders” to training. In the study, researchers took 78 healthy adults and had them complete the same endurance training program, but with different weekly doses ranging from 60 to 300 minutes per week. The more people exercised, the fewer of them were classified as non-responders.

The people initially labeled as non-responders then went on to do another 6 weeks of training, this time with an extra 120 minutes of exercise per week. Once the dose increased, they responded… non-response essentially disappeared. To me, that is such an important finding because it suggests that many so-called non-responders are probably not true non-responders at all. They may just be people who need a larger training stimulus to cross whatever threshold is required for adaptation. That idea makes a lot more physiological sense to me than the idea that exercise just somehow doesn’t “work” for a meaningful subset of people.

Putting this study aside, the idea that we all respond differently to the same training stimulus makes sense. Human physiology is variable. Biology is variable. It would be surprising if every person responded the same way to the exact same training plan. So the real question is not whether responses differ—they clearly do—but why.

What explains why one person responds robustly while another barely budges? Are there underlying biological differences driving that variability? Could genetics play a role? And are there measurable molecular or physiological markers that could help predict who is likely to respond to a given exercise program?

That is the premise of a new study pointing to a potential biomarker in the blood: a protein called insulin-like growth factor binding protein 7, or IGFBP7. In humans, higher levels predicted a worse response to training and were even associated with a range of cardiometabolic diseases. And in mice, deleting this “molecular brake” produced an enhanced training response.1

Let’s get into it.

The study comes from a multi-institutional group that included researchers from Massachusetts General Hospital, Harvard, the University of Michigan, and the Norwegian University of Science and Technology. Their work builds on the Generation 100 trial in Norway, which was a randomized clinical trial involving 1,567 older adults with an average age of 73 years.

The researchers focused on the trial’s high-intensity interval training (HIIT) arm. Participants performed two supervised HIIT sessions per week for a full year, with each session consisting of four 4-minute intervals at 90% of peak heart rate, separated by 3-minute active recovery periods (it’s the classic Norwegian 4x4 interval workout).

The variation in the responses to HIIT was enormous. After a year of identical training, changes in peak VO₂ ranged from a 56% increase to a 28% decline.

That naturally raises a deeper question and goes back to the idea of exercise non-responders we talked about earlier. What is going on biologically in the people who fail to adapt?

IGFBP1 is a “molecular brake” on fitness

To figure out what might be blocking adaptation, the researchers moved from whole-body performance to the blood. They selected the extremes—10 high responders, who improved peak VO₂ by an average of 22%, and 10 low responders, who showed no gain or a decline. Crucially, they matched them carefully before training. Same age. Same sex. Same baseline fitness. Same lean mass. This ensured that the difference between these people was not apparent in their outward phenotype.

The team measured 305 proteins under four conditions:

• At rest before training,

• Immediately after acute maximal exercise before training,

• At rest after the year-long training intervention, and

• Immediately after acute maximal exercise after training.

Now we can understand how the proteome responded to acute stress and how it changed over time after long-term training.

One of the first really important findings was that low responders were not failing to register the workout. Acute exercise produced major proteomic shifts in both groups. In fact, 659 proteins changed in high responders, while 783 proteins changed in low responders. So the people who ultimately failed to improve were not “responding less” to exercise. Their bodies absolutely detected the stress, and if anything, the acute perturbation was even larger.

After 12 months of HIIT, the high responders showed 394 significant changes in their resting proteome. Their biological baseline had changed. The low responders, by contrast, showed zero significant changes in their resting proteome. Zero. I think that is one of the most striking findings in the paper. Both groups repeatedly experienced acute stress and mounted an immediate response to exercise. But only one group appeared to ingrain this into their physiology and actually “remodel” their resting proteome.

The next step was to ask whether future responsiveness could be predicted before training even started. Using the baseline blood samples alone, the researchers identified 228 proteins that were associated with later fitness gains. And among all of these candidate proteins, one stood out most clearly: IGFBP7, or insulin-like growth factor binding protein 7.

IGFBP7 showed a striking inverse relationship with training response. Higher baseline levels predicted worse gains in fitness, and lower baseline levels predicted better gains. Baseline IGFBP7 accounted for about 80% of the variance in trainability among the participants. That is an enormous signal.

This gets even more interesting (okay, at least to me) when we consider what IGFBP7 actually is. The protein is classified as a senescence-associated secreted protein, or SASP factor, which means it is part of the inflammatory and suppressive cocktail released by senescent cells—the so-called “zombie cells” that accumulate with age. That provides a direct biological bridge between aging and blunted adaptation to exercise.

Of course, a strong correlation does not prove causation. But the problem is, without genetic engineering (which presents its own ethical problems and isn’t yet acceptable for most human research), we can’t really establish causation in humans.

So the authors turned to mouse models and started manipulating the system directly. They used IGFBP7 knockout mice, animals genetically engineered so they could not produce the protein at all. Interestingly, these mice had 14–15% less muscle mass in the heart and leg muscles, and the female knockout mice had 61% more fat mass than controls (who were able to produce IGFBP7). Yet despite these differences in body composition, the knockout mice had similar baseline exercise capacity to normal mice (just like the human study).

Once the mice started training, the difference became obvious. In a treadmill training protocol, the knockout mice improved dramatically more than wild-type controls. After four weeks, they gained 3.3 times more fitness overall. Male knockouts gained 5.7 times more.

The researchers then tested whether this advantage would hold up in a different kind of exercise setting. Instead of forced treadmill work, they gave the mice voluntary running wheels. Over four weeks, the animals ran 5–7 kilometers per day, which for a mouse is a huge training volume. Both groups improved more than they did on the treadmill, but the knockout mice still outperformed the wild-types by 54%. By week two, the knockouts had already pulled away. So the absence of IGFBP7 raised both the ceiling of adaptation and accelerated the kinetics, with mice adapting faster and to a greater extent when they lacked IGFBP7.

But there is still an obvious caveat with knockout models: if you remove a gene starting from conception, maybe the animal develops differently in all kinds of ways unrelated to the protein’s immediate role in adulthood. The researchers addressed that too. They increased circulating IGFBP7 in adult mice by about fourfold. Even though the manipulated mice still ran the same distances on the wheel (exercise behavior didn’t change), the enhanced trainability disappeared. This suggests IGFBP7 is not merely a biomarker of poor adaptation. It appears to actively constrain it.

So what is this protein actually doing?

IGFBP7 seems to act like a systems-level brake on several core components of exercise adaptation. One major axis is muscle growth and repair.

• The paper points to evidence that IGFBP7 interferes with insulin-like growth factor-1 (IGF-1) signaling, essentially blocking one of the body’s main anabolic pathways. In the knockout mice, circulating IGF-1 was 40% higher, and the animals gained 9% more muscle mass across multiple muscles during training.

• Another major axis is blood vessel growth. Trained knockout mice had about double the increase in capillary density compared with controls.

• The study also found broad metabolic adaptations across the muscle, heart, and liver. With training, the knockout mice appeared to shift into a more advanced fuel-handling strategy, exhibiting greater fatty acid metabolism in skeletal muscle, more Krebs cycle and amino acid breakdown in the heart, and enhanced aerobic and fat metabolism in the liver.

The final layer of the paper zooms out from exercise performance to long-term health (something we are all interested in) using UK Biobank data from 52,033 participants followed for about 16 years. After adjusting for age and sex, lower IGFBP7 levels were associated with a lower risk of all-cause mortality, heart failure, COPD, cirrhosis, chronic kidney disease, and type 2 diabetes. When participants were grouped based on their baseline levels of IGFBP7, those with the highest levels had a 2.9- to 11-fold greater disease rate than those with the lowest levels across these outcomes.

There’s a bit of a philosophical conclusion to this paper that I really dig.

The authors propose that trainability may reflect something deeper than exercise response per se. It may be a visible readout of cellular resilience. A hard workout is, at the cellular level, a controlled crisis. Body temperature rises, blood acidity shifts, energy demand spikes, and blood flow stress changes rapidly. Those same kinds of disturbances also show up in disease states.

The same molecular systems that determine whether your body responds to a training block may also help determine how well it resists heart failure, kidney disease, diabetes, or the slow erosion of function that comes with age. And IGFBP7 may be one of the clearest molecular signals yet identified that helps explain why. In fact, this could be one potential explanation for the broader link between VO₂ max and longevity that I’ve covered so extensively. While I do think that aerobic fitness is protective in the sense that it reflects the body’s overall capacity to coordinate oxygen delivery and energy production, this paper would suggest it may also reflect physiological plasticity—the processes that allow someone to obtain a high level of fitness in the first place are also important for guarding against death and disease.

This does not mean the obvious next step is to block IGFBP7 and call it a day. The therapeutic angle is much trickier than that. Because IGFBP7 is tied to senescence and growth control, lowering it could come with serious tradeoffs (prior work has shown that knockout mice can develop certain types of cancer). So the same brake that may limit adaptation could also exist for a reason (biology isn’t so dumb after all). It may prevent a system from becoming too permissive. The paper raises the possibility that transient or context-specific inhibition could one day help older or frail individuals get more biological return from lower-intensity activity, but that is still a speculative therapeutic vision.

Still, even setting aside the pharmaceutical angle, this is a fascinating piece of science. It gives us a candidate molecular explanation for one of the most persistent mysteries in exercise physiology. It links age-related senescence biology to adaptation and shows that the body can fully register the stress of exercise and yet still fail to remodel. And it suggests that trainability may be less about motivation or willpower than about whether someone (or some mouse) is biochemically capable of upgrading itself in response to stress.

More than anything, this paper makes me think about aging a little differently.

We often think of aging as the slow accumulation of damage. But studies like this hint that maybe aging is also a progressive loss of adaptive capacity. If that is true, then the future of healthy aging may depend on preserving the body’s ability to adapt in the first place. And this study suggests IGFBP7 might be one of the proteins sitting directly in the middle of that story.

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 yeah, their gummies actually contain creatine, unlike some other brands. 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). Take 35% off a subscription.

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.

Today, I’m discussing what I think is probably one of the most important studies on sleep in the last decade.

It suggests that the timing and consistency of your sleep (especially when you go to bed) may be just as important as how long you sleep.

Sleep health research has been handicapped because we’ve been looking at a question that’s much too simple: how much sleep do people get?

That question has produced an enormous literature linking both short (and long) sleep duration with cardiometabolic disease, mortality, impaired glucose regulation, hypertension, and obesity… among other maladies. “The shorter your sleep, the shorter your life.”

But duration increasingly looks like only one dimension of sleep health. A person can sleep for an apparently adequate number of hours while still living in a state of circadian misalignment—going to bed at widely varying times, waking at inconsistent hours, and forcing their physiology to adapt to shifting time schedules.

The emerging idea is that sleep may not merely be a matter of quantity or even quality, but also of consistency and regularity… whether the timing of sleep is stably embedded within your body’s natural 24-hour cycle.

Cardiovascular physiology is profoundly circadian. Blood pressure, endothelial function, hormone secretion, glucose handling, and even our susceptibility to heart attacks (they’re more common in the morning) all fluctuate across the day-night cycle. When behavior repeatedly misaligns with those oscillations—as in shift work, late chronotypes (“night owls”), or erratic sleep timing—the result is far worse than just poor sleep. For systems like the cardiovascular system that depend on some level of “biological predictability,” this may spell disaster for long-term health.

In fact, the American Heart Association has recently updated its stance on sleep to reflect this emerging data.1 Their recent scientific statement marks a clear shift from treating sleep mainly as a duration issue to treating it as a multidimensional health behavior, with sleep regularity elevated to a core component of cardiometabolic health. The AHA explicitly frames healthy sleep as including not just duration, but also continuity, timing, regularity, daytime functioning, sleep architecture, and the absence of sleep disorders. Regularity is now being emphasized alongside quantity and quality as something that may shape blood pressure, glucose regulation, adiposity, and other cardiometabolic pathways.

The authors of a new study position sleep timing regularity within exactly this framework… as a measurable expression of circadian stability. And they find that regularity matters, a LOT. Especially if you’re not sleeping enough.2

The study, from the Northern Finland Birth Cohort 1966, asks a more specific question than much of the existing sleep-regularity literature. Rather than relying only on composite (and frankly difficult to understand) metrics such as the Sleep Regularity Index or interdaily stability (which are inherently hard to calculate and even harder to implement practically), it isolates three highly interpretable timing variables:

• Bedtime

• Wake-up time

• The midpoint of the sleep period

A standard deviation in bedtime or wake-up time is immediately legible as a behavioral pattern. If risk concentrates there, the biology becomes easier to interpret, and the intervention target becomes more concrete. And that’s one of the reasons this study is so knowledgeable and practical.

The cohort included 3,231 adults, all around midlife, drawn from participants in the 46-year follow-up of the study conducted in 2012–2014. These individuals wore a wrist-based activity monitor continuously for up to two weeks, and sleep timing variables were derived using a sleep-detection algorithm that’s been validated against both self-reported sleep diaries and smart-ring-derived sleep periods. In other words, it’s pretty accurate at assessing sleep.

The authors used the first seven consecutive days of valid monitoring, reasoning that a seven-day window captures both weekday and weekend structure and is sufficient to estimate someone’s habitual timing variability.

Bedtime, wake-up time, and sleep midpoint were each quantified as the standard deviation across those seven days—the main outcome being sleep timing regularity. Participants were categorized into one of three sleep timing regularity categories:

• Regular

• Fairly regular

• Irregular

To get a better idea of how “regular” or “irregular” these people’s sleep patterns were, let’s look at the median values for sleep timing across each of these groups. In other words, how much did bedtime, wake-up time, and the midpoint of sleep vary from night to night?

• For regular sleepers, bedtime had a variability of 33 minutes, wake-up time had a variability of 41 minutes, and the midpoint of sleep had a variability of 33 minutes.

• For fairly regular sleepers, variability for bedtime, wake-up time, and sleep midpoint was 59 minutes, 73 minutes, and 55 minutes, respectively.

• For the irregular sleepers, variability was 108 minutes, 114 minutes, and 93 minutes for bedtime, wake-up time, and sleep midpoint, respectively.

Let’s put this in perspective. This means that someone with an irregular sleep schedule might have a bedtime or wake-up time that changes by 1.5 to 2 hours from night to night. They might usually go to bed at 11 pm, but might also go to bed at 9 pm on some nights and as late as 1 am on others. But someone with a regular schedule and an average bedtime of 11 pm will be in bed between 10:30 and 11:30 every single night.

The primary endpoint of this study was major adverse cardiac events (obtained from a national health registry), defined as the first time someone experienced acute myocardial infarction, unstable angina, stroke, hospitalization for heart failure, or cardiovascular death.

The authors also divided participants based on the median sleep duration of the group—7 hours 56 minutes—creating below-median and above-median sleeper groups (let’s just refer to them as “short sleepers” and “normal sleepers.”

During a follow-up period of about 130 months, 128 participants—4.0% of the sample—experienced a major cardiovascular event. But surprisingly, those who had an event did not differ significantly from those who didn’t in average bedtime, average wake-up time, sleep midpoint, or how many hours they slept each night. On the surface, then, there was no simple signal that people who later developed cardiovascular events were just sleeping later, waking later, or sleeping less overall.

And this is where the paper becomes interesting…

Among participants whose sleep period duration fell at or below the median—7 hours 56 minutes or less—irregular sleep timing predicted a higher cardiovascular risk.

• Compared with those in the most regular bedtime category, participants with irregular bedtimes had twice the risk of experiencing a major cardiovascular event during the follow-up.

• Participants with irregular sleep midpoints also had a 2-fold greater risk of a major cardiovascular event compared to regular sleepers.

• Wake-up time irregularity was not significantly associated with risk.

Importantly, none of the three timing variables predicted cardiovascular events among participants with “normal sleep”—those getting more than 7 hours and 56 minutes of sleep per night!

This is a very particular result, and it somewhat contradicts previous findings that sleep regularity is harmful even among people getting enough sleep. This study wouldn’t support that. It’s only among people sleeping somewhat less than eight hours that the instability of when one goes to bed (and their midpoint of sleep) seems to matter for heart disease risk.

A few more important nuances. Even when the researchers excluded the 12 participants who experienced a major cardiovascular event within the first two years of follow-up, the results did not materially change, which argues against the simplest version of reverse causation (the idea that subclinical cardiovascular disease at baseline was already disrupting sleep timing and driving the association).

Excluding shift workers also did not change the results. In fact, the associations became slightly stronger when shift workers (a group with notoriously altered circadian rhythms) were excluded. After removing shift workers, participants with irregular bedtimes and sleep midpoints had a 2.25–2.3x greater risk of cardiovascular events during the follow-up.

That matters because it suggests irregular sleep timing in ordinary life—outside classic occupational circadian disruption—may itself mark a meaningful health hazard. It wasn’t the shift workers in the study “artificially” driving the association.

One of the more intriguing (and to me, surprising) features of the study is the interaction, or at least the modification, of sleep duration. The association appears only in those with “short sleep.” This can be read in two ways.

One interpretation is that irregular timing becomes especially harmful when it is layered onto relatively shorter sleep, because the combination compounds insufficient recovery and circadian disruption.

Another is that longer sleep may buffer some of the physiological consequences of timing irregularity. The authors lean toward the latter possibility in their own conclusion, suggesting that sufficient sleep may offer partial protection against an irregular bedtime.

And I think this matters for how you should think about your own sleep. If you aren’t getting enough sleep each night, then your strategy needs to be to anchor when you go to bed as close to the same time as possible every night. But if you’re getting enough sleep, you have more “wiggle room.”

The study suggests that not all components of sleep regularity are equivalent. It may be the consistency of initiating sleep—or the consistency of the overall phase of the sleep episode—rather than the consistency of waking per se, that carries more relevance to cardiovascular health. Why might that be?

One plausible explanation is that bedtime is the “entry point” into the nighttime restorative window, whereas wake-up time is often a more downstream, socially constrained event. Sleep onset is tightly coupled to circadian phase. People typically fall asleep as melatonin is rising, core body temperature is falling, and the circadian system is shifting toward the nighttime state.

If bedtime is pushed around from night to night, that phase relationship becomes unstable, so the person is not just sleeping at different clock times but repeatedly asking the cardiovascular, endocrine, and autonomic systems to enter sleep from different circadian states (different “body times”).

A second reason bedtime may matter more is that it likely has a greater influence over sleep architecture and early-night recovery biology. Slow-wave sleep and slow-wave activity are concentrated in the early part of the night, whereas REM sleep predominates later in the night. So when bedtime shifts later or becomes erratic, the body may repeatedly alter the alignment between the first part of sleep and the conditions that normally favor restorative processes. Wake-up time variability, in contrast, may mostly affect the tail end of sleep and may be less “biologically informative” if many people still wake at roughly similar times because of work or family obligations. In that sense, bedtime irregularity may be a better marker of chronic circadian misalignment and of disrupted access to the most important portion of sleep.

We have to note one of the main limitations here. Sleep timing regularity was measured over only seven days at baseline, which may or may not capture an individual’s longer-term habitual behavior across seasons, stressors, or life transitions. How someone slept during one particular week might not reflect how they slept during the nearly 11-year follow-up period.

What this paper ultimately does is suggest that cardiovascular sleep epidemiology (and our own lifestyle practices) may need to move beyond how long people sleep and even beyond when they usually sleep, toward how stably sleep is placed from one day to the next. Regularity and consistency should become a focus of sleep health equal to that of sleep duration.

For now, this study does not argue that sleep regularity matters more than every other cardiovascular risk factor, but it does show that the stability of sleep—specifically bedtime and sleep midpoint—predicts future major cardiovascular events in a way that average sleep timing does not.

I think this may prove to be one of the most consequential conceptual shifts in modern sleep health—from thinking of sleep as a quantity, to understanding it as a rhythm.

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 yeah, their gummies actually contain creatine, unlike some other brands. 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). Take 35% off a subscription.

VO₂ max is probably one of the topics I’ve written about most. And hopefully, I’ve not beaten a dead horse here. I just think there’s endless interest in it, and I don’t think it’s the “fad” people make it out to be.

Even though the importance of VO₂ max has been underscored by myself and others on numerous occasions, VO₂ max has made its way back into the mainstream conversation for a different reason—people are questioning its validity as a true “longevity biomarker.” Because of that, I felt like it would be nice to provide a “state-of-the-science” update.

I’ve been doing the podcast rounds lately, and it has allowed me to brush up on the research regarding VO₂ max as a longevity biomarker. That’s what this post is about, plus the most up-to-date research on how to improve it with training and other tactics. If you want a somewhat deeper dive into the science, you can pick up my book “VO₂ Max Essentials” on Amazon.

Why VO₂ max still matters

VO₂ max remains one of the most discussed metrics in exercise physiology, and for good reason. It is the maximal rate at which the body can take up, transport, and utilize oxygen during intense exercise, and it is widely regarded as the gold-standard laboratory measure of cardiorespiratory fitness (CRF). The American Heart Association reinforced the clinical importance of CRF in their latest update, arguing that it should be routinely assessed in healthcare and even framing it as a clinical vital sign.1

That said, VO₂ max is often discussed too loosely. It is not a standalone “longevity score,” and it is not interchangeable with every estimate of aerobic fitness produced by a treadmill test, population equation, or (especially) wearable. It is a specific physiological construct that we should interpret with nuance.

What VO₂ max actually reflects

Physiologically, VO₂ max is best understood as an integrative property of the oxygen transport system. It depends on pulmonary gas exchange, cardiac output, blood oxygen carrying capacity, distribution of blood flow, and the ability of working muscles to extract and use oxygen. It reflects how well the body can deliver and utilize oxygen when the demand for aerobic energy production is at its highest (e.g., during maximal exercise).

That systems-level nature is what, in my opinion, makes VO₂ max so compelling.

It is not simply a marker of “cardio” in the casual sense. It is a summary readout of how multiple organ systems perform together under stress. At the same time, it does not fully determine endurance performance on its own. Endurance outcomes also depend heavily on economy, durability, and the fraction of VO₂ max that can be sustained near threshold, hence why the guy or girl with the highest VO₂ max doesn’t always win the race.

Where the longevity evidence is strongest

There’s no question that a higher level of fitness is associated with a lower risk of dying.

A 2024 overview of meta-analyses2 synthesized 26 systematic reviews representing 199 unique cohort studies and more than 20.9 million observations.

• Across those data, higher CRF was strongly and consistently associated with lower all-cause mortality, lower cardiovascular mortality, and lower risk of several chronic disease outcomes.

• High versus low CRF was associated with a 53% reduction in all-cause mortality risk, and each 1 metabolic equivalent (1-MET, equal to 3.5 ml/kg/min of oxygen uptake) was associated with an 11% to 17% lower risk of all-cause mortality depending on the meta-analysis.

Those are impressive associations, but the certainty should not be overstated. The same overview rated the certainty of evidence across outcomes from very low to moderate. That does not weaken the overall signal, which is clearly strong and consistent, but it does argue for some caution when translating these epidemiologic associations into sweeping mechanistic claims. And I should note that many studies here were not actually about directly measured VO₂ max. They are about CRF more broadly. So let’s discuss that…

VO₂ max and CRF are related, but they are not interchangeable

A recent source of controversy is not whether aerobic fitness is important, but whether VO₂ max is a useful, meaningful marker worth measuring (separately from CRF, that is).

This arose because many of the most cited mortality studies do not rely on direct breath-by-breath laboratory measurement of VO₂ max. Instead, they often use objectively measured exercise capacity expressed in METs, treadmill-estimated CRF, or even non-exercise CRF estimation models.

How much does that matter? Maybe not a lot if we’re talking strength of associations.

A 2025 systematic review and meta-analysis3 of 42 studies representing 35 cohorts and 3.8 million observations found:

• Objectively measured and estimated CRF showed broadly similar dose-response associations with all-cause and cardiovascular mortality.

• Per 1-MET higher CRF, all-cause and cardiovascular mortality dropped by 14% and 16%, respectively, without statistically significant differences between objective and estimated approaches.

That is important because it supports the broader conclusion that fitness is a powerful risk marker, regardless of how it’s measured. Nevertheless, the epidemiology is strongest for CRF as a construct. VO₂ max is the gold-standard laboratory expression of that construct, but the two are not perfectly synonymous in the literature. I’m willing to accept that, but I’m not quite convinced the semantics matter if we’re talking about longevity in the general sense.

Is VO₂ max a biomarker?

Whether VO₂ max should be called a biomarker depends largely on how the term is being used. If the intended meaning is an objective, reproducible measure associated with future health outcomes, then VO₂ max or CRF clearly behaves like one.

If the intended meaning is a singular mechanistic readout of biological aging, the label becomes much harder to defend. The American Heart Association’s framing is more conservative and more useful: CRF is a vital sign because it provides meaningful prognostic information that improves risk assessment and clinical management. That is, it tells you more about your health when paired with common cardiovascular disease biomarkers (and probably more on its own than any single risk factor like cholesterol, blood glucose, or whether or not you smoke).

I think the most defensible description is that VO₂ max is an integrative functional marker. It compresses a great deal of physiology into one number, but it does not function like a magic molecular biomarker that fully explains why one person lives longer or ages better than another.

How to reliably improve VO₂ max

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.

The fitter you are, the less likely you are to die of nearly anything.

That’s not a controversial statement at this point.

The associations between cardiorespiratory fitness and a lower risk of cardiovascular disease, metabolic disease, cancer, and all-cause mortality are well established. I’ve written about that plenty before (you can find the latest example here).

But while the body-side benefits of fitness are widely appreciated, the brain side is still catching up in the broader conversation.

We already know that what is good for the heart is often good for the brain. Better vascular health, better metabolic health, better mitochondrial function, better inflammatory control… these are not body-only phenomena. The brain is downstream (technically upstream, directionally speaking) of all of them. So it’s not a stretch to think that better cardiorespiratory fitness may also confer some protection against mental disorders, neurodegeneration, or age-related cognitive decline.

That idea gets even more interesting when you make the important distinction that fitness is not the same thing as exercise. I say it’s interesting because there’s overwhelming evidence that participating in exercise and physical activity directly confers benefits to mental and cognitive health.

But exercise is the behavior. Fitness is, in part, the physiological result.

If higher cardiorespiratory fitness itself is associated with a lower risk of depression, dementia, or other neuropsychiatric conditions, that suggests something more than “people who exercise are healthier.” It suggests that the physiological machinery that allows someone to achieve and maintain better aerobic fitness (the integrated function of the heart, lungs, vasculature, skeletal muscle, and cellular energetics) may also track with better long-term brain and mental health.

The idea is compelling and logically sound, but as always, better to have data than assumptions.

A new systematic review and meta-analysis provides the most up-to-date evidence on the link between aerobic fitness and long-term brain health, asking whether people with higher cardiorespiratory fitness are less likely to go on to develop mental disorders or dementia later in life.1

This was a meta-analysis of 22 cohort studies involving more than 4 million participants, generally between 18 and 64 years old, who had fitness assessed at baseline and were then followed for anywhere from 4 to 29 years. Fitness was measured in several different ways across studies. Some cohorts used direct VO₂ max testing, others used indirect maximal or submaximal exercise tests, and others used estimated or field-based metrics like METs, peak workload, exercise duration, or distance covered. So while the paper is about cardiorespiratory fitness, it is not exclusively about directly measured VO₂ max (this has become an especially important nuance to point out, since some folks on social media get angry if one doesn’t specify).

Across studies, higher cardiorespiratory fitness was associated with a substantially lower future risk of depression, all-cause dementia, and psychotic disorders, but not clearly with anxiety.

Compared to people with low fitness, those with high fitness had:

• a 36% lower risk of depression.

• a 39% lower risk of all-cause dementia.

• a 29% lower risk of psychotic disorders.

And when fitness was analyzed continuously rather than categorically, each 1-MET (3.5 ml/kg/min) increase in cardiorespiratory fitness was associated with a 5% lower risk of depression and a 19% lower risk of dementia. This is perhaps the more important stat in my opinion, because it shows how a small but meaningful fitness bump affects long-term disease risk (we don’t have hard numbers for the low- versus high-fitness categories, unfortunately).

The results were also broadly similar across several subgroup analyses, including people above and below age 50, men and women, and studies using indirect maximal or submaximal testing rather than direct lab-based VO₂ max measures.

The authors also discussed several outcomes that were not meta-analyzed because only one or two studies were available. Even so, those individual studies suggested that higher fitness may also be associated with lower risk of bipolar-related disorders, dissociative disorders, obsessive-compulsive and stressor-related disorders, somatic symptom disorders, sleep apnea, as well as anxiety and ADHD in children. Depression in girls also appeared lower with higher fitness.

So taken at face value, the signal is broad: higher cardiorespiratory fitness seems to track with lower risk across a wide range of psychiatric and neurocognitive outcomes.

That said, this is still observational evidence, and observational evidence always comes with some limitations.

The first is what’s known as residual confounding. Even in well-adjusted cohort studies, there are always variables that are incompletely captured or not captured at all.

Factors like genetic predisposition, chronic pain, other comorbidities, social support, smoking, diet, and general physical activity habits are potential confounders. It is entirely possible that higher-fitness individuals differ from lower-fitness individuals in multiple ways beyond fitness itself, and some of those differences could independently influence mental health or dementia risk.

The second is reverse causation, which is especially important here.

Early or subclinical symptoms of depression, neurodegeneration, or other psychiatric disease may reduce motivation, physical activity, energy levels, or exercise capacity before a formal diagnosis is ever made. In that scenario, lower fitness would not necessarily cause later disease. It might instead be an early marker of disease already beginning to develop.

The included studies tried to address this by excluding people with diagnosed conditions at baseline, but that only goes so far. Disease can exist for years before diagnosis, especially in dementia.

So while the associations are compelling, they are not proof that improving fitness will directly prevent depression, dementia, or psychotic disorders. To know that, we’d need study designs that measure aerobic fitness at several time points over years to decades to see whether increasing or decreasing fitness is associated with a lower or higher disease prevalence. Ideally, we’d want a randomized controlled trial lasting two decades or more… a guy can dream.

And to the authors’ credit, they do not overclaim. They conclude that higher cardiorespiratory fitness appears to be associated with a lower risk of several mental and neurocognitive disorders, and cardiorespiratory fitness may be a useful candidate marker for risk stratification.

The biological plausibility is real

Even though causality is not established in an observational study like this, the biology here is not hand-wavy. There are several plausible mechanisms linking higher cardiorespiratory fitness to better mental and neurocognitive outcomes, including greater neuroplasticity (the brain’s ability to “rewire” itself), improved brain blood flow and vascular function, reduced inflammation and oxidative stress, and a more stable response to stress. There’s also broader exercise-related pathways involving brain-derived neurotrophic factor (BDNF) signaling (Dr. Rhonda Patrick is the go-to source here), angiogenesis, mitochondrial health, immune regulation, and psychosocial factors like self-efficacy and social support. It’s impossible to say “this one mechanism explains the benefit,” as it’s likely a combination of several factors that explain why fitness (and exercise) have tight links to brain health.

To me, one of the most compelling pieces of the story is the structural brain literature.

In an earlier newsletter, I covered a study suggesting that the relationship between aerobic fitness and brain health may be partly structural, not just functional. That study directly measured both VO₂ max and brain myelin content (myelin being the protective and super-important insulation around our neurons) in 125 cognitively normal adults across two aging cohorts. Higher aerobic fitness was associated with greater myelination across much of the brain, with the strongest differences showing up in middle-aged and older adults. Furthermore, fitter people appeared to reach peak myelination later and then lose it more slowly with age. Across the full sample, myelin peaked around age 31, but in the lowest-fitness group, it peaked before age 22, whereas in the highest-fitness group, it didn’t peak until around age 41. Higher cardiorespiratory fitness has also been associated with less grey and white matter deterioration in adults across the lifespan.

Again, this is not proof that raising fitness prevents dementia. But it strengthens the idea that cardiorespiratory fitness may be a meaningful marker of long-term brain-aging risk.

Mental disorders and neurodegeneration are complex, multifactorial, and deeply heterogeneous. So I am not going to be the person who says, “exercise is the answer.”

Maybe it is one answer. And maybe it is an important one. But I am generally skeptical of the overly simplistic line that “exercise is just as good as medication for depression” (or insert your favorite mental health condition). Improving mood, reducing depressive symptoms, and treating major clinical depression are not interchangeable ideas. And while there is good evidence that exercise and physical activity can help with depressive symptoms, I think the health and fitness world sometimes overshoots by making it sound as though all it takes is a little movement. That is too reductive for a condition as complex as depression.

With dementia and Alzheimer’s disease, I am somewhat more bullish on the role of activity and fitness. Not because I think they are magic bullets, but because the pathways involved, including vascular dysfunction, metabolic dysfunction, inflammation, neurodegeneration, and reduced cerebral blood flow, are exactly the kinds of processes that fitness influences. If there is one lifestyle-related trait I would want on my side for healthy brain aging, high cardiorespiratory fitness would be near the top of the list.

And despite VO₂ max and cardiorespiratory fitness getting some pushback lately as “not true longevity markers,” I still do not see the case against them.

If anything, the opposite seems to be happening. The evidence continues to accumulate that cardiorespiratory fitness is associated not only with lower risk of physical disease and premature death, but also with better brain health, lower dementia risk, and perhaps lower risk of certain mental disorders as well.

And that matters because healthspan is not only about how well the body can hold up with age, but also about the brain that comes along for the ride (and is really in the driver’s seat).

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 yeah, their gummies actually contain creatine, unlike some other brands. 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). Take 35% off a subscription.

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.

This week, I’m sharing a video podcast I recorded with my ‘Run Long, Run Healthy’ podcast co-host . We break down a new review on antioxidant supplements for athletes. And while the conversation mainly focuses on runners, I think it applies more broadly!

Here’s a link to a post I wrote on the review for the ‘Run Long, Run Healthy’ newsletter.

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 yeah, their gummies actually contain creatine, unlike some other brands. 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). Take 35% off a subscription.

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 don’t claim to have all the answers when it comes to health and fitness. And I don’t pride myself on being one of those people who tries to “debunk” everything. But when I see some science that I know is clearly being misrepresented, I can’t help but call it out.

That’s what happened this week with a viral post claiming that regular exercise is linked to slower biological aging, but only in people sleeping 7+ hours per night—and that people sleeping under 6 hours who exercise “actually age faster.”

It made for a great (and sadly viral) social-media claim. It’s also not what the study, nor the broader literature, shows.

The post (and paper) in question was a cross-sectional NHANES analysis looking at sleep duration, phenotypic age, and exercise activity in 13,569 U.S. adults. Sleep was self-reported. The paper’s goal was to look at associations between sleep duration and a biomarker-based estimate of biological aging called phenotypic age, and then examine whether exercise participation might modify that relationship. That’s an interesting question. But right away, there are limitations. This was observational, cross-sectional, and based on self-reported sleep. So it cannot tell us that exercise causes faster aging in short sleepers. It cannot even really tell us the direction of the relationship.

And then there’s the bigger problem that the subgroup results that went viral were read backwards.

In the paper’s Figure 4a, the no-exercise group showed positive associations between short sleep, extreme short sleep, and long sleep and phenotypic age (higher phenotypic age is not a good thing in this context). But in the group doing more than 150 minutes per week of exercise activity, short sleep, extreme short sleep, and long sleep actually had a lowerphenotypic age relative to normal sleep in that same activity group!

The authors then say that “the short sleep group with more exercise tended to have a higher phenotypic age.” That’s their interpretation of that figure. But that is very different from saying the study showed that exercising while sleeping under 6 hours “ages you faster.” It didn’t. At minimum, the results are mixed and messy.

Maybe it seems like I’m being nit-picky. But I don’t think posts like this are inconsequential. Especially when they get millions of views. Because it potentially changes health behaviors.

If someone comes away from that viral post thinking, “I’m not sleeping enough, so maybe I shouldn’t exercise either,” that is a genuinely bad takeaway. Sleep matters. A lot. But “sleep matters” is not the same thing as “exercise becomes harmful when sleep isn’t perfect.” Those are very different claims, and the evidence here does not justify the second one. In fact, it suggests exactly the opposite—exercise is protective in the context of insufficient sleep.

One example…

A much better recent study followed 59,078 UK Biobank participants prospectively and used device-measured sleep and physical activity rather than relying only on self-report. It tracked people for a median of 8.1 years and looked at how sleep, moderate-to-vigorous physical activity, and diet interacted to influence lifespan and healthspan. The big picture was not “exercise only helps if sleep is already perfect.” It was that modest concurrent improvements across these behaviors were associated with meaningful gains in lifespan and healthspan. And importantly, the authors noted that MVPA appeared to be the primary contributor to those gains. In fact, several of the lower-sleep, higher-MVPA groups did better on both lifespan and healthspan than groups with more normal sleep but low activity. Sleep still matters, but inactivity is not some neutral fallback position. In a way, you can out-exercise poor sleep, but you can’t outsleep inactivity.

That paper also found that the minimum combined pattern associated with better lifespan and healthspan became apparent once people moved into the moderate MVPA category, regardless of the corresponding sleep and diet patterns. In other words, physical activity was one of the main drivers of benefit.

Of course, the highest gains were seen in people with high MVPA, moderate sleep, and high diet quality, but the broader pattern was clear—activity was protective, not dangerous.

That is why I think the viral interpretation of the first study is technically wrong (at best) and probably harmful (at worst).

A lot of people already have an all-or-nothing mindset with health. If sleep isn’t perfect, they assume the workout doesn’t count. If the diet isn’t perfect, they assume they blew the day. If recovery isn’t perfect, they assume training is pointless. That mindset is already a problem. And a message like “exercise may age you faster if you sleep under 6 hours” is not helping anyone.

The better message is that yes, poor sleep is a problem. Yes, you should work on it. But poor sleep is usually a reason to improve sleep and keep exercising—not a reason to avoid exercise.

To be clear, I’m not saying the first paper is worthless. It adds to the literature showing that abnormal sleep duration is associated with worse health-related outcomes and that the relationship between sleep and biological aging is complicated. It also raises an interesting hypothesis about how sleep duration and activity might interact. But hypothesis-generating is not the same thing as proving a clean public-health message. And it definitely is not the same thing as telling millions of people that exercise might be aging them faster if they didn’t sleep enough the night before.

A paper with self-reported sleep, cross-sectional data, and internally messy subgroup findings became a viral warning against exercise in short sleepers. Meanwhile, the broader literature points in the other direction. Overwhelmingly, physical activity remains one of the strongest protective behaviors we have, including in the context of imperfect sleep.

That’s the real story here.

And unfortunately, the version that spread left people with exactly the wrong idea. And what’s even more frustrating is that dozens of health influencers quoted that same post reinforcing the message, even though it was clear they didn’t even take a glance at the study that was being referenced.

That’s all I have for now. But safe to say this won’t be the last time I make a post like this. Unfortunately.

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 yeah, their gummies actually contain creatine, unlike some other brands. 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). Take 35% off a subscription.

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 became interested in ketones (the exogenous type that you take as a “shot,” rather than the endogenous ones your body produces when you fast or eat a ketogenic diet) several years ago.

They were an up-and-coming supplement in the endurance sports world. Around that time, I also started writing some blog articles for H.V.M.N. (now Ketone IQ, one of the prominent companies in the exogenous ketones space) on the science of ketones, exercise performance, and other topics like fasting and cognition.

(Full disclosure: I sit on the Science Advisory Board of Ketone IQ, because it’s a company I believe in and a group of people I trust and admire.)

Back then, the hype around exogenous ketones centered on their potential as a performance-enhancing supplement, mainly as an alternative energy source (to carbs) during endurance exercise. A few studies at the time showed some modest benefits for time to exhaustion when participants took ketones before or during a prolonged endurance session, and there were even reports that Tour de France cycling teams were ordering ketones by the carton.

The performance fuel side is still one of the major selling points of ketone supplements, and there are definitely some interesting benefits shown in recent studies, like enhanced cognitive performance during ultramarathon running, for example.

But to be honest, I’m less enthused about the ergogenic effects of ketones.

Instead, my enthusiasm lately has been around ketones as a post-exercise recovery tool—a way to help the body adapt better to exercise training over time. The evidence here is incredibly robust (and growing). In fact, I published a review article over 7 years ago, when the first study came out showing that taking ketones during a chronic heavy endurance training block prevented symptoms of overtraining in cyclists.

That single study changed how I thought about (and used) ketones. When taken post-workout or during heavy periods of training, they may act like an “adaptation signal” for the body. Quicker recovery, and potentially fewer symptoms of “I feel like crap.”

But it turns out they may be doing even more than that. According to a recent study, ketones don’t just enhance recovery… they may actually enhance training adaptations, allowing already fit athletes to gain more aerobic fitness, performance, and mitochondrial gains when layered on top of training.1

The research positions post-exercise ketones as “a promising nutritional strategy to amplify mitochondrial remodeling and endurance performance.”

If you want to try ketones for yourself and experience what all the hype is about, I’d encourage you to try out my preferred ketone supplement, Ketone IQ. Visit ketone.com/BRADY for 30% OFF your subscription order plus receive a free gift with your second shipment—fun surprises like a free 6-pack, Ketone-IQ merch, and more (raspberry lemonade, caffeinated and non-caffeinated, is my favorite).

Twenty-eight trained male cyclists (average VO₂peak of ~50–55 ml/kg/min, so pretty fit) completed an 8-week endurance training intervention that comprised two 4-week blocks: 3 weeks of a progressive increase in training load followed by a 1-week “taper” (training load reduced by 40–50%), followed by another 3-week progression and then a final taper week. The participants trained 5 days per week, with 1–2 of those days including 2 training sessions, and they completed a variety of endurance and high-intensity workouts ranging from steady-state (“zone 2”) sessions to all-out 30-second sprints.

Here’s where the groups differed. After every training session and 30 minutes before sleep on training days, one group of participants consumed 25 grams of an exogenous ketone ester (i.e., 50 grams per day on training days). The other group (the control group) consumed a taste-matched placebo.

At baseline (before training), after week 3 of training, after week 7 of training, and at the end of the final taper week (week 8), the participants performed a 30-minute time trial test and a VO₂max test to assess average 30-minute power output, maximal oxygen consumption, and peak power output. Researchers also measured heart function and cardiac output, took muscle biopsies to assess markers of mitochondrial function, and even assessed the athletes’ subjective rest and recovery. It was one of the most comprehensive “performance workups” you could ask for from a study like this.

A few important notes before getting into the main results.

First, training load and diet were the same between the ketone and control groups throughout the study. That’s important because it means we can attribute any differences to the supplement, not to some nuance like the athletes in the ketone group training harder or fueling better (one potential flaw in the “overtraining study” I mentioned earlier was that the ketone group ended up eating more throughout the training intervention). Second, athletes who took the ketone supplement saw a rise in their blood ketone levels after exercise, with blood BHB reaching 2.6 mM. That’s relevant because it gives us a target range when we start to think about the potential applications of this study for our own training and recovery.

As a result of training, both groups improved their average power output during the 30-minute time trial by about 10% after 3 weeks (from 250 watts to 275 watts). But by week 7, the ketone group increased their average power output by 4% compared to the control group (for a final difference of 11 Watts; 302 watts versus 291 watts), a difference that persisted even after the final taper week (week 8 of the study).

Both groups also improved their peak power output by about 5% after 3 weeks of training. But while the control group didn’t further increase peak power output from week 3 to week 7 (they plateaued), the ketone group did, increasing it by an extra 7% from week 3 to week 7. Overall, the ketone group increased their peak power output by 52 watts during the 8-week study, compared to a 25-watt improvement in the control group.

The participants who took ketones also saw a greater improvement in VO₂peak, which increased by 6.4 ml/kg/min from pre- to post-training, compared to a 3.3 ml/kg/min increase in the control group.

So we have greater increases in cycling performance (time-trial power output), peak power output, and peak oxygen consumption in athletes who supplemented with ketones during training—an incredible result in its own right. But that might not even be the most interesting part of this study.

When the researchers looked at markers of muscle mitochondrial content, they observed that the ketone group had more than twice the increase in the activity of citrate synthase, an enzyme considered a marker of mitochondrial content (which rose by 15% in the control group and 32% in the ketone group). They had higher citrate synthase activity overall compared to the control group at the end of the study as well. There was also a 25% increase in the protein content of complex II of the electron transport chain (the energy-producing pathway in mitochondria) in the ketone group, but no change in the control group.

What about the heart? Improvements here didn’t show any between-group differences — athletes in both groups increased peak cardiac output and stroke volume, classic endurance training adaptations. But adding ketones to training didn’t appear to alter structural or functional cardiac adaptations over and above a placebo.

Lastly—and this was something I found surprising—ketones didn’t appear to provide any benefit for subjective stress and recovery scores. All athletes experienced a similar decline in their stress-recovery state throughout the training period (it got worse). I only say this was “surprising” on account of the older overtraining data. I expected the ketone group to at least feel slightly less “stressed” and a bit more recovered.

If you weren’t on the post-exercise ketones bandwagon already, you should be now.

That’s because this wasn’t a study in an untrained group, and it didn’t involve a brutal training intervention designed to drive athletes into the ground.

No—this was a reasonable endurance training intervention conducted in already well-trained cyclists. That’s key for a few reasons, the first of which is that trained athletes have typically squeezed out nearly every last bit of adaptation they can get through training, diet, sleep, or supplementation. Usually, adding a supplement or recovery protocol leads to marginal gains, if any, especially when athletes are already training intensely.

But in this study, adding ketones to an already optimized training plan allowed these athletes to eke out several percentage-point improvements on top of training alone. Usually, those types of gains are reserved for unfit, sedentary people, not fit athletes undergoing routine endurance training.

What’s really exciting about this study is the mechanism: ketones appear to be helping build more mitochondria during training, suggesting they’re driving muscular adaptations rather than central (cardiac) ones. This might seem surprising, but it’s well known that in addition to their role as “energy molecules,” ketones are also signaling molecules that induce a wide array of genetic and epigenetic changes throughout the body with relevance to health, longevity, and now, performance.

So what are the practical applications here? For the recreational amateur athlete like you and me (unless you’re one of the pros who reads my newsletter), I think they’re huge.

While increasing training volume is the clearest and most logical way to gain fitness, not everyone can just “train more.” So if you have a hard cap on your training volume, targeted ketone supplementation around training (post-exercise and pre-sleep) could be the ultimate biological lever—a way to artificially amplify your cellular “return on investment” from the time you spend training.

Ketones appear to be one (but not the only) way to maximize the process of recovery and adaptation to exercise. It’s similar to the benefits I see with post-exercise sauna or hot-water immersion. Not replacements for training, but effective adjuncts, a tool you can leverage alongside training.

That’s what makes them, in my mind, unique and exciting. Some of this research is honestly showing that post-exercise ketones might be the closest thing to a “biohack” we have in the world of endurance sports. Especially when you add this study to the literature that already exists on EPO production and hormonal signaling, which ketones also appear to influence.

Of course, you still have to do the work of sweating through the intervals. But when you’re done, ketones may be there to amplify the effort.

It’s still a growing area of research, and we’ve got a lot to learn and trials to run, including studies in less-fit and more-fit individuals, as well as women.

But I’m bullish on ketones. And if you’re serious about getting more out of your training, they might be something interesting to experiment with.

Thanks for reading. See you next Friday.

~Brady~

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.

The physical activity guidelines are good. But like most public health recommendations, they’re not perfect.

Part of that imperfection (or at least their real-world ineffectiveness) probably has nothing to do with the guidelines themselves, and everything to do with the fact that most people don’t follow them. Only around 25% of adults in the United States meet the weekly physical activity guidelines for aerobic and strength training.1

So yes, one could argue this reflects a human limitation more than a guideline problem.

But there’s a deeper issue. As I’ve discussed in a prior newsletter—and even talked about with Dr. Rhonda Patrick on her podcast—the guidelines rely on a somewhat anachronistic way of equating exercise intensity. They assume that one minute of vigorous exercise is “worth” two minutes of moderate exercise. That equivalence makes sense for calorie burn. But when it comes to health outcomes and chronic disease risk, vigorous activity’s benefits often look disproportionately (even exponentially) larger than those of light- or moderate-intensity activity.

That brings up another limitation of the guidelines, one that’s especially relevant for disease prevention. They largely assume that everyone, regardless of health status or disease risk, will benefit from the same basic target of 150 to 300 minutes of activity per week (or 75 to 150 minutes if that activity is more intense). In other words, they’re essentially one-size-fits-all recommendations (which, in some ways, feels a bit like an exercise version of the Dietary Guidelines for Americans… which I have some thoughts on).

The problem is that physiology is about as far from one-size-fits-all as it gets. Genetics, environment, and lifestyle constraints all shape what someone can do (and what they should do), especially when the goal is reducing disease risk.

That’s why this new study caught my attention.2 It tried to tackle the idea of personalized physical activity prescriptions for reducing cardiovascular disease risk, based on a person’s predisposition, or baseline risk, for developing cardiovascular disease. The authors even put some specific numbers and thresholds on total activity, duration, and intensity, which is helpful. But what stood out to me even more was the broader theme that cardiovascular risk should probably be part of the conversation when we’re telling people how to move and train.

The study drew on data from 72,884 participants in the UK Biobank cohort. At the start, everyone wore an accelerometer (an activity-tracking device) for 7 days, giving researchers an objective look at how much moderate-to-vigorous, moderate-intensity, and vigorous-intensity physical activity people did, along with their sleep and sedentary time.

Researchers then followed participants for about 13 years, tracking cardiovascular disease events including heart disease, stroke, and cardiovascular-related mortality. But instead of simply comparing event rates across different activity levels (which has been done plenty of times before), the novelty was how they framed risk. Participants were first grouped based on how “at risk” they were for cardiovascular disease, using factors like age, total cholesterol and HDL cholesterol, blood pressure, and smoking status; as well as whether they had kidney disease, diabetes, or a family history of high cholesterol. From there, they were classified as low-to-moderate risk, high risk, or very high risk.

With those risk categories in place, physical activity was brought in to answer the study’s central question: “What are the optimal physical activity patterns to promote cardiovascular health among people with different levels of cardiovascular disease risk?”

More activity means lower risk (but it’s complicated)

Some of the initial findings were straightforward. Overall, higher levels of physical activity were associated with lower rates of cardiovascular disease across all risk groups in a dose-response manner.

Compared to people who got less than 150 minutes per week, those who achieved 150–300 minutes, 300–450 minutes, and >450 minutes per week had a 28%, 46%, and 58% lower risk of cardiovascular disease (more was better with no apparent upper limit). On the flip side, being sedentary for 7 or more hours per day was associated with a 23–28% greater cardiovascular disease risk (again, no surprise there).

Where things get more interesting is when you layer those relationships onto someone’s baseline risk. In the very high-risk group, additional activity appeared to “matter more” than it did in the low-to-moderate or high-risk groups. For very high-risk individuals, increasing weekly activity by 150 minutes per week was associated with a 20% reduction in cardiovascular disease risk—compared to “just” a 16% reduction for the lower-risk groups.

More moderate activity benefits high-risk groups

At this point, it would be easy to assume the takeaway is simply that more moderate-to-vigorous activity (and especially more vigorous activity) is always better, regardless of risk status. But that’s not exactly what the authors observed.

Instead, the benefits of increasing physical activity differed depending on where someone fell along the cardiovascular risk spectrum.

The authors walk through an example of someone “reallocating” 300 minutes of sedentary time to 300 minutes of moderate- or vigorous-intensity activity.

For someone at low-to-moderate cardiovascular disease risk, shifting 300 minutes toward moderate or vigorous activity (and away from sedentary time) reduced their 10-year risk of cardiovascular disease by 0.55% (moderate-intensity) and 0.85% (vigorous-intensity). That’s a small risk reduction, but remember these were already low-risk individuals.

In the high-risk group, the pattern flipped. Replacing sedentary time with 300 minutes of moderate-intensity activity reduced 10-year risk by 2.23%, while replacing it with vigorous activity reduced risk by only 1.47% (i.e., less than moderate-intensity activity). In the very high-risk group, the 10-year risk reduction from 300 minutes more of moderate activity was 4.36%, and for vigorous activity, it was 2.17%.

In short, the benefits of adding more vigorous-intensity activity were less pronounced than adding more moderate-intensity activity for individuals at higher cardiovascular disease risk, suggesting higher-risk individuals may benefit more from swapping sedentary time with moderate activity instead of vigorous (after a certain point, as we’ll see). For low-risk individuals, though, vigorous activity yielded a slightly greater risk reduction compared to the same duration of moderate activity.

The ideal “activity distribution”

The same general theme showed up when the researchers looked at the optimal mix of moderate and vigorous activity.

For low-to-moderate risk individuals, there didn’t seem to be an upper threshold for vigorous activity—spending a higher proportion of weekly activity time at vigorous intensity continued to yield additional benefits.

For high-risk individuals, however, risk reduction peaked when vigorous activity made up about 20% of their total weekly physical activity (about 60 minutes per week for someone engaging in 300 minutes per week). And for very high-risk individuals, the peak occurred when vigorous activity comprised about 14% of weekly physical activity (about 42 minutes per week). Beyond those points, the benefits of adding more vigorous activity started to decline. To be clear, risk never went up (above 0), but the benefits began to plateau or reverse when higher-risk individuals started adding more vigorous activity to their week. Moderate activity, on the other hand, appeared to have no plateau in terms of its benefits when replacing weekly sedentary time.

Whenever there’s a “surprising” finding—even (or perhaps especially) in observational research like the study we’ve been discussing—my first instinct is to ask: why? I think it helps to bring some applicability to what otherwise is just an association.

Why would someone at higher cardiovascular risk not derive the same (or even greater) benefit from adding more vigorous or high-intensity activity as someone at lower risk? On the surface, it feels counterintuitive.

To their credit, the authors did offer some speculation. They suggest that in high-risk individuals—who often already have elevated blood pressure and chronic inflammation—the more intense physiological stress of vigorous activity (on blood pressure, inflammatory molecules, and even hemodynamic stress within blood vessels) could potentially blunt some of its added benefits.

That could be true. But given the broader body of evidence, including randomized controlled trials showing benefits of high-intensity activity in people with preexisting conditions, I’m not fully sold that this is the main explanation.

Instead, I think this result may be less about vigorous activity having limited benefits per se and more about tradeoffs.

Because the substitution model the authors used holds total moderate-to-vigorous activity constant, meaning that “more vigorous” automatically means “less moderate.” And for higher-risk individuals, vigorous minutes may not represent the same physiological dose in the first place. What gets labeled as “vigorous” by an accelerometer could feel much closer to all-out effort for someone who’s less fit or has more comorbidities. Put those two together, and it’s easy to see how, beyond a certain point, swapping moderate minutes for vigorous minutes might stop adding extra protection.

There’s another, simpler possibility that moderate activity may already be doing so much heavy lifting in higher-risk people that the marginal gains from stepping up to vigorous intensity just aren’t as dramatic. When baseline risk is high, any consistent movement can substantially move the needle, so the jump from moderate to vigorous may look smaller than we’d expect.

Whatever the mechanism, one thing feels clear, and it has very little to do with the hazard ratios and modeling details that dominate papers like this.

Personalized activity guidelines are a no-brainer.

The idea that everyone benefits equally from 150–300 minutes of activity per week (or that 75–100 minutes of it should be intense) is insultingly simple. If your goal is reducing cardiovascular disease risk, you should likely move differently than someone whose primary goal is weight loss. And as this study highlights, baseline cardiovascular risk probably deserves a seat at the table when we think about how to distribute intensity across the week.

What’s somewhat serendipitous is that this study echoes a pattern we’ve seen for decades in endurance athletes—the “80/20” approach, where roughly ~80% of training is lower intensity and ~20% is higher-intensity work. In this study, the plateau for vigorous activity among high-risk individuals appeared right around that same 20% threshold.

Does that mean you should train like an athlete if your goal is to maximally reduce cardiovascular disease risk?

It might not hurt.

Thanks for reading. See you next Friday.

~Brady~

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