Greetings from very soggy California. It’s going to rain non-stop here all week, so no golf for the wicked. Little in the comments and emails this week that we need to cover, so that being the case, best get on with the show.

How Exercise Reverses Muscle Aging (And Why Your Diet Matters, Too)

It is a well-known fact that as we age, we seem to get weaker…even if we are active. You might have also noticed that some older adults maintain impressive strength while others, most perhaps, struggle. It is also a well-known fact that if people engage in resistance or strength training as they age, they tend to keep or even increase their muscle mass. The big questions are: Why do we get weaker with age? And why does resistance training forestall the loss of muscle mass?

It should be obvious that we get stronger and increase our muscle mass if we do resistance training, but what is the process by which this happens? And why is it that if we don’t do it, most of us become sarcopenic. (See photo below.)

A fascinating new study (Dropbox pdf link) published in the Proceedings of the National Academy of Sciences (PNAS) just shed some serious light on this mystery, and the findings are pretty remarkable.

The business side of healthcare

If your healthcare news feels scattered, that’s because it probably is.

Healthcare Brew pulls it together—covering pharma, policy, health tech, and hospital operations in a free newsletter built for the business side of healthcare.

Clear context. Industry interviews. Engaging reporting. Read by 135,000+ professionals who want to know what matters without digging for it.

Subscribe for free

Researchers at Duke-NUS Medical School in Singapore discovered something really interesting about how our muscles age and how exercise can actually reverse that aging process. The key player? A protein named DEAF1 (Deformed Epidermal Autoregulatory Factor 1). No wonder it’s referred to as DEAF1.

As we get older, our muscles produce more and more of this DEAF1 protein. When DEAF1 levels go up, it turns on another important system in our cells called mTORC1 (mechanistic target of rapamycin complex 1), which I’ve written about a number of times. Now, mTORC1 can be thought of as a master switch in your cells that controls protein production and autophagy (your body’s cellular cleanup system).

Think of it like this. mTORC1 is supposed to be like a thermostat (for lack of a better term) that keeps your house at the perfect temperature. When you’re young, it works great–turning up protein production when you need to build muscle, and turning it down so your cells can clean house. But as you age, DEAF1 cranks that thermostat way up and breaks the dial. Your muscles go into overdrive making proteins, but they stop cleaning up the cellular junk. This leads to damaged proteins piling up, oxidative stress, and eventually your muscles start to waste away. It’s called sarcopenia, and it affects a huge number of older adults.

The really engrossing part of the process, for me, anyway, is how DEAF1 works.
Exercise suppresses DEAF1 expression. When you work out, your body activates proteins called FOXO transcription factors, which essentially tell DEAF1 to calm down. This brings mTORC1 activity back to normal levels, restores the balance between protein production and cleanup, and helps reverse muscle aging. Just what we want to have happen, right?

This paper has changed my view on the whole mTORC1 process. I’ve always thought that exercise increased mTORC1, and that the more active mTORC1 increased muscle mass. But these authors have discovered that mTORC1 needs to operate at an optimal rate, which allows cellular garbage removal along with muscle building.

(Note: The paper doesn’t distinguish between aerobic exercise and resistance exercise, but my staunch belief–based on my own self and many other papers I’ve read–is that resistance exercise works better than aerobic exercise to increase strength and muscle mass.)

This wasn’t just some cell culture experiment done in a petri dish. The researchers tested their findings across multiple systems:

1. Fruit flies (Drosophila) Yes, those annoying little bugs are actually amazing for genetics research. I’ll write about them again in this Arrow.

2. Mouse muscle cells (C2C12 myotubes): Lab-grown muscle tissue.

3. Actual mice Including aged mice put through exercise programs.

4. Multiple exercise types Both treadmill running and resistance wheel exercise.

The fact that they found the same FOXO-DEAF1-mTORC1 pathway working across all these different models makes their findings way more persuasive. It shows that the process is conserved through various species, and is thus likely to work in humans, too. Plus, they didn’t just show correlation–they showed causation by manipulating each piece of the puzzle and watching what happened.

When they blocked FOXO or artificially increased DEAF1 in exercising mice, the benefits of exercise disappeared. The mice’s muscles still aged and weakened despite working out. On the flip side, when they knocked down DEAF1 or activated FOXO in sedentary old mice, they got many of the same benefits as exercise–reduced muscle aging, better protein balance, less cellular senescence.

The mTORC1 Paradox. Good Guy or Bad Guy?

Here’s where things get interesting to me, or for anyone who follows nutrition science.

mTORC1 has a complicated reputation. On one hand, activating mTORC1 is crucial for building muscle–it’s why eating the right protein (containing branched-chain amino acids with a fair amount of l-leucine–plant proteins don’t cut it) helps you gain strength. Athletes and bodybuilders know this instinctively. When mTORC1 is active, it promotes protein synthesis, making your muscles bigger and stronger.

But–and this is a big but–chronic overactivation of mTORC1 is linked to accelerated aging, not just in muscles but throughout the body. It’s even involved in cancer growth, metabolic dysfunction, and shortened lifespan. This is why some longevity researchers are obsessed with rapamycin, a drug that inhibits mTORC1.

So we’ve got this weird situation where you want mTORC1 to spike temporarily when you exercise (to build muscle), but you don’t want it chronically elevated the rest of the time. It’s all about balance and timing.

Which brings me to…

The Low-Carb Connection Not Mentioned In the Study

Now here’s where I’m going to put on my low-carb-keto-enthusiast hat and point out something the researchers didn’t really explore: the potential connection to diet, specifically carbohydrate intake.

The study found that aged muscles have chronically elevated mTORC1 activity independent of the insulin/AKT pathway. The researchers specifically noted that “AKT phosphorylation remains unchanged in aging muscles,” suggesting the problem isn’t coming from typical insulin signaling. Instead, the over-activation comes from increased mTOR gene expression driven by DEAF1.

But here’s what got me thinking: while the direct cause of elevated mTORC1 in this study was increased DEAF1 expression, diet still influences the overall mTORC1 system. High-carbohydrate diets, especially those that cause frequent insulin spikes, are known to chronically activate mTORC1 through the insulin/IGF-1 pathway. Could a Standard American Diet high in refined carbs and sugars be making the DEAF1 problem even worse?

Think about it this way: You’ve already got age-related DEAF1 turning up the mTORC1 dial. Now add on top of that multiple blood sugar spikes throughout the day from bagels, pasta, sodas, and snacks. You’re basically hitting mTORC1 from two angles: transcriptional up-regulation from DEAF1, plus post-translational activation from insulin signaling. That’s a recipe for serious metabolic dysfunction.

Could a Low-carb/Ketogenic Diet Help?

This is not from the study and is speculative on my part. The study didn’t test different diets, but there are some intriguing possibilities here. Ketogenic diets and intermittent fasting are known to:

1. Reduce insulin levels: Less chronic mTORC1 activation through the insulin pathway

2. Activate AMPK: An energy sensor that inhibits mTORC1 and promotes autophagy (cellular cleanup)

3. Promote autophagy: The very process that gets impaired when mTORC1 is overactive

4. May activate FOXO: Some research suggests metabolic stress from keto can activate FOXO transcription factors (the same proteins that exercise uses to suppress DEAF1)

The study showed that FOXO activation is key to exercise’s anti-aging benefits. FOXO suppresses DEAF1 transcription, which normalizes mTOR expression and restores balance. Interestingly, FOXO factors are known as “longevity genes” and are activated by various forms of metabolic stress, not just exercise, but also caloric restriction and potentially ketosis.

Could a well-formulated ketogenic diet provide some of the same benefits as exercise by activating FOXO and keeping mTORC1 in check? I would guess so. We definitely need research specifically evaluating this. But I would say the mechanistic overlap is highly probable.

To be clear, I’m not suggesting diet could replace exercise, although activating AMPK does help. This study showed that exercise provides benefits through multiple pathways beyond just FOXO-DEAF1-mTORC1. Exercise improves mitochondrial function, reduces inflammation, maintains neuromuscular connections, and much more. You can’t get all of that from just changing what you eat.

But what if the combination of exercise and a low-carb or ketogenic diet could be synergistic? What if keeping insulin low through diet makes the FOXO activation from exercise even more effective? That’s the kind of question that gets me fired up.

The Autophagy Angle

One of the most important findings in this study was how DEAF1 and mTORC1 affect autophagy. Autophagy is your body’s recycling system. It breaks down old, damaged proteins and organelles and recycles their parts. It’s absolutely critical for healthy aging. I wrote a blog post on ketosis and autophagy 20 years ago, and, as far as I know, nothing has changed since then.

The researchers found that aged muscles have impaired autophagy, which leads to accumulation of protein aggregates (basically cellular junk) and damaged mitochondria. When they reduced DEAF1 or blocked mTORC1 with rapamycin, autophagy increased and muscles looked younger and healthier.

This is directly relevant to low-carb eating because ketogenic diets are one of the most powerful dietary interventions for promoting autophagy (See my linked post above). When you restrict carbohydrates and keep insulin low, especially combined with intermittent fasting, you create metabolic conditions that strongly favor autophagy.

The study showed exercise restores autophagy by suppressing DEAF1 and normalizing mTORC1. Could ketogenic diets work through a similar mechanism? We know keto promotes autophagy, but the specific pathway might be different. Some research suggests keto works partly through AMPK activation (which inhibits mTORC1 from a different angle) and partly through reducing insulin/IGF-1 signaling.

What About Protein Intake?

Here’s another interesting question the study raises: How much protein should older adults eat? This is actually a hot debate in the nutrition world, with two camps:

Camp 1: Older adults need MORE protein to combat muscle loss. Studies show higher protein intake helps preserve muscle mass during aging. This makes sense because you need amino acids, especially l-leucine, to build and maintain muscle.

Camp 2: Excess protein chronically activates mTORC1, which might accelerate aging. Some longevity researchers advocate for lower protein intake, especially from animal sources high in leucine and methionine which are particularly effective at activating mTORC1.

This study actually suggests both camps might be partially right. The key isn’t necessarily eating less protein overall, but rather optimizing the timing and context of protein intake.

Here’s my take. You want protein intake to be pulsatile rather than constant. Spike mTORC1 temporarily after exercise when you want to build muscle, but keep it lower the rest of the time. This is actually one area where the low-carb community and longevity researchers might find common ground. The idea that used to be promoted was that you should snack all day, i.e., eat a lot of small meals throughout the day. Fortunately, that advice has fallen by the wayside. You need a good slab of protein to build muscle, but you want to eat it just a few times per day.

The research is all over the map on when is the optimal time. Is it before the workout or after? Or does it matter? Experts in protein and muscle mass vary in their opinions. My best guess would be after the workout, but I’m not absolutely positive about that.

Many people eating ketogenic diets naturally adopt a pattern of time-restricted eating or intermittent fasting, which creates periods of low mTORC1 activity alternating with protein-rich meals. This could be ideal, because you get the muscle-building benefits of protein without the aging-promoting effects of chronic mTORC1 activation.

Does the Type of Exercise Matter?

The study tested two types of exercise in old mice: exhaustive treadmill running and resistance wheel exercise. Both worked to suppress DEAF1 and restore muscle health. This suggests the benefits aren’t specific to one type of exercise.
However, again, from a practical standpoint, I think resistance training might be especially important for older adults. Here’s why:

1. Muscle building: Resistance exercise is the most effective way to build muscle mass and increase strength, which matters as you age.

2. Bone density: Weight-bearing exercise helps maintain bone strength. Yes, resistance exercise strengthens bones along with muscles. You’ve got to have strong bones to hang those strong muscles on.

3. Metabolic health: More muscle mass means better insulin sensitivity and metabolic flexibility. Even stronger bones help in this endeavor.

4. Practical strength: Functional movements help with daily activities and make you move through life with less care. (Remember: strong people are harder to kill. So there’s that advantage as well!)

The study showed that as long as you’re activating FOXO transcription factors, you’ll get the DEAF1-suppressing, mTORC1-normalizing benefits. Different types of exercise might activate FOXO through slightly different mechanisms (AMPK activation from cardio, mechanical stress from resistance training), but the end result is similar.

For older adults, I’d argue for primarily resistance training for muscle mass and bone density improvement. I’m sure it wouldn’t hurt to throw in a little aerobic training, too. Especially if you enjoy it.

Here Are the Practical Takeaways (As I See Them)

Okay, so what does all this mean for you in real life? Here are my main takeaways:

1. Exercise is non-negotiable for healthy aging. This study provides yet another mechanism explaining why exercise helps you age better. It literally reverses molecular markers of muscle aging by restoring protein balance and cellular cleanup.

2. Both cardio and resistance training matter. The study tested both types and both worked. The study implies that you shouldn’t neglect either one. I would recommend resistance over aerobics.

3. Consistency is key. The benefits came from regular, ongoing exercise. You can’t just work out intensely for a month and expect lasting changes. This is a lifestyle intervention.

4. Consider your diet, too. While the study didn’t directly test diet, the mechanisms involved (mTORC1, autophagy, FOXO activation) are all influenced by nutrition. A diet that keeps insulin and mTORC1 in check most of the time, with strategic protein timing around workouts, might be ideal.

5. Don’t fear protein. Some people in the longevity community are overly worried about protein and mTORC1. This study shows the problems come from chronic over-activation of mTORC1, not from temporary spikes after meals or exercise. Older adults especially need adequate protein to maintain muscle.

6. Time might matter as much as amount. Pulsatile protein intake (concentrated around workouts or in specific feeding windows) is better than grazing on protein all day long, at least in MHO.

7. Autophagy is important. This study reinforces that cellular cleanup is critical for healthy aging. Anything you can do to promote autophagy—exercise, fasting, keeping insulin low—is unquestionably beneficial.

The Bigger Picture

What I love about this study is that it connects so many dots. We’ve known for a long time that:

• Exercise helps you age better

• mTORC1 over-activation accelerates aging

• Protein balance matters for muscle health

• Autophagy declines with age
  
  But this research shows HOW these pieces fit together. The FOXO-DEAF1-mTORC1 pathway provides a unifying framework that explains multiple aging phenomena.

It also highlights something important about scientific research: the best interventions often work through multiple mechanisms simultaneously. Exercise doesn’t just suppress DEAF1. It also improves mitochondrial function, reduces inflammation, enhances insulin sensitivity, promotes neuromuscular connections, releases beneficial myokines, and much more.

That’s why exercise is so consistently effective across different health outcomes—it’s not doing just one thing, it’s doing dozens of beneficial things at once. And crucially, many of these benefits can’t easily be replicated with pills or simple dietary changes.

Based on the amount of time I’ve spent on this section, it should be obvious that I love this study.

If I could design the follow-up studies to this research, here’s what I’d want to see:

Study 1: Test whether ketogenic diets or intermittent fasting can enhance the DEAF1-suppressing effects of exercise in aged mice. Measure DEAF1 expression, mTOR levels, autophagy markers, and muscle function across different diet and exercise combinations.

Study 2: Look at DEAF1 expression in humans across different ages, diets, and exercise habits. Are there people who maintain low DEAF1 into old age? What are they doing differently?

Study 3: Test whether the timing of protein intake matters. Compare eating the same amount of protein spread throughout the day versus concentrated around workouts. Measure effects on DEAF1, mTORC1, muscle protein synthesis, and autophagy markers.

Study 4: Take a look at DEAF1’s role in other tissues. Does the same mechanism contribute to brain aging, cardiovascular aging, immune system aging? And will resistance exercise and protein intake improve those? I would bet it does.

This study is a great example of how science can reveal the molecular mechanisms behind things we’ve observed for a long time. We’ve known exercise helps people age better since ancient Greece. But understanding how it works at a molecular level opens up new possibilities for interventions and optimization.

From my perspective as someone who advocates for low-carb and ketogenic diets, I see potential synergies between diet and exercise that this study hints at but doesn’t directly test. The mechanisms involved—mTORC1, FOXO, autophagy—are all influenced by both exercise and nutrition. Understanding how these factors interact could help us design more effective anti-aging strategies.

But here’s the bottom line: You need to exercise. No diet, no matter how perfect, can fully replace the benefits of physical activity. Exercise is medicine, and this study provides yet another mechanism explaining why.

At the same time, I think there’s good reason to believe that the right dietary approach could enhance and complement the benefits of exercise. Keeping insulin and mTORC1 in check most of the time through carbohydrate restriction and strategic protein timing might make your body more responsive to the positive signals from exercise.

The FOXO-DEAF1-mTORC1 pathway is just one piece of the aging puzzle, but it’s an important piece. And the fact that we can influence it through our lifestyle choices—how we eat, how we move—is empowering. You’re not helpless against aging. Every workout, every dietary choice, every lifestyle decision is sending signals to your cells that influence how you age.

Choose wisely.

Do Meat Eaters Make It to 100 Years Old More Often Than Vegetarians?

There's this new study making the rounds that claims vegetarians are less likely to become centenarians--people who live to 100 or older. The study has been all over the media, so I tried to track it down to see what it was all about. I got links to the study but couldn’t get the full text. I wrote to the authors (who are in China) asking for a pdf but couldn’t get any of them to respond.

I started searching around for the same authors on PubMed and found a paper with basically the same info by the same authors published in JAMA Network Open. This happens more than you would think. Authors want to get two papers out of one project, so they publish in first one journal, then another.

I’ve got to provide a caution on this one. It comes from China, and Chinese researchers in China are not to always be trusted. The Chinese government gives awards and promotions based on the number of papers published in Western journals and on the prestige of the journal in which the research is published. It is a setup for fraud, and a recent paper interviewing Chinese researchers showed that over half of them admitted to committing academic publishing fraud. I would bet the actual numbers are a lot higher than those reported. Whenever you read any serious report of academic fraud by country, China is always at the top of the list.

So, I always take papers out of China with a tablespoon or two more than a grain of salt. The only reason I’m even writing about this one is because it confirms other much better research, which we’ll get to later.

The Study

The research followed over 5,200 Chinese adults aged 80 and older. The researchers identified 1,454 people who made it to 100 and compared them to 3,768 folks who died before hitting that milestone. Here's what caught everyone's attention: the people who avoided animal products entirely—especially vegans—were less likely to reach centenarian status.

But here's where it gets interesting from a low-carb perspective. The study found that three lifestyle factors stood out as most important for reaching 100: never smoking, exercising regularly, and having dietary diversity. Notice what's not on that list? They specifically removed body mass index (BMI) and alcohol consumption from their final "healthy lifestyle score" because these factors didn't show the expected associations with longevity in this very old population.

But What About the Carbs?

Here's what bothers me about this study and how it's being reported. Nowhere does it examine carbohydrate intake. The researchers focused on whether people ate meat or not, but they completely glossed over what these folks were eating instead of meat. If they’re vegans, all they can be eating are rice, noodles, and other refined carbohydrates with some vegetables thrown in.

The study talks about "dietary diversity," but their definition is pretty vague. They looked at consumption of fruits, vegetables, fish, beans, and tea. That's it. No mention of bread, rice, pasta, sugar, or processed foods. It’s impossible to determine what the subjects were really eating.

Here's what we do know from metabolic research that this study doesn't address. Chronically elevated blood sugar and insulin resistance are major drivers of aging. When you're constantly spiking your blood glucose with refined carbs, you're essentially accelerating the aging process through several mechanisms: glycation, inflammation, and insulin resistance.

The real irony? A well-formulated ketogenic diet—one that's actually quite restrictive—has been shown in numerous studies to improve markers of metabolic health, reduce inflammation, and even promote autophagy. Yet this study would probably categorize such a diet unfavorably because it lacks "dietary diversity."

Another issue with this study is the negative association between vegetarian diets and longevity was seen only in underweight participants. This tells us something crucial. Thanks to the lack of meat in their diets, the vegetarians are probably not getting adequate nutrition.

Elderly people face unique nutritional challenges. They need protein to maintain muscle mass, they need B12 for cognitive function, they need adequate calories to prevent wasting. A poorly planned vegetarian diet can fail on all these counts, especially if it's heavy on rice, bread, and pasta—the foods that often replace animal products in traditional diets. Even a well planned vegetarian diet can fall short unless it is supplemented.

When you dig into the details, this study is less about the dangers of vegetarianism and more about the importance of adequate protein and key nutrients in very old age. The people who ate fish, eggs, or dairy (pesco-vegetarians and ovo-lacto vegetarians) did just fine compared to meat eaters. It was only the vegans who showed worse outcomes. Which, given the info in the study on DEAF1, should not come as a surprise.

Foods of animal origin include complete proteins with all essential amino acids, vitamin B12 (crucial for brain health and found only in animal products), easily absorbed forms of iron and zinc, omega-3 fatty acids (especially in fish), and such fat-soluble vitamins as K2.

When your diet includes adequate protein and fat from these sources, you naturally eat fewer carbohydrates. You feel fuller, your blood sugar stays stable, and you avoid the glucose rollercoaster that accelerates aging.

What I find interesting about this paper is that it more or less shows what the work of one of my favorite researchers, Michael Rose, has found. Dr. Rose is an evolutionary biologist who has worked with thousands of generations of fruit flies.

He has determined the ancestral diets of fruit flies. And has fed fruit flies their ancestral diet for thousands of fruit fly generations. He has also fed fruit flies novel diets that would compare to humans going from hunting to agriculture.

What he has found is that early on, it doesn’t much matter what the fruit flies eat. They could eat the neolithic version of the fruit fly diet and do fine (or even better than those on the ancestral diet), but as they aged, those flies converting to the ancestral diet had the greatest longevity.

Now you may think fruit flies can’t be compared to humans, and they can’t on a one to one basis. But how else can lifespans be calculated in a research lab? Even mice live a couple of years, and it would take many a lifetime to follow mice for the equivalent of 10,000 of human existence. Fruit flies have a lifespan counted in days, so their ancestral lives can be measured over a career in research, which is what Dr. Rose and his team have done.

Most of his papers are incredibly math heavy and difficult to understand without a deep mathematical foundation. I had math through 5 years of calculus and found it daunting.

A few years ago, he spoke at an Ancestral Health Symposium and laid out his research in non-mathematical parlance. I was asked to speak at the same conference, but I had a conflict. Had I known Michael Rose was going to be there, I would have bagged my conflict somehow (I don’t even remember now what it was) and gone to the meeting. It was a missed opportunity to meet with one of my academic heroes.

Here is his talk. When you watch it, you will see why the paper discussed above attracted my attention. Enjoy!

Five Steps to a Longer Life

This is not a carryover from the Michael Rose talk, but it’s on the same subject of longevity.

I came across this video on X/Twitter a few days ago and reposted it. Someone replied that it was made with AI. It may well have been, but even if so, it is excellent advice. Excellent advice from which I have profited within a single day. I have a tendency to binge write, and when I do, I sit for several hours at a time. The narrator of the video—be he an AI invention or a real person—says to make a habit of getting up for ten minutes of each hour sitting and taking a walk. I’ve been doing this for just a few days now, and I can’t tell you how much better I feel.

He may be AI, but I agree. And I’m not AI. I endorse all five of his tips for longevity. Watch the video. You won’t regret it.

Odds and Ends

In case you're wondering what happens to your brain when you're sleep deprived...

Fine tuned. Scientists study the exquisite sensitivity of the whiskers on an elephant's trunk. Who knew this? 

Good to know there are still really good, kind, selfless kids in the world. Like this one.

Virtual forest bathing in the most beautiful forests on the planet. 

What if Mozart had been born in 2000? What kind of music might he have written? Something like this, maybe? These guys are amazing!

Newsletter Recommendations

I recently came across a newsletter that I really enjoy. It’s from a doc who is like-minded and has a sense of humor. It comes out each Saturday. It’s short, easy to read, and actionable. Best of all, it’s free. Click on the image below to take a look or click on this link.

Video of the Week

Okay, the VOTW this week is not one I would usually put up because I never watch this guy. I know who he is, but somehow I never get his stuff fed to me on YouTube or X/Twitter, so I never see it.

People send me videos every week, but they are all different. This past week, at least half a dozen people sent me the video below. Which makes me think it must have struck a chord with a lot of folks.

So here it is as the VOTW. If you don’t like it, do not blame me. Blame your fellow readers.

Time for the poll, so you can grade my performance this week.

That’s about it for this week. Keep in good cheer, and I’ll be back soon.

Please help me out by clicking the Like button, assuming, of course, that you like it.

This newsletter is for informational and educational purposes only. It is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment and should never be relied upon for specific medical advice.

Thanks for reading all the way to the end. Really, thanks. If you got something out of it, please consider becoming a paid subscriber if you aren’t yet. I would really appreciate it.

Finally, don’t forget to take a look at what our kind sponsors have to offer: HLTH Code, Precision Health Reports, and Jaquish Biomedical.

And don’t forget my newest affiliate sponsor Lumen. Highly recommended to determine whether you’re burning fat or burning carbs.