Summary
Andrew Huberman speaks with Dr. Gabrielle Lyon, a board-certified physician trained in geriatrics and nutrition, about how skeletal muscle is the organ of longevity and why maintaining muscle health is central to preventing disease, preserving brain function, and extending healthspan. Dr. Lyon argues that the primary problem in metabolic disease is not being "over-fat" but "under-muscled" -- that healthy skeletal muscle serves as a metabolic sink for glucose, produces anti-inflammatory myokines during contraction, and generates BDNF that supports brain health.
The conversation provides specific nutritional recommendations: consuming at least 30-50g of quality protein in the first meal to trigger muscle protein synthesis (the leucine threshold), distributing protein across 3-4 meals, and aiming for 1g per pound of ideal body weight daily. They discuss animal vs. plant protein bioavailability (animal protein produces higher muscle protein synthesis rates in matched studies), why protein does not increase cancer risk through mTOR at recommended levels, the role of creatine supplementation, and why older adults need more protein and resistance training, not less. For exercise, Dr. Lyon emphasizes "high ground" compound movements (squats, deadlifts, overhead press), maintaining VO2 max, and the importance of starting resistance training at any age.
Key Points
- Skeletal muscle is the organ of longevity: it serves as a glucose sink, produces anti-inflammatory myokines, generates brain-supporting BDNF, and protects against metabolic disease
- The first meal should contain 30-50g of quality protein to reach the leucine threshold needed to trigger muscle protein synthesis
- Total daily protein intake should target approximately 1g per pound of ideal body weight, distributed across 3-4 meals
- Animal protein produces measurably higher muscle protein synthesis rates than isocaloric plant protein in controlled studies
- Older adults need more protein and resistance training, not less -- muscle protein synthesis becomes less efficient with age, requiring higher stimulus and intake
- Creatine monohydrate (3-5g daily) supports both muscle and brain health with strong safety data across decades of research
- "High ground" compound movements (squats, deadlifts, overhead press, rows) provide the most efficient stimulus for building and maintaining functional muscle mass
Key Moments
Carbs and resistance training: hard lifting for 1 hour only burns 200-300g extra glycogen
Most people quickly exceed 130g of carbs daily. An hour of hard resistance training only affords an extra couple hundred grams of carbohydrate use, and the brain itself is highly metabolically active.
"Even if exercising with resistance training, say hard for an hour, which can afford somebody maybe another couple hundred, 300 grams of carbohydrates — probably not that much."
40% of women over 60 are protein-deficient — even without lifting, more protein helps
The average woman eats only 68g protein daily, and 40% of women over 60 eat below the RDA. The body turns over 300g of protein daily. Eating for skeletal muscle needs means everything else falls into place.
"But when we think about muscle protein synthesis, there's really four inputs. There's resistance training, there's energy, there's insulin, growth hormones, and then there's leucine. When you are younger, your body is driven by more of the anabolic hormones, which is one reason why we believe that a younger individual can get away with 5 to 10 grams to 15 grams of dietary protein. Because their levels of testosterone and or estrogen are driving protein synthesis in a way that lets them offset any dietary deficiencies? Well, that their body is just highly anabolic. They're growing. They're growing up. They're growing. When an individual like your mom, who's now stopped growing, the body becomes much more reliant on leucine and resistance training because the main pathway that these things go towards is something called mTOR, mammalian target of rapamycin. The influence on those pathways changes as we age. So the lever in which you pull changes, and the importance of that lever changes. So the best thing that your mom could do to maintain skeletal muscle, so why and what happens to skeletal muscle as we age? Skeletal muscle, if it is not contracted and utilized, gets this fat infiltration, mitochondria changes, protein turnover changes, it becomes less efficient at sensing amino acids, there's a decrease in capillary perfusion, which is one reason why exercise is so important. In order for her skeletal muscle to respond like a younger muscle, what she should do is do some kind of resistance training and then add in some kind of dietary protein."
Resistance training releases myokines that stimulate BDNF and neurogenesis in the brain
Skeletal muscle releases cathepsin B and irisin during training, which stimulate BDNF release in the brain. BDNF consolidates neural connections and counteracts age-related decline in gray matter volume.
"When you train and you release these myokines, which are based on the intensity and duration of your activity, release something called capsepsin B and irisin, these myokines then stimulate BDNF release in the brain."
Unskilled lifters should use machines — the goal is always hypertrophy, not just maintenance
Dr. Lyon recommends machines over free weights for unskilled lifters to avoid injury. The goal should be hypertrophy because maintaining and growing muscle gets harder with age. Rule one is train but don't get hurt.
"It is hard to achieve, but you must focus because maintaining and growing skeletal muscle mass as you age, it becomes much more challenging. And so choosing high ground movements, I would not have someone who is an unskilled lifter go in and do a front loaded goblet squat."
Protein timing matters more if you're older: eat within 1 hour of lifting
If you're young and eating 1g per pound of protein, timing doesn't matter much. But older adults or those on lower protein diets should consume protein within an hour of resistance training to lower anabolic resistance.
"However, if you're older and you want to take advantage of resistance training plus dietary protein than consuming within an hour or so. And again, that number is, the way in which I think about it is really about that blood flow, is how long that blood flow is still getting to the skeletal muscle because you're delivering nutrients. If you are older or have a chronic condition, then there would be no downside. And there is evidence in the literature if you consume dietary protein around resistance training due to that synergistic effect, if you are eating a lower protein diet and or older."
Strength training improves VO2 max, blood pressure, triglycerides — not just cardio
Improving strength and hypertrophy also improves VO2 max, blood pressure, triglycerides, and fasting glucose. Higher protein diets can show elevated blood glucose and creatinine, which is usually benign in muscular people.
"Individuals that take urolithin A, I happen to be one of them, there are many papers out there that it improves mitophagy, which is the health of mitochondria, the turnover of mitochondria, helps with the renewal of mitochondria. But what's so fascinating is there are trials in human individuals that it increases strength and endurance. Interesting. What milligram doses do you recommend? So I take between 500 and 1,000 of urolithin A. Really, I wish that I had actually created this or found this out. Truly, if I could make one supplement, I know, I would probably make a mix of urolithin A with creatine and some whey protein and maybe 25 milligrams of collagen. And I would have my perfect supplement. Is it taken with food or without food? It doesn't matter. Interesting. Morning or night? It also doesn't matter. What's so interesting about urolithin A is that it comes from, again, it's made in the gut from the gut microbiome from things like pomegranate or walnut. It's made from something called an alagitannin. And it is really, again, what I think of as this gut muscle connection, which I do believe is going to be the next frontier. So interesting. I recall a few studies that Dr. Andy Galpin put on his social media. These were in mice, mind you, but looking at how disruption of the gut microbiome could offset some of the strength and hypertrophy increases of resistance training, pointing to the fact that having a healthy gut microbiome is critical for translating resistance training into actual improvements in muscle health. Yes. And one of the things that we do see is that as individuals increase their activity, talking about more endurance type running, there's this very interesting inflection point. There's this idea of optimal performance."
Creatine plus urolithin A: Dr. Lyon's dream supplement stack for muscle and mitochondria
Dr. Lyon recommends creatine monohydrate (especially for postmenopausal women) plus urolithin A (500-1000mg) which improves mitophagy and increases strength and endurance via a gut-muscle connection.
"Individuals that take urolithin A, I happen to be one of them, there are many papers out there that it improves mitophagy, which is the health of mitochondria, the turnover of mitochondria, helps with the renewal of mitochondria. But what's so fascinating is there are trials in human individuals that it increases strength and endurance. Interesting. What milligram doses do you recommend? So I take between 500 and 1,000 of urolithin A. Really, I wish that I had actually created this or found this out. Truly, if I could make one supplement, I know, I would probably make a mix of urolithin A with creatine and some whey protein and maybe 25 milligrams of collagen. And I would have my perfect supplement. Is it taken with food or without food? It doesn't matter. Interesting. Morning or night? It also doesn't matter. What's so interesting about urolithin A is that it comes from, again, it's made in the gut from the gut microbiome from things like pomegranate or walnut. It's made from something called an alagitannin. And it is really, again, what I think of as this gut muscle connection, which I do believe is going to be the next frontier. So interesting. I recall a few studies that Dr. Andy Galpin put on his social media. These were in mice, mind you, but looking at how disruption of the gut microbiome could offset some of the strength and hypertrophy increases of resistance training, pointing to the fact that having a healthy gut microbiome is critical for translating resistance training into actual improvements in muscle health. Yes. And one of the things that we do see is that as individuals increase their activity, talking about more endurance type running, there's this very interesting inflection point. There's this idea of optimal performance."
Ibuprofen, statins, and fluoroquinolones can all sabotage muscle growth
High-dose ibuprofen and NSAIDs can suppress hypertrophy. Statins deplete CoQ10 and cause myalgia. Fluoroquinolone antibiotics damage collagen and tendons. Proton pump inhibitors reduce vitamin/mineral absorption.
"One thing that people often use is ibuprofen. And ibuprofen, while not inherently bad, there's some evidence to suggest that higher doses of ibuprofen can impact muscle health, whether it's hypertrophy or strength."
Dr. Lyon's exercise hierarchy: resistance training non-negotiable, then HIIT over steady-state
Prioritize protein first, then carbs based on metabolic health, then fat. Resistance training is non-negotiable starting at 2 days/week. Choose HIIT over steady-state cardio for more impact in less time.
"Resistance training is non-negotiable. The only way someone could do it wrong is to not do it. Then add high-intensity interval training over slow steady state cardio."
