How to Upgrade Your Mitochondria (Beginner → Advanced)

People think of mitochondria as the powerhouse of the cell. Mitochondria is the powerhouse of the cell. Mitochondria is the powerhouse of the cell. But that's dead wrong. They are so much more than that. They are living, breathing, dancing signaling networks. Trillions of hormonal factories interspersed throughout your body, and how you choose to live your days, how you choose to feed yourself, feed them, determines everything about you as a human being at the most fundamental level, including how you age. In fact, if you look for the biological signatures that distinguish the longest-lived humans, the superagers, including a of a woman who lived to 117. What stands out in healthy aging is healthy mitochondria. But the amazing thing about mitochondria is that unlike a battery or a car engine, mitochondria can heal, recover, and renew themselves. And you can make them do this starting today with free tools and also cutting-edge performance-enhancing mitochondrial peptides and hormones. Which raises the deeper question: Why do people lose energy as they age, and is that decline reversible? In fact, little spoiler, when I used one of these tools for a week, I felt supercharged. It was insane. And I gotta tell you about it. But at a high level today, we're gonna unpack the tools, the fundamental tools to help you reset and upgrade your mitochondria to accomplish better health at a fundamental level, better energy, better aging, all of it. We're gonna start with the most accessible and free tools and then progress to something that's more experimental. Let's go. Obesity, processed foods, circadian disruption, environmental pollutants, and physical inactivity. A root cause of autoimmune and inflammatory diseases that when it comes to long-term mitochondrial health and your overall health, the fundamentals are critical. Crohn's disease is when your immune system attacks itself. They effectively become more powerful and efficient.

Their metabolic rate in their fat tissue was more than twice.

There are a lot of mitochondria. Now, real quick before we begin, some of you may have noticed I'm trying a new format where I consolidate a series of Stay Curious Metabolism letters covering dozens of papers into a single coherent story. And today that story is all about upgrading your mitochondria, rebooting and upgrading your body's batteries. That said, if you really want to dive into the fundamentals and primary literature, I do encourage you to check out our Stay Curious Metabolism community. It has quickly become one of the best-selling science newsletters on Substack in the world. And I'm proud to say subscribers call it the best investment they've made in their health. For an example, one subscriber Victor said, "I can't believe you provide 40,000 words of graduate-level education for less than the cost of one run to Starbucks per month." Am I blushing? Anyway, if you want to go even deeper with me and gain insights you won't gain elsewhere on all things metabolic health, please check it out after watching this video. But with that said, let's build our roadmap like mitochondria build ATP. In part 1, we're going to talk about free and foundational tools for your mitochondria, things you can do outdoors in the morning, in your kitchen, in your daily routine. Then we'll move to the more advanced tier, part 2, mitochondrial peptides, one that is FDA approved for mitochondrial disease and another remarkable mitochondrial-derived hormone. And then finally, in part 3, we're going to get a glimpse of the future of mitochondrial health. So let's begin part 1, free and foundational tools. Let's start at the beginning of your day, when you wake up to greet the sun. Unless of course you live in Boston in the winter and spend several months of the year like a vitamin D-starved Gollum. Jokes aside, exposure to morning sunlight does something interesting. It kicks off a mitochondrial dance. What do I mean by this? Well, your mitochondria aren't fixed static little batteries. They ebb and flow. They literally fuse together, then break apart in a dynamic process known as fusion and fission. And this mitochondrial dance of fusion and fission is critically important for maintaining mitochondrial function. When mitochondria fuse together, they effectively become more powerful and efficient. But breaking apart, the fission part, matters too. It helps segregate out old, damaged mitochondrial components so they can be broken down and recycled in a process known as mitophagy. Or to simplify and by way of analogy, imagine if the batteries in your phone could merge together in a super battery when demand increased and then split apart to repair themselves. That's basically what's happening in your body with your mitochondria trillions and trillions of times per day. Yeah, trillions with a T. There are a lot of mitochondria. Anyway, this balance between fusion and fission, building up and breaking down, is dictated by light and circadian rhythm. In fact, there was a fascinating paper out of Oxford last year, coincidentally published from the exact same department where I did my PhD, the Department of Physiology, Anatomy, and Genetics, Anyway, it identified the dance of mitochondrial fusion and fission as one of the key drivers of sleep. Now, there are some experiments you just can't do in humans for ethical or practical reasons. Like, you can't gene edit a full human to make mitochondria dance differently. But when researchers manipulate mitochondrial fusion and fission in animals, they can actually alter sleep drive and desire to sleep. And it's a bidirectional dance. Light regulates mitochondrial dynamics, mitochondrial dancing, and mitochondrial dynamics regulate sleep. So, stepping back, if light helps regulate mitochondrial dynamics, and mitochondrial dynamics ultimately dictate the long-term function of basically every organ in your body, we return to that question: what's the actionable insight? Well, here it is. As best you can, get exposure to morning sunlight, or if that's not feasible, get a 10,000-lux lamp. It's like $40 on Amazon. $40 on Amazon. And What a time for mine to break, like literally right now. And minimize exposure to bright artificial light at night. As basic as this sounds, basically what it does is it helps initiate and synchronize the mitochondrial dance, your mitochondrial fusion and fission dynamics, as part of an evolutionarily appropriate circadian rhythm. And in doing so, it likely helps preserve mitochondrial function and health over the long term, over years, over decades, across your whole body. So basically, getting morning sunlight and minimizing exposure to artificial light at night is like getting an orchestra conductor to lead a harmonious symphony. So when the sun comes up, say hi. Stay curious side quest. But now I do need to take you on a little Stay Curious Side Quest because there's a fascinating hypothesis about mitochondria, specifically leaky mitochondria, as a root cause of autoimmune inflammatory diseases. A paper published in Nature proposes something remarkable: that many autoimmune and inflammatory diseases stem from a breakdown of the ancient relationship between your body and your mitochondria. Now, to understand this, you need to remember that mitochondria were once free-living bacteria-like organisms that fused with our cells roughly 2 billion years ago in a process known as endosymbiosis. Endo meaning within or inside, syn meaning together, and biosis meaning living. Endosymbiosis. Basically, your mitochondria are like ancient bacterial refugees that struck a peace treaty with your cells billions of years ago. But consider that because of their foreign origins, mitochondria still retain bacteria-like signatures that our human immune systems can recognize as the other or invader. What are you doing in my swamp? Normally mitochondria are kept safely within the cell, but under conditions of stress and dysfunction, mitochondria contents can leak out and trigger inflammatory immune signaling. And the researchers argue that this break in endosymbiosis, or leaky mitochondria, may be one of the root causes of inflammatory and autoimmune diseases, things like inflammatory bowel disease. Yeah, when I was 15, I just started going to the bathroom 8, 9, 10 times a day, not digesting any food. Lupus, rheumatoid arthritis, multiple sclerosis. In other words, autoimmune diseases may represent a breakdown in the diplomatic relations between our cells and their ancient bacterial energy partners, mitochondria. And really importantly, what seems to drive leaky mitochondria in the first place? Features of modern living: obesity, processed foods, I'm making waffles, circadian disruption, environmental pollutants, and physical inactivity. So, am I saying that routine trips to McDonald's can break open your mitochondria, causing spillage that triggers chronic disease? Well, I'm not not saying that. Stay curious, SciQuest. Now, I want to get back to our main narrative, but before I get to the more advanced topics, I want to emphasize that when it comes to long-term mitochondrial health and your overall health, the fundamentals are critical: sleep, exercise, avoiding environmental pollutants as best as you can, eating a minimally processed diet. If you aren't doing those things, then finagling at the margins like we're about to do is kinda like adding a multivitamin gummy onto a fast food diet. That said, if your foundations are nearly optimized, there may be ways to further top off your mitochondrial function, upgrade your mitochondria. And one particularly interesting approach is a ketogenic diet. Now, you've probably heard of ketogenic diets in the context of weight loss, blood sugar control, or generating ketone bodies to fuel the brain. But their effects appear to extend further and much deeper into the foundation of our energy metabolism. Affecting our mitochondria. After all, if you cut carbs and shift your entire body's metabolism from running on carbs to running on fat, maybe it's unsurprising that the organelles responsible for generating energy from fat, mitochondria, change as well. Specifically, when animals are fed a ketogenic diet, their mitochondria appear to become physically larger, more numerous, and more powerful. You can see that here. This is an electron microscopy image, and the M is visible enlargement of the mitochondria on a ketogenic diet. You can also take a look at the L. These are lipid droplets. Unlike the mitochondria which became bigger, the lipid droplets become smaller, more numerous, effectively increasing surface area and improving the tissue's ability to burn fat for energy. So in other words, ketogenic diets literally remodel fat tissue towards enhanced fat burning. Bigger mitochondria and smaller, more numerous lipid droplets. And if you think about it, this makes perfect sense. If carbs become scarce, your body needs to upgrade the machinery required to run on fat, including mitochondria. Now, I did say animal data. Do we see any signals in the human data? We do. In human-controlled feeding studies, when carb calories are progressively swapped for fat calories while trying to maintain weight, energy expenditure in humans increases on the lower-carb diets. And when researchers take muscle biopsies from these humans in these studies, what do they find? Increased mitochondrial power. In other words, exactly the sort of mitochondrial adaptations we'd expect. But don't just take my word for that. I actually reached out to the lead author of this research, Professor Ben Bikman, a respected academic name you guys know and a friend of mine. Here's what he had to say.

What we found is that when ketones are elevated, fat cells are burning faster, or in other words, their metabolic rate went up. In fact, we confirmed this in all three commonly used biomedical models: in fat cells grown in a petri dish, in adipose tissue from rodents, and even adipose tissue from humans. Where we took little fat biopsies from the belly. In fact, in the humans, when they were in ketosis, their metabolic rate in their fat tissue was more than twice of what it was when their ketones were not elevated.

So now a bigger picture starts to emerge. At the microscopic level, ketogenic diets and lower-carb diets remodel mitochondrial structure and function. And at the whole body level, humans exhibit increases in mitochondrial capacity and energy expenditure when on ketogenic diets. Okay, I swear, last tangent, then we're gonna get onto the more advanced tools. But I do need to tell you about a foundational tool and a new paper that came out yesterday as I record this that blew my mind. It was published in Nature Aging, July 3rd, 2026. And what they did was they took muscle biopsies from humans, young adults and older adults split across the fitness and training spectrum. So trained, normal, and then physically impaired. And they asked the question, what changes in human muscles in terms of gene expression as we age and what doesn't if adults are trained and fit. And the punchline is in trained, fit older adults, 55% of the gene expression changes we associate with age didn't happen. They were absent. And those 55% were enriched in mitochondrial and energy metabolism pathways. So the punchline is those changes we think happen in muscle with age to slow your metabolism, decreases in mitochondrial complex 1 and 4, for example, they don't happen if you stay trained, fit, and exercise. So really what I'm saying here is that exercise isn't just building a muscular reserve, it changes the operating system of your mitochondria to preserve youth as you age. How amazing is that? But more information below. But now, as I promised, we're going to get to the more advanced topics. But now let's move to something more cutting edge. What happens when we target mitochondria directly? This brings us to part 2, mitochondrial peptides. Let's take things a step further and talk about peptides, starting with one called SS31, which stands Super Soldier 31. Not really, I totally made that up. But wouldn't that be cool? Anyway, to understand why SS31 matters, you need to understand a bit more about mitochondrial biology, so hang on with me while we dive into the mitochondria, literally. Inside mitochondria is a highly folded inner membrane where energy production actually occurs. It's like packing an entire power plant into microscopic origami folds. And embedded Within that inner mitochondrial membrane are the complexes of the electron transport chain, the literal machinery that generates ATP energy keeping you alive. Now let's double-click on those inner membrane folds. These are critical. They do two things: one, they increase surface area for energy production, but maybe more importantly, they organize how the machinery in mitochondria interacts with one another. By way of analogy, and sorry to mix analogies, it's like if you're cooking a dish. You want all the ingredients and tools in one place, what the French call mise en place, rather than running around to grab ingredients and tools as you're cooking. This is much more efficient. And this is kind of how mitochondria work—the inner membrane organizes the complexes needed to generate energy. Okay, now enter something called cardiolipin. Cardiolipin maintains the structure of this inner membrane and thereby provides essential support for mitochondrial energy production. Or to extend the origami analogy from earlier, cardiolipin acts like adding glue to your origami power plant. Really holds the structures together, at least when you're healthy. But when cardiolipin isn't doing its job to support mitochondria, energy metabolism begins to fall apart at the most fundamental level. There are in fact human defects in cardiolipin that manifest in a condition known as Barth syndrome, with muscle weakness, heart problems, and extreme fatigue. More on Barth syndrome in a moment. Anyway, as mitochondria become damaged with aging and disease, cardiolipin becomes destabilized, which means mitochondrial structure literally deteriorates, and energy production starts to fail. This is where our peptide friend SS31 finally comes in to rescue the day. "Stay! Stay!" "I left!" "Come on!" SS31 is a mitochondrial-targeting peptide that homes to the inner mitochondrial membrane like a smart heat-seeking missile, binds to cardiolipin itself, and helps stabilize the machinery responsible for energy production in your mitochondria. So if cardiolipin is like Elmer's glue, the SS31 turns it into super glue, And this isn't just fringe biohacker speculation—SS31 was FDA-approved for Barth syndrome, a devastating rare mitochondrial condition characterized by cardiolipin dysfunction. Wow, we deployed that knowledge on Barth syndrome pretty fast. Now, in a randomized placebo-controlled human trial, SS31 improved fatigue and physical performance in these patients. But I know what you're thinking. I don't have Barth syndrome. You don't have Barth syndrome. Almost none of you have Barth syndrome. But mitochondrial dysfunction is not unique to rare diseases. It's a hallmark of aging itself, along with chronic diseases like heart disease, diabetes, neurodegeneration, and metabolic dysfunction more broadly. That is why researchers are now exploring SS31 in the context of heart disease, Alzheimer's disease, diabetes, and so on. The preclinical literature on SS31 is really promising. SS31 has been shown to preserve mitochondrial structure, reduce scarring of the heart after injury, restore mitochondrial integrity in diabetic retinas, and even improved cognitive function in animal models of Alzheimer's disease. Which is freaking cool! Now, to be clear, this does not mean SS31 is some proven anti-aging peptide miracle. Human efficacy data remains limited outside of this rare mitochondrial disease we talked about. But if you want a glimpse into the future of mitochondrial medicine, it might be worth watching this molecule. With that, let's pivot and talk about another mitochondrial peptide that's become increasingly popular and better known than SS31. It's called MOTC. Now, MOTC is a peptide, but I like to call it a mitochondrial hormone because it's that as well. MOTC is actually encoded by the mitochondrial DNA itself. That's right, mitochondria don't just generate energy, they also have their own miniature genomes, which is a remnant of their ancient bacteria-like origins. And this mitochondrial DNA is capable of producing signaling molecules called mitokines, which literally means mitochondrial hormones, including MOTC. Now, one thing that makes MOTC interesting to me is that it's naturally stimulated in humans by exercise. In human studies, exercise increases MOTC levels nearly 12-fold within muscle. MOTC kind of functions like an internal exercise memo sent from mitochondria to the rest of the body. So that begs the question, what if you just give the MOTC exercise memo even without exercise? Well, animals treated with MOTC demonstrated dramatic improvements in endurance and power. In one experiment, 16.6% of control animals could complete the highest treadmill speed on a running test. But when they were given MOTC, 100%, every single animal could beat the test, completely obliterate the test. Whoa! And it wasn't just exercise performance. MOTC also reduced fat gain while preserving lean mass. At a very high level, you can think of MOTC as a mitochondrial signal telling the organism, the whole organism, to adapt, become stronger, faster, better. With that, I do want to emphasize MOTC is experimental, and this is very much a don't necessarily do what I do sort of situation. That said, I did have to experiment with it myself. I ran a short week-long cycle over which I wouldn't expect major changes in body composition, but I absolutely noticed my exercise performance increased. Particularly with endurance. For example, during my high-intensity interval sessions, my times improved, my fatigue diminished. In general, workouts just felt more easier and more pleasurable. I also noticed a strong spontaneous drive to move throughout the day even more than normal, which ultimately showed up in activity metrics. Since I started this MOTC a few days ago, I just had this incredible compulsion to move, like 18, 20, 22,000 steps per day spontaneously. I've actually been taking a lot of my calls outside. Because I just don't want to sit down, which also means I'm getting more sunlight, which makes a nice little self-reinforcing mitochondrial health loop. How about that? And my experience lined up remarkably well with both the animal literature and a growing body of anecdotal reports emerging from the biohacker community. To share just a few comments I received from friends after I did my experiment, people say things like, "It feels like an amplifier for my morning workout," or, "It's like having an extra gear I didn't know I could access." or "My afternoon fatigue just vanished. Poof." Those are the kind of comments people are reporting when taking MOTC. So if SS31 is about stabilizing the structure and machinery of mitochondria, MOTC appears to be more about metabolic signaling, adaptation, and resilience. And together they offer a fascinating glimpse into what the future of mitochondrial medicine might look like. But that brings us to this future, part 3: the future of mitochondrial health. Because peptides like SS31 and MOTC may just be the beginning. In fact, we're already seeing early work on something that seems fantastical, ambitious: mitochondrial transplantations. Don't let it touch your eyes! Ah! Eyes! Eyes! While this sounds like science fiction, there are already compelling animal data and even early-stage human trials beginning to emerge. For example, a recent 2026 study published in Cell explored transplanting mitochondria wrapped in red blood cell membranes into animals to rescue mitochondrial dysfunction. And in a mouse model of Parkinson's disease, which is typified by mitochondrial dysfunction, these mitochondrial transplants reduced neuron loss, improved motor function, and restored mitochondrial activity within the affected brain regions. This isn't just incremental progress. It's a leap forward in regenerative medicine. I'm getting goosebumps just talking about it. Seriously, imagine not far from now having a a literal mitochondrial bioreactor in your kitchen, maybe next to your coffee machine, generating fresh, highly functional mitochondria that can be infused back into the body periodically, maybe paired with compounds like SS31 to heal and preserve the integrity of mitochondria. I know that sounds futuristic, but here's what I need to tell you: that future is closer than most people think.