Biological systems are self-maintaining. They have to be. Your cells are little factories, performing tasks crucial to maintaining this thing we call life. And just like in factories, machinery (organelles) break down. Waste (metabolic byproducts) must be managed. Security teams need to be in place to keep intruders (bacteria and viruses) from disrupting operations.
For life to sustain itself, cells must perform this crucial work themselves. It’s not like we can send in microscopic maintenance workers, mechanics, and security details to handle the dirty work from the outside. Not really, not yet anyway. One of the most important types of biological maintenance is a process called autophagy.
Not that long ago, nobody except the most hard-core biohackers talked about autophagy. It has become a hot topic, though, as scientists have made considerable progress toward understanding the ins and outs of autophagy in the past few decades. Now, anyone with a passing interest in longevity or intermittent fasting tosses the word around in casual conversation.
But for all the popular interest in autophagy, I’m willing to bet that the average person doesn’t understand it all that well. They probably believe that autophagy is desirable, and they may know that intermittent fasting will net them more of it, but that’s about it. So today I’m going to answer some autophagy FAQs—what it is, how to induce it, and where you may need to be cautious.
What Is Autophagy?
Autophagy: the word comes from the Greek for “self-eating,” and that’s a very accurate description. There are several different types of autophagy. The one that we generally mean when we say “autophagy” involves organelles within the cell called lysosomes “eating”—or rather, using enzymes to degrade—parts of the cell that are damaged or malfunctioning.
The overarching goal of autophagy is to maintain homeostasis within the cell—to keep the factory running smoothly. It’s a type of cellular recycling process, allowing organelles, proteins, and other structures to be broken down and reused by the cell for energy or building new components. Lysosomes can also degrade pathogens that threaten the integrity of the cell.
What Activates Autophagy in the Cells?
Autophagy is operating all the time to manage the basic cellular housekeeping, but anything that threatens homeostasis in the cell will ramp it up. Oxygen deprivation (hypoxia), DNA damage, infection, or cellular damage due to factors like oxidative stress can all trigger a rise in autophagy. The trigger we talk about most is nutrient deprivation.
Your cells are exquisitely tuned in to how much energy is available. They have multiple systems in place to sense if energy supplies are adequate and to flag when they are low. When energy is abundant, autophagy operates in the background; but when your cells sense that energy is low, they go into conservation mode, and autophagy really kicks in. You can understand why this would be. In lean times, your cells must be more frugal, using what they already have on hand. Breaking down damaged proteins and organelles for firewood and parts to build new machines, so to speak, just makes sense.
Some of the signals that indicate low energy availability and dial up autophagy are low glucose, low insulin, low mTOR signaling, high AMPK, and high glucagon. Not coincidentally, these are the same biological markers that characterize a fasted metabolic state.
The reverse is also true, when glucose, insulin, and mTOR signaling are high, and AMPK and glucagon are low, autophagy is inhibited. (This, by the way, is why we say that protein intake breaks a fast. Because when you eat protein, especially the amino acid leucine, you activate the mTOR pathway and downregulate autophagy.)
What Roles Does It Play in the Body?
By maintaining homeostasis and preventing cell damage, autophagy contributes to the health of all your tissues and organs. Its specific effects depend somewhat on where the cells in question are located.
In the liver, autophagy kicks in during fasting to degrade proteins into amino acids that can be used for energy production, thus maintaining whole body energy levels even in the absence of incoming food.1
In the muscles, autophagy enables the building of strength and endurance when we exercise. Muscle damage is a hallmark of exercise and is crucial to the adaptation process, but without autophagy, muscles couldn’t recover from said damage.23
In the brain, autophagy helps clear out the waste and debris that would otherwise accumulate in neurons and lead to cognitive decline. Scientists are actively working on developing strategies to upregulate autophagy in the brain as a means to stave off and treat neurodegenerative diseases like Alzheimer’s and Parkinsons—devastating conditions for which existing treatments have proven largely ineffective.4
So Autophagy Is Always Desirable, Right?
Not so fast. I see a lot of people out there undertaking extreme fasting regimens or other biohacking strategies in the name of maximizing autophagy. This seems ill-advised given that we don’t know if more autophagy is necessarily better. In fact, we know there are times when it is not.
There’s the fact that unchecked autophagy can increase existing cancer in some cases. There’s the fact that too much autophagy in the wrong place might be bad. There’s the fact that most things in nature follow the Goldilocks principle: too much is bad, and too little is bad. The “just right” amount is somewhere in the middle.
At this point, we simply don’t know what “optimal autophagy” looks like. We know it’s important, but scientists are still working to decipher when it’s good (most of the time, probably) and when, and under what circumstances, it becomes problematic.
When Does Autophagy Start? What Are the Signs That It’s Taking Place?
The biggest conundrum for those who are interested in optimizing autophagy is that we can’t really measure it. Scientists have identified various biomarkers that signal that autophagy is taking place, but they aren’t the kinds of things we can see in real time in a person walking around in a fasted state. There are no continuous autophagy monitors to slap on the backs of our arms that will tell us how much autophagy is happening in our cells—yet.
In lieu of that, probably the best proxies we have right now are metabolic markers that our bodies are in a fasted state—low glucose, low insulin, high ketones, high glucagon. But here we have the measurement problem again. With the exception of glucose, we can’t continuously monitor these variables. And even if we could—and I do expect that continuous ketone and insulin monitors are coming soon—we still don’t know what exactly we’re aiming for.
The bottom line is, we can only infer that autophagy is happening because we are subjecting our bodies, and hence our cells, to desirable, adaptive stressors. That’s about what we have to go on.
How to Induce Autophagy
I just got done telling you that we can’t monitor autophagy and that it’s not always good—but that doesn’t mean we don’t want to induce it. We do. We must. And the way we do it is by engaging in the types of behaviors that we talk about here all the time. Fasting and exercise—both high- and low-intensity—are two of the most prominent, but there are others. Anything that stresses the cell will likely induce autophagy.
What to Do with This Information
This can’t be underscored enough: Autophagy is a long game, a lifelong pursuit attained by regular doses of exercise and not overeating every time you sit down to a meal. Doing epic seven-day fasts every month, making sure you end every day with fully depleted liver glycogen, never going over 20 grams of carbs in a day—these strategies might be “effective,” but obsessively trying to hit some “perfect” level of constant autophagy isn’t the point and is likely to activate or trigger neurotic behavior.
Autophagy happens largely when you just live a healthy lifestyle.Be active. Go hard every now and then. Sleep deeply. Recover well. Don’t eat carbohydrates you don’t need. Reach ketosis sometimes. Don’t eat more food than you need.
Start with those basics. Once you have them nailed, and all caveats aside, I see the utility in doing a big “autophagy session” a few times a year. Here’s how mine looks:
Do a big training session incorporating strength training and sprints. Lots of intense bursts. This will trigger autophagy.
Fast for a couple days. This will push autophagy even further.
Stay busy throughout the fast. Take as many walks as possible. This will really ramp up the fat burning and get you quickly into ketosis, another autophagy trigger.
Drink coffee throughout the fast. Coffee is a nice boost to autophagy. Decaf is fine.
I know people are often skeptical of using “Grok logic,” but it’s likely that most human ancestors experienced similar perfect storms of deprivation-induced autophagy on occasion. They tracked an animal for a couple days and came up short. They nibbled on various stimulants plucked from the land along the way. They walked a ton, sprinted some, and lifted heavy things. And then they ate.
If you find yourself aging well, you’re on the right track. If you’re not progressing from insulin resistance to diabetes, if you’re maintaining and even building your muscle despite qualifying for the blue plate special, if you’re thinking clearly, I wouldn’t worry.
That’s it for today, folks. If you have any more questions about autophagy, leave them down below and I’ll try to get to all of them in future posts.
Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.