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How to Increase Metabolic Autophagy and Why You Should

Analysis by Dr. Joseph Mercola Fact Checked

Story at-a-glance -

  • Autophagy refers to the biological process in which your cellular parts are recycled and converted back into replacements. It’s a recycling mechanism that prevents the accumulation of old and worn-out organelles
  • Autophagy gets activated during nutrient starvation and energy deprivation. Whenever your body is deficient in vital nutrients, autophagy is activated, allowing your body to recycle components. You can get similar results through intermittent fasting and regular fasting
  • When it comes to muscle building, the timing of anabolism activation can make a big difference. To optimize muscle building, do heavy resistance training while in a fasted state and then refeed directly afterward. Eating a small amount of protein before your workout can also be beneficial
  • Working out fasted might slightly reduce your maximum performance, but you don’t need to work out at your personal max to improve strength and muscle development
  • As you age, growth hormone levels tend to decline and your ability to synthesize protein and build tissue goes down. As a result, maintaining muscle will require different strategies depending on your age

Siim Land,1 a sociocultural anthropologist, entrepreneur and high-performance coach, is also the author of an excellent book, "Metabolic Autophagy: Practice Intermittent Fasting and Resistance Training to Build Muscle and Promote Longevity (Metabolic Autophagy Diet Book 1)."

I met Land at Dave Asprey's 2019 Upgrade Labs' event, formally known as the Bulletproof Conference, and was impressed with his depth of knowledge. "Metabolic Autophagy" is a marvelous companion book to "Fat for Fuel: A Revolutionary Diet to Combat Cancer, Boost Brain Power, and Increase Your Energy."

That said, it's still a great standalone, as it goes into great detail and provides specific protocols for you to follow. Importantly, it clears up one of the primary confusions about autophagy. A common fallacy is that since autophagy is a good thing, you should activate it continuously. This simply isn't true, and could backfire rather severely, especially if you're older.

One way to remain in autophagy is to minimize protein, and if you're on a chronic low-protein diet, you never really activate anabolism, the building of muscle tissue. Land does a magnificent job of clearing up that confusion and giving very specific cycling protocols to help make sure you're maintaining your muscle mass and getting the full benefits of autophagy.

Intermittent Fasting and Autophagy

Land's interest in autophagy began in high school, when he began doing intermittent fasting. One of his primary aims was to improve his body composition in the easiest way possible.

"At first, I didn't delve into the longevity aspect of it, but after a while, it kind of just emerged — this idea of autophagy and stem cells," he says. "I went down the rabbit hole and started to realize that it's a very critical part of antiaging, as well as just general homeostasis of your cellular functioning.

The reason I started writing the book was because there were a lot of misconceptions about autophagy and fasting. 'It's the best thing. You want to have it all the time.' But coming from this background of doing some amateur bodybuilding, I realized it doesn't actually make sense to chronically activate autophagy.

You don't want to be in this fasted, ketosis state all the time. I wanted to refute some of the misconceptions about it, especially [issues relating to] protein and mammalian target of rapamycin (mTOR) and anabolism, because those are important aspects of healthy aging, like having more muscle."

Autophagy 101

For those who have not studied biochemistry and are unfamiliar with molecular biology, Land does a terrific job of breaking it down to the basics. Reading his book can save you hundreds of hours of reading intense molecular biology literature.

In brief, autophagy translates into "self-eating." It refers to the biological process in which your cellular parts are recycled. "Simplistically put, it's a recycling mechanism that prevents the accumulation of old and worn-out organelles, whether that be broken-down mitochondria, reactive oxygen species [or] inflammatory cytokines," Land explains.

"Autophagy is this process that your body goes through when it wants to or when it needs to repair and heal itself. It has a critical role in many of the diseases that we suffer from. Conditions like insulin resistance [and] liver disease can benefit from autophagy.

Even Alzheimer's and heart failure — they're kind of connected with the processes of autophagy. Deficient autophagy has been shown to be very causative for those things and promotes these diseases."

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How to Activate Autophagy

Autophagy gets activated during nutrient starvation and energy deprivation. Whenever your body is deficient in critical nutrients such as amino acids, proteins, carbide, glucose or carbon, just to name a few, autophagy is activated, allowing your body to recycle these components.

Other downstream pathways also come into play to support this rejuvenating process, such as sirtuins, AMP-activated protein kinase (AMPK) and forkhead box (FOX) proteins. "All of them have been found to be the central components of longevity when it comes to things like caloric restriction and exercise," Land says.

"In mice … blocking autophagy while being on caloric restriction doesn't promote [increased] lifespan, whereas when they have autophagy activated, then they will live longer when put on caloric restriction. Caloric restriction is one of the few known ways of promoting lifespan and one of the most effective ways.

Actually, the focus shouldn't be on caloric restriction. The focus should be on autophagy, because if you won't get autophagy even when you're storing, then you won't see those desired benefits. That's one of the critical components."

The problem with calorie restriction is that it's enormously difficult to do, and compliance is low. The good news is that calorie restriction is not necessary. You can get the same results through intermittent fasting and regular fasting. Calorie restriction also has drawbacks, such as malnutrition, frailty, loss of muscle mass and bone density, for example, which are side stepped when intermittently fasting.

"Intermittent fasting is literally like biohacking caloric restriction, because you mimic most of the benefits of caloric restriction. You will get more autophagy from intermittent fasting because you're in a fasted state and you don't necessarily need to restrict your calories, restrict your protein or become malnourished to gain those benefits."

Like me, Land uses a restricted eating window, eating all of his meals within four-hours every day. I use a four- to five-hour window. Importantly, this is not the same as calorie restriction. You're not restricting the amounts of calories you consume; you're simply restricting the time in which you eat them, and by so doing, you're able to activate autophagy.

Autophagy Is Easily Disrupted by Food

As explained by Land, even small amounts of food will inhibit autophagy. "Eating a bagel is going to stop autophagy. That's literally the breakfast of most people in the world," he says. "They're immediately inhibiting the benefits of caloric restriction and the benefits of intermittent fasting if they break autophagy immediately in the morning."

The key is to maintain a close-to-zero-calorie state that isn't going to raise your insulin and put you in an anabolic state (which is a fed state). In other words, the fasted state is what allows your body to remain in autophagy. Granted, there are degrees of inhibition depending on the type of nutrients you eat. Land explains:

"The nutrient status is being constantly monitored by fuel censors like mTOR, the main growth pathway. The opposite of that is AMPK. These two are like the yin and yang of your metabolism. They're constantly monitoring what kind of fuel is burning through your bloodstream.

Based upon that information, they're going to decide whether they're going to grow or whether they're going to activate autophagy to recycle themselves. Throughout the entire day, those fuel sensors are balancing each other out, so they can't coexist a lot.

Whenever you eat the bagel, the bagel is going to raise insulin levels and activate mTOR and it will put you in the feasted state, which will inhibit autophagy.

But at the same time, if you eat something more along the lines of a ketogenic meal, then that's going to have a significantly lower anabolic response because it doesn't raise insulin and it doesn't have extra amino acids.

So, there's definitely degrees [of autophagy inhibition], with high amounts of carbs and high amounts of protein being more anabolic and more mTOR-stimulating. Things like low-carb, moderate-protein and higher fat, those would be more AMPK-stimulating, [thus] they are able to maintain autophagy for longer or much more easily."

Of course, the length of your fast will also have an effect. For instance, after a 24- or 48-hour fast, your AMPK will be much higher and mTOR significantly suppressed — far more so than after a 16-hour fast. In this case, your buffer zone is greater, meaning certain foods will not have as great an impact on autophagy.

"In that case, taking collagen protein or something that doesn't have the anabolic amino acids … wouldn't interfere with autophagy that much, as long as you stay within a certain threshold of calories," Land says.

Land's Personal Program

Land, who has the physique of a well-trained gymnast, is a sterling role model for how a well-planned program that cycles through autophagy and anabolism can transform your body. His own program typically consists of 20 hours of fasting per day and eating all of his meals within four hours.

When breaking his fast sooner, say after 16 or 18 hours instead of 20, he does it by drinking bone broth or something similar. This breaks the fast, yet doesn't do it completely. "I'll still maintain the semi-fasted state until I have the rest of the calories," he says. He also dispels concerns about losing muscle mass through fasting.

"The truth is you won't be losing muscle when you are fasting as long as you're in ketosis and you're keto-adapted, because your body will become very efficient at using ketones and fat for fuel, and then it becomes much more muscle-preserving.

But at the same time, if you're trying to build muscle, then having some source of amino acids circulating in the bloodstream during exercise or during resistance training will help to maintain more muscle and also help to recover faster.

For that, whenever I'm doing like a heavier resistance training or workout or doing some gymnastic rings or something like that, then I'll have a little bit of protein powder or some collagen protein during the workout to shield any potential negative side effects of working out in a fasted state …

… because at that point, I don't care if I stop autophagy because I've already been fasting for 18 to 20 hours. Having the protein shake isn't going to be interfering with my goals. It's going to actually build [muscle]."

Catabolism/Anabolism — You Need Both but Not Simultaneously

There are two distinct metabolic pathways you can activate: autophagy (catabolism, the breakdown or repair of your tissues) and mTOR (anabolism, which is the rebuilding process). The mTOR pathway is essentially a protein sensing pathway, and is activated by protein and insulin.

I used to be overly concerned about activating mTOR, thinking it was probably best to avoid activating it as much as possible, as mTOR is a major driver of chronic disease and aging. This isn't completely true and Land's book does an excellent job of clearing up this common misconception.

As with autophagy, you don't want mTOR chronically activated, but you do want to cyclically activate it on a regular basis. Now, if you're doing a two-day fast, that's not the time to do heavy resistance training, because that would result in trying to activate anabolism and autophagy at the same time. It's like pressing the brake and accelerator on your car simultaneously, which isn't a good idea. So, when fasting, remember why you're doing it. Land explains:

"You can't really build muscle doing extended fasts. The goal of any prolonged fast is to go into deeper autophagy and essentially promote cellular clearance [and] heal yourself.

At that point, I don't see a point in trying to have a heavy resistance training workout, because first of all, you don't have enough energy to actually reach your personal record. Secondly, your body doesn't respond to it as beneficially. You may potentially just put additional stress on your body.

What I like to do on these longer fasts is some easier workouts with body weight or resistance bands just to stimulate the muscle. That would just signal the body that it still needs to preserve more lean tissue. If I were to do a heavy workout and then not eat anything afterwards either, I'll set myself up for failure. That's going to inevitably lead to more muscle catabolism.

You shouldn't think of trying to catch two rabbits at the same time. You'd want to focus on one thing at a time: either deeper autophagy or trying to build lean tissue with the deactivation of mTOR. It's supposed to be cyclical, punctuated almost. If you're trying to do both at the same time, then you end up not getting the benefits of either."

Anabolic Timing and Benefits

When it comes to muscle building, the timing of anabolism activation can make a big difference. To optimize muscle building, you want to do heavy resistance training while in a fasted state and then refeed directly afterward. As noted by Land, working out fasted might slightly reduce your maximum performance, but you don't need to work out at your personal max to improve strength and muscle development.

"The key is to do it consistently, and send the right signal to your body on a daily basis, within this 24-hour period," he says. "It's smarter to backload most of your calories into the post-workout scenario because, in that case, you can get away with mild caloric restriction and still be able to build muscle.

If you were to eat all of your calories before the workout, and then not eat anything after the workout, then it's harder to maintain more muscle in a caloric deficit. You may be able to do it without a caloric surplus, but staying in a caloric surplus all the time isn't going to be good …

By back loading [i.e., eating after your workout] … you still gain the anabolic response from resistance training and still recover adequately despite having worked out in a fasted state and despite eating only within a few hours of the day."

That said, there may be some benefit to eating a small amount of protein right before your workout. From this discussion in Land's book, I started eating two raw eggs before my workout.

"For the goal of muscle growth and muscle preservation, it's definitely a good idea to have some amino acids and some protein in the system while you are working out. It doesn't have to be a lot. You probably can get away even with even just 10 grams of protein. That's going to be enough and it won't spike insulin. It won't kick you out of a fasted state completely," Land says.

The Basics of Hormesis

Land also does a fine job defining hormesis in his book. It's an important concept that can be summarized as "Whatever doesn't kill you is going to make you stronger." It's a biological strategy that allows your body to adapt to environmental stressors, be it calorie restriction, starvation, cold or heat, for example.

Hormesis also produces effects similar to that of autophagy because it's stimulated by similar pathways, including AMPK, FOXO proteins and sirtuins. Intermittent fasting, for example, is a mild stressor that activates hormesis. High-intensity exercise is another, more intense activator.

"Those hormetic stressors, they kind of carry over to different areas of stress exposure. Like if I'm able to fast, then I at least notice that I'm also able to endure more cold and heat, or have more endurance … Other ways of activating hormesis is doing saunas and combining that with cold [exposure] like an ice bath or ice plunge."

In our interview, we also discuss other benefits of near-infrared saunas and heat-shock proteins, which are a corollary to autophagy. In summary, a primary function of heat-shock proteins is to properly refold misfolded proteins, which is one of the reasons why sauna therapy is so beneficial for overall health. Heat also stimulates autophagy.

Customize Your Strategy to Your Age

We also discuss the importance of nicotinamide adenine dinucleotide (NAD+), a coenzyme found in all cells that is required for biological processes, including energy homeostasis. During our youth, NAD supplementation is a nonissue, but with age, your NAD level starts to decline. 

One of the greatest consumers of the NAD+ molecule is poly-ADP ribose polymerase (PARP), a DNA repair enzyme. I'm currently researching this issue, and it appears the dose in NAD augmentation therapy is highly dependent on your age.

For people under the age of 30 or 40, it's likely a nonissue unless you have a chronic health issue. Once you're in your 40s, however, NAD augmentation becomes an important strategy.

The good news is there are many ways to boost NAD naturally, such as exercise, which dramatically increases a rate-limiting enzyme for NAD called nicotinamide phosphoribosyltransferase or NAMPT. Fasting will also increase NAD, which is yet another of its benefits.

The problem most people face is that they stop or radically reduce their exercising when they get older. The frailty associated with old age is in part because nicotinamide builds up and is not converted back to NAD. Nicotinamide also inhibits sirtuins, important longevity proteins. Once you stop getting the benefits of sirtuins and NAD, longevity suffers.

"All these pathways are very context-dependent," Land notes. "What's the optimal amount of autophagy? Or what's the optimal amount of NAD+? It depends upon your age. It depends upon your medical condition and physical conditions as well. I can get away with probably a little bit more fasting compared to someone who is very old.

Because the older the person, they're experiencing more anabolic resistance as well, so it's harder for them to maintain muscle. They shouldn't fast that long. They would actually benefit from increased protein intake and definitely maintaining resistance training to promote anabolism and make sure they don't lose muscle …"

Protein Requirements Increase With Age

This is an important point that Land expounds upon in his book. Protein levels, specifically, change with age, and maintaining muscle will require different strategies depending on your age. Along with decreasing NAD levels, you'll also see a reduction in growth hormone with age, and your ability to synthesize protein and build tissue goes down.

"To compensate for that, you just need to increase your protein intake a little bit to have a bigger bank of amino acids to pull from, making sure that the stimulus for muscle hypertrophy and muscle growth is still there in the example of lifting weights and doing resistance training.

That's a very important part of avoiding the negative side effects of aging, such as muscle loss, because if you lose your muscle, then you also become more predisposed to all the other diseases, like diabetes. You're predisposed to insulin resistance and even Alzheimer's …

Muscle mass is like a huge pension fund for healthy aging, because with more muscle, you're more insulin-sensitive. You have bigger glycogen stores. You can get away with eating more calories. You essentially have a bigger protection against all different diseases.

You also don't need to restrict yourself that much when it comes to fasting and calories, because muscle mass helps you to live longer. It seems like one of the predictors of all-cause mortality is the amount of muscle mass. That's being used more and more in research and other research as well."

Land also recommends cycling the amounts of protein you consume. For instance, on a fasting day, protein intake can be low, because you don't need it for muscle recovery, whereas higher protein intake will benefit you the most on days you're doing strength training.

Land recommends a protein intake of 0.6 grams per pound of lean body mass on the low end and 0.8 to 1.0 gram per pound of lean body weight on the high end. To calculate your lean body mass, determine your percentage of body fat and deduct that from your total weight. So, if you have 20% body fat, then your lean mass would be 80% of your total weight. Then multiply that by, say, 0.8 grams to calculate your protein requirement.

More Information

In closing, I highly recommend picking up a copy of Land's book, "Metabolic Autophagy: Practice Intermittent Fasting and Resistance Training to Build Muscle and Promote Longevity (Metabolic Autophagy Diet Book 1)." You can also find a wealth of information on Land's YouTube channel and website, SiimLand.com.

We discuss a lot more than I've summarized here, so for more information, please listen to the interview in its entirety. Toward the end, we review the benefits of KAATSU training, for example, also referred to as blood flow restriction training, which allows you to boost muscle growth using far less weight. Another topic we delve into is the importance of sleep, and the negative side effects of sleep deprivation.

The take-home message of this interview though, is the importance of time-restricted eating. Even if you eat high-quality food, if you're grazing for 16 hours a day, you're sabotaging your health. A related point is to eat your last meal at least three of four hours before bed. Land recommends four hours. I typically try to aim for five hours.

Time-restricted eating may even allow you to get away with a diet that isn't entirely ideal, as it blocks many of the harmful effects of a poor diet, likely because you're regularly activating autophagy.

"Time-restricted eating and intermittent fasting is definitely one of the most important, most effective ways of promoting healthy aging and longevity, as well as improving body composition," Land says.

"You shouldn't worry about restricting your protein, et cetera, if you're doing some form of fasting, because you're already suppressing the anabolic pathways area to approaching overconsumption whether you're in a fasted state, so you don't have to worry about it because you're doing it more diligently and you're getting a bigger effect from that."

+ Sources and References