Autophagy Part 2 - How to maximize results


Last week, I went over how fasting triggers the process of autophagy to clean up damaged and dangerous cells in order to prevent diseases like cancer and dementia, improve your overall health and well-being, and actually slow the process of aging and extend your lifespan. This week I’ll go over multiple ways to trigger autophagy and things you can do to increase it on a daily basis, even without fasting.

The pathways of autophagy

Let’s get the boring stuff out of the way quickly so you can understand why certain things enhance autophagy and others block it. Like anything else in the body, it’s incredibly complex and involves hundreds of different proteins and enzymes. However, there are three major triggers of system-wide autophagy that researchers have been able to identify:

  1. Decrease of Acetyl CoA (Acetyl Coenzyme A): This enzyme is involved in the metabolism of glucose, fatty acids, and branched-chain amino acids (BCAA), and it’s considered one of the central metabolic regulators of autophagy]( Depletion of these nutrients depletes the overall pool of Acetyl CoA and triggers cellular autophagy throughout your body.

  2. Decrease of mTOR (mechanistic target of rapamycin): mTOR is another important enzyme that regulates things like cell growth, cell survival, protein synthesis, and autophagy. It also promotes the activation of insulin and IGF-1 receptors. This is why the presence of IGF-1 (from eating meat) and insulin (from eating sugar) increases the amount of mTOR. You need to down-regulate mTOR in order to trigger autophagy. As an additional benefit, decreasing mTOR also causes senescent cells to down-regulate the release of inflammatory secretions. This means even if you don’t kill those cells through autophagy, you at least stop them from inflicting damage to the surrounding cells for months afterwards.

  3. Increase of AMP kinase (AMPK): AMP kinase acts as the monitor of cellular energy, and ATP is the currency of energy exchange. As cells use ATP for energy, it turns into ADP. When the balance of ADP becomes much greater than ATP, AMP kinase is activated to trigger the metabolism of fatty acids and to increase glucose uptake by cells. You want to increase AMP kinase to trigger autophagy. One way to increase this molecule is through fasting, the other is through exercise.

Prolonged fasting promotes regeneration

The most important thing to understand about autophagy is that it’s not just about destroying old, damaged cells, it’s about replacing them with healthy new ones. My whole life I heard that starving yourself causes your body to eat your muscles and organs alongside any body fat. It sounded horrifying and dangerous, but it also seemed like a huge design flaw in our biology. Why would your body act to inflict irreversible harm so quickly?

It tuns out it isn’t irreversible, and as with many adaptations in the body, it’s a positive response to an outside stressor. Just like how exercise is a stressor that breaks down muscles so they can be rebuilt stronger, prolonged fasting causes system-wide autophagy within your muscles and organs to clear out the dead-weight and then activates stem cells to allow your body to quickly replace what was lost when you feed again.

I understand where this misconception came from. It seems like we only grow and develop for 20 years or so and then spend the next 80 in decline. In reality, cells get damaged far too frequently, and if we lost the ability to replace them after age 20, we likely wouldn’t see 30. Losing the ability to replace certain cells as we age is an old assumptions that we’re realizing it is completely wrong. As a recent example, a new study counters the old belief that we stop developing new neurons after the age of 13. The researchers examined a region in the hippocampus of 26 recently deceased individuals between the ages of 14 and 79 and they found that people no matter their age had the same amount of new neurons and progenitor cells. All our cells are designed to defend against damage and then replace themselves when too much is inflicted. This process slows as we age, but it doesn’t stop.

What exactly does prolonged mean?

So time for the big question, how long do you have to fast to significantly activate autophagy? First, let me quickly address how they can tell. Researchers have discovered they can view a marker for autophagy called LC3 through immunofluorescence to see when autophagy is triggered in cells. The easiest cells to view in humans are leukocytes (white blood cells), but they can also see it in other tissues through biopsies (if anyone is willing to have a sample cut out of their muscles and organs).

In mice, whole body autophagy without a major depletion of circulating amino acids or dangerous levels of hypoglycemia occurs after 2 days of fasting. This translates to 4 days of prolonged fasting in humans. Without getting too invasive with multiple biopsies, researchers have indeed been able to see significant autophagy in leukocytes after 3 days of fasting and similar decreases in muscle and organ mass size after 4 days (remember, it comes back better than before).


Fasting mimicking diet

For those not up for a 4-day water fast, you can try the 5-day fasting mimicking diet pioneered by Dr. Valter Longo. I mentioned it briefly last week but I wanted to go more in-depth this week. In their research, they found it was as effective as a pure water fast at triggering autophagy, and in human trials it was much easier to tolerate. I would suggest it to anyone trying a first-time prolonged fast. It’s much easier to mentally grasp the concept of eating less versus eating absolutely nothing. The breakdown is pretty simple:

Day 1: 1090 calories, 10% protein, 56% fat, 34% carbs

Days 2 through 5: 725 calories, 9% protein, 44% fat, 47% carbs

You’ll notice a significant reduction in protein to suppress IGF-1 and mTOR levels. I would also recommend checking out Prolon for a straight-forward and conveniently packaged version of everything you need for your 5-day fast. It’s been proven in clinical trials with human patients and has actually received a patent for being able to induce stem-cell regeneration.

The researchers behind it have also thought through the importance of each ingredient to an extent that most people won’t. They don’t just throw in any kind of fat, but rather essential fatty acids to keep your brain and cells healthy. Instead of simple carbs that will leave you hungry again within minutes, they use high fiber sources that will not only help you feel more satisfied, but will limit insulin secretions (which interfere with autophagy) and supply important prebiotic fibers to keep your microbiome strong and releasing substances that further increase autophagy (more on that below). They also contain a daily vitamin pack that provides all the micronutrients needed for optimal health without including ones that could possibly interfere with autophagy.

I just want to say that I am not affiliated with Prolon and I receive no compensation for recommending their products. I just think it’s a much easier way for people to experiment with prolonged fasting. You can read more about them here.

Increase daily autophagy

A prolonged fast triggers major, system-wide autophagy, but there are things you can do every day to activate this important healing process. I want to quickly go through proven ways to increase autophagy:


Curcumin: I’ve written about curcumin previously. This compound is extracted from turmeric root, a spice commonly used in curry. Curcumin is an effective anti-inflammatory and has been shown to protect against dementia and cancer, improve insulin sensitivity, increase levels of brain-derived neurotrophic factor (to grow new brain cells), and protect against weight gain. Since these are also benefits associated with autophagy, it’s no wonder it’s one of the mechanisms curcumin triggers.

Spermidine: Spermidine is a type of molecule known as a polyamine. It regulates many biological processes like lipid metabolism, cell growth, cell death, inflammation reduction, and of course, it’s also been shown to induce autophagy. It’s common in wheat germ, soy beans and the fermented soy product known as natto. It’s also in blue cheese and aged cheddar cheese. One third of the spermidine in your body is produced in your microbiome by strains of bacteria that like the prebiotic fiber pectin. You can find pectin in fruits like oranges, grapefruits, apples, pears, and peaches and vegetables like carrots, peas, and green beens.

Hydroxycitrate: This molecule is extracted from garcinia cambogia. It’s been used as an appetite suppressant and weight loss aid for a while now, and it has also been shown to promote autophagy.


Resveratrol: Resveratrol is a powerful antioxidant that also activates AMP kinase and induces autophagy. This well-known anti-aging compound is found in the skin of grapes, blueberries, raspberries, mulberries, and most-popularly in red wine. It’s the reason we constantly debate whether red wine is good for you or not. Despite the harmful effects of alcohol, a large amount of healthy individuals living to an older age seem to drink red wine. Resveratrol itself has been shown to protect against dementia, increase insulin sensitivity, and extend lifespans.

Endurance exercise: Cardio exercise induces autophagy in skeletal muscles to help the body adapt to the stressor of exercise. In one study using genetically modified mice incapable of triggering autophagy after exercise, they showed decreased endurance, impaired glucose metabolism during exercise, and exercise did not protect them from high-fat-diet-induced glucose intolerance like it did in the control group. It’s just another example of how the body needs to break itself down to build itself back up stronger.

Time-restricted eating: As I mentioned above, it takes 3 days of fasting to see significant autophagy in the leukocytes. That doesn’t mean autophagy isn’t taking place in other tissues before then. It’s difficult to check and pretty invasive, so we don’t have easy ways to see if autophagy is working on a daily basis. That said, it seems pretty likely that it is. IGF-1 has a serum half-life in humans of about 12 hours following fasting. Restricting your calorie consumption with a fasting window between 12 and 16 hours a day should induce autophagy to some extent. Fasting for 15 hours has been shown to double cardio endurance during time-to-exhaustion tests because of an increased presence of ketone bodies. During a prolonged fast, the production of ketones increases 9-fold on the second day. This increase in ketones during time-restricted eating doesn’t prove autophagy is taking place, but it’s a good indicator that similar mechanisms are being activated. It has been shown that circadian rhythms and autophagy are linked. Dysfunctions in circadian rhythms trigger dysfunctions in the mechanisms of autophagy and vice versa. Eating within the proper time window will improve your sleep-wake cycle, increase autophagy, and condition your body so a prolonged fast is much easier to tolerate. Consider it like training for a fasting marathon. You’ll have a much easier time trying a prolonged fast if you build up your tolerance and chemistry with daily short-term fasts.

Ginger: Ginger has been shown to inhibit mTOR and encourage autophagy.


Sulforaphane: I’ve written previously about the incredible protective effects of sulforaphane. This isothiocyanate is found in vegetables like broccoli, Brussels sprouts, cabbage, cauliflower, horseradish, and arugula. Not only does it induce autophagy in neural cells, it activates some of the body’s most powerful detoxifying and antioxidant pathways to protect against pollutants, cancer, cardiovascular disease, neurodegenerative diseases, depression, diabetes, and obesity.

Green tea: Polyphenols in green tea have been shown to increase autophagy in vascular endothelial cells which is part of the reason why it has been shown to protect against cardiovascular disease. Other studies have shown that green tea alleviates the inhibiting effects of high glucose levels on autophagy in endothelial cells, helping protect against hyperglycemia, diabetes, and obesity.


Coffee: The polyphenols in coffee have been shown to induce autophagy independent of caffeine. This is why large amounts of daily coffee drinking (3 to 4 cups) is associated with health benefits and minimal risks, despite the higher caffeine amounts.

Fasting vs Time-Restricted Eating

As I mentioned above, coffee induces autophagy. You may also remember from my article on time-restricted eating, that even nearly-no-calorie black coffee starts the clock on your eating window and ends your fasting window. I see a lot of confusion on whether coffee breaks a fast or not. The problem is that people are talking about two separate things - fasting vs time-restricted eating. They’re very similar and invoke many of the same benefits, but ultimately they have different names for a reason.

Time-restricted eating is all about working with your circadian rhythms to prevent metabolites from stacking up and causing dysfunction at the end of the day. Coffee matters a great deal in this case because it sends a signal to start your daily clock, which then determines the end point for your last meal. If you eat after that point, you will experience issues with easy fat storage, poor insulin sensitivity, inhibition of important healing systems (like autophagy and DNA repair), and disruption of your sleep cycle.

When you’re doing long-term fasting or doing a fasting mimicking diet, the calories are so low that you have no fear of stacking up metabolites outside of your circadian rhythms. In other words, coffee will not break the fast during a prolonged fast.

Time-restricted eating also doesn’t care about restricting nutrients. The purpose of a prolonged fast is to down-regulate Acetyl CoA and mTOR and up-regulate AMP Kinase to trigger autophagy. You can do this by cutting all nutrients or selectively reducing nutrients like protein with the fasting mimicking diet.

I think both are important and practicing time-restricted eating first is an excellent way to improve your body’s chemistry to make a prolonged fast much easier to handle. Time-restricted eating also triggers autophagy, but on a much smaller scale. Dr. Satchin Panda (one of the research pioneers of time-restricted eating) had an excellent analogy on why both are needed. He said time-restricted eating is like cleaning up your house each day to keep it neat and organized, but a few times a year, it’s best to do a deep “spring cleaning” to really get your house in order.

Work up to it

I get that the idea of a 4-day water fast or 5-day fasting mimicking diet sounds like a daunting undertaking, but you shouldn’t go from gorging to trying one anyway. Start with time-restricted eating and get comfortable with the idea of a eating less than you’re used to. You’ll experience a ton of benefits from that alone plus it will condition your body to turn body fat into ketones. This is probably one of the hardest transition points for people; switching from sugar to fat for fuel. People that have tried a ketogenic diet often struggle with the low carb flu. This is the point where your body runs out of glucose and stored glycogen but hasn’t yet produced enough enzymes to properly fuel your brain with ketones. The benefit of working up to a 15-hour time-restricted fasting window is that your body is more prepared to create ketones so you won’t suffer the effects of a transitional period.

You can also quit at any time. If you only make it a day or two, you’ve still activated autophagy to a lesser extent and performed some important clean up. You can always try again later, and like with anything, every attempt makes it easier to go a little farther.

Take it easy while fasting

Remember, a sever calorie restriction is going to result in a real decrease in energy. This means you’ll feel more tired throughout the day (particularly on the second and third day as you adjust) and strenuous activities could cause you to feel light-headed or even faint. Try to keep your activity light and don’t put your self in situations where drowsiness could be dangerous when you’re feeling tired (like driving). You will also be less able to regulate your body temperature. In general day-to-day activities this won’t matter much, but saunas and jacuzzis could pose problems as could cold environments like swimming. Just take it easy, keep the activity light, and get plenty of sleep.


Consult your doctor first (for real)

I know that everyone says consult your doctor before you do this or that as a way to protect against liability and most people just ignore that advice, but this isn’t a minor endeavor. If you have any conditions or are on any medications, you MUST consult your doctor first. This is a significant stressor to illicit major health improvements. Your doctor will likely applaud your willingness to take this bold step to improve your health and will offer advice on how to tailor it to your specific needs.

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