Quick! I just have to share with you this story about Frank. You see, one day, Frank was starving. And then he ate himself…Now Frank’s still alive and even stronger than before. This is because of a cellular pathway called autophagy. In this article, I’m going to explain to you what is autophagy and how it can help you to live a longer and healthier life. It’s autophagy explained.

What Is Autophagy

Autophagy or autophagocytosis in fancy science language translates from the Ancient Greek word autóphagos which means self-digestion or ‘eating of self’[i].

Autophagy is a metabolic process during which cells disassemble and remove their dysfunctional components[ii]. You’re basically recycling cellular debris and taking out the trash.

Initially, it was thought that autophagy was a hormonal response to starvation but recent research has shown autophagy to have many other roles in biology.

There are many benefits to autophagy:

Reduction in inflammation

Improved immune system[iii]

Prevention of genotoxic stress

Anti-Aging and longevity boosting effects [iv]

Suppression of cancerous and tumor cells

Elimination of infectious pathogens and toxins[iii]

Inability to cause autophagy makes rats fatter, less active, have higher cholesterol and impaired brain function[v]

Compromised autophagy pathways will lower the body’s ability to eliminate and heal the organism from inflammation, accumulation of toxins, and parasitic infections.

On the 3rd of October, 2016, a Japanese researcher Yoshinori Ohsumi was rewarded the Nobel Prize in Physiology or Medicine for “discoveries of the mechanisms for autophagy.” His research is done in simple organisms like baker’s yeast but the autophagy-related pathways have been found to be similar to autophagy in mammals as well.

Autophagy Explained

So, how does it work?

When autophagy gets activated, the organelles of your healthy cells start to hunt out dead or diseased cells and then consume them.

Autophagy is mediated by an organelle called the autophagosome, which combines with other cellular components like the endosome and lysosome to form a double membrane around the cell that’s going to be eaten. The autophagosome then dissolves the cell that’s sentenced to death and converts it into energy.[vi]

Where and how the autophagosome gets formed is currently a mystery for researchers. In yeast, it’s been identified to occur when many Atg (autophagy related) proteins converge at a site that’s called “pre-autophagosomal structure (PAS)”[vii]. Some equivalent structures have been located in mammalian cells as well but detailed information about the PAS is still unknown.

Autophagy Activation Explained

Autophagy gets triggered mostly by nutrient deprivation.

In yeast, starvation of nitrogen and other essential factors like carbon, nucleic acid, auxotrophic amino acids, and even sulfate can activate autophagy to some degree[viii].

In plant cells, nitrogen and carbon starvation can also trigger autophagy[ix][x]

In mammals, autophagy happens in various tissues in different degrees. Depletion of amino acids is a strong signal for triggering autophagy but that depends on the type of cell and amino acids because amino acid metabolism differs among tissues. Some proteins can actually trigger phase 2 detox pathways in the liver which inherently are linked to mild autophagy.

In vivo, it’s thought that autophagy is regulated mostly by the endocrine system, particularly by insulin, which is a hormone responsible for shuttling nutrients into cells. Insulin suppresses liver autophagy by raising blood sugar and signaling the presence of nutrients Glucagon, which is the counterpart of insulin, releases liver glycogen to be burnt for energy, and that increases autophagy [xi]



Both amino acids and insulin-like growth factors are regulated by the nutrient signaling of mTOR (mammalian target of rapamycin). Suppressing TOR with things like rapamycin and CCI-779 has been shown to induce autophagy in yeast[xii] and other animals[xiii]. However, not all of the autophagy signaling happens through mTOR as some amino acid signaling can suppress autophagy independent of mTOR[xiv].

Even more, recent reports have shown many other factors to be involved in autophagy regulation, such as Nf-kb[xv], reactive oxygen species[xvi], calcium[xvii], AMPK[xviii], and many more[xix]. So, what I propose is to look at autophagy not as a binary on-and-off switch but more of like a degree dependent state that’s mediated through how depleted and deprived the organism is.

What Stops Autophagy

The main inhibitor of autophagy in muscles is a kinase called Akt. It can regulate autophagy mainly in two ways: (1) a rapid regulation of mTOR activation, and (2) a slower response of gene transcription via FoxO3[xx]. FoxO3 controls the transcription of autophagy-related genes, such as LC3 and Bnip3, which mediate the effect of FoxO3 on autophagy[xxi]. Akt activation blocks FoxO3 and autophagy.

Although there’s still much to learn about autophagy, current research is showing that most of the signaling happens through the pathways of mTOR and AMPK[xxii]

mTOR or mammalian target of rapamycin is the body’s master nutrient regulator that affects cellular growth, protein synthesis, and anabolism. It promotes the activation of insulin receptors and the creation of new tissue.

AMPK or AMP-activated protein kinase is a fuel sensor that is involved with balancing energy deprived states by maintaining energy homeostasis and mobilizing the body’s backup fuel

MTOR inhibits autophagy because it makes your body grow, whereas AMPK supports autophagy due to the energy-deprived state and burning of internal energy stores[xxiii]. When under nutrient deprivation, AMPK starts to inhibit cellular growth by suppressing the mTORC1 pathway[xxiv][xxv], which in turn forces the body to catabolize its weakest components.

Autophagy and Growth

Autophagy is a catabolic pathway that makes you break down old cells. Although you’re causing protein breakdown, autophagy is needed for muscle homeostasis. With poor autophagy functioning, your body wouldn’t be able to maintain lean tissue. It improves your body’s ability to deal with catabolism and atrophy by promoting protein sparingness. A weakened or inadequate state of autophagy may contribute to aging, and muscle wasting through sarcopenia[xxvi]. That’s why it’s incredibly vital for not only living longer but also to age slower.

However, defective as well as excessive autophagy can lead to substantial muscle disorders and loss of lean tissue[xxvii], which in turn can promote premature aging.

You need these anabolic pathways like mTOR and insulin to build new tissue and keep your cells alive. That’s why strength athletes and bodybuilders are so focused on supporting anabolism and preventing muscle catabolism by taking different amino acid supplements and consuming foods that make them grow more. They’re probably over-doing it but that’s a whole nother story with potential consequences on their long-term health.

With that being said, a constant supply of nutrients and access to energy inhibits the body’s ability to induce autophagy and protect against catabolism. In fact, a continuous circulation of both macro- and micronutrients all the time blocks their usage and uptake by making the cells less responsive to them because they’re so readily available. It means that to actually absorb the nutrients you’re feeding yourself, you need to go through periods of nutrient starvation and deprivation as you’ll be more sensitive to those nutrients afterward again.

Are You Living in Over Abundance

Your body has many built-in mechanisms for maintaining energy and nutrient homeostasis.

An abundant supply of all the nutrients you need all the time would make your body less efficient at metabolizing them. You may be eating all these foods and getting all the vitamins but because your body perceives their abundant presence in the near future, it’ll downregulate their utilization.

In contrast, short episodes of starvation during which you’re not getting all the macros and minerals, you’re triggering a hormetic response that is going to make you more efficient with the nutrients you receive after the fact.

This has been shown by the fact that fasting for up to 72 hours resets the immune system and triggers stem cell growth, which will actually make your body stronger than if you were to have been eating during that entire time.

I’ve noticed this to be true during my extended fasts. Every time I fast for 3-5 days, I experience a short-term boost in my energy levels and even muscle performance. It’s as if fasting opens up the valve of nutrients that are already stored inside my cells and allows me to actually use it.

That’s why it’s important to be like Frank – to starve and then eat yourself. Because an over-abundance of supplies will inhibit your cells’ potential to function properly.

Autophagy and Exercise

Autophagy is essential to support skeletal muscle plasticity in response to endurance exercise[xxviii]. To activate the activation of autophagy during exercise, the activation of AMPK is also needed[xxix].

AMPK regulates both protein synthesis and breakdown pathways. AMPK has a vital role in skeletal muscle homeostasis[xxx]. It’s activated by conditions of energy stress, including nutrient deprivation and vigorous exercise[xxxi].

Exercise performed in a fasted state shows a higher increase in LC3B-II level compared with a fed state, which suggests exercise done while fasting to have a better autophagic response[xxxii]. This makes sense because you’ll be tapping straight into your body fat for energy instead of burning through the food you ate.

When activated, AMPK increases the flux of glycolysis[xxxiii] and fatty acid oxidation ([xxxiv],[xxxv],[xxxvi],[xxxvii]), while at the same time inhibiting glucogenogenesis ([xxxviii],[xxxix]) and fatty acid and cholesterol synthesis.

In addition, AMPK has been recently showed to be a critical regulator of skeletal muscle protein turnover[xl]. Protein turnover is the balance between protein build up and protein breakdown over the course of the day. If your protein synthesis exceeds the amount protein’s being broken down, then you’re in a more anabolic state.

Your body is always in a flux between anabolism and catabolism – growing and degrading. Both of these ends of the spectrum are vital for a healthy life – you want to promote the growth and repair of your vital organs and muscles but you also want to eliminate and break down the old worn out cells and metabolic debris.

How Long Until Autophagy?

But how much time do you need to starve to activate autophagy? That’s a difficult question because autophagy happens in varying tissues in varying degrees. It’s not as binary as you’d think but it’s definitely not something you can hack very easily.

In general, suppressing mTOR and insulin will already begin to elevate autophagy in a dose-specific degree.

Low blood glucose levels and depleted liver glycogen stores are indicators of energy starting to run low in the body. As energy depletion continues, the body upregulates its metabolic pathways that are associated with burning stored fat for fuel. Eventually, this leads to a ketotic state with elevated levels of ketones in the blood.

Although autophagy is usually accompanied by ketosis, you can still be in ketosis without activating autophagy and you can activate autophagy without being in ketosis. The reason is that of nutrient signaling and mTOR. Fats and exogenous ketones have a negligible effect on insulin but they may still raise mTOR if you consume them in copious amounts and under the wrong circumstances. Likewise, you can see trace amounts of autophagy even while having fasted for 24 hours on a carbohydrate-rich diet.

To really gain the benefits of autophagy, you’d have to be fasting for over 48 hours to allow the stem cells and immune system to do their work. That’s why I recommend everyone to fast for at least 3-5 days 2-3 times per year. These extended fasts not only make you burn a lot of body fat very easily but they’ll also recycle the weak cells that are simply dragging you down and giving you potential issues.

The reason is that contemporary eating habits like 3 square meals a day, snacking, high carb foods and processed ingredients are all anti-autophagy and they inhibit the recycling of old waste material.

Even people who eat „clean foods“ but don’t go through nutrient starvation may potentially be walking trash cans. There are many other sources of toxins and inflammation all of us get exposed to starting from air pollution, water, GMOs, plastics, heavy metals and who knows what else. What looks good on the outside doesn’t mean that everything is okay on the inside. Having your autophagy pathways live and active is even more important for living in the modern world.

How to Stimulate Autophagy

The easiest way to promote autophagy is to fast and consume no calories for a few days. Here are a few ways of doing intermittent fasting for health and longevity.

Fast and don’t eat any calories for at least 16 hours every day. This isn’t enough to activate autophagy but it’ll at least deplete your liver glycogen, lower blood glucose and keep you in mild ketosis most parts of the day. Check out the Full Guide to Intermittent Fasting FREE BOOK!

This isn’t enough to activate autophagy but it’ll at least deplete your liver glycogen, lower blood glucose and keep you in mild ketosis most parts of the day. Check out the Full Guide to Intermittent Fasting FREE BOOK! Keep insulin and blood sugar levels low. Carbs and some proteins will elevate insulin, which is going to suppress autophagy. That’s okay in some cases, for instance, when you’re trying to build muscle, but you don’t want to elevate insulin and activate mTOR if you haven’t caused any damage to the muscle cells. If you haven’t trained but elevate insulin, then that signal will be more likely to accelerate aging and fat gain, not muscle growth. You want to keep your blood sugar and insulin low most of the time even if you’re not eating a strict ketogenic diet because it’ll promote longevity and greater insulin sensitivity.

Carbs and some proteins will elevate insulin, which is going to suppress autophagy. That’s okay in some cases, for instance, when you’re trying to build muscle, but you don’t want to elevate insulin and activate mTOR if you haven’t caused any damage to the muscle cells. If you haven’t trained but elevate insulin, then that signal will be more likely to accelerate aging and fat gain, not muscle growth. You want to keep your blood sugar and insulin low most of the time even if you’re not eating a strict ketogenic diet because it’ll promote longevity and greater insulin sensitivity. Don’t eat too much protein or carbs . Too high levels of mTOR and IGF-1 accelerate aging and promote cancer cell growth. With that being said, mTOR can also make you build muscle. You simply don’t want to be in a constantly anabolic state because you may die sooner. That’s why it’s important to practice intermittent fasting even if you’re working out hard and are trying to get bigger. It’ll actually boost your performance and health.

. Too high levels of mTOR and IGF-1 accelerate aging and promote cancer cell growth. With that being said, mTOR can also make you build muscle. You simply don’t want to be in a constantly anabolic state because you may die sooner. That’s why it’s important to practice intermittent fasting even if you’re working out hard and are trying to get bigger. It’ll actually boost your performance and health. Still, do resistance training and eat protein – At the same time, too much autophagy and too little mTOR can also be detrimental as you’ll end up losing lean muscle tissue which is incredibly important for longevity. As you age, you’re more prone to muscle loss and other metabolic issues. That’s why it’s important to keep exercising with resistance training and to still be consuming protein to not become frail. What’s more, more muscle tissue will act like a huge sponge for calories and glycogen – you’ll be able to burn more energy from food without having to fear metabolic disease or premature death. I myself deliberately aim to activate mTOR after doing resistance training to promote muscle growth and recovery.

– At the same time, too much autophagy and too little mTOR can also be detrimental as you’ll end up losing lean muscle tissue which is incredibly important for longevity. As you age, you’re more prone to muscle loss and other metabolic issues. That’s why it’s important to keep exercising with resistance training and to still be consuming protein to not become frail. What’s more, more muscle tissue will act like a huge sponge for calories and glycogen – you’ll be able to burn more energy from food without having to fear metabolic disease or premature death. I myself deliberately aim to activate mTOR after doing resistance training to promote muscle growth and recovery. Here’s my strategy for gaining the benefits of both autophagy and building muscle. Fast as long as I can every day Consume autophagy boosting foods like coffee, green tea, turmeric, Chaga mushroom, and others Do resistance training in a depleted and low glycogen state to elevate growth hormones After the workout consume some anabolic amino acids and protein like leucine, HMB, and others Post-workout eat an adequate amount of protein as a minimal effective dose to not overstimulate mTOR for too long After finishing my one meal a day dinner I want to get back into a fasted state very fast by lowering my insulin with apple cider vinegar and other supplements The next day I keep stimulating autophagy with aerobic exercise, saunas, rebounding, and such In my opinion, this helps me to gain the benefits of both worlds thanks to eating only one meal a day and thus increasing my insulin sensitivity through the roof.

Exercise can also stimulate autophagy . Like we mentioned earlier, fasted exercise activates autophagy a lot more than fed exercise[xli]. Doing this on a glycogen depleted and ketotic state would have a similar effect. Cardio on an empty stomach will put you into ketosis faster and increases fat oxidation.

. Like we mentioned earlier, fasted exercise activates autophagy a lot more than fed exercise[xli]. Doing this on a glycogen depleted and ketotic state would have a similar effect. Cardio on an empty stomach will put you into ketosis faster and increases fat oxidation. Have extended fasts for 3-5 days a few times per year. It should be mandatory if you want to get any significant benefit from autophagy. Honestly, 48-72 hours should be the minimum. The optimal range is 3-5 days and in most cases you don’t need to fast any longer than 7 days because after that you’ll start lowering your metabolic rate quite severely. I’m having 3-5 day fasts about 3-4 times per year.

Autophagy fights against many viruses and pathogens[xlii] but there are others that use autophagy to replicate themselves rather than be eliminated by it[xliii]. That’s why it’s important to take it with a grain of salt and keep in mind that it’s a very complex thing. Autophagy all the time isn’t ideal and not good for longevity. That’s why you still need to balance it out with anabolism, muscle growth and mTOR, especially if you’re physically more active and as you get older.

Lymph Flow and Autophagy

Everything that stimulates the lymph system will have a carry over effect to autophagy as well because of increasing microcirculation.

Sweating through exercise, hot yoga, heat saunas, infrared saunas, red light therapy, rebounding, bouncing around – everything that keeps your blood flowing can at least help with flushing out the toxins in your body.

You want to get a good sweat on every day, whether through exercise, thermal heat, yoga, or consuming spicy foods. This keeps your detox pathways activated and enables you to tap into autophagy faster as well.

Foods good for the lymph system include coffee, teas, Cayenne pepper, spirulina, activated charcoal, cruciferous vegetables, medicinal mushrooms, and spicy herbs.

Foods That Increase Autophagy

Now, let’s talk about other ways of activating autophagy without fasting and exercise. Here are some of the autophagy boosting foods that help with cleansing.

Sulforaphane induces autophagy through ERK activation in neuronal cells[xliv]. Cruciferous vegetables and dark leafy greens like kale have sulforaphane.

Azuki bean extract has been shown to reduce oxidative stress and stimulates autophagy[xlv]

Quercetin compounds induce autophagy[xlvi]. Foods high in quercetin are onions, pomegranate, red onions, cranberries. Garlic contains quercetin but it specifically stimulates autophagy as well[xlvii].

Medicinal mushrooms like Reishi and Chaga induce autophagy and can fight cancer[xlviii]. The Beta-Glucan signaling of these mushrooms is also connected to autophagy[xlix]

Falcarindiol is a compound found in carrots that contributes to autophagy[l].

Punicalagin is a compound found in pomegranates that promotes autophagy.

Silibinin is a natural flavonoid that increases autophagy via mitochondria and reactive oxygen species signalling[li]. Milk thistle has silibinin

6-Shogaol is a compound in ginger induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer[lii].

Resveratrol inhibits breast cancer stem-like cells and induces autophagy[liii]. Resveratrol is found in dark grapes, berries, cherries, and red wine.

Excess zinc can also support the stimulation of autophagy[liv]. Foods rich in zinc are oysters, liver, red meat, eggs, salmon, pumpkin seeds.

Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway[lv]

Curcumin induces autophagy by activating AMPK[lvi]. Piperine which is a compound found in black pepper induces autophagy[lvii] and it also boosts the bioavailability of curcumin, which makes it a double wammy!

Tart cherry supplementation improves working memory, hippocampal inflammation, and autophagy in aged rats[lviii]

Omega-3 Polyunsaturated Fatty Acids induce autophagy[lix]. DHA found in fish is also critical for cellular metabolism and mitochondrial functioning.

Coffee induces autophagy[lx] and has benefits on cellular metabolism.

Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy[lxi]

Ursolic acid induces autophagy and suppresses inflammatory responses[lxii]. Apple skins, grape skins, and berries have ursolic acid.

Capsaicin found in cayenne pepper induces autophagy[lxiii].

Theobromine found in cacao and dark chocolate have protective elements on the mitochondria and cells by preventing apoptosis and promoting autophagy[lxiv].

Vitamin K2 has been shown to trigger both autophagy and apoptosis simultaneously in leukemia cells[lxv].

Apigenin, a bioflavonoid in celery, causes AMPK activation in human keratinocytes[lxvi].

Fenugreek extract can also induce cellular death via autophagy[lxvii]

A cranberry proanthocyanidin rich extract induces both apoptosis and autophagy in human SEG-1 esophageal adenocarcinoma cells[lxviii]

Caloric restriction mimicing ingredients like Malabar tamarind (Hydroxycitrate), Berberine, Rapamycin trigger autophagy[lxix].

Betanin-Enriched Red Beetroot (Beta vulgaris L.) Extract Induces Apoptosis and Autophagic Cell Death[lxx]

Polyphenols regulate autophagy[lxxi]. Polyphenols and flavonoids are found in dark berries, dark leafy green vegetables, and all kinds of herbs and spices.

Extra virgin olive oil contains polyphenol like oleuropein and oleocanthal which trigger autophagy[lxxii][lxxiii] and promote pro-longevity FOXO3[lxxiv]. Funny enough, a recent 2017 study found that rats who were fed more olive oil in addition to their regular diet had better memory scores and higher levels of autophagy compared to the ones who just ate their regular chow[xii].

Stay Autophagic

The idea of autophagy is to remove the old wasteful material in your body that’s causing chronic inflammation and disease. That same principle of self-digestion and breaking down can be applied to your overall life.

You don’t want to be catabolic all the time because you have to balance it with anabolism and growth. The key is to have your autophagic pathways alive and well with these practices we’ve been talking here. If you don’t use it you lose it and that’s why so many people suffer from constipation, some autoimmune disorders, infections, toxicity, obesity, and rapid aging.

Maintaining good fat burning and detox pathways are incredibly important for health and longevity. Most diseases are rooted in your body’s poor ability to produce energy and sustain the system.

We don’t know a lot about autophagy but this is what we know so far and we’ll probably be getting more research that will connect circadian rhythms, environmental toxins, movement, diet and sleep with it’s functioning as well.

If you want to know how to follow an autophagic lifestyle that incorporates diet, exercise, and other biohacks for increased longevity, then check out my METABOLIC AUTOPHAGY PROGRAM!

Stay Empowered

Siim

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