The Definitive Guide To Autophagy (and 7 Ways To Induce It)

Biological systems are self-maintaining. They have to be. We don’t have maintenance workers, mechanics, troubleshooters that can “take a look inside” and make sure everything’s running smoothly. Doctors perform a kind of biological maintenance, but even they are working blind from the outside.

No, for life to sustain itself, it has to perform automatic maintenance work on its cells, tissues, organs, and biological processes. One of the most important types of biological maintenance is a process called autophagy.

Autophagy: the word comes from the Greek for “self-eating,” and that’s a very accurate description: Autophagy is when a cell consumes the parts of itself that are damaged or malfunctioning. Lysosomes—members of the innate immune system that also degrade pathogens—degrade the damaged cellular material, making it available for energy and other metabolites.  It’s cellular pruning, and it’s an important part of staving off the worst parts of the aging process.

In study after study, we find that impairment to or reductions of normal levels of autophagy are linked to almost every age-related degenerative disease and malady you can imagine.

  • Cancer: Autophagy can inhibit the establishment of cancer by removing malfunctioning cellular material before it becomes problematic. Once cancer is established, however, autophagy can enhance tumor growth.
  • Diabetes: Impaired autophagy enables the progression from obesity to diabetes via pancreatic beta cell degradation and insulin resistance. Impaired autophagy also accompanies the serious complications related to diabetes, like kidney disease and heart failure.
  • Heart disease: Autophagy plays an important role in all aspects of heart health.
  • Osteoporosis: Both human and animal studies indicate that autophagy dysfunction precedes osteoporosis.
  • Alzheimer’s disease: Early stage Alzheimer’s disease is linked to deficits in autophagy.
  • Muscle loss: Autophagy preserves muscle tissue; loss of autophagy begins the process of age-related muscle atrophy.

Okay, so autophagy is rather important. It’s fundamental to health.

But how does autophagy happen?

The way it’s supposed to happen is this:

Humans traditionally and historically lived in a very different food environment. Traditionally and historically, humans were feasters and fasters. While I don’t think our paleolithic ancestors were miserable, wretched, perpetually starving creatures scuttling from one rare meal to the next—the fossil records show incredibly robust remains, with powerful bones and healthy teeth and little sign of nutritional deficits—they also couldn’t stroll down to the local Whole Foods for a cart full of ingredients. Going without food from time to time was a fundamental aspect of human ancestral life.

They worked for their food. I don’t mean “sat in a cubicle to get a paycheck to spend on groceries.” I mean they expended calories to obtain food. They hunted—and sometimes came back empty handed. They dug and climbed and rooted around and gathered. They walked, ran, stalked, jumped, lifted. Movement was a necessity.

In short, they experienced energy deficits on a regular basis. And energy deficits, particularly sustained energy deficits, are the primary triggers for autophagy. Without energy deficits, you remain in fed mode and never quite hit the fasted mode required for autophagy.

Now compare that ancestral food environment to the modern food environment:

Almost no one goes hungry. Food is cheap and plentiful, with the tastiest and most calorie-rich stuff tending to be the cheapest and most widely available.

Few people have to physically work for their food. We drive to the store and walk a couple hundred steps, hand over some money, and—BOOM—obtain thirty thousand calories, just like that. Or someone comes to our house and delivers the food directly.

We eat all the time. Unless you set out to do it, chances are you’ll be grazing, snacking, and nibbling throughout the day. We’re in a perpetually fed state.

The average person in a modern society eating a modern industrial diet rarely goes long enough without eating something to trigger autophagy. Nor are they expending enough energy to create an energy deficit from the other end—the output. It’s understandable. If our ancestors were thrust into our current situation, many would fall all over themselves to take advantage of the modern food environment. But that doesn’t make it desirable, or good for you. It just means that figuring out how to trigger autophagy becomes that much more vital for modern humans.

Here are 7 ways to induce autophagy with regular lifestyle choices.

1) Fast

There’s no better way to quickly and reliably induce a large energy deficit than not eating anything at all. There are no definitive studies identifying “optimal” fasting guidelines for autophagy in humans. Longer fasts probably allow deeper levels of autophagy, but shorter fasts are no slouch.

2) Get Keto-Adapted

When you’re keto- and fat-adapted, it takes you less time to hit serious autophagy upon commencing a fast. You’re already halfway there.

3) Train Regularly

With exercise-related autophagy, the biggest effects are seen with lifelong training, not acute. In mice, for example, the mice who are subjected to lifelong exercise see the most autophagy-related benefits. In people, those who have played soccer (football) for their entire lives have far more autophagy-related markers of gene activity than people of the same age who have not trained their whole lives.

4) Train Hard

In studies of acute exercise-induced autophagy, the intensity of the exercise is the biggest predictor of autophagy—even more than whether the athletes are in the fed or fasted state.

5) Drink Coffee

At least in mice, both caffeinated and decaffeinated coffee induce autophagy in the liver, muscle tissue, and heart. This effect persists even when the coffee is given alongside ad libitum food. These mice didn’t have to fast for the coffee to induce autophagy.

Certain nutrients can trigger autophagy, too….

6) Eat Turmeric

Curcumin, the primary phytonutrient in turmeric, is especially effective at inducing autophagy in the mitochondria (mitophagy).

7) Consume Extra Virgin Olive Oil

The anticancer potential of its main antioxidant, oleuropein, likely occurs via autophagy.

Disclaimer: The autophagy/nutrient literature is anything but definitive. Most studies take place in test tube settings, not living humans. Eating some turmeric probably won’t flip a switch and trigger autophagy right away, but it won’t hurt.

Autophagy is a long game.

This can’t be underscored enough: Autophagy is a lifelong pursuit attained by regular doses of exercise and not overeating every time you sit down to a meal. Staying so ketotic your pee tests look like a Prince album cover, doing epic 7-day fasts every month, fasting every other day, making sure you end every day with fully depleted liver glycogen—while these strategies might be “effective,” obsessing over their measures to hit some “optimal” level of constant autophagy isn’t the point and is likely to activate or trigger neurotic behavior.

Besides, we don’t know what “optimal autophagy” looks like. Autophagy isn’t easy to measure in live humans. You can’t order an “autophagy test” from your doc. We don’t even know if more autophagy is necessarily better. There’s the fact that unchecked autophagy can actually increase existing cancer in some cases. There’s the fact that too much autophagy in the wrong place might be bad. We just don’t know very much. Autophagy is important. It’s good to have some happening. That’s what we have to go on.

Putting These Tips Into Practice

Autophagy happens largely when you just live a healthy lifestyle. Get some exercise and daily activity. Go hard every now and then. Sleep deeply. Recover well. Don’t eat carbohydrates you don’t need and haven’t earned (and I don’t just mean “earned through glycogen depleting-exercise”). Reach ketosis sometimes. Don’t eat more food than you need. Drink coffee, even decaf.

All those caveats aside, I see the utility in doing a big “autophagy session” a few times a year. Here’s how mine looks:

  1. Do a big training session incorporating strength training and sprints. Lots of intense bursts. This will trigger autophagy.
  2. Fast for two or three days. This will push autophagy even further.
  3. 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.
  4. 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 throughout the year. You track an animal for a couple days and come up short, or it takes that long to make the kill. You nibble on various stimulants plucked from the land along the way. You walk a ton and sprint some, then lift heavy. And finally, maybe, you get to eat.

If you find yourself aging well, you’re on the right track. If you’re not progressing from obesity to diabetes, you’re good to go. If you’re maintaining and even building your muscle despite qualifying for the blue plate special, you’ve probably dipping into the autophagy pathway. If you’re thinking clearly, I wouldn’t worry. Obviously, we can’t really see what’s happening on the inside. But if everything you can verify is going well, keep it up.

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.

Thanks for reading!

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References:

Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10(9):1533-41.

Barlow AD, Thomas DC. Autophagy in diabetes: ?-cell dysfunction, insulin resistance, and complications. DNA Cell Biol. 2015;34(4):252-60.

Sasaki Y, Ikeda Y, Iwabayashi M, Akasaki Y, Ohishi M. The Impact of Autophagy on Cardiovascular Senescence and Diseases. Int Heart J. 2017;58(5):666-673.

Florencio-silva R, Sasso GR, Simões MJ, et al. Osteoporosis and autophagy: What is the relationship?. Rev Assoc Med Bras (1992). 2017;63(2):173-179.

Li Q, Liu Y, Sun M. Autophagy and Alzheimer’s Disease. Cell Mol Neurobiol. 2017;37(3):377-388.

Jiao J, Demontis F. Skeletal muscle autophagy and its role in sarcopenia and organismal aging. Curr Opin Pharmacol. 2017;34:1-6.

Schwalm C, Jamart C, Benoit N, et al. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J. 2015;29(8):3515-26.

De oliveira MR, Jardim FR, Setzer WN, Nabavi SM, Nabavi SF. Curcumin, mitochondrial biogenesis, and mitophagy: Exploring recent data and indicating future needs. Biotechnol Adv. 2016;34(5):813-826.

Przychodzen P, Wyszkowska R, Gorzynik-debicka M, Kostrzewa T, Kuban-jankowska A, Gorska-ponikowska M. Anticancer Potential of Oleuropein, the Polyphenol of Olive Oil, With 2-Methoxyestradiol, Separately or in Combination, in Human Osteosarcoma Cells. Anticancer Res. 2019;39(3):1243-1251.

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Dear Mark: How Does LDL Even Penetrate the Arteries, New Zealand Farmed Salmon, Elevated Ferritin

For today’s edition of Dear Mark, I’m answering three questions. First, can LDL actually infiltrate the arteries, or is there more to the story? Malcolm Kendrick says there’s more to the story, so I dig into some literature to see if they corroborate his position. Second, is New Zealand farmed salmon good to eat? And finally, what should you do about elevated ferritin levels—and why else might they be elevated if not because of your iron?

Let’s go:

My reading of this post by Malcolm Kendrick MD is that LDL particles cannot infiltrate the endothelial lining of our arteries:
https://drmalcolmkendrick.org/2018/08/16/what-causes-heart-disease-part-52/

Great read. Malcolm Kendrick is consistently fascinating, insightful, and enlightening.

He’s basically suggesting that LDL particles can’t manhandle their way into the artery wall, which are equipped with tight junctions—the same kind that regulate passage through our gut lining. Something has to “allow” them in. The something he finds most plausible is injury, trauma, or insult to the endothelial lining (artery wall, for lack of a better phrase).

A free public textbook available on PubMed since last month called The Role of Lipids and Lipoproteins in Atherosclerosis tackles the topic head on. In the abstract, they say:

Population studies have demonstrated that elevated levels of LDL cholesterol and apolipoprotein B (apoB) 100 [note: ApoB is a stand-in for LDL particle number, as each LDL-P has an ApoB attached to it], the main structural protein of LDL, are directly associated with risk for atherosclerotic cardiovascular events (ASCVE). Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.

This seems to posit that infiltration of the LDL particle into the artery wall is a critical initiating event. But is it the critical initiating event? Does something come before it? How does the infiltration happen, exactly? Moving on:

Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space. Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation.

If I’m reading this correctly, they’re saying that “arterial injury” is another critical initiating event—perhaps the critical initiating event, since the injury causes “endothelial dysfunction,” which in turn modifies (or oxidizes) the LDL particles. But wait: so they’re saying the LDL particles are already there when the arterial injury occurs. They’ve already made it into the endothelial walls, and they’re just…waiting around until the arteries get injured. Okay, okay, but, just like Malcolm Kendrick points out, nowhere in the abstract have the authors actually identified how the LDL particles enter the endothelial lining. Maybe it’s “common knowledge,” but I’d like to see it explained in full.

Moving on:

In atherosclerosis susceptible regions, reduced expression of eNOS and SOD leads to compromised endothelial barrier integrity (), leading to increased accumulation and retention of subendothelial atherogenic apolipoprotein B (apoB)-containing lipoproteins (low-density lipoproteins (LDL)) and remnants of very low-density lipoproteins (VLDL) and chylomicrons)

Ah ha! So, in regions of the arteries that are prone to atherosclerosis, low levels of nitric oxide synthase (eNOS)—the method our bodies use to make nitric oxide, a compound that improves endothelial function and makes our blood flow better—and superoxide dismutase—an important antioxidant our bodies make—compromise the integrity of the arterial lining. The compromised arterial lining allows more LDL particles to gain entry and stick around. So, are low levels of nitric oxide and impaired antioxidant activity the critical initiators? That’s pretty much what Malcolm Kendrick said in his blog post.

Still—high LDL particle numbers are a strong predictor of heart disease risk, at least in the studies we have. They clearly have something to do with the whole process. They’re necessary, but are they sufficient? And how necessary are they? And how might that necessariness (yes, a word) be modified by diet?

I’ll explore this more in the future.

In regards to the oily fish article (and more indirectly given the omega 6 concern- the Israeli Paradox) What do you think of NZ farmed salmon? I’m in Australia, & occasionally like a fresh piece of salmon- there are no wild caught available here sadly, but I am wondering how it measures up as an alternative?

Last year, I explored the health effects of eating farmed salmon and found that it’s actually a pretty decent alternative to wild-caught salmon, at least from a personal health standpoint—the environmental impact may be a different story.

I wasn’t able to pull up any nutrition data for New Zealand farmed salmon, called King or Chinook salmon. Next time you’re at the store, check out the nutritional facts on a NZ farmed salmon product, like smoked salmon. The producer will have actually had to run tests on their products to determine the omega-3 content, so it should be pretty accurate. Fresh is great but won’t have the nutritional facts available. I don’t see why NZ salmon would be any worse than the farmed salmon I discussed last year.

According to the NZ salmon folks, they don’t use any pesticides or antibiotics. That’s fantastic if true.

I used to eat a lot of King salmon over in California, and it’s fantastic stuff. Very fatty, full of omega-3s. If your farmed King salmon comes from similar stock, go for it.

ok can someone tell me how to reduce ferritin? Is is just by giving blood?

Giving blood is a reliable method for reducing ferritin. It’s quick, effective, simple, and you’re helping out another person in need. Multiple wins.

Someone in the comment board recommended avoiding cast iron pans in addition to giving blood. While using cast iron pans can increase iron intake and even change iron status in severe deficiency, most don’t have to go that far. Giving blood will cover you.

Ferritin is also an acute phase reactant, a marker of inflammation—it goes up in response to infections (bacterial or viral) and intense exercise (an Ironman will increase ferritin). In fact, in obese and overweight Pakistani adults, elevated ferritin seems to be a reliable indicator of inflammatory status rather than iron status.

Thanks for reading, everyone. Take care and be well!

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References:

Birgegård G, Hällgren R, Killander A, Strömberg A, Venge P, Wide L. Serum ferritin during infection. A longitudinal study. Scand J Haematol. 1978;21(4):333-40.

Comassi M, Vitolo E, Pratali L, et al. Acute effects of different degrees of ultra-endurance exercise on systemic inflammatory responses. Intern Med J. 2015;45(1):74-9.

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