science of us

What Is Autophagy?

Photo: Matthäus Merian

Recently Twitter co-founder Jack Dorsey tweeted about his experiments with intermittent fasting: “I do a 22-hour fast daily (dinner only),” he wrote, “and recently did a three-day water fast. Biggest thing I notice is how much time slows down.”

The subsequent chatter around Dorsey’s eating regimen focused on intermittent fasting, but really, this was a step beyond fasting; this was extreme fasting, the kind that supposedly kicks off a process called autophagy. Autophagy is sort of like an “advanced” version of fasting, or Fasting 2.0, and as interest in intermittent fasting increases, interest in autophagy has followed: A few weeks after Dorsey’s tweet, the popular paleo-living site Mark’s Daily Apple published a “Definitive Guide to Autophagy” (calling it “cellular pruning”) — and a couple weeks earlier, Vox had mentioned autophagy in a story about how fasting diets are going mainstream. The key difference between intermittent fasting and autophagy, however, is that people typically fast for weight control but attempt to trigger autophagy for disease protection.

The basic idea behind autophagy is that in the absence of external sources of food, the body begins to eat itself (auto: self, phage: eat), destroying and recycling its own damaged cell bits and proteins, so that new and healthy versions can be built. Autophagy is believed to be essential for helping protect against diseases like cancer and dementia, among others.

The word autophagy was coined by Belgian biochemist Christian de Duve in 1963, but our understanding of the process has progressed significantly in this century, and in 2016 Japanese biologist Yoshinori Ohsumi won a Nobel Prize for his discoveries and research on the mechanisms underlying autophagy. As researchers are quick to point out, however, the field is still new and much of autophagy remains a mystery.

Here are a few of our own autophagy questions, answered.

What is autophagy exactly?
To quote a few studies from the past several years, autophagy is “a process of cellular housekeeping” that’s crucial for “cellular quality control,” and that allows for cells to better “adapt to stress.”

I also like the simplicity of this 2015 Nature article title: “Eat Thyself, Sustain Thyself.”

Personally, I’ve been thinking of autophagy as a kind of KonMari decluttering method, but on a cellular level — and instead of throwing things away, my body burns them and then makes new things out of the “ash.”

And fasting triggers autophagy?
It seems to, although most research on fasting-induced autophagy has been in animals. Fasting and calorie restriction have traditionally been associated with slower aging and longer lifespan, although their explicit role in triggering autophagy is still emerging. As one 2018 paper put it: “the evidence overwhelmingly [suggests] that autophagy is induced in a wide variety of tissues and organs in response to food deprivation.”

And the fasts have to be for 24 hours or longer?
It’s not clear. The 24-hour marker was pulled from mice studies, and mouse metabolism doesn’t necessarily correspond to human metabolism.

In an interview with the Cut, nephrologist (kidney doctor) and fasting researcher Jason Fung suggested that autophagy, in which “your body will take the oldest, junkiest proteins and burn them for energy,” happens “probably in the later stages of a long fast — somewhere around 20 to 24 hours, is my guess, and it probably maxes out somewhere around 32 hours, again is my best guess.”

Would autophagy be happening anyway, even if I never fast for that long?
Yes, although it’s hard to measure (more on that below). From what I understand, autophagy is a process that occurs regularly within certain organisms (like people, mice, and yeast), but fasting and other forms of stress, like exercise, appear to accelerate it into a kind of cleansing overdrive.

Defects in autophagy-related genes, however, are easier to study and have been associated with the onset of certain human illnesses, like certain forms of cancer, neurodegenerative diseases (like Parkinson’s and Alzheimer’s), metabolic diseases, and autoimmune diseases.

How do you pronounce autophagy?
Aw-TOFF-uh-gee,” although I’ve been told “otto-FAY-gee” is okay, too, but maybe the person who said that was just being polite.

How does autophagy benefit people?
On a basic level, autophagy is already a crucial part of cell function, in which “unnecessary or dysfunctional” cell components are disassembled, such as ones that might otherwise lead to illness.

Some studies have found autophagy to help fight infectious disease, regulate inflammation, and bolster the immune system. Autophagy deficits have also been associated with depression and schizophrenia.

In people, it’s possible that increased autophagy could also contribute to increased longevity, although the connection remains hazy. (Again, most of the studies on autophagy have been done on animals. In some studies, mice whose autophagy responses had been turned on, via drugs or fasting, “tend to live longer and be in better overall shape,” as one molecular neurogenetics professor told the BBC last year.)

Researchers are especially interested in the way fasting-induced autophagy interacts with cancer, although its effects are complicated and unclear. Longevity researcher Valter Longo, Ph.D., recently said, on the podcast Science Vs., “Once the cancer is confused and weakened by fasting, if you then add traditional medicine, like chemotherapy, then it’s like a one-two punch.”

On the other hand, studies have also shown that autophagy can have the opposite effect, making tumors stronger and more resistant to radiation. “Autophagy has dual roles in cancer,” per one 2011 report, “acting as both a tumor suppressor” and as a mechanism to “promote the growth of established tumors.” Also, from a 2016 autophagy overview: “Autophagy has both positive and negative roles in cancer, and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy.”

There are also concerns that too much fasting-induced weight loss could be dangerous, especially among cancer patients.

So when autophagy happens, is it just happening all over my body, everywhere?
Basically, with a notable exception: Fasting appears to induce autophagy in most organs (like the liver, muscle, and pancreas), but “not in the brain.”

Are there any benefits of autophagy that sound too good to be true but you want to include them anyway, because you never know?
Well, it sort of all sounds too good to be true — this incredibly easy way to just clean up internal problems — but I especially like the vague idea that autophagy could be good for the complexion and potentially for skin diseases like psoriasis.

I also like the anecdotal stories about people who lost a lot of weight via fasting but didn’t need skin-removal surgeries afterward because their bodies “ate” the leftover skin. As Jason Fung told me, of his fasting clinics, “We’ve never sent a single person for skin-removal surgery. We have anecdotal cases where people have lost 120, 130 pounds, and they said their skin also shrank, too. I’m like, ‘Yeah because all that excess protein needed to be burned. Not excess fat. The body’s just not that stupid to keep around all this excess skin. Because remember, during fasting, you’re activating a pathway within your body that says, ‘Okay, we need to buckle down because we’re in a time of famine, so to speak, and we don’t need all that extra skin, so let’s burn it. And if you need it, we’ll build it again.’”

What fasting-induced autophagy studies have been done on people?
It wasn’t on autophagy, necessarily, but a 2016 JAMA Oncology study on women with breast cancer found that those who fasted for more than 13 hours a day had lower rates of cancer recurrence.

Several other studies are in the works — on the effects of fasting on lung cancer, prostate cancer, glioblastoma, and breast and ovarian cancers — the results of which are due to come out in the coming years.

Research on fasting-induced autophagy in particular, in humans, is still developing. A 2018 paper on autophagy and human disease summarized autophagy as playing a role in “an increasing number” of disorders, “from bacterial and viral infections to cancer, and more recently in neurodegenerative and other age-related diseases.”

Can autophagy be harmful?
Autophagy has been described as a “double-edged sword” for its seeming ability to both “exacerbate or mitigate injury.”

Fasting in general can contribute to the development of gallstones, which can develop when bile stored in the gallbladder hardens into stonelike matter.

Fasting in general is also not recommended for underweight people, pregnant people, children, and the very elderly.

Could fasting to induce autophagy be considered an eating disorder?Not inherently, although excessive fasting to induce autophagy could overlap with anorexia. Many people fast for benefits beyond weight control, though, including disease prevention, muscle retention, and mental clarity.

Can you fast to induce autophagy too much, or too frequently?
Yes. There are no exact rules or recommendations (yet?), but researchers agree that extended fasting for autophagy — like going for 36, 48, or even 72 hours without food (like Jack Dorsey’s three-day water fast) — is something that healthy people should do at most 2 or 3 times a year, and only after conferring with a doctor.

Is there a way to know for sure whether or not autophagy is happening in my own body? Is there a way to measure it?
Not yet. Measuring autophagy in humans — or, measuring “autophagic flux” — is tricky, because it involves the rising and falling ratios of certain tiny proteins (like the protein LC3 and its variants).

There’s no such thing as an “autophagometer,” for instance, and a 2017 study noted that it’s “practically impossible to monitor autophagy properly in humans.” In the meantime, you can measure things like glucose and ketones, which are affected by fasting. (And LC3 levels can be compared on a protein-identifying Western blot, or immunoblot, blood test.)

Did you come across any poems about autophagy?
Funny you should ask. First I came across this one (“All Fluxed Up”), but then I came across another one (“Autophagy and Cancer”) by the same author — Roberta Gottlieb, M.D., editor of Autophagy in Health and Disease and head of the Gottlieb Lab at Cedars-Sinai — and the whole thing is great, but this was my favorite part:

Autophagy’s good, autophagy’s bad

The confusion’s enough to drive us all mad

So study we must, and learn ever more

Til enlightenment finally opens the door

Oncologists must heed the tumor’s agenda

And decide whether autophagy is foe or a friend-a.

What Is Autophagy?