Is Autophagy the Secret to Life Extension?
Understanding and promoting your body’s natural cleanup mechanism for repairing and removing damaged cells
There’s a popular theory — commonly misattributed to Cliff Calvin from Cheers — that drinking alcohol actually makes you smarter. According to this theory, alcohol kills off the slowest and weakest brain cells. Because these cells slow down the entire brain, their death strengthens the brain as a whole.
Unfortunately, this isn’t true. Alcohol damages brain cells without killing them and doesn’t selectively target the weakest cells. The good news is that there’s something else which does work in kind of a similar manner: autophagy.
Autophagy kills off the weakest, sickest cells — not just in your brain, but throughout your entire body. And it doesn’t just kill entire cells. More often, it kills sick or damaged organelles or strands of damaged DNA and RNA within cells.
So what is autophagy? Fans of the Greek language may recognize that the name means “self-eating.” As scary as that sounds, it’s a good thing: autophagy is a process by which the body breaks down and recycles damaged components at the cellular and sub-cellular level.
Without autophagy, your body would gradually fill up with junk DNA and dead tissues, eventually becoming unable to function as a result. There’s growing evidence that autophagy is a critical process in preventing cancer, slowing down the aging process, defending against pathogens, and even building muscle and stamina in response to exercise.
In this article, I’m going to explain how autophagy works, review the evidence for its various purported health benefits, and provide some practical guidelines for using autophagy to reduce your risk of cancer and infectious diseases, get into better shape, and extend your lifespan.
How Autophagy Works
There are several types and many subtypes of autophagy, depending on what exactly is being recycled.
All types of autophagy are ultimately conducted by lysosomes, a spherical organelle (specialized subunit within a cell) with the specialized purpose of breaking down biological matter. Lysosomes contain more than a hundred enzymes and specialized proteins which help them to break down anything from small snippets of damaged RNA to damaged and dead organelles like mitochondria and ribosomes. Under certain circumstances, lysosomes may even break down entire cells; this is still unclear and in need of further investigation. Lysosomes come in a wide variety of sizes, depending on what type of material they’re specialized in recycling.
The majority of autophagic activity falls under the category of macroautophagy. This is the process by which damaged proteins, organelles, and free-floating bits of damaged DNA and RNA get recycled. In macroautophagy, a small spherical organelle called an autophagosome is formed on the endoplasmic reticulum inside the cell. The autophagosome then travels to the damaged material that needs to be recycled and engulfs it. It then travels to a lysosome and attaches to it. The lysosome then breaks down the autophagosome and its contents.
To use an analogy, the lysosome is like a recycling plant, and the autophagosome is like a disposable dump truck that gets recycled after making just one trip.
Crucially, because the autophagosome is generated in response to a specific need for autophagy and then quickly disposed of after doing one job, autophagy does not happen on a continual basis, unlike other cellular processes such as respiration. Autophagy only happens intermittently — it requires a signal of some sort to begin the process. I’ll explain how to trigger autophagy later in this article.
Macroautophagy has many different subtypes, including mitoautophagy — the disposal of mitochondria — and lipoautophagy, the disposal of lipids (fats). They all work essentially the same way. Macroautophagy also seems to be used to kill viruses and bacteria (more on that later).
Microautophagy, as the name suggests, is concerned with breaking down even smaller things than macroautophagy. Specifically, it’s the process by which cytoplasm, the fluid medium that fills body cells, is recycled. This is done via invagination — the lysosome opens up and then engulfs a section of cytoplasm, a process that looks a bit like Pac-Man taking a bite.
Unlike other forms of autophagy, microautophagy is less about recycling damaged material and more about recycling nutrients in the cytoplasm, particularly lipids, in response to starvation conditions. It thus tends to happen as a result of fasting and exercise.
Chaperone-mediated autophagy (CMA) is a more specialized form of autophagy in which specific proteins are targeted to be transported to the lysosomes for disposal. Compared to other forms of autophagy, it’s notable for how selective it is. Specific proteins are identified, targeted, and disposed of one molecule at a time.
A decline in CMA has been implicated in aging, as well as in neurodegenerative diseases such as Parkinson’s. Mice that were genetically modified to not experience a decline in CMA over their lifetime were seen to have “cleaner” cells with less junk material accumulating, to have a better response to stress, and most importantly, to enjoy a better health-span.
However, certain forms of cancer are associated with an increase in chaperone-mediated autophagy, and several experimental cancer treatments have successfully shrunk tumors in mice by down-regulating CMA.
The big takeaway here is that autophagy isn’t always good, and what we need is not more autophagy all the time. Rather, we want our bodies to get better at using autophagy selectively— doing more of it much of the time, but less of it some of the time, particularly in response to certain forms of cancer and tumor growth.
How Autophagy May Defend Against Cancer
Autophagy plays several important roles in cancer, both in fighting cancer and suppressing tumors as well as occasionally helping tumors to survive and grow.
A protein called beclin 1 plays a role in the regulation of autophagy. Some types of breast, ovarian and prostate cancers delete the gene responsible for production of beclin 1; genetic knockout studies have shown that mice without the beclin 1 gene become more prone to tumor growth. However, some scientists have suggested that beclin 1 may actually protect against cancer through a separate mechanism that is unrelated to autophagy; the knockout of other autophagy-inducing genes doesn’t always have the same effect on cancer growth.
Less controversially, autophagy can indirectly limit cancer growth by cutting down on necrosis and chronic inflammation. There is no doubt at this point that chronic inflammation contributes to most types of cancer, and reducing overall levels of systemic inflammation has been shown to reduce overall cancer risk. Autophagy is of course just one way of reducing inflammation. Other ways include weight loss, sleeping better, and reducing stress.
Fat loss, in particular, has been shown to reduce cancer risk, in part via reducing inflammation. However, as we’ll see, diet and exercise can also induce autophagy, so in practice, the benefits of fat loss are not easily separable from the benefits of increasing rates of autophagy.
While autophagy helps to prevent cancer, the story shifts once cancer has already taken hold. Autophagy within a cancerous cell or a tumor can actually help the tumor to survive and cancer to spread.
Remember, one of the roles of autophagy — and microautophagy in particular — is to help cells get more use out of the nutrients they have during times of starvation. Many of the body’s defenses against cancer — as well as many cancer drugs — work by trying to starve cancer cells, such as by inhibiting the capillary formation or the uptake of glucose through the cell membrane. Thus, autophagy within cancerous cells can help those cells survive the body’s defenses and resist some cancer treatments by conserving energy.
Autophagy also helps cells to weather certain stressors. Again, this is usually good, and being able to deal with stress better usually lowers cancer risk. But autophagy can also help cancer cells survive stressors, even including radiation.
Autophagy can thus prevent or promote cancer, depending on the exact circumstances in which it happens. On the whole, autophagy helps prevent cancer more often than it promotes cancer, so more autophagy overall would be better. But of course, that isn’t ideal; ideally, you’d want the body to get more selective about when it induces autophagy.
At a high level, there are two ways to do this. First, you can intermittently activate the body’s natural autophagy processes through natural means, such as diet and exercise. I’ll explain how later in the article.
Second, you could use drugs. Many cancer drugs currently in development are intended to work by selectively activating or suppressing autophagy, either in cancerous cells or in cells that are in danger of becoming cancerous.
The bottom line: when it comes to cancer, autophagy is good more often than not, but ideally you’d want to be selective about when and how often it happens. More isn’t always better.
Autophagy As Immune Response Against Pathogens
Macroautophagy has been shown to be used as a defense mechanism against certain viruses and infectious bacteria. Technically, this is called xenophagy — the eating of other life forms that come from outside one’s body — but it happens as an extension of your body’s autophagy mechanisms.
A molecule called galectin-8, which is found in the cytoplasm, acts as a detector for infectious bacteria like salmonella and listeria. It can either detect the bacteria directly or indirectly by detecting the damage inflicted by them on cellular machinery. When either of those things happens, it triggers the formation of a new autophagosome, which then hunts down the invading bacterium.
When it comes to viruses, the autophagosomes themselves play a role in the initial detection of the pathogen. While viruses can be detected by T-cells as well as some detection molecules in the cells, they also sometimes get incidentally swept up by the autophagosomes, even when the viruses aren’t being specifically looked for. When this happens, the virus is identified after the autophagosome comes into contact with toll-like receptor 7 on the endosome, at which point anti-viral defense mechanisms such as the production of interferon are activated.
Crucially, this requires an autophagosome to already exist for some other purpose before the virus is even detected. In other words, the periodic initiation of autophagy — even for reasons unrelated to immune response — is a crucial component in the working of the immune system.
However, autophagy once again has a downside: certain bacteria directly attack the body’s autophagic machinery to prevent autophagy. Worse, some viruses have even evolved ways of subverting the autophagy process and using it to facilitate their own replication. Thus, when faced with these types of viruses, you’d want to temporarily stop autophagy in the affected cells until the infection is cleared. Once again, more autophagy isn’t always better.
Anti-Aging Benefits: Autophagy as Life Extension
One of the main functions of autophagy is to break down damaged organelles, cell membranes, proteins, and RNA sequences. All of these things inevitably build up inside the body over time. Individual proteins, and most organelles, don’t have an innate self-repair capability, so they need to be recycled once they’re damaged. Aging happens in part because the buildup of these damaged bits of biological material outpaces the body’s ability to break them down. This buildup is all but non-existent in children, slow in young to middle-aged adults, but starts to accelerate in old age because autophagy declines with aging. Thus, many avenues of current longevity research are focused on promoting autophagy to help the body keep up with this degradation and maintain “clean” cells free of biological detritus.
Autophagy is important not just to aging in general, but to many of the specific maladies associated with age. Dysfunctions in the lysosomes, the “recycling plant” organelle responsible for autophagy, have been implicated in age-related degenerative diseases like Alzheimer’s and Parkinson’s, as well as an overall decrease in lifespan.
Studying human longevity is difficult because scientists (for both ethical and practical reasons) can’t spend decades manipulating someone’s autophagic processes to see if it makes them live longer or die sooner. They can do this to animals, however. A plethora of studies have demonstrated that on the whole, animal models live longer when autophagy is up-regulated, and die younger when it’s prevented.
Most of what we know about autophagy centers around the recycling of damaged sub-cellular components, like organelles, proteins, and cytoplasm, which helps the cell live longer. However, entire cells sometimes become irreparably damaged. This can be caused by a specific stressor such as radiation or infection, or it can happen simply because the cell is too old or has replicated too many times, a phenomenon called cellular senescence.
These sick and useless cells become a drain on the body’s resources at best, and a potential source of illnesses, such as cancer, at worst. As such, they have to be killed off, a process known as programmed cell death. Cells undergoing programmed cell death show an increase in autophagy. However, it is currently unclear whether this autophagy is a cause of programmed cell death or a last desperate attempt to prevent cell death.
What is clear is that programmed cell death, like autophagy, is crucial for extending lifespans and limiting the effects of aging. It’s just unclear whether autophagy enables it, inhibits it, or can do either depending on circumstances. In short, autophagy mostly seems to extend lifespan, but it’s possible that in some circumstances autophagy may actually work against one of the body’s other anti-aging mechanisms- more research is needed here.
Autophagy and Physical Fitness
Autophagy plays a role in exercise, both during exercise and in recovery post-exercise. During exercise, microautophagy is needed to maintain glucose homeostasis and amino acid reserves within muscle cells. Without autophagy, cells would quickly run out of energy during exercise. Indeed, mice genetically modified for reduced autophagy show a decrease in endurance during bouts of exercise.
In fact, without autophagy, exercise becomes downright bad for you. After all, exercise initially damages the body — you only become stronger after recovering from it. It is therefore unsurprising that in mice with an autophagy-promoting gene knocked out, exercise leads to muscular degeneration, a buildup of damaged mitochondria inside the muscle cells, and a dramatic increase in muscle cell death. This damage was prevented or reversed by artificially inducing autophagy.
Another study found that when autophagy was prevented in the muscle tissues of genetically-modified flies, the flies not only failed to gain muscle post-exercise but were even weaker during exercise. Autophagy — specifically, chaperone-assisted selective autophagy — appears to be a necessary part of the process by which muscles maintain themselves while under mechanical tension. In other words, without autophagy, you would become weaker immediately, not just in the long run.
Autophagy appears to be just as important in the growth and maintenance of bone tissue as it is with muscle tissue. Age-related declines in autophagy have been shown to contribute to osteoarthritis. Since weight training has been shown to help build and maintain bone mass and prevent osteoarthritis, a decline in autophagy inflicts a one-two punch on your bones, both directly weakening them and making you less able to strengthen them with exercise.
Autophagy thus contributes to many of the known benefits of exercise. At the very least, to improvements in stamina, muscle mass, and bone mass. Indeed, it may well be a critical component in all of the body’s responses to exercise. Thus, autophagy is an important angle to consider both from the standpoint of staying healthy as you age, as well as enhancing athletic performance.
Ways of Inducing Autophagy
To some degree, autophagy is always happening in the body. But as we’ve seen, most people would benefit from more autophagy, most of the time. There are several ways to induce more autophagy, including fasting, ketogenic dieting, exercise, and drugs.
Unfortunately, almost all of the experiments on autophagy are performed on mice, or even insects — it can be very difficult to study in humans, depending on which specific body tissues scientists are trying to detect autophagy in. The overall mechanisms of autophagy are likely to be the same — if fasting induces autophagy in mice, it probably does in humans. However, the specifics, like how long you have to fast for or how much exercise you need, should be viewed as tentative and taken with a grain of salt.
Fasting, beyond a certain period of time, will lead to an increase in autophagy, as will caloric restriction. This is unsurprising since one of the purposes of autophagy is to help cells survive periods of nutrient deprivation.
In mice, an uptick in autophagy has been demonstrated after as little as 12 hours of fasting. Importantly, this didn’t require caloric restriction; the mice in question were fed only twice a day, but still got the same overall amount of food as control mice and mice that were fed less food, but on a normal schedule. The mice fed only twice a day, without caloric restriction, also lost fat and built more muscle, whereas mice that were fed fewer calories on a normal schedule lost both fat and muscle.
Not all body tissues begin seeing an uptick in autophagy after the same time period, however. Some tissues run out of glucose faster than others. In particular, the brain appears to be metabolically privileged — since it’s so important, it gets first dibs on the body’s glucose during times of starvation, and thus it takes a longer period of fasting to induce autophagy in the brain. In mice, an increase in autophagy becomes apparent only after 24 hours of fasting.
After 48 hours of fasting, some markers of autophagy increase even further, but others have started to reduce to normal levels by that time. Thus, fasts of at least 24 hours may be necessary to induce a state of heightened autophagy in all body tissues, while fasting much more than 48 hours is probably not helpful and may become counterproductive at some point.
The ketogenic diet
The ketogenic diet is a diet that contains extremely low levels of carbohydrate, moderate amounts of protein, and extremely high levels of fat. Consuming this kind of diet causes the body to enter a state called ketosis, in which fats are converted into ketone bodies, an alternative source of energy. Multiple studies have shown that autophagy occurs at an increased rate during ketosis, which can have benefits for both health and fitness.
A 2018 study by Li et al found that a ketogenic diet caused more autophagy in the calf muscles of mice, which enhanced mitochondrial function. In other words, the calf muscles developed more endurance.
A 2015 study found that a ketogenic diet promoted autophagy in the brain- again, in mice.
The ketogenic diet protects rats against neuronal injury in part via an increase in autophagy.
While studies have rarely been able to directly measure the effects of the ketogenic diet on autophagy in humans, there is strong indirect evidence that ketosis causes enhanced autophagy in humans. For instance, ketosis up-regulates mTOR, a genetic pathway that plays a role in regulating autophagy.
It should also be noted that while research on whether ketosis promotes autophagy in humans is lacking, there is ample research to show that ketosis can provide the benefits attributed to autophagy, such as better insulin metabolism, protection from neural injury and neurodegenerative diseases, and improved endurance. It just hasn’t been proven yet that autophagy is the mechanism by which these benefits are delivered.
For more information, read my complete beginner’s guide to the ketogenic diet.
Because exercise acutely depletes the energy stores of the targeted muscle tissues, it induces autophagy in them. As mentioned earlier, autophagy plays a critical role in maintaining cellular energy stores during exercise.
So how much exercise does it take to induce autophagy? 60 minutes of moderate-speed cycling was enough to induce autophagy in the leg muscles of moderately-trained young men. Their capacity for autophagy also improved over the course of the 8-week experiment. Not only does exercise cause autophagy, but increasing your capacity for autophagy appears to be part of the way the body adapts to exercise, just like building more muscle or increasing the heart’s stroke volume.
60 minutes of exercise for one specific muscle group may actually be more than enough to induce autophagy. A research review found that autophagy is more readily induced when exercise is more intense — when you work harder and start tiring yourself out faster. The same study also noted that autophagy happens more readily when training in a fasted state. This makes logical sense because autophagy is induced by a lack of energy in the cell. The main factor here may simply be how much energy you burn within a given muscle during exercise.
The same review noted that muscle autophagosome content actually starts to decrease after 60–120 minutes of moderate-intensity exercise, or after 20 minutes of low-intensity exercise following initial induction of autophagy. Since autophagosomes are disposable, being recycled themselves after delivering one load of material to the liposomes, this may indicate that beyond a certain point, exercise starts to “use up” the cell’s autophagosomes and outpace the body’s capacity for autophagy.
Note that unlike fasting, exercise depletes energy reserves in specific muscle cells, not the whole body- at least until you exercise for the better part of the day, long enough to cause whole-body glycogen depletion. Therefore, exercise-induced autophagy should primarily be thought of as an avenue for athletic performance, while diet-induced autophagy is likely of more use for life extension and cancer prevention.
As mentioned earlier, many drugs are currently being developed and studied which aim to increase — or in some cases, decrease — autophagy. Most are intended to do so selectively, in order to target cancers and degenerative diseases.
Logically, there should be some natural compounds and dietary supplements which can help to induce autophagy; unfortunately, there’s not much research in this area.
There are some studies which suggest that resveratrol may enhance or help to regulate autophagy, which may make it useful in preventing and treating Alzheimer’s Disease, and possibly other degenerative illnesses, and may also be the reason behind resveratrol’s apparent life-extension properties. However, the full effects of resveratrol are still poorly understood: as that same paper notes in its conclusion, the precise molecular mechanisms and the direct molecular targets of resveratrol for regulating autophagy remains largely unclear, and future studies should explore the therapeutic potential of resveratrol in vivo models.
A wide variety of natural compounds, including vitamin C, vitamin K, piperine, and ursolic acid, have been found to affect levels of autophagy in the prostate gland, thus making them potentially useful in fighting prostate cancer. As the study notes, autophagy can prevent prostate cancer, but also help it survive once it’s started. Some of the listed compounds help cells survive, while others actually increase the rate of cell death.
Part of the issue here is that it’s hard to know at any given time whether you want more or less autophagy in any given part of your body at any given time. There’s also not enough information on how any given compound will affect different body tissues- resveratrol is reputed to help cells survive, for instance, but that prostate cancer study found resveratrol increased the rate of prostate cell death.
Since the global effects of natural compounds on autophagy are so unclear, it’s probably best not to rely on them too much—instead, diet and exercise should be your main focus.
How to Use This Information
Autophagy can be a double-edged sword, but on balance, it’s a good thing. In short, you want more autophagy throughout your body most of the time, and that should be your focus. The cases where you want less autophagy are mostly medical in nature. If you don’t have cancer, your focus should be on increasing autophagy on an intermittent basis, giving the body time to recover in between bouts of heightened autophagy.
A few practical guidelines:
- Fast for 12–16 hours at least once a week, and maybe as often as every day.
- Fast for around 36 hours at least a few times a year, and no more than once a week.
- Exercise several times a week for at least an hour, and no more than two hours.
- Exercise each individual muscle group at least twice a week for at least 20 minutes, and no more than an hour.
- Exercise each muscle group to the point of exhaustion at least once a week. In other words, deplete that muscle’s glycogen stores.
- Eat at a caloric deficit for most of the year, except when specifically trying to build muscle.
- Spend a few months out of the year in a state of ketosis by following a ketogenic diet.
- Maybe take resveratrol for part of the year, cycling on and off it every so often. The full effects and optimal dosing protocol are unknown, however.
You don’t need to do all of the above, but you should be doing at least two of them—ideally, at least one of the diet habits and one of the exercise habits.
If some of those sound a lot like general guidelines for living a healthy life, that’s no mistake. While autophagy is in some ways a new frontier for biological research, in other ways it merely provides a mechanistic explanation for things we knew all along. Autophagy is part of the reason why diet and exercise are good for you- but at the end of the day, you don’t need to fully understand why diet and exercise work to know that they do work.
In other words — live a healthy lifestyle, and you’ll get more autophagy as a matter of course.