Autophagy and Fasting

Dr Jason Fung, nephrologist and best-selling author, shares his experiences utilising an individualised approach to fasting, to successfully treat thousands of overweight, metabolically ill and diabetic patients.  Being a doctor who specialises in kidney disease gives him a unique insight into early indications of metabolic disease. Let's listen to Dr Jason Fung.

Does Drinking Coffee during Fasting break the Autophagy phenomenon?

Yeah, that's a tough question to answer, because there's no data to answer. It's because autophagy is a relatively newly described phenomenon. It hasn't been around for a long time. Well, we do know about it. That autophagy is one of the primary regulators, called the mechanistic target of rapamycin or mTOR. So, mTOR is a nutrient sensor which senses that nutrients are coming in. Insulin is also a nutrient sensor that tells the body that nutrients are coming in.

They evolved separately. And in fact, mTOR seems to be a much more ancient sort of a pathway compared to insulin. If you look at unicellular organisms, the mTOR has been around a lot longer than insulin has. So, it seems to be very important. And when mTOR and Insulin are activated, they tell the body that the nutrients are coming in. Thus, they turn off autophagy. Autophagy comes from the Greek word for self-eating. 

It's a cellular cleansing process where you take these proteins that you don't need. And you break them up, either reuse the parts to make new proteins. Or you burn it for energy if you don't have enough energy coming in. In a state of sort of excessive nutrition that is in our some kind of modern state, we are more concerned about obesity than malnutrition. 

Autophagy may be one of the beneficial things that we don't get a lot of anymore. The mTOR seems to be very, very sensitive to protein and to specific amino acids, it’s very sensitive. But to how sensitive is coffee enough to do it? I have no idea. So, for those people who want to make sure that they get the autophagy, then you would have to do one of the classic fast, which is water-only fast. Dry fasting is a more extreme sort of version of water fast. 

But those things, if you want to get there at some point, they may help. They may find at what threshold you turn on the mTOR and turn off autophagy. But it seems to be very, very sensitive to it. And the reason is that it's the body which links the incoming nutrients to the growth of the cells. If you think about yeast, when there's no water and no sugar, it wrinkles up and stays dormant. It doesn't die. It just stays dormant. You don't want to be growing if the yeast were to continue growing in the state where there are no nutrients. If so, it's going to die eventually, and you don't want to do that. And so is the same for the cell in our body.

 You don't want to expend all your energy growing unless there's food coming in. You want to do the opposite, which is break down of these proteins and so on. That's why nutrient sensors are so crucial for growth pathways. Everybody gets the wrong idea of that growth is excellent. And I've always argued about this. For adults, growth is mostly not good. Because, if you look at obesity, it's a disease of too much growth.

To be a simple, cancer is a disease of too much growth. Alzheimer's disease is a growth of too much of this. There's too much protein that's junking up the system. Type II diabetes, with the fatty liver and fatty pancreas, is a disease of excessive growth. Atherosclerosis is the hardening of the arteries. The narrowing of the arteries is not due to blockage by cholesterol. It's a disease of growth. You have white cells and foam-filled cells. And the stimulation of these smooth muscle cells results in narrowing of the artery. This narrowing of the artery is also a disease of too much growth. 

If you have a disease of too much growth, restricting nutrients can be beneficial. Two hundred years ago, people didn't have obesity and didn't have to worry about too much growth or too many nutrients. If you're on this side of the path, restricting nutrients is not a good thing. But these days, it may be a very beneficial thing. 

So that's the long answer. If you want autophagy, I would suggest avoiding coffee because you don't know how much it's going to take.

Fasting for autophagy and fasting for weight loss can be two different goals?

Yeah, absolutely. What we always say also is to keep your goals in mind.  Because if you're trying to lose weight, you don't need autophagy.  It's not necessary. You can follow a ketogenic diet, which still has plenty of protein in it, like moderate protein, adequate protein. And you can again lose weight with the ketogenic diet—no question about it. You're not going to get any autophagy because that protein that you're eating is going to turn off the autophagy.

The flip side is that it's fasting for weight loss, which is a lot easier to measure because you have a kind of a yardstick. There's no yardstick that you can say, are you getting it's having even. For ketosis, there's a yardstick. You can do the breath test, the blood tests to know whether you're in ketosis or not. But you can't say the same for autophagy. Maybe we will get there one day. But there isn't anything currently. So, the only thing we mean is that you got to make sure. Otherwise, I can't tell you whether it's there or not.

 The nutrient sensors (mTOR and the insulin) sends different things. Protein is the main thing for mTOR. And for insulin sensor, it’s both protein and carbohydrates. But everybody thinks insulin is just about carbohydrates. That's wrong. If you look at the insulin response to animal protein, the response is very high. But it's less so for vegetarian protein. For example, if you eat tofu and beans, there's less insulin response.

But your blood sugar is not affected because there are other compensatory hormones in it. For example, if you eat a steak, which has lots of animal protein, your insulin may go up quite a bit. But your blood sugar won't go up at all. So, they're (insulin and blood sugar) two separate things. And I think this is one of the things that is always confusing to people is saying, “Oh, I eat the steak and my blood sugar didn't go up at all. What's this whole insulin then?”.

Your blood sugar level shouldn’t go up at all. It doesn't mean your insulin hasn't gone up at all. And that was one of the things that Joseph Kraft made a significant distinction that you have to understand that insulin is different from blood glucose. I mean, they're related, but there are distinct things. You have to be kind of zeroed down on your protein if you're after autophagy.

Should autophagy be our main goal while fasting?

The benefits of autophagy are still mostly theoretical. There seems to be a lot of future research, which is really good and exciting and so on. I have no idea if it is going to help you or not as opposed to say if you are fasting for your blood sugar and you want to get off of your insulin. We know that if you go from, a hundred units of insulin a day to zero, you're a lot healthier.

And that's going to have a huge impact on you. You may or may not need fasting. You may not or may need autophagy for that. For example, you could do well with the ketogenic diet. So, it's crucial for us to sort of, as Megan says, to make that priority because I have no idea, I just posted an article about autophagy and cancer.

And some people think that too much autophagy may worsen the cancer. And the reason for that is that the autophagy is a survival mechanism. And if you already have the cancer cells and then you start to stimulate autophagy, those cancer cells may be protected. It’s because these cells are breaking down proteins for energy and they're getting an energy source.

So, there's a lot we don't know about it. Yes, it seems to be very interesting in terms of preventing cancer. But it may not be the best thing if you have cancer. Nobody knows too much about that. So, I wouldn't go crazy on this because I don't know if it helps or not.

Is there a time over which you should fast to maximise autophagy?

I can guess. But it’s again we don’t know. If you look at what happens during fasting, we know that you mostly use glycogen during the first 24 hours, roughly 24 hours. And then there is the period of gluconeogenesis. It is from 24 to 36 hours. So that's the period, where there is going to be the most sort of autophagy and so on. 

Because you’re breaking down the proteins at that point for gluconeogenesis. This is the sticking point with a lot of people in fasting. They say, “Oh, Hey, you're breaking down protein, you are going to burn your muscle in 24 to 36 hours period.”. It’s possible, but I don't think that the research on alternate daily fasting bears that out. However, I think that's a good thing. 

One you are taking down old protein. And then because of growth hormone increase, you’re going to rebuild new proteins. I think it’s not breaking down process. It’s a renewal process if you look only at the breakdown at 24 to 36 hours. And if you miss that burst of activity, you’re going to miss the whole picture. You are going to say, “Oh, Well, you know you're just breaking it down, but you don't miss”.  You don't see the fact that it's balanced now keeping in mind that the body always works in this way.

For example, if you look at your bones, they are not static. There are osteoclasts and osteoblasts. When you go through life, you have cells called osteoclasts which eat away at your bone, and you might say, “Oh, Wow. That’s terrible”. But actually, not bad. Because when osteoclasts eat away the bone, it stimulates the osteoblasts to produce new bone. If you only look at the one side of it, you would term these cells to be terrible. 

But the fact is it’s likely; you are going to have terrible brittle bones. That’s what happened with some of the drugs we use, like bisphosphonates. We started seeing brittle bones after like ten years. It was because the bones might have more calcium, but they're old and not renewed. The same thing happens in this 24 to 36-hour period of time. You are breaking down protein, and it need not be muscle; it can also be connective tissue. But this is a pure guess.

Nobody knows. This is my guess as to the best place (24 to 36 hour) for the autophagy to maximise itself. If you are trying to maximise this for trying to break down skin or connective tissue or Alzheimer’s disease, where you may have excess protein in the brain, the following would be my guess. It would be most beneficial to do these 24 to 36 hours fast once in a while. And once in every month. And then once in every couple of months, to do an extended fast.

 The reason we do this is that we don’t know where the best sort of benefits lies. Therefore, I’m going to cover all my bases. Do an occasional long fast with some of these alternate daily fast, 24 to 36 hours, trying to focus on the protein breaking down period. And when you do these 24 to 36 hours fast, there’s no coffee, There’s no anything, but water and salt alone. That’s it for the autophagy. 

Few specific people come to us, and they say, “You know to our knowledge this is going to be the best protocol for you”. But nobody has proven this. Nobody has confirmed any of this. It’s up to you that you can or cannot do it.

In a 2-day Fast, Will having Coffee with Cream on the First Day Impede the Burning of Glycogen?

It doesn't really. The way that fat is metabolised is entirely different. The reason why both carbohydrates and protein stimulate insulin is that they both go to the liver for metabolism. If you think about it, you got proteins and carbs. When you absorb them, carbohydrates get broken down into glucose, and proteins get broken down into amino acids. They both get absorbed through the small intestine, into the portal vein which flows straight into the liver. At the liver, it decides what to do with them. 

Either you package them into glycogen or de novo lipogenesis, they package them into fat. Proteins get used up to the amino acids for new protein. And then any excess protein does get turned into fat. But fat doesn’t do that. Fat is entirely separate. Dietary fat, which is triglycerides, get absorbed through the lymphatic system and goes straight into the blood vessel and then to your adipocytes. So, fat primarily gets stored directly, and that's why there's no insulin. It's because you need insulin signalling for the liver to know what to do with it. So, the insulin goes up, and your body says, “Okay. Now we need to store some of this energy.” Fat is completely different. It goes straight into your fat cells which is why you can do this fat fast as it will have no insulin effect.

 You still get your glycogen down and then eventually you’ll get to your body fat. But if you’re increasing your body fat, stores at the same time, you’re working against yourself. It doesn’t make the insulin fall though.

 So, the question is, how can you ever lose weight if you're eating all this fat like on a ketogenic diet. The point is you're letting your insulin levels fall, and it's a battle between insulin and leptin. Because when your fat cells enlarge, you're not going to have any insulin effect at all diet of pure fat.

For example, if you just drink olive oil, your fat cells will enlarge. At some point, as your fat cells expand, your brain stimulates leptin. This goes to your brain and tells you to stop eating. So that you can use up this fat because your body doesn’t want to be too fat. Stimulation of leptin is not a survival mechanism. You don’t want to be skinny and too fat either because you’re going to get eaten and killed.

So, leptin is a sort of regulator of body fatness. Insulin, on the other hand, tells the body to store body fat. It’s kind of insulin versus leptin. If you drop your insulin, then you can let your leptin eventually become sensitive. Then your body will activate other mechanisms to stop eating. 

That’s how you can still eat a lot of dietary fat and lose weight because your body will tell you to activate these satiety mechanisms. They'll ask you to stop eating and so on. And that's one of the things we like to do when people are fasting. To allow the insulin level really drop low and then re-sensitise to the leptin, to eat your body fat. 

To make fasting easier for some people, can you give them the fat on the first day while burning glycogen and then on the 2nd-day switch to water and salt?

Yeah, I think that's a perfectly reasonable strategy. The dietary fat, for example, the cream you take up in day one is not going to impede burning of glycogen. The fat is not going to hamper your insulin falling which is what we want. We want the insulin to fall and wanted to stay low for a reasonable period so that you break the insulin resistance. It will re-sensitise the leptin because it’s kind of head-to-head insulin vs leptin.

You become obese when insulin wins. That’s the bottom line. You have to knock down the insulin as best as you can. We tried to give and increase leptin, and it didn't work. It wasn't strong enough to overcome insulin. We know from insulin that it’s the sugar from the fructose, which causes insulin resistance and fatty liver. And also, the frequency of meals are all those, which are pumping insulin all the time. If you're eating ten times a day, you will be injecting insulin in, all the time. And you’re going to knock down that leptin. When you’ve got the insulin taking over leptin, that’s when you become obese.

Why doesn't if (say one keto meal a day) throw your body into a Starvation mode? (Although I’m certain I could gorge down enough Calories in one sitting to achieve my macros for the day, I don’t see it as a viable option)

Yeah, that’s a good question. A lot of people ask this because they get confused with the insulin hypothesis and the calorie hypothesis. When people think that it’s all about cutting calories, they say “Well, 24 hours, a period, 2000 calories should be the same whether you take a single meal or you take it kind of constantly spaced out through the day”. But it’s not true. That's not how the body works.

It is like you could have an average temperature at Death Valley, say 20 degrees. But you wouldn’t say that it’s comfortable there. You would face scorching hot during the day and cold at night. So, the average temperature doesn’t tell you anything. You got to realise that insulin is based on two things.

It’s based on how high the insulin spike goes and how long it persists. If you have a high peak and then low for the other sort of 23 out of 24 hours, it's a lot different from a physiologic standpoint. It is different when compared to taking a little bit regularly throughout the day, just like the Death Valley. But the body works that way. 

If you look at hormones like growth hormone, it does the same thing. You get a big spike sort of four a.m., five a.m. and then it goes undetectable through most of the day. Parathyroid hormone and most of the hormones are actually like that. You get a single spike and suddenly becomes quiet. And that’s because you don’t want to stimulate it all the time as you develop resistance that way. For example, if you look at even drugs, you’re going to develop resistance to it when taken continuously. 

If you stimulate the nerve cell it all the time, you just develop resistance. The whole thing is the same. It is similar to the boy who cries wolf. If you cry wolf and you do it all the time, people just ignore you. If you cry wolf once, and then you don't cry wolf for like another year and then cried again, people will respond when you come back. So, it’s the same thing with the body. 

We’re not talking about it. It's because we're not trying to influence calories. Calories is a fairly useless concept, and everybody says “Well, are you saying that calories don’t count.?”  I’m saying that it’s the entirely wrong way to think about it. What you’re trying to influence is, it’s insulin resistance, which indirectly affects your body set point. I believe body set-point is what controls your body weight. And it’s mostly dependent upon insulin resistance like there are other things like cortisol and so on. So, there’s a lot of things that matter. 

That’s the kind of answer. You eat 2000 calories at a single sitting once a day versus 2000 calories spaced throughout the day. There's a different response in terms of insulin and insulin resistance even though the calories are the same. And that's why the fasting is entirely different than the calories. The whole reason people get confused between calories is that they say “Well, does that mean I can eat, you know, as much as I want, as long as it has no carbs, I’ll just eat steak all day and lots of protein?” It’s No.

 The reason people get confused with the calories is that everything that you eat practically stimulates insulin unless you drink like pure fat which is nothing but bulletproof coffee. It is not something realistic, as nobody eats sticks of butter. You know the bulletproof coffee is an excellent example because that's a hack where people deliberately take something sort of unnatural to gain the benefits of it. 

Because it has a ton of calories and almost no insulin effect. The reason is that if you look at real foods, they contain a blend of carbohydrates, protein and fat. So, all foods will stimulate insulin. For example, all foods also contain calories, but they’re not the same. Calories don't count, but it's the calorie-containing foods, which also have varying degrees of insulin effect. That’s the bottom line.

 That’s why people get confused. It’s not like you can say “Well, Avocados are good so I can eat 50 avocados a day and I should lose weight”. You might or you might not because it’s still going to have that insulin effect. And if you're insulin resistant, then certain foods are going to be worse. It means practically; not all foods are equally fattening, which again is something intuitive. If you eat grilled salmon, it’s not as fattening as brownies. It’s not like that. But the calorie people insist that 600 calories of a doughnut are the same as steak and eggs of 600 calories. 

No, it’s completely different. It’s because the insulin effect of the two is different. And if you look at the genetic contributions to obesity, you see that different people respond differently. Some people are much prone to obesity. But it doesn’t explain how an entire population becomes obese. For example, the United States genetic pool hasn't changed a considerable amount. But in the sort of past 40 to 50 years, there's been a massive change in obesity.

Genetics can’t explain that, but it can tell the difference between one person and the next. They will have different responses to insulin. Some will produce a lot and therefore have a real propensity to gain weight. And everybody knows that some eat whatever they want and they never gain weight.

If people are stuck on the calories-in calories-out mechanism, would it be better if they focus on increasing the rate at which calories go out?

The total calories thing is a huge obstacle for people to overcome. And that's why they can't understand why 2000 calories at a single sitting, you know “Oh, I’m going to go into starvation mode because when I took the 1500 calories spread over eight meals a day, my metabolism got shot to hell. So, if I take 1500 calories in a single sitting, it’s not going to be”.  It’s No. Because what you’re trying to do is to take the 1500 calories for that day and then take 500 calories from your stored fat. And burn that. Then you'll burn 2000, which is what we want. What we’re trying to do is open up the stores of fat for burning because those are all stores of energy.

I mean that’s what fat is. It’s a store of food energy. You want to take the amount that you are and take about an amount of body fat. Then slop it in and burn the whole thing. But you can’t do that very easily when you’re eating all the time. It is why we focus a lot on meal frequency and intermittent fasting. Things like time-restricted eating, which is a nicer way to put it, don't freak people out when compared to fasting. But we focus on that a lot because people don’t talk about it. Because of the calories theory, they assume that 1500 calories throughout the day and 1500 calories at one sitting are the same. No, you have to get out of this.  

The thing is that there are people out there, who say, “Well, we’re all genetically programmed to eat and therefore now we live in a world of food all the time. We can’t help ourselves". It's a big NO. It's because your body has a very, very powerful mechanism to stop overeating. If you eat a buffet, you go to the all you can eat. And you’re sufficiently stuffed, and then somebody says, “Here take another pork chop”. You’d be like, “Blah, I want to throw up”.  Your body has these mechanisms that stop you from eating, and there are multiple ones, and they overlap. 

For example, there are stretch receptors in the stomach that is if you have a lot of stuff in your stomach, then you can't put any more. For example, with bezoar, people who swallow their hair and stuff, their stomach gets filled with hair and nothing goes down. It’s like they're full. They can't eat because they're so full. Or they eat a little bit, and then they feel full. It is because of the stretch receptors in the stomach. There’s Peptide YY, which is very sensitive to protein.  

When you have a high protein meal, there are incretins which we also use therapeutically. Incretins are sensitive to protein. For example, if you inject yourself with incretins or incretin stimulating agents, then you become full. And when you go over that, you become super nauseated. It is one of the mechanisms why these incretin drugs like senetide or exenatide produce not only nausea but also cause weight loss. So, there are peptide yy, incretins, gastric stretch receptors, cholecystokinin, which is sensitive to fat. 

 If you eat fat, cholecystokinin goes up and then ultimately there’s leptin. So, leptin is when your fat cells are too big. You can see that your body has all these mechanisms to prevent you from overeating. Because it knows that if you get too fat, you’re going to die and it doesn't want you to die.  

Why do we sometimes feel ravenously hungry even though we are absolutely full?

I think that the reason for real food like carbohydrate-containing foods being difficult to overeat is that we’ve devised these sorts of satiety mechanisms to it. For example, if you take the white potato like a baked potato, its satiety index is exceptionally high. For the same amount of calories, the amount of satiety you produce from a potato is very high. There may be other mechanisms or maybe resistant starch and whatever. That’s why I say it’s not just about the carbohydrates; it’s all about the insulin which is not the same things as to say that it’s all about the carbs. It is because there are so many other factors that have to go into it. The thing is that when you start getting a lot of these processed foods, they begin evading all of these satiety mechanisms.

You can take something like wheat and then process the hell out of it to get rid of all protein. It is going to get rid of the satiating fat. You’re left with pure glucose and then grind it into fine dust which is very quickly absorbed. You take tapioca starch versus tapioca root; people have been eating tapioca for a long time. People eat sweet potatoes in Okinawa and do well. But you can’t take these potato starch and flour, and pretend that it's the same thing. But it’s not. They’re processed. They’re in an unnatural form, so they’re not the same thing.

 Processing evades a lot of the satiety mechanisms. Is it deliberate? In some sense, it is intentional because you know companies want you to eat more of it. So, they make sugar. Adding sugar makes it much easier to evade these satiating mechanisms. Same thing you go to the buffet, and it’s like you can’t eat another pork chop but you could eat some ice cream. Or you could eat some candy, or you could eat some apple pie. It is because refined carbohydrates evade these sorts of satiety mechanisms.