Yoshinori Ohsumi
On October 3rd, the Nobel Assembly at Karolinska Institutet has awarded the Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.
But what is autophagy? The word derives from the Greek auto (self) and phagein (to eat). So the word literally means to eat oneself. Essentially, this is the body’s mechanism of getting rid of all the broken down, old cell machinery (organelles, proteins and cell membranes) when there’s no longer enough energy to sustain it. It is a regulated, orderly process to degrade and recycle cellular components.
There is a similar, better known process called apoptosis, also known as programmed cell death. Cells, after a certain number of divisions, are programmed to die. While this may sound kind of macabre at first, realize that this process is essential in maintaining good health. For example, suppose you own a car. You love this car. You have great memories in it. You love to ride it.
But after a few years, it starts to look kind of beat up. After a few more, it’s not looking so great. The car is costing you thousands of dollars every year to maintain. It’s breaking down all the time. Is it better to keep it around when it’s nothing but a hunk of junk? Obviously not. So you get rid of it and buy a snazzy new car.
The same thing happens in the body. Cells become old and junky. It is better that they be programmed to die when their useful life is done. It sounds really cruel, but that’s life. That’s the process of apoptosis, where cells are pre-destined to die after a certain amount of time. It’s like leasing a car. After a certain amount of time, you get rid of the car, whether it’s still working or not. Then you get a new car. You don’t have to worry about it breaking down at the worst possible time.
Autophagy – replacing old parts of the cell
The same process also happens at a sub-cellular level. You don’t necessarily need to replace the entire car. Sometimes, you just need to replace the battery, throw out the old one and get a new one. This also happens in the cells. Instead of killing off the entire cell (apoptosis), you only want to replace some cell parts. That is the process of autophagy, where sub-cellular organelles are destroyed and new ones are rebuilt to replace it. Old cell membranes, organelles and other cellular debris can be removed. This is done by sending it to the lysosome which is a specialized organelle containing enzymes to degrade proteins.
Autophagy was first described in 1962 when researchers noted an increase in the number of lysosomes (the part of the cell that destroys stuff) in rat liver cells after infusing glucagon. The Nobel prize winning scientist Christian de Duve coined the term autophagy. Damaged sub cellular parts and unused proteins become marked for destruction and then sent to the lysosomes to finish the job.
One of the key regulators of autophagy is the kinase called mammalian target of rapamycin (mTOR). When mTOR is activated, it suppresses autophagy, and when dormant, it promotes it.
What activates autophagy?
Nutrient deprivation is the key activator of autophagy. Remember that glucagon is kind of the opposite hormone to insulin. It’s like the game we played as kids – ‘opposite day’. If insulin goes up, glucagon goes down. If insulin goes down, glucagon goes up. As we eat, insulin goes up and glucagon goes down. When we don’t eat (fast) insulin goes down and glucagon goes up. This increase in glucagon stimulates the process of autophagy. In fact, fasting (raises glucagon) provides the greatest known boost to autophagy.
Fasting is actually far more beneficial than just stimulating autophagy. It does two good things. By stimulating autophagy, we are clearing out all our old, junky proteins and cellular parts. At the same time, fasting also stimulates growth hormone, which tells our body to start producing some new snazzy parts for the body. We are really giving our bodies the complete renovation.
You need to get rid of the old stuff before you can put in new stuff. Think about renovating your kitchen. If you have old 1970s style lime green cabinets sitting around, you need to junk them before putting in some new ones. So the process of destruction (removal) is just as important as the process of creation. If you simply tried to put in new cabinets without taking out the old ones, it wouldn’t look so hot. So fasting may in some ways reverse the aging process, by getting rid of old cellular junk and replacing it with new parts.
A highly controlled process
Autophagy is a highly regulated process. If it runs amok, out of control, this would be detrimental, so it must be carefully controlled. In mammalian cells, total depletion of amino acids is a strong signal for autophagy, but the role of individual amino acids is more variable. However, the plasma amino acid levels vary only a little. Amino acid signals and growth factor / insulin signals are thought to converge on the mTOR pathway – sometimes called the master regulator of nutrient signalling.
So, during autophagy, old cell components are broken down into the component amino acids (the building blocks of proteins). What happens to these amino acids? In the early stages of starvation, amino acid levels start to increase. It is thought that these amino acids derived from autophagy are delivered to the liver for gluconeogenesis. They can also be broken down into glucose through the tricarboxylic acid (TCA) cycle. The third potential fate of amino acids is to be incorporated into new proteins.
The consequences of accumulating old junky proteins all over the place can be seen in two main conditions – Alzheimer’s Disease (AD) and cancer. Alzheimer’s Disease involves the accumulation of abnormal protein – either amyloid beta or Tau protein which gums up the brain system. Although we don’t yet have clinical trial evidence for this, it would make sense that a process like autophagy that has the ability to clear out old protein could prevent the development of AD.
What turns off autophagy? Eating. Glucose, insulin (or decreased glucagon) and proteins all turn off this self-cleaning process. And it doesn’t take much. Even a small amount of amino acid (leucine) could stop autophagy cold. So this process of autophagy is unique to fasting – something not found in simple caloric restriction or dieting.
There is a balance here, of course. You get sick from too much autophagy as well as too little. Which gets us back to the natural cycle of life – feast and fast. Not constant dieting. This allows for cell growth during eating, and cellular cleansing during fasting – balance. Life is all about balance.
Growth Hormone and Fasting
Could fasting help build muscle and unleash anti-aging properties, via the release of human growth hormone?
The physiology of fasting is fascinating. The power of fasting lies not in the mere reduction of calories, but the beneficial hormonal changes. One of the main benefits comes from reducing insulin, but there are also increases in nor-adrenalin, cortisol, and growth hormone.
Collectively, these are known as the counter-regulatory hormones, since they all serve to increase blood glucose at a time that the body is not getting glucose from food. Here we focus on human growth hormone (HGH).
Human growth hormone
HGH is a hormone made by the pituitary gland (the master gland), which plays a huge role in the normal development of children and adolescents as the name implies. However, it also plays a role in adults. HGH deficiency in adults leads to higher levels of body fat, lower lean body mass (sarcopenia) and decreased bone mass (osteopenia).
Once released by the pituitary gland, HGH only lasts a few minutes in the bloodstream. It goes to the liver for metabolism, where it is converted into a number of other growth factors, the most important of which is Insulin-Like Growth Factor 1 (IGF1).
This is the same IGF1 that is connected to high insulin levels and many poor health outcomes, but remember, that this brief pulse of IGF1 from HGH lasts a few minutes at most. Most hormones are secreted naturally in brief bursts to prevent the development of resistance, which usually requires both high levels and persistence of those levels (this is indeed how insulin resistance develops).
Scientists first harvested HGH from cadavers in the 1950s (eeewww), but only synthesized it in labs in the early 1980s. Soon afterwards, it became a popular performance enhancing drug. Normal levels of HGH peak in puberty (as you might expect) and gradually decrease thereafter.
Growth hormone is typically secreted during sleep and is one of the so-called counter-regulatory hormones. HGH along with cortisol and epinephrine increases blood glucose by breaking down glycogen – so it counters the effect of insulin, hence the name counter-regulatory hormone. These hormones are typically secreted in a pulse just before waking (4 am or so) during the ‘counter-regulatory surge’. This is normal and is meant to get the body ready for the upcoming day by pushing some glucose out of storage and into the blood where it is available for energy.
When people say that you ‘must’ eat breakfast to have energy for the day, they are simply wrong. Your body has already given you a big shot of the good stuff and fueled you up for the day ahead. You don’t need to eat sugary cereals and toast with jam to have energy. This is also the reason why hunger frequently is lowest first thing in the morning (8 am) even though you have not eaten for 12 hours or so.
HGH for anti-aging and building muscle
HGH typically goes down with age and abnormally low levels may lead to lower muscle and bone mass. So, what are the effects of giving HGH in older people with very low levels? This was studied in 1990 in a New England Journal of Medicine article.
Group 1 is the HGH group and Group 2 is the control group (no HGH). Over 6 months, weight overall did not change between the two groups. But look at the lean body mass!
The HGH group packed on 3.7 kg (8.8%) more lean mass. That’s 8 pounds of lean mass! Fat mass decreased an extra 2.4 kg (5.3 pounds)! Thats a decrease of 14.2%. Even the skin thickness improved. Whoa, nelly. Loss of fat and gain of lean mass (muscle, bone and skin). That’s anti-aging, baby!
In a 2002 JAMA article, similar results were obtained in women as well. Sounds pretty great. So, why aren’t we using it for everybody? Well, there’s a little thing called side effects. Remember that this study only used it for people with very low HGH levels, not in people with normal levels.
There was an increase in blood sugars. This makes sense, since HGH is a counter-regulatory hormone. Pre-diabetes also significantly increased. There was an increase in fluid retention as well as blood pressure, too. Over the long term, there is also a theoretical risk of increased prostate cancer and heart problems (enlarged heart). So, that’s not very good news.
So artificial injections of HGH are out. What if there is an all-natural method of increasing growth hormone? What about, say, fasting?
Fasting to increase growth hormone
In 1982, Kerndt et al published a study of a single patient who decided to undergo a 40-day fast for religious purposes. Glucose goes down. From 96 initially, it drops to 56. Insulin goes way, way down. Starting at 13.5, it quickly drops to 2.91 and stays down. That is almost an 80% drop! If you are concerned about a disease such as type 2 diabetes, with hyperinsulinemia, fasting is an effective way to bring down those sky high insulin levels.
But our concern here is HGH. It starts at 0.73 and peaks at 9.86. That is a 1,250% increase in growth hormone. A shorter 5 day fast gives a 300% increase. All this HGH increases without drugs.
What about the potential side effects? Increased glucose? Nope. Increased blood pressure? Nope. Higher risk of cancer? Hardly.
Other studies have shown the same increase in growth hormone. In 1988, Ho KY et al studied fasting and HGH. On the control day, you can see that meals (marked M) very effectively suppress HGH secretion. This is to be expected. Like cortisol, HGH increases glucose and thus is suppressed during feeding.
Fasting is a great stimulus to HGH secretion. During fasting, there is the spike in the early morning, but there is regular secretion throughout the day as well. Hartman et al also showed a 5 fold increase in HGH in response to a 2 day fast.
This HGH likely helps in the maintenance of lean mass – both muscle and bone. One of the major concerns about fasting is the loss of lean mass. Some people claim that fasting a single day causes loss of ¼ pound of muscle. Studies prove that this does not occur. In fact, the opposite can happen. In comparing caloric reduction diets to fasting, the short term fasting was 4 times better at preserving lean mass! Think about this for a second.
Let’s imagine that we are living in Paleolithic times. During the summer of plenty, we eat lots of food and store some of that as fat on our body. Now it is winter, and there is nothing to eat. What do you suppose our body does? Should we start burning our muscle while preserving our stored food (fat)? That doesn’t make much evolutionary sense.
It’s as if you store firewood for a wood-burning oven. You pack lots of firewood away in your storage unit. In fact, you have so much, it is spilling out all over your house and you don’t even have enough room for all the wood you’ve stored. But when the time comes to start up the oven, you immediately chop up your sofa and throw that into the oven.
The logical thing to do is to start burning the stored wood. In the case of the body, we start to burn the stored food (fat stores) instead of burning muscle. Some protein is catabolized for gluconeogenesis, but the increase in HGH maintains lean mass during fasting (however, this is likely different for those without excess fat stores and they may experience a greater loss of lean body mass with fasting).
Implications for athletes
This has enormous implications for athletes. This is called ‘training in the fasted state’. Increased nor-adrenalin from fasting may pump you up to train harder. At the same time, the elevated HGH stimulated by fasting should increase muscle mass and make recovery from a workout easier and faster. This could be an important advantage in elite level athletes, and we are seeing more and more interest in doing this exact sort of protocol, although high quality studies are lacking.
It is not by accident that many of the early proponents of training in the fasted state are bodybuilders. This is a sport that demands, in particular, high intensity training and extremely low body fat for definition.
For example, Brad Pilon, who wrote the book “Eat, Stop, Eat” is a bodybuilder, as is Martin Berkhan, who popularized the ‘lean gains’ method of fasting. Somehow, I don’t think that fasting for these two fellows was ‘eating’ their muscle.
So, for all those people who thought that fasting would make you tired, or that you could not exercise during fasting, well, hopefully you now see a different perspective. Fasting will not ‘burn’ muscle when there is adequate excess fat to burn.
Rather, fasting has the potential to increase the beneficial effects of HGH without any of the problems of excessive HGH (prostate cancer, increased blood sugar, increased blood pressure). For those interested in athletic performance, the benefits are potentially even greater.
So, let’s see. When done right, intermittent fasting can help: Train harder. Lose weight. Faster recovery. Decrease insulin and insulin resistance. Decrease blood sugars. All of these benefits are achieved without drugs, supplements or cost. Yes, like all the best things in life, it’s free. So why is everybody so against it?
