Autophagy Part 1 - Why it matters
We evolved to live in an environment where food is scarce. Our unbelievably complex physiology developed countless ways to keep us functioning and healthy on virtually no calories so we would have enough energy to seek out food and survive. We also evolved intricate cellular repair processes that enabled us to heal and repair damage caused from environmental factors like radiation from the sun, dangerous chemicals and pathogens, and even incidental damage caused from metabolism and immune system activation. One process that handles both needs is autophagy. In the absence of calories (in a fasted state), your body recycles old, damaged cells so they can be used for energy or as components for new cells. This important clean up process prevents age-related damage from accumulating and turning into devastating diseases like cancer and dementia.
Autophagy works best when you’re fasting or sleeping (or both). Unfortunately, we’ve all been conditioned for decades by “experts” that the only way to stay healthy is to eat all the time. Seeing as how 40 percent of American adults are obese and another third are overweight, this advice doesn’t seem to be working. It’s not only making us fat, but it’s interfering with the repair processes that ward off things like cancer, dementia, and cellular aging in general.
Food sales vs health
I’ve previously written about why our dietary advice keeps changing, but it’s important to quickly touch on a few important points since the advice I’m going to give will likely be contrary to what you’ve heard your entire life.
1. The USDA’s job is selling food. All our “official” dietary advice comes from the USDA, which stands for the United States Department of Agriculture. There’s a pretty big hint in that name. It’s not the United States Department of Health, it’s the Department of Agriculture. Their primary job is to promote and support American farmers, ranchers, and food manufacturers. This is why the USDA overrode Luise Light’s original recommendations for the first Food Pyramid and altered it to include more refined grains, meat, dairy, commercial snacks and fast foods. She knew even back then that these altered recommendations would lead to rampant obesity.
2. The food industry learned from the tobacco industry. Companies like Coca Cola injected millions of dollars into nutrition research to confuse consumers and prevent a backlash against their unhealthy products. Lots of this research was picked up by “experts” and news outlets and disseminated throughout the culture. “Eat 6 times a day to keep your metabolism up,” “never exercise on an empty stomach,” and “eat tons of protein so your body doesn’t eat muscle” are all common refrains that have been disproven with research yet are still pervasive advice. I admit that I have personally written about the last one more than once. We do lose muscle when we diet and eating a lot of protein will prevent that from happening. What I didn’t know then (and what many still don’t know) is that this is just part of a natural process to clean up old damaged cells and replace them with healthy new ones called autophagy. You may lose muscle at the time, but you get it back (and it functions better).
Muscle grows back
Losing muscle is a legitimate concern when dieting, and the primary reason all the “eat more to lose fat” advice is so prevalent. I’ll get into the reasons why you don’t need to worry, but I want to start with an example so you can realize you’ve already witnessed the truth in it yourself. At some point in your life, you or someone you know broke a bone and had to have an arm or leg completely immobilized in a cast. After 6 to 10 weeks of healing, the cast comes off and the limb is half the size of the other one due to atrophy (muscle loss). Within months of use, all the lost muscle regrows and the healed limb looks identical to the other one. We gain and lose muscle all the time. Exercise itself breaks down muscle so it can be rebuilt stronger and more capable of handling the same stress in the future. No one wants to lose muscle, but unless you plan to never move again, it comes back.
When you lift weights, your body first adds additional myonuclei to the muscle fibers before hypertrophy (muscle growth) can occur. They’ve found that these additional myonuclei are not lost due to atrophy which allows the muscle to quickly bounce back after mass is lost. It’s one of the big reasons you should lift weights before you turn 40. When you’re young, you gain muscle mass by adding new muscle fibers as well as by adding size to the current fibers, but after 40, all you can do is bulk up the old fibers. You don’t add new ones. Laying the foundation in your youth will allow you to maintain important muscle mass as you age.
The IGF-1 trade off
On the subject of muscle growth, I need to take a little detour to also talk abut the growth factor known as IGF-1. Frequent studies and news stories try to paint red meat as the cause of cancer. As I’ve written before, many epidemiological studies do find a correlation between high red meat consumption and cancer risk. Most of these studies throw in the “minor” caveat deep in the study saying that “people that ate red meat also tended to smoke more, drink more, exercise the least, and eat low amounts of fruits and vegetables.” Each of these alone is a far greater risk factor, and lumping them together as incidental factors is flat out fraud and a sign of bias.
However, there is a legitimate issue with red meat that the more honest researchers have pointed out. Red meat raises IGF-1 levels and if you’ve already suffered DNA damage, this growth factor can help precancerous cells proliferate. There is also a link between low IGF-1 levels and longer lifespans. It’s been shown in animals that decreasing IGF-1 levels increases overall lifespan and centenarians (people living past 100) tend to have a polymorphism that causes decreased IGF-1 levels. It’s also one of the reasons why calorie-restricted diets show increased lifespans in animals and possibly humans.
The problem is that IGF-1 also offers a host of benefits. It’s a growth factor after all. It helps build and repair muscles and bones, triggers neurogenesis in the brain and protects against dementia, and has antioxidant and anti-inflammatory properties. In general, it helps you feel stronger and more vital as you age. Those centenarians with low lifetime IGF-1 levels also tend to be smaller and more frail. It’s the IGF-1 trade-off that you’ll see on many sports and nutrition sites. High IGF-1 levels improve overall performance but the trade-off is it could lead to a shortened lifespan.
One of the primary benefits of intermittent fasting is that it works around the IGF-1 trade-off. Fasting lowers IGF-1 levels to trigger autophagy, but once the fast is done, the refeeding raises levels again to power regeneration and overall performance and vitality. No one knows if it will offer the same life extension benefits as continuous caloric restriction, but it’s definitely a more realistic option than depriving yourself for the rest of your life.
Get rid of senescent cells
In oder to understand why autophagy is so important, you first need to understand the damage it fixes and what happens if you don’t take care of it. As I mentioned above, we incur cellular damage all the time. Some of it comes from external sources like solar radiation, pollution, and infectious bacteria and viruses, but other damage is a simple byproduct of living. Metabolism creates reactive oxidative species that can damage DNA, and while your adaptive immune system creates fine-tuned instruments to deal with specific invaders, the innate immune system is a blunt hammer that quickly smashes the invader and all surrounding tissue before any pathogens can take root. The innate immune system actually creates chemicals like hydrogen peroxide and hypochlorite (bleach) to quickly deal with any kind of invading organism. This fast response is necessary for survival, but it does cause unintended damage to your own cells.
When a cell incurs too much DNA damage, it loses the ability to divide and becomes senescent. This is actually a vital part of healing and an important defense mechanism to excessive stress. If a cell with damaged DNA was able to divide, it could allow dangerous mutations to spread throughout your system and lead to cancer. When a cell becomes senescent, it not only stops replicating, but it sends out dozens of signaling molecules to alert your body that this damaged cell should be destroyed and replaced. Senescent cells release pro-inflammatory cytokines and prostaglandins to attract immune cells and kill the damaged cell. They also release growth factors and proteases to aid the surrounding cells and help them replace the senescent one. It’s an important part of wound healing and regeneration, but problems occur when we don’t activate the autophagy system to deal with these damaged cells.
Autophagy mainly occurs in the absence of food. In our world of overabundance and constantly available calories, we rarely activate this important recycling system. This causes senescent cells to accumulate. As the damaged cells stack up, they pump out inflammatory signals that encourage your innate immune system to supply a steady dose of hydrogen peroxide and bleach to all the surrounding cells causing them to age more rapidly and incur constant damage. In addition, those growth factors that were supposed to help usher in the replacement cell can instead push the damaged cell over the edge into a cancer cell.
This barrage of inflammatory cytokines not only causes major age-related health problems like cardiovascular disease, osteoarthritis, dementia, type 2 diabetes, glaucoma, sarcopenia (age-related muscle loss), and cancer, but many see chronic inflammation as the cause of aging in general. More to the point, it causes poor aging. Chronic inflammation makes all of the surrounding cells function poorly and age more rapidly. Even things like graying hair and thinning hair are caused by senescent cells harming their neighboring hair follicles.
Senescent cells also trigger decreased function in the adaptive immune system which forces us to rely more on the innate immune system as we age. As your body relies more and more on the hammer instead of the scalpel to deal with invaders, you incur more and more inflammatory damage.
Autophagy restores proper function
We’ve known about autophagy for 50 years, but recent research is pointing out how vital it is to successful aging. When researchers block the mechanisms of autophagy, they find it increases tissue degeneration associated with aging. In fact, when autophagy is blocked it even inhibits the lifespan-extending effects of a calorie-restricted diet. One mouse study showed that over-expressed proteins in autophagy caused a 17 percent increase in lifespan, improved insulin sensitivity, and helped maintain leanness.
Another interesting mouse study used a specific peptide to trigger cell death in the senescent cells in aging mice. They found that the ones that received the treatment to kill senescent cells had hair regrow in bald spots within 10 days and after three weeks they could run twice as far on a treadmill as the control group. They also experienced improved kidney function.
Autophagy improves insulin sensitive and glucose tolerance and impaired autophagy promotes insulin resistance, which leads to obesity and metabolic syndrome.
Immune function normally decreases with age as the adaptive immune system declines and the innate system takes over. Autophagy restores adaptive immune function and prevents the age-related switch to increased activation of the innate immune system. This allows better response to infection and keeps inflammation in check which prevents degenerative aging.
A mouse study looked at fasting to improve autoimmune inflammation associated with multiple sclerosis. In multiple sclerosis, the immune system attacks the myelin-forming oligodendrocytes of the central nervous system causing various symptoms like weakness, dizziness, spasms, and pain. Fasting reduced autoimmune response and promoted oligodendrocyte precursor cell regeneration. It actually completely reversed symptoms in 20 percent of the animals.
Another big cause of age-related degeneration is declining mitochondrial function. Metabolism causes damage to cells so it makes sense that mitochondria, the power plants of the cells, would also accumulate damage over time. This damage leads to decreased energy production, increased aging of the cells, and decreased stem cell activation. A specialized type of autophagy called mitophagy selectively recycles defective mitochondria and replaces them with new organelles. This restores proper function and prevents the cell from further degradation into a senescent cell.
For most people, the number one benefit of autophagy is fat loss. Autophagy is designed to clean up damaged cells but it’s also meant to stimulate energy production when outside calories are absent. It would be pretty stupid for the body to go through the effort of recycling cells when readily available lipids are available in fat cells. Indeed fasting drastically accelerates the digesting of lipids during autophagy and drastically increases the production of ketone bodies.
Differential stress resistance
Valter Longo, PhD has been studying an aspect of fasting and autophagy that is fascinating enough, I wanted to include it in it’s own section. One area of his research focuses on how fasting induces differential stress resistance to make chemotherapy far more effective. In a food scarce environment, normal cells become more resistant to oxidative stress, but cancer cells don’t. Remember, cancer cells are broken cells. Something went wrong with them and they are replicating out of control. Being broken means they don’t retain all the typical functions and protective mechanisms of normal cells, like antioxidant generation. That’s one of the reasons cancer cells switch their metabolism from oxidative phosphorylation to glycolysis even in the presence of oxygen. It’s known as the Warburg effect. There are many theories on why this happens, but one is because cancer cells are more sensitive to the reactive oxygen species created during normal metabolism.
Eating creates an environment where cancer cells thrive and normal cells are stressed. Cancer cells need an environment rich with sugar, growth factors (like IGF-1) and amino acids like glutamine. For normal cells, metabolism creates reactive oxygen species and triggers an immune response to deal with all the pathogens riding along on top of your meals. However, when you fast, normal cells become 1000 times more resistant to reactive oxygen species, but cancer cells do not. This same starvation-protection also makes normal cells far more resistant to chemotherapy drugs.
Fasting also causes an anti-Warburg effect in cancer cells, forcing them to try to switch back from glycolysis to normal respiration. In colon cancer cells, the increased free radical generation was shown to lead to cell death. Those that survived were (once again) far more susceptible to chemotherapy drugs.
It’s a very exciting therapeutic target for anyone undergoing cancer treatment. As Dr. Longo says, people tend to fall into two camps - traditional medicine or alternative medicine, but combing the benefits of the two camps makes the overall treatment more effective. If you or someone you know is going through chemotherapy, bring up his research with the treating physician. Dr. Longo also developed a fasting mimicking diet to make the act of fasting a bit less intense. I’ll go over that diet more in depth next week, but for those in need of answers now, you can check it out on the Prolon website.
Better aging and disease protection
None of us can live forever, but the fear for most of us is to suffer a steep decline in health as we age. That’s the real purpose of autophagy. It will help you fight off the deleterious effects of aging and let you live better, longer. It’s also a great way to improve your body’s chemistry and composition for the long term. Next week I’ll go over how to fast for autophagy, certain compounds that encourage autophagy without fasting, and go into detail on the fasting-mimicking diet for those wanting to try a less intense form of prolonged fasting.