Chapter 184
FGF21
In 2000, a new human hormone was discovered. It was the 21st documented fibroblast growth factor and was called FGF21. Since its discovery, it has proven to be a crucial factor in promoting a healthy metabolism and healthy arteries, leanness, and longevity. If obese monkeys are injected with FGF21, they lose weight without eating less—and not just a little: at the same food intake they lose 27 percent of their body fat. In mice, FGF21 increases life span by 30 to 40 percent, comparable to lifelong calorie restriction, just without reducing food intake. FGF21 appears to act through multiple pathways of aging: it revs up AMPK and sirtuin activity while simultaneously inhibiting the IGF-1 and mTOR signaling pathways. The idea that FGF21 could be used as a hormone therapy to extend life span makes Big Pharma salivate and raises the question: Can the aging process be "treated" with drugs?
The notion of treating obesity, diabetes, and high blood pressure with a single drug while also slowing aging seemed impossible, but suddenly it is a highly tempting prospect. You can’t simply give people pure FGF21, because in the body it is broken down quickly, which means you’d need an injection every one to two hours around the clock. Therefore, pharmaceutical manufacturers began filing patents on a range of longer-acting FGF21-like agents. And indeed: if you give people PF-05231023, they can lose up to ten kilos in 25 days, and at the same time triglyceride and cholesterol levels drop dramatically. But then the side effects of these newfangled drugs show up. But what if you packed the FGF21 gene into a virus and then injected this virus so that it inserts additional FGF21 genes into the person’s DNA? Or you could just go jogging.
Exercise and fasting to increase FGF21
Exercise raises FGF21 levels, which is also why it is so healthy for us. In the blood, FGF21 rises immediately after a strenuous session, reaches its peak an hour later, and returns to baseline after three hours. But what works better—aerobic exercise (eight weeks of running training) or resistance training (eight weeks of weightlifting)? The answer: both, but strength training did more than running, increasing FGF21 levels by 42 and 25 percent, respectively.
And what can we accomplish with diet? Wouldn’t it be easier to stimulate our body’s own natural production through diet rather than through genetic manipulation or injections? One option would be to stop eating altogether. FGF21 is both the "life-extending" hormone and the "hunger hormone." Fasting brings on FGF21, but not after just a day or two. Unlike mice, in whom FGF21 rises after just six hours of fasting, humans have to go without food for a week before an increase is noticeable. Fasting can quadruple FGF21, but to do that you have to fast for ten days, which is the epitome of improper nutrition.
Increasing FGF21 with food
How do you get the benefits of fasting without starving? Could a ketogenic (low-carb) diet simulate fasting? In rodents, keto eating raises FGF21 levels, but in humans it doesn’t work. In fact, after one to three months of ketogenic eating, FGF21 levels can drop by 40 percent. A high-fat diet can even blunt the boost you get from exercise, as a twelve-week study with high-intensity interval training showed. Fortunately, the hunger hormone, which is also referred to as a "systemic longevity enhancer," can be revved up through less drastic measures than prolonged fasting—namely by consuming more carbohydrates and less protein.
Even without restricted protein intake, FGF21 values shoot up when you eat a lot of starchy foods. The healthiest sources are probably legumes and whole grains. FGF21 is increased by butyrate, the short-chain fatty acid our good gut flora produces from fiber, and by the starch-blocking agent acarbose (at least in mice). That would mean that slowly digestible starches like those in pasta, beans, and whole grains have a similar "life-extending" effect.
The level of FGF21 in the bloodstream is also increased "quickly and reliably" by dietary protein restriction. Researchers observed an increase in FGF21 levels of more than 150 percent after four weeks, even with excessive calorie intake. And the protein "restriction" reduced protein only from the typical excess of most Americans down to roughly the recommended amount.
The recommended intake for protein is around 50 grams per day (46 grams for women, 56 grams for men). Researchers randomized men who, on average, consumed about twice that—112 grams, the average of what many US men eat—and put them on 64 grams of protein per day. That way, this "protein-reduced" group still got more than enough protein. In this manner, FGF21 levels in the blood can be doubled in about six weeks. That could explain why the participants lost more body fat despite significantly higher calorie intake. How can you consume hundreds more calories every day and still lose a kilo of body fat? By simply reducing your protein intake to the recommended levels. Who hasn’t dreamed of a diet that allows plenty of calories because they are effortlessly burned because fat burning is ramped up? The researchers concluded that "even a diet with quite modest protein restriction can offer substantial clinical benefits."
A similar study found that an even smaller protein restriction, in which men received 73 grams per day, led to a sixfold increase in FGF21 levels after just one week, accompanied by a significant increase in insulin sensitivity. The scientists concluded from this that in humans, "reducing protein in the diet" promotes a healthy metabolism. When men and women were switched from a high-protein diet of 138 grams per day to a still more than sufficient amount of 67 grams, their FGF21 levels in the blood also increased sixfold, but after just four days.
FGF21 may be an explanation for the growing evidence that lower protein intake brings better health and a longer life expectancy. Interestingly, in both studies the participants received about 9 percent of calories from protein, which corresponded to the diet of the people of Okinawa back when they were among the longest-lived populations in the world. However, not all proteins are the same.
Animal and plant protein
With some proteins, it may be more important to restrict them than with others. FGF21 is considered the most important mediator of the metabolic benefits that come with restricting the amino acid methionine. As we know, amino acids are the building blocks of proteins. There are about 20 of them, roughly as many as letters of the alphabet. And just as different combinations of letters can form different sentences, the various proteins are formed by stringing together different sequences of the various amino acids. Since methionine is one such amino acid and is found primarily in animal protein, you could increase FGF21 levels by reducing methionine intake, even without changing total protein intake overall, simply by switching from animal protein sources to plant-based ones. Legumes (beans, split peas, chickpeas, and lentils) provide five- to tenfold less methionine than meat.
FGF21 is a possible explanation for the protection against cancer, autoimmune diseases, obesity, and diabetes that vegan diets provide. Perhaps that is one of the reasons why plant-based interventions have produced such outstanding results. For example, the work of Dr. Esselstyn shows that heart disease, our number one killer, can largely be halted or reversed with a whole-food, low-fat, plant-based diet, and the risk of a heart attack is nearly eliminated. This benefit cannot be explained solely by lowering cholesterol, since we now have effective drugs that can drive cholesterol down just as low as a healthy diet can, but the pills appear to be far weaker. So perhaps it’s not just fat and cholesterol that play a role, but also the quantity and quality of protein.