The Longevity Solution

by Jason Fung

  Fig. 2.2: Restricting calories enhances life span in animals

  Calorie restriction is the only non-pharmacological method of consistently extending life span and protecting against many age-related diseases. When food is plentiful, animals, including humans, develop and grow, but they also age quickly. All animals have nutrient sensors, which are intricately linked to growth pathways. When animals detect a low availability of nutrients, growth is turned all the way down, which might induce longevity pathways in the essential balance between growth and longevity.9 Of course, such restriction has its limits. Starvation and nutrient depletion cause death and disability. But calorie restriction with optimal nutrient intake is highly beneficial.

  On its surface, this paradigm shift is fascinating. We often think about food as nourishment, so more should be better. But it’s not. Instead, strategically depriving animals of food doesn’t reduce life span; it extends it.

  The Mechanisms of Calorie Restriction

  Initially, the descriptions of life extension with calorie restriction seem radical, but studies have confirmed the relationship many times over in multiple species.10

  Essentially, slower development and lower growth also resulted in longer life spans. Why? There are many potential mechanisms.

  Low body fat is perhaps the most obvious effect of chronic calorie restriction in animals, but low visceral fat is of particular importance. High visceral fat, which is stored inside the abdomen and around major organs, poses a significant health risk to humans and is closely associated with decreased insulin sensitivity, obesity, type 2 diabetes, and atherosclerosis.

  Mice genetically engineered to have very low body fat live longer. FIRKO (Fat Insulin Receptor Knock Out) mice have disrupted insulin receptors. Because insulin normally tells the body to gain fat, these genetically engineered mice cannot become obese, and they also live longer than unaltered mice. Both FIRKO and calorie-restricted mice have greatly reduced body fat, which suggests that less body fat might be the common denominator that extends life span.11

  But that’s not the whole story because being underweight or having lower-than-normal levels of fat also is associated with health risks. However, there’s a large confounding factor here. Underweight people may have hidden illnesses, such as cancer, that cause the underweight condition, so it is unknown if deliberately lowering body fat below normal is healthy or harmful.

  Chronic calorie restriction decreases the metabolic rate. If you eat fewer calories, your body responds by burning fewer calories. At first, this may not seem beneficial, but a lower metabolic rate correlates with less oxidative damage to DNA and therefore might affect aging.12 Different animals have widely varying metabolic rates. In general, the higher the metabolic rate, the shorter the animal lives, possibly due to more free radical or oxidative damage.13 If you are constantly revving your car’s engine, it will go faster but burn out sooner. In humans, lower levels of free triiodothyronine (T3), a hormone important for metabolic rate, are associated with longer life.14 Although calorie restriction can lower the overall metabolic rate, energy expenditure per gram of body weight may be higher.15 Some reports have found healthy centenarians to have both greater muscle mass and a higher metabolic rate, both of which are correlated.16

  Nutrient Sensors

  The science of longevity always comes back to the competing interests of growth versus longevity. Higher growth generally results in lower longevity and vice versa. So, maximizing longevity often depends on reducing growth, and one of the ways we can influence this is through our nutrient sensors.

  Primitive single-celled organisms live in a nutrient soup and can respond quickly to a decrease in nutrient availability by stopping growth. Yeast and bacteria, for example, go into a dormant (spore) form that can survive for thousands of years before becoming reanimated when water and nutrients are available. As we became complex multicellular creatures, we still needed to know whether nutrients were available. During a period of famine, we don’t want to increase growth and metabolism, as this would hasten our demise. Having a lot of children during a famine might kill both mother and children, which is the reason that women without sufficient body fat stop ovulating. On the other hand, when food is plentiful, our bodies need to activate growth pathways to develop as quickly as possible. As the saying goes, make hay while the sun shines. Survival of all animals depends on both having nutrient sensors and linking them closely to growth pathways.

  There are three known nutrient-sensing pathways: insulin, mTOR (mechanistic target of rapamycin), and AMPK (AMP-activated protein kinase). Extending longevity depends on decreasing growth and metabolism, which is best done by decreasing nutrient-sensing pathways by adjusting our diets. Reducing insulin (by lowering calories, but more specifically reducing refined grains and sugar), lowering mTOR (by reducing animal protein and using more plant proteins), and activating AMPK (by lowering calories) have all been linked to longevity.

  INSULIN

  The hormone insulin is the best known nutrient sensor. Food contains a mixture of the three macronutrients: carbohydrates, protein, and fat. When we eat, our bodies respond to these macronutrients by increasing the production of certain hormones. Insulin increases in response to eating carbohydrates and protein, but dietary fat does not stimulate insulin secretion. Insulin allows the cells of the body to use some ingested glucose for energy by acting on the protein GLUT4. As such, insulin fulfills the role of a nutrient sensor by signaling the availability of certain nutrients to the rest of the body.

  But that’s only one of insulin’s roles. When insulin activates its receptor on the cell surface, it also activates the PI3K pathway, which results in protein synthesis and cell growth and division. This activation of PI3K happens simultaneously and automatically because these nutrient sensors link inextricably to growth pathways. Insulin plays a role in metabolism as well as in increasing growth, which is normally highly conducive to species survival because animals need to grow while food is available and stop growing when it is not.

  Animal studies confirm that increasing nutrient availability decreases life span. Adding glucose to the food of the worm C. elegans shortens its life.17 The high glucose stimulates insulin and promotes growth at the expense of a decreased life span. In humans, high insulin levels and insulin resistance, which are common in aging, have been consistently linked to increased risk of many age-related diseases, including cancer and heart disease.

  During calorie restriction and fasting, blood glucose and insulin levels decline precipitously.18 Lower insulin signaling decreases growth signaling but extends life span in several species of animals.19 Decreasing carbohydrates in the diet is another natural method of decreasing insulin. Cynthia Kenyon, the scientist who discovered the roles of insulin and glucose in life extension, found the results so compelling that she went on a low-carbohydrate diet.20 Increasing insulin sensitivity and lowering insulin levels may be an important mechanism in calorie restriction.

  INSULIN-LIKE GROWTH FACTOR 1

  A hormone closely related to insulin that plays a role in aging is insulin-like growth factor 1, or IGF-1. Growth hormone (GH), which is secreted by the pituitary gland, had always been assumed to be responsible for increasing growth in children. In the 1950s, Israeli endocrinologist Zvi Laron set up that country’s first pediatric endocrine clinic. Among his first patients were several siblings with stunted growth. He assumed that they lacked GH, but when he measured their hormone levels, they were sky high. What was going on? Several decades of research would be needed before the answer was known.

  Growth hormone acts on its cell receptor to produce IGF-1, which is the actual mediator of the growth effects. The children Laron encountered, who were suffering from what is now known as Laron dwarfism, had plenty of GH, but, because of a genetic defect in the receptor, they did not produce IGF-1. This lack of IGF-1 accounted for the children’s short stature. Mystery solved. Later, though, a discovery in the Laron dwarfs would set the longevity world on fire in 2013.


  In a remote corner of Ecuador lives a community of about 300 members known as the Laron dwarfs. A group of Spanish Jews in the fifteenth century fled the Inquisition, and genetic inbreeding led to this group of people who completely lack the hormone IGF-1. They grow to an average height of four feet but are otherwise normally formed. Dr. Guevara-Aguirre, a local physician, described and followed this community over several decades. He and his colleague, Dr. Valter Longo from the University of Southern California, made the startling discovery that these Laron dwarfs seemed to be completely immune to cancer!21 By comparison, unaffected relatives (those who do not have the syndrome) of these Laron dwarfs had a 20 percent rate of cancer.

  Dr. Longo’s interest in the longevity effect of less growth started in 2001 when he discovered that a long-lived yeast had the same type of growth pathway inhibition. Mice genetically deficient in growth hormone live 40 percent longer—the human equivalent of 110 years. Animals genetically engineered for high levels of growth hormone have short lives. Insulin and IGF-1 share many of the same features, and in some animals, the receptor is identical. This finding supports the notion that there’s a fundamental trade-off between growth and longevity.

  mTOR

  Mammalian (or mechanistic) target of rapamycin (mTOR) is another important cellular nutrient sensor that is sensitive to dietary proteins and amino acids. When you eat protein, it gets broken down into its component amino acids for absorption by the intestines, and mTOR increases. Eating sufficient protein to obtain the necessary amino acids is important for overall health, but avoiding excessive mTOR is also important for life span extension.22 Dietary protein restriction and fasting can decrease mTOR.

  Like insulin, mTOR is a nutrient sensor, and its activation is inextricably linked to growth pathways. When you detect the availability of protein, your body goes into growth mode and begins producing new proteins. This is an example of antagonistic pleiotropy. In early life, mTOR promotes growth and development, but this mechanism harms us in later life by causing aging. Some of the benefits of protein restriction may be related to mTOR’s effect on autophagy.

  Autophagy is a cellular recycling process by which old proteins and subcellular organelles are broken down. This process provides energy and the amino acids necessary to rebuild new proteins to replace the old proteins, a key factor in cell maintenance. Autophagy is the critical first step for maintaining a cell in pristine condition, and aging is characterized by a decline in the rate of autophagy as damaged molecules accumulate in the cell and impede its function. In rats, there is as much as a six-fold difference between young and old animals.23 Declining autophagy rates means that damaged cell components like lipid membranes and mitochondria hang around longer.

  The most potent stimulus to turning off autophagy is mTOR. Even a little bit of dietary protein raises mTOR, turning off autophagy and the cellular renewal process. Fasting greatly increases the rate of autophagy and, in yeast, is essential to the life span–extending effects of calorie restriction.24 Drugs that block mTOR, such as rapamycin, can extend life span in yeast, largely through its effect on autophagy.25

  AMPK

  The third nutrient sensor is known as AMP-activated protein kinase (AMPK). It acts as a sort of reverse fuel gauge of cellular energy stores. In your car, if you have lots of energy in the form of gasoline, the gauge reads high. In your cells, if you have lots of energy in the form of ATP (adenosine triphosphate), then AMPK is low.26 Low cellular energy levels raise AMPK levels. Thus, AMPK acts as a sort of cellular fuel gauge but in reverse. Like mTOR and insulin, the nutrient sensor AMPK is linked to growth pathways. AMPK down-regulates synthesis of biological molecules, including those needed for growth (anabolism). Unlike insulin or mTOR, AMPK is not responsive to any specific dietary macronutrient but assesses the overall availability of cellular energy.

  Substances that activate AMPK (mimicking low cellular energy stores) are known for promoting health. Examples include the diabetes drug metformin, resveratrol from grapes and red wine, epigallocatechin gallate (EGCG) from green tea and dark chocolate, capsaicin from peppers, curcumin from the spice turmeric, garlic, and the traditional Chinese medical herb berberine. Calorie restriction also activates AMPK, and this fact may be important to AMPK’s effects on aging.27

  AMPK enhances the uptake of glucose into muscle cells and increases the generation of mitochondria, leading to an increased capacity for burning fat. (See Figure 2.3.28) AMPK also increases autophagy, the important cellular self-cleansing process that rids cells of junk and recycles it, which we discuss in more detail later.

  Fig. 2.3: Nutrient status

  Intermittent Fasting

  Intermittent fasting, which means going without food for some time, might have benefits for antiaging beyond simple calorie restriction. There are many different fasting regimens. One common form involves a sixteen-hour fast (including sleep time) and an eight-hour “feeding window.” Some people practice alternate-day fasting, in which they eat little to no food on one day, and on the next day, eating is unrestricted.

  Animals fed every other day behave physiologically like calorie-restricted animals, even though they eat almost the same amount of food as fully fed animals.29 The animals that are fed every other day eat more on feeding days to compensate for their fasting days. This finding casts some doubt on whether fewer calories are essential to the life span extension. Although total calories are similar between calorie restriction and every-other-day fasting, the hormonal effects of fasting are very different. During fasting, all the nutrient sensor pathways are engaged—insulin and mTOR decrease while AMPK increases. Other hormones, known as the counterregulatory hormones, increase. These hormones include adrenaline, noradrenaline, and growth hormone. The increase in counterregulatory hormones has the effect of increasing energy and maintaining basal metabolic rate. These hormonal changes do not occur with simple chronic calorie reduction. The calories might be the same, but the physiologic effect is not. For example, reducing dietary fat reduces calories but not insulin or mTOR because the carbohydrate and protein intake may be unchanged.

  Calorie-restricted (CR) animals are always hungry because of increased hunger hormone signaling.30 Because hunger is such a fundamental instinct, it’s virtually impossible to ignore hunger over the long term; hunger dooms many weight-loss programs to failure. Fasting, on the other hand, often paradoxically decreases food cravings and hunger. Many patients note decreased hunger when using intermittent fasting for weight loss. They often comment that they think their stomach shrank when, in reality, hunger signaling decreased.

  Rats and mice placed on an every-other-day feeding/fasting regimen live longer than fully fed animals. This result occurs without necessarily decreasing body weight, depending on the particular species of animal used.31

  The Downsides of Calorie Restriction

  Calorie restriction is useful only if you maintain adequate nutrition. You can take calorie restriction too far. Once a person falls below a certain threshold of body fat, there are concerns about decreased immune function,32 low testosterone, feeling hunger, and feeling cold. These issues are not a major concern for the majority of Americans who are facing an obesity epidemic. Perhaps the most important problem with chronic calorie restriction is that it’s difficult to maintain. You need to count every calorie scrupulously. You need to prepare all your food. You need to carefully calculate macronutrient ratios to make sure you get enough of each. You need to avoid junk food. These things aren’t easy to do, and, in a lot of cases, it’s not possible to do all of them all the time. Calorie restriction works on animals only when they are locked in cages. It doesn’t work on most humans who have free will.

  That’s why scientists are so keen to discover the antiaging mechanisms behind calorie restriction. By understanding those mechanisms, we could mimic most of the benefits in a reasonable manner compatible with everyday life in twenty-first-century America.33 There’s good evidence that fewer calories may not lie at the heart o
f calorie restriction’s benefits. Because the human body does not contain calorie receptors or calorie counters, the hormonal changes caused by dietary change must drive the benefits. Knowing these changes can lead us to natural “biohacks” (including changing dietary protein and consuming coffee, tea, and red wine, which we discuss further in subsequent chapters) that deliver all the same benefits.

  In 1964, Georges Nógrády, a microbiologist at the University of Montreal, traveled to Easter Island, also known by its Polynesian name of Rapa Nui, to study the local population and collect soil samples. From those specimens, Dr. Suren Sehgal, who was working with a pharmaceutical company in Montreal, Canada, in 1972, isolated the bacterium Streptomyces hygroscopicus. This made a potent antifungal compound, which he isolated and named rapamycin, after the island of its origin. He hoped to make an antifungal cream for the topical treatment of athlete’s foot, but the discovery turned out to be far more important.1

  When Dr. Sehgal abruptly transferred to New Jersey, he couldn’t bear the thought of destroying those samples. Instead, he wrapped some vials of rapamycin in heavy plastic, took them home, and stored them in his family freezer next to the ice cream with a label that said “DON’T EAT.” Dr. Sehgal didn’t resume work on rapamycin until 1987, when his company was bought out. Its antifungal properties turned out to be its least impressive feature.