The Longevity Solution

by Jason Fung

  Rapamycin suppresses the human immune system, so it’s useful for treating eczema and as an antirejection medication in organ transplantation. By 1999, it was being used routinely in liver and kidney transplantation when scientists noted something odd. Most immune-suppressing drugs also increase the rates of cancer, but rapamycin did not. It decreased the risk of cancer! Rapamycin prevented cells from multiplying, and it displayed potent activity against solid tumors, both preventing new ones and curing pre-existing ones. Of course, this discovery was a breakthrough in cancer research.2 Rapamycin derivatives also could slow the growth of cysts in the treatment of polycystic kidney disease.

  More tantalizing was the realization that rapamycin might do something even more powerful—extend life span. Was the mythical fountain of youth sitting under the eternal gaze of Easter Island’s famous Moai statues? This story is not science fiction; it’s a tale in the thrilling world of real-life science.

  How Does Rapamycin Work?

  For decades after its discovery, what rapamycin did in the human body was a complete mystery. With rapamycin in hand, scientists could look for the targets within cells that interacted with this newly discovered drug. Like a homing beacon, rapamycin led them straight to a previously unknown biochemical pathway named (imaginatively) mammalian target of rapamycin (mTOR). That was astounding—the sort of thing that shouldn’t happen. It was like suddenly discovering a new continent. Thousands of years of medical science had somehow missed this fundamental biological system. This nutrient-sensing pathway (mTOR) was so fundamental to life that it is conserved in animals from yeast all the way to humans. It is old in an evolutionary sense, older even than the much better-known insulin. The mTOR pathway is so critical that it is in virtually all life forms, rather than just mammals, so the name was changed to mechanistic target of rapamycin.

  Nutrient sensors such as insulin and mTOR play a crucial role in an animal’s survival by closely matching growth to nutrient availability. Think about a seed in the ground. When the proper conditions of available water, sunlight, and temperature exist, it will sprout. If the seed stays in a paper bag, it remains dormant. This ensures that the seed will not sprout into a hostile environment where it cannot survive. Animal cells are similar. If no nutrients are available to a cell, then it will not, and should not, grow. Instead, the cell slows growth and stays as “dormant” as possible. Nutrient sensors serve as the crucial link between nutrients and cell growth. If nutrients are available, then mTOR and insulin go up, and growth increases. If nutrients are not available, then mTOR and insulin go down, and growth slows. Growth depends on nutrients. And excessive growth may not be conducive to longevity.

  The hormone insulin is sensitive to both dietary carbohydrates and protein, where mTOR is mostly stimulated by protein. mTOR plays a vital role in the health of mitochondria, the cell’s energy generators. Like autophagy for mitochondria, low mTOR stimulates a process called mitophagy, where old, decrepit mitochondria are slated for breakdown. Once nutrients are again available, new mitochondria are produced. This renewal cycle ensures that the cells are maximally efficient during these feast/famine cycles—an important component of longevity and healthy aging.

  The mTOR pathway is critical for regulating growth. There are two separate pathways, called the mechanistic target of rapamycin complex 1 and complex 2 (mTORC1 and mTORC2). Rapamycin, produced by bacteria to fight fungi, blocks mTOR and shuts down the fungi’s growth pathways, putting them into a dormant state. In humans, slowing growth may prevent certain types of cancer, thus making it useful as a cancer medication. In the immune system, blocking mTOR could slow the growth of immune cells like the B and T cells, making it useful as an immune suppressant. In polycystic kidneys, blocking mTOR blocked the growth of new cysts. Rapamycin might also be useful for treating HIV infections, psoriasis, multiple sclerosis, and perhaps even Parkinson’s disease.3

  Many of these diseases happen to be associated with aging, which leads to one exciting proposition: Rapamycin is perhaps the most promising antiaging drug known. By slowing the growth mechanism of mTOR, it can not only prevent age-related diseases but also can slow down aging itself. Lower growth may equal more longevity. But is this being too optimistic?

  An Antidote to Aging?

  Since 1840, thanks to the Industrial Revolution, life expectancy has steadily increased around the world, especially in developed countries. The result is a fast-growing elderly population, which is estimated to double by 2050.4 Along with the aging population come age-related diseases, including cancer, cardiovascular disease, type 2 diabetes, osteoporosis, and Alzheimer’s.5 Although lack of physical activity and smoking are important risk factors for heart disease, aging is by far the biggest risk factor.6 It’s pretty obvious when you think about it. Plenty of teenagers smoke and don’t exercise, but they virtually never have heart attacks. On the other hand, there are plenty of 75-year-old people who don’t smoke and do their exercise and still have heart attacks. Preventing such diseases goes hand in hand with slowing the aging process.

  The discovery of rapamycin brought new life to the age-old dream of a life-extension pill. In animal models, rapamycin extends life span and its associated illnesses, although human studies are lacking. The first breakthrough came in 2006, when the life span of yeast more than doubled when the yeast was given rapamycin.7 Subsequently, researchers found similar results in nematode worms (C. elegans),8 who lived at least 20 percent longer on rapamycin, and then fruit flies, whose lives were extended by about 10 percent.9

  Mice fed rapamycin lived 9 to 14 percent longer,10 the first time a drug could extend the life of a mammal—with clear implications for humans. Currently, the only known way to extend the life of a rodent is through severe caloric restriction. Interestingly, this effect occurred no matter when the mouse started receiving the drug, whether the mouse was nine months (human equivalent thirty-five years) or twenty months (human equivalent sixty-five years).11 To put this into perspective, a 10 percent increase in life span equates to an extra seven to eight years of life for a human being. Rapamycin improved heart function in middle-aged dogs,12 marmosets,13 and mice. It can block disease progression in mouse models of Alzheimer’s disease14 by increasing neuronal autophagy. When mice receive rapamycin early, it prevents age-related learning and memory deficits in mice.15 Giving rapamycin to aging obese rats can reduce appetite and body fat.16 Other benefits indicated by animal studies include potential prevention of age-related retinopathy (the most common cause of blindness in Western countries)17 and improvements in depression and anxiety, autism, and autoimmune disorders.18

  Fig. 3.1: The effect of rapamycin on the life span of mice

  But what about the effect on humans? The story is a little more complicated. All drugs have side effects, and rapamycin is no exception. Suppressing the immune system increases the risk of infections. Growth-suppressing effects may increase lung toxicity, ulceration of the mouth, diabetes, and hair loss.19 Consequently, by taking rapamycin, you might extend your life span or cut it short from an infection.20 The optimal dosing schedule is still unknown because almost all human studies have been done in specific disease conditions, such as cancer, post-transplant, or polycystic kidney disease. On the other hand, long-term rapamycin treatment may cause significant metabolic side effects.21

  The chronic use of rapamycin can cause insulin resistance and raise cholesterol and triglyceride levels.22 But intermittent use of rapamycin might lower the incidence of these side effects, which could help realize its full potential. Shorter-term, intermittent treatment could still extend life span and reduce disease.23 Rapamycin treatment delivered just once every five days showed significant impact on T-cells without affecting glucose tolerance.24 This intermittent, rather than constant, blockage of mTOR is likely crucial because our natural diets alternate periods of feasting and fasting. Insulin and mTOR should naturally be periodically cycling between high and low levels rather than staying high or low constantly. It is in the balance of
growth and longevity that we find optimal health.

  For longevity, lower doses of rapamycin might be more effective. With age, mTOR might be overactive, driving the body’s growth pathways more than the maintenance pathways. Turning down the mTOR activity might help organs, including the immune system.25 High mTOR during childhood and youth is normal because growth is more important than longevity during this phase of life.

  The nutrient sensor AMPK goes in the opposite direction of insulin and mTOR, like a seesaw (see Figures 3.2 and 3.3). If nutrients are available, mTOR, insulin, and IGF-1 are high, and AMPK is low, which favors growth and reproduction. When nutrients are not available, mTOR, insulin, and IGF-1 are low, and AMPK is high. The cells have low energy and favor maintenance, repair, and survival. Health lies in the balance. Sometimes we need growth, and other times we need maintenance and repair. So the ideal schedule is to cycle these states regularly, something that is easier with intermittent fasting. Certain drugs and foods can also influence these levels.

  Fig. 3.2: High nutrient availability

  Fig. 3.3: Low nutrient availability

  When a person follows a plan of intermittent fasting, he restricts calorie intake within a defined period. For example, he might eat during eight hours of each day and fast for the remaining sixteen hours. This pattern naturally cycles the body through both high and low nutrient availability and might maximize both growth and longevity pathways. Since as early as the 1940s, we’ve known that intermittent fasting makes rats live longer.26 Recent studies in humans show that intermittent fasting increases SIRT1 and SIRT3, mitochondrial proteins that can promote longevity in response to oxidative stress.

  Ultimately, to slow aging and reduce age-related diseases without the downsides of rapamycin, we need to target the mTOR pathway in a different but more natural way—through our diets. Specifically, we need to talk more about the main stimulus to mTOR: dietary protein.

  Protein Restriction, IGF-1, and mTOR

  Since the 1960s, we’ve gone from discussing foods to discussing macronutrients, the three main components of food: proteins, fats, and carbohydrates. Reducing dietary fat and cholesterol to prevent heart disease has been a key public health message. This recommendation turned out to be far too simplistic, with recent studies showing that dietary saturated fat and cholesterol have little effect on heart disease risk.27 The Dietary Guidelines for Americans encouraged eating more carbohydrates, like white bread and pasta, and by the late-1970s, the obesity epidemic began. Some forty years later, it continues to accelerate. Currently, about 70 percent of Americans are overweight or obese. Much ink has been spilled on the various pitfalls of eating too much or too little fat and carbohydrates, but protein is largely forgotten. Should we eat more or less? How much is too much? How much is too little? What types of protein are best? These are all critical questions for our health.

  Most of our bodies’ structural systems, such as skeletal muscle, bone, and organs, are largely made up of proteins. The enzymes and hormones that control our biochemistry are proteins, too. There are an estimated 250,000 to 1 million different types of protein molecules in the human body.28 The building blocks to make all the necessary proteins are called amino acids, and they come mostly from our diet. The body digests and absorbs protein from food as amino acids, and our bodies reassemble these into new proteins necessary for normal, healthy functioning.

  Each protein is made by stringing amino acids together in a specific sequence, so each protein has a unique structure and function. All of the thousands of different proteins in the human body are made by only twenty amino acids, just as the twenty-six letters of the alphabet can be arranged to make millions of different words.

  Of the twenty amino acids, eleven are nonessential because humans can synthesize them. The other nine are called essential amino acids because humans must obtain them from food. Being deficient in even one essential amino acid forces the body to break down its own proteins to get the required amino acid. Prolonged deficiency results in illness or even death. The body stores very little amino acids, so you must eat a diet that supplies adequate amounts of essential amino acids. If you eat more amino acids than necessary, the body may use them as a source of energy by transforming them into glucose via a process known as gluconeogenesis.

  Consuming adequate amounts of protein is important for maintaining muscle mass. In the modern Western world, the elderly are more susceptible to excessive muscle loss known as sarcopenia. Loss of muscle strength may cause falls, broken bones, and an inability to carry out the activities of daily living, leading to institutionalization. Extreme cases of protein deficiency cause a disease known as kwashiorkor, which is characterized by a large belly and thin extremities. But the possibility that excess protein could also be a problem has been largely ignored, as we’ll discuss later.

  Protein-rich animal foods (meat or eggs) are much more expensive than carbohydrate-rich foods (bread or rice). Affluent Western nations tend to eat more protein, which increases the risk of overconsumption and lowers the risk of protein deficiency. Plant proteins differ from animal protein in their amino acid composition, which has important consequences for health and disease. Different stages of life have different protein demands. Fine-tuning protein intake can slow aging, prevent illness, and increase strength.

  The recommended daily allowance (RDA) of protein as set by the U.S. government is 0.8 gram per kilogram of body weight; that’s considered a minimum. At least half of American men consume more than 1.34 grams per kilogram of body weight. Vegetarians generally consume less protein, about 0.75 gram per kilogram on average, and have significantly lower IGF-1 levels. Again, this is likely a good thing because IGF-1 stimulates growth, which may reduce longevity. The beneficial effects of calorie restriction, despite its name and method, may not depend on eating fewer calories at all.29 Restricting protein without lowering calories can promote health and longevity, too.30

  Protein restriction, which reduces IGF-1 and mTOR, might be responsible for the majority of the benefits of calorie reduction.31 Restricting calories without restricting protein does not lower IGF-1 levels, which might promote growth, but not longevity. Lowering protein reduces IGF-1 by 25 percent, which may be a large component of “anticancer and anti-aging dietary interventions.”32 But how much protein we need depends on our circumstances. Athletes need more protein than other people, and cutting down on protein too much may be harmful. The key is to find the balance between too much protein and too little—a topic we discuss inChapter 6.

  Other Ways to Reduce mTOR

  Aside from diet, there are other ways to reduce mTOR. Rapamycin is one example of a drug known to block mTOR. Aspirin, curcumin, and green tea extract seem to be mTOR inhibitors and extend life span. Epigallocatechin 3-gallate (EGCG), which is in green tea, might protect against cancer, reduce weight, and stimulate fat loss.33 Polyphenols are naturally occurring antioxidants found in plants that may slow aging by targeting the mTOR and AMPK pathways.34 Allspice, hibiscus, curcumin, and pomegranate are rich in polyphenols and may inhibit cancer by suppressing mTOR.35 The polyphenol from red wine, resveratrol, generated much initial scientific excitement,36 but resveratrol supplements showed disappointing results that didn’t live up to the hype.

  The type 2 diabetes drug metformin is derived from a medicinal plant that humans have used for hundreds of years. It lowers glucose and insulin, which may be due to its ability to stimulate AMPK and inhibit mTOR.37 This reason might be why metformin, like rapamycin, is associated with a lower risk of cancer.38 Most intriguingly, though, diabetics who take metformin appear to live longer than nondiabetics who do not.39

  Growth Versus Longevity

  Fast growth allows animals to mature quickly and have children, which propagates their genes into the next generation. High growth improves the odds of animals reproducing, but that fast growth rate may increase aging. To the gene, however, faster aging is irrelevant, because aging and death generally occur long after reproduction. If the a
nimal has offspring, the gene will survive even after the individual animal perishes. Evolution requires constant renewal, and longevity is a deterrent to this goal, so it can be considered somewhat “unnatural.” The gene “rejuvenates” itself by letting an older individual die and renewing itself in that person’s children.

  Evolution favors constant renewal over longevity.

  To slow aging, we must counteract our embedded evolutionary heritage. In the battle between growth and longevity, besides the nutrient sensors, it is worth considering growth hormone (GH) and the related insulin-like growth factor 1 (IGF-1).

  Several decades ago, before the concept of growth versus longevity was well known, some researchers had what seemed like a brilliant idea. The genes for GH had been sequenced, and it had just become possible to produce human GH relatively easily with recombinant DNA technology. Before that, injectable GH to treat the relatively rare disease of GH deficiency was produced by grinding up the pituitary gland of cadavers (dead bodies) and purifying the GH. The process was difficult, expensive, and rather gross. Now that pure GH was easily producible, perhaps it could be used as an antiaging treatment to rejuvenate the bodies of older adults.

  A 1990 study showed that injecting growth hormone in older people caused them to lose body fat, gain muscle, and have improved energy and sex drive.40 Sounds pretty great, right? But there was a dark side. The injections also promoted cancer, heart failure, and diabetes, demonstrating that growth hormone potently promotes aging. People who suffer from excessive growth hormone keep growing and die early—growth versus longevity.