The Longevity Solution

by Jason Fung

  Fig. 1.1: Causes of inflammaging

  Evolutionarily Conserved Mechanisms

  Simple one-celled organisms called prokaryotes, such as bacteria, are the earliest forms of life on earth and are still abundant today. Eukaryotes, more complex but still single-celled organisms, first appeared approximately 1.5 billion years later. From those humble beginnings came the multicellular life forms called metazoans. All animal cells, including in humans, are eukaryotic cells. Since they share a common origin, they bear a resemblance to one another. Many molecular mechanisms (genes, enzymes, and so on) and biochemical pathways are conserved throughout evolution toward more complex organisms.

  Humans share approximately 98.8 percent of their genes with chimpanzees. This 1.2 percent genetic difference is enough to account for the differences between the two species. It might be even more surprising to learn that organisms as far apart as yeast and humans have many genes in common. At least 20 percent of genes in humans that play a role in causing disease have counterparts in yeast.7 When scientists spliced more than 400 different human genes into the yeast Saccharomyces cerevisiae, they found that a full 47 percent functionally replaced the yeast’s genes.8

  With more complex organisms, such as the mouse, we find even greater similarities. Of more than 4,000 genes studied, fewer than ten were found to be different between humans and mice. Of all protein-coding genes—excluding the so-called “junk” DNA—the genes of mice and humans are 85 percent identical. Mice and humans are highly similar at the genetic level.9

  Many aging-related genes are conserved throughout species, enabling scientists to study yeast and mice to learn important lessons about human biology. Many of the studies cited in this book involve organisms as diverse as yeast, rats, and rhesus monkeys, and they vary in the degree of their similarity to humans. Not every result applies to humans, but in most cases, the results are close enough that you can learn a great deal about aging from them. Although it is ideal to have human studies, in many cases these do not exist, which forces us to rely on animal studies.

  Fig. 1.2: Genomic similarities between humans and animals

  Theories of Aging

  The following sections outline the principles of several theories of aging and our verdict on the plausibility of each.

  DISPOSABLE SOMA THEORY

  The disposable soma theory of aging, originally proposed by University of Newcastle professor Thomas Kirkwood, holds that organisms have a finite amount of energy that can be used either in maintenance and repair of the body (soma) or in reproduction.10 Like antagonistic pleiotropy, there is a trade-off: If you allocate energy to maintenance and repair, then you have fewer resources available for reproduction. Because evolution directs more energy toward reproduction, which helps propagate its genes to the next generation, the individual’s soma after reproduction is largely disposable. Why devote precious resources to living longer, which doesn’t help to pass on the genes? In some cases, the best strategy is for the individual to have as many offspring as possible and then die.

  The Pacific salmon is one such example; it reproduces once in its lifetime and then dies. The salmon expends all of its resources for reproduction, after which it tends “simply to fall apart.”11 If there’s little chance that a salmon would survive predators and other hazards to complete another round of reproduction, then evolution will not have shaped it to age more slowly. Mice reproduce quite prodigiously, reaching sexual maturity by two months of age. Subject to heavy predation, mice allocate more energy to reproduction than to fighting the deterioration of their bodies.

  On the other hand, a longer life span may allow for the development of better repair mechanisms. A 2-year-old mouse is elderly, whereas a 2-year-old elephant is just starting its life. In elephants, more energy is devoted to growth, and they produce far fewer offspring. The gestation period of an elephant is eighteen to twenty-two months, and the result is only one living offspring. Mice produce up to fourteen young in a litter and can have five to ten litters per year.

  Although it’s a useful framework, there are problems with the disposable soma theory. This theory would predict that deliberate calorie restriction, which limits overall resources, would result in less reproduction or a shorter life span. But calorie-restricted animals, even to the point of near starvation, do not die younger—they live much longer. This effect is seen consistently in many different types of animals. In effect, depriving animals of food causes them to allocate more resources to fighting aging.

  Further, the females of most species live longer than the males. Disposable soma would predict the opposite because females are forced to devote much more energy to reproduction and thus would have less energy or resources to allocate to maintenance.

  Verdict: It fits some of the facts but has some definite problems. The disposable soma theory is either incomplete or incorrect.

  FREE RADICAL THEORY

  Biological processes generate free radicals, which are molecules that can damage surrounding tissues. Cells neutralize them with antioxidants, but this process is imperfect, so damage accumulates over time, causing the effects of aging. Large-scale clinical research trials show that supplementation with antioxidant vitamins like vitamin C and vitamin E may paradoxically increase death rates or result in worse health. Some factors known to improve health or increase life span, such as calorie restriction and exercise, increase the production of free radicals, which act as signals to cells to upgrade their cellular defenses and energy-generating mitochondria. Antioxidants can abolish the health-promoting effects of exercise.12

  Verdict: Unfortunately, some facts contradict the free radical theory. It, too, is either incomplete or incorrect.

  MITOCHONDRIAL THEORY

  Mitochondria are the parts of the cells (organelles) that generate energy, so, as mentioned earlier, they are often called the powerhouses of the cells. It’s a tough job, and mitochondria sustain a lot of molecular damage, so they must be recycled and replaced periodically to maintain peak efficiency. Cells undergo autophagy; mitochondria have a similar process of culling defective organelles for replacement, called mitophagy. The mitochondria contain their own DNA, which accumulates damage over time. The result is less-efficient mitochondria, which in turn produces more damage in a vicious cycle. Without adequate energy, cells may die, a manifestation of aging.

  Muscle atrophy is related to high levels of mitochondrial damage.13 But in comparing energy production in mitochondria in young and old people, little difference was found.14 In mice, very high rates of mutation in mitochondrial DNA did not result in accelerated aging.15

  Verdict: This is an interesting theory, but the research is very preliminary and ongoing. Arguments can be made both for and against it.

  HORMESIS

  In 120 BC, Mithridates VI was heir to Pontus, a region in Asia Minor, or modern-day Turkey. During a banquet, his mother poisoned his father so that she could ascend the throne. Mithridates ran away and spent seven years in the wilderness. Paranoid about being poisoned, he chronically took small doses of poison to make himself immune. He returned as a man to overthrow his mother and claim the throne. He became a powerful king. During his reign, he opposed the Roman Empire but was unable to hold the Romans back. Before his capture, Mithridates decided to commit suicide by drinking poison. Despite taking large doses, “The Poison King” failed to die, and the exact cause of his death is still unknown.16 What doesn’t kill you may indeed make you stronger.

  Hormesis is a phenomenon in which low doses of stressors that are normally toxic instead strengthen an organism and make it more resistant to higher doses of the same toxins or stressors. Fans of the movie The Princess Bride may remember that the hero, Westley, had taken small doses of iocane powder for years, which made him immune to its toxic effects. Thus, when Westley put the poison in both Vizzini’s drink and his own, Westley was the only one to survive. This is hormesis.

  Hormesis is not a theory of aging, but it has huge implications for other theories
. The basic tenet of toxicology is “The dose makes the poison.” Low doses of “toxin” may make you healthier.

  Exercise and calorie restriction are examples of hormesis. Exercise, for example, puts stress on muscles causing the body to react by increasing muscular strength. Weight-bearing exercise puts stress on bones, causing the body to react by increasing bone strength. Being bedridden or going into zero gravity, as astronauts do, causes rapid weakening of muscles and bones.

  Calorie restriction can be considered a stressor because it causes a rise in cortisol, commonly known as the stress hormone. This rise in cortisol increases the production of heat shock proteins (a family of proteins that help to stabilize new proteins or repair damaged ones) and resistance to subsequent stressors.17 So, calorie restriction also satisfies the requirements of hormesis. Because both exercise and calorie restriction are forms of stress, they involve the production of free radicals.

  Hormesis is not a rare phenomenon. Alcohol, for example, acts via hormesis. Moderate alcohol use is consistently associated with better health than complete abstention. But heavier drinkers have worse health and often develop liver disease. Exercise is well known to have beneficial health effects, but extreme exercise can worsen health by causing stress fractures. Even small doses of radiation can improve health, whereas large doses will kill you.18

  Some of the beneficial effects of certain foods may be due to hormesis. Polyphenols are compounds in fruits and vegetables, as well as coffee, chocolate, and red wine, and they improve health, possibly in part by acting as low-dose toxins, thereby upregulating your body’s natural endogenous antioxidant enzymes.

  Why is hormesis important for aging? Other theories of aging presuppose that all damage is bad and accumulates over time. But the phenomenon of hormesis shows that the body has potent damage-repair capabilities that can be beneficial when activated. Take exercise as an example. Weight lifting causes microscopic tears in our muscles. That sounds pretty bad, but the process of repairing those muscles makes them stronger. Gravity puts stress on our bones. Weight-bearing exercise such as running causes microfractures of our bones. In the process of repair, our bones become stronger. The opposite situation exists in the zero gravity of outer space. Without the stress of gravity, bones become osteoporotic and weak.

  Not all damage is bad—in fact, small doses of damage are good. What we are describing is a cycle of renewal. Hormesis allows the breakdown of tissue like muscle or bone that is then rebuilt to be better able to withstand the stresses placed upon it. Muscles and bones can grow stronger, but that growth can’t happen without breakdown and repair.

  Verdict: Hormesis has plenty of evidence that it’s a true biological response to small doses of damage.

  Growth Versus Longevity

  Hormesis, like the disposable soma theory, suggests that there is a fundamental trade-off between growth and longevity. The larger and faster an organism grows, the faster it ages. Antagonistic pleiotropy may play a role in that some genes that are beneficial early in life may be detrimental later in life. When you compare life spans within the same species, such as in mice19 and in dogs, smaller animals (the ones with less growth) live longer.20 Women, on average smaller than men, also live longer. Among men, shorter men live longer.21 Think about a person who is 100 years old. Do you imagine a muscular 6-foot-6-inch man, or do you picture a small woman?

  Comparing across species, however, larger animals live longer. Elephants, for example, live longer than mice. But this difference can be explained by the slower development of larger animals.22 The relative lack of predators for large animals has meant that evolution has favored slower growth and slower aging. Small animals that have fewer predators than other animals of the same size, such as bats, also live longer.

  Aging isn’t deliberately programmed, but the same physiologic mechanisms that drive growth also drive aging. Aging is simply the continuation of the same growth program, and it’s driven by the same growth factors and nutrients. If you rev a car’s engine, you can reach high speeds very quickly, but continuing to rev the engine results in burnout. It’s the same essential program, but different time scales—short-term performance versus longevity. All the theories of aging point out this essential trade-off. This is powerful information because certain programs may be beneficial at certain times in our lives. During youth, for example, we need to grow. During middle and older age, however, this high growth program may cause premature aging, and it would be beneficial to slow growth. Because the foods we eat play a large role in this programming, we can make deliberate adjustments to our diet to preserve our life span as well as our “health span.”

  The Calorie Restriction Society, which boasts more than 7,000 members, routinely restricts calories in the hope of living longer. Does that sound like a fantasy? Actually, among life-extension practices, perhaps the best described is calorie restriction, with animal studies dating back many decades. Calorie restriction (CR) with adequate nutrition is perhaps the most effective antiaging intervention currently known.1

  Animal studies from as early as 1917 show that calorie restriction can prolong life. Restricting food intake in young female rats delays menopause, leaving them fertile far longer than normal. By 1935, researcher Clive McCay noted that reduced growth in white rats induced by calorie restriction resulted in increased longevity.2 However, the animals must not be malnourished. Inadequate intake of essential vitamins and minerals causes many types of diseases, and malnourished mice generally do poorly and die young. Restricting energy (calories) while providing all the essential nutrients had the ability to extend life span, something previously unheard of.

  Researchers have generally used a 40 percent calorie restriction, but even a 10 percent calorie restriction in rats gives nearly the same benefits.3 A 10 percent calorie restriction increased life in these rats by about 15 percent, whereas animals restricted 40 percent lived about 20 percent longer. In 1942, researchers showed for the first time that calorie restriction in animals could prevent the development of cancer.4 Controlled human studies are not available because they are virtually impossible to perform ethically. For the remainder of the book, we use the term calorie restriction with the implicit understanding that malnourishment must be avoided.

  Calorie restriction extends the life span of every organism so far tested, including yeast, worms, flies, rodents, and monkeys. It also slows or even prevents age-related diseases, including dementia, diabetes, cardiovascular and coronary disease, neurodegenerative disorders, and several types of cancer. Researchers in 1946 insightfully noted that implementing a calorie-restricted diet in a plentiful food environment would be difficult or indeed impossible, as the ensuing decades would prove. Instead, they mused whether a more realistic form of calorie restriction could be implemented with a periodic fasting schedule. Rat experiments proved that this strategy was successful for life extension and cancer prevention.5

  Extending this idea to humans, Ross, in 1959, noted that coronary heart disease is uncommon in nutritionally deprived communities.6 In other words, populations that consume few calories seem to develop less heart disease. Researchers during this period also found a lesser effect of protein restriction on longevity. High casein (a form of dietary protein) in rat diets shortens life span.7

  Fig. 2.1: The effects of calorie restriction

  During the 1970s, Dr. Roy Walford at UCLA became the leading proponent of calorie restriction for longevity. He would later become the physician of Biosphere 2. This early 1990s experimental project was a self-contained greenhouse where eight “Terranauts” lived in a completely closed environment. They grew their own food and recycled their waste. However, they were unable to grow as much food as initially planned. Dr. Walford persuaded the other team members to finish their two-year mission while following a calorie-restricted diet. Unfortunately, things did not quite go as he had hoped. The Terranauts were likely not receiving adequate nutrition in addition to following a calorie-restricted diet. Dr. Walford lost 25 pou
nds from his already spare 145-pound frame and came out of Biosphere 2 considerably aged. He later developed Lou Gehrig’s disease and died at age 79.

  The 1980s saw the increasing acceptance of the calorie-restriction model and serious consideration of how to apply these animal studies to humans. More and more research publications are pushing the boundaries of knowledge of how calorie restriction can be a key component of longevity.

  One of the most compelling examples of calorie restriction in prolonging human life span is in the Japanese prefecture of Okinawa. Traditionally, the Okinawan people follow a practice called Hari Hachi Bu, which is a sort of mindfulness eating. The Okinawans deliberately remind themselves to stop eating when they are 80 percent full, in effect self-imposing a 20 percent calorie restriction. There are a whopping four to five times more centenarians among their population than in most industrialized countries, and this trend has been associated with their low-calorie diets, which contain about 20 percent fewer calories than other Japanese people.8 However, this impressive statistic doesn’t extend to Okinawans who are younger than 65 years old, which might be linked to an increasingly Western-influenced diet that began to seep into their lifestyle starting in the 1960s. We talk more about the diet and life span of the Okinawans and other long-living cultures (in areas known as Blue Zones) in Chapter 12.