Main The Longevity Solution: Rediscovering Centuries-Old Secrets to a Healthy, Long Life
Book cover The Longevity Solution: Rediscovering Centuries-Old Secrets to a Healthy, Long Life


Getting older doesn’t have to mean experiencing more pain and illness, becoming less mobile, or developing disease. Renowned cardiovascular research scientist and doctor of pharmacy Dr. James DiNicolantonio partners with leading physician and bestselling author Dr. Jason Fung to deliverThe Longevity Solution,a groundbreaking new book that unlocks the secrets of healthy aging. Using evidence drawn from their years of medical research and clinical practice, Dr. DiNicolantonio and Dr. Fung lay out five simple, easy-to-follow steps you can take now for a longer, fuller, healthier life.

The Longevity Solutionexplains how to incorporate time-honored wellness traditions while doing away with fads, unnecessary supplements, and unsubstantiated wellness practices. It investigates the dietary habits and other practices of the healthiest, longest-lived humans on the planet, who live in regions known as Blue Zones, as a model for what and how we should eat. It teaches the benefits of intermittent fasting and calorie restriction, which have been shown to slow the aging process, while consuming proper ratios of protein and healthy fats. It also looks at how red wine, tea, and coffee play key roles in optimizing health and why salt is an ally, not an enemy, in the longevity equation.

In this comprehensive guide, Dr. DiNicolantonio and Dr. Fung unveil cutting-edge science in an approachable format that is easy to understand and can be put into practice immediately. Simple dietary changes can help you break the cycle of carbohydrate dependence, kick your metabolism into high gear, and jump-start your longevity genes.The Longevity Solutionputs healthy aging back in your control!

Year: 2019
Edition: Paperback
Language: english
Pages: 304
ISBN 10: 1628603798
ISBN 13: 9781628603798
File: EPUB, 2.68 MB
Download (epub, 2.68 MB)

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First Published in 2019 by Victory Belt Publishing Inc.

Copyright © Dr. James DiNicolantonio and Dr. Jason Fung

All rights reserved

No part of this publication may be reproduced or distributed in any form or by any means, electronic or mechanical, or stored in a database or retrieval system, without prior written permission from the publisher.

ISBN-13: 978-1-628603-79-8

The information included in this book is for educational purposes only. It is not intended or implied to be a substitute for professional medical advice. The reader should always consult his or her health-care provider to determine the appropriateness of the information for his or her own situation or if he or she has any questions regarding a medical condition or treatment plan. Reading the information in this book does not constitute a physician-patient relationship. The statements in this book have not been evaluated by the Food and Drug Administration. The products or supplements in this book are not intended to diagnose, treat, cure, or prevent any disease. The authors and publisher expressly disclaim responsibility for any adverse effects that may result from the use or application of the information contained in this book.

Author photos by Megan DiNicolantonio and Dean Macdonell

Cover design by Justin-Aaron Velasco

Interior design by Elita San Juan and Charisse Reyes

Printed in Canada

TC 0119



















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A Note from Dr. DiNicolantonio

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In my previous two books, The Salt Fix and Superfuel, I tackled several long-standing nutritional fallacies, particularly the forty-year-old lies that salt is bad for you and vegetable oils are good for you. The Longevity Solution builds upon these works by exploring the mysteries of mTOR, dietary protein, and calorie restriction and looking at the dietary habits of the healthiest humans on the planet to unlock the secrets of healthy aging. The Longevity Solution also covers the benefits of intermittent fasting, collagen and glycine, green tea, coffee, and red wine. Finally, Dr. Fung and I lay out five easy-to-follow steps for a longer, healthier life.

Perhaps you believe that following the government’s Dietary Guidelines for Americans, with its familiar mantra of less salt, more vegetable oils, and more carbohydrates, will keep you healthy. Unfortunately, my years of cardiovascular research and Dr. Fung’s years of practical clinical experience have convinced us that this dietary advice is almost completely wrong. For example, eating meals based on highly refined carbohydrates will put you in a perpetual cycle of high and low blood glucose that keeps you hooked on these foods (a state known as carbohydrate dependence). The Dietary Guidelines also neglect to mention that the Japanese and other long-lived Asians tend to eat high-salt seafood dishes and avoid refined vegetable oils—doing the exact opposite of the U.S. government’s recommendations.

Simple dietary changes can help you break the cycle of carbohydrate dependence, kick your metabolism into high gear, and jump-start your longevity genes. Intermittent fasting is a great example of one such simple change. Fasting resets your metabolism, allowing new, better cells and proteins to replace older ones. This “out with the old cells, in with the new” process of self-repair is called autophagy, and increasing autophagy through fasting is just one “biohack” that might help extend your life span as the body is busy with self-repair instead of growth, which promotes aging. Other dietary patterns commonly found in long-lived populations, such as drinking red wine, tea, and coffee, are easy to follow and improve both health and longevity.

Let The Longevity Solution be your official guide to improving your health with simple, easy changes to your diet and lifestyle that you can start implementing now! Activate your longevity genes and start promoting cellular repair rather than cellular despair.

A Note from Dr. Fung

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People often believe that the secrets to longevity lie in the newest gee-whiz technology or the latest, greatest supplement. Paradoxically, the secrets to healthy aging have been communicated to us for centuries, and sometimes millennia, as they’ve been handed down from generation to generation. The Longevity Solution rediscovers these ancient lost secrets—and shows how they’re supported by what we now know about biology. Recent research has uncovered the science behind ancient longevity-promoting practices such as restricting calories; optimizing dietary protein; drinking tea, coffee, and red wine; and eating more salt and natural fats. The more things change, the more things stay the same.

These ideas are not the latest and greatest fads. They are tried and true. They have been used since antiquity and were traditionally accepted as important facets of wellness. Ancient peoples knew that they worked, but modern science is just now figuring out the reasons behind their success. These secrets have been hiding in plain sight. We just didn’t know where to look.

People are always searching for what they can add to their diet to extend life and improve health. Over the years, the list has become endless. Supplements of vitamins A, B, C, D, and E have been touted as the next great cure-alls. One after the other has failed, sometimes miserably. The problem is that we’re not asking the right questions. In addition to asking “What do I need to eat more of to get better?” we need to ask “What do I need to eat less of to get better?” The Longevity Solution asks both questions—and, more importantly, answers them.

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The legendary Spanish conquistador Juan Ponce de León (1460–1521), like many of his bloodthirsty contemporaries, sought fame and fortune through exploration of the New World. He settled in the part of Hispaniola that is now the Dominican Republic, before serving as the governor of Puerto Rico for two years. When Christopher Columbus’s son, Diego, replaced de León, he was forced to set sail once again. He had heard native tales of a fountain that would restore youth to anyone who drank from it. As part of his next phase of exploration, Ponce de Léon searched for this elusive source of longevity.

He explored much of the Bahamas and is believed to have landed near the present-day town of St. Augustine in northeast Florida in 1513. He named this “newly discovered” land Florida, from the Spanish word florido, meaning “full of flowers.” He continued his explorations throughout the Florida coast and the Florida Keys but died never having found the elusive fountain of youth.

This well-known story is likely entirely fictional. Ponce de León’s writings make no mention of his search for the fountain of youth, and his vigorous explorations were for more pedestrian reasons—to find gold, identify lands for colonization, and spread Christianity. But the notion of a mystical substance that can reverse aging is so powerful that this legend has endured all these years. Interestingly, the legend of a fountain of youth predates de León; similar stories are part of the Middle Eastern, medieval European, and ancient Grecian cultures. Can aging really be reversed? Has science succeeded where Ponce de León failed?


What Is Aging?

Let’s start by looking at what aging is. Everyone instinctively knows what it means to age, but to successfully tackle any problem, science requires an accurate definition. We can view aging in several ways.

First, aging is often obvious because of a change in appearance. Gray hair, wrinkled skin, and other superficial changes signal age. These physical changes reflect underlying physiological changes, like decreased pigment production in hair follicles and decreased skin elasticity. Cosmetic surgery changes appearance but not the underlying physiology.

Second, we can view aging as a loss of function. Over time, women have decreasing fertility until ovulation eventually ceases completely during menopause, in a process largely determined by age. Bones become weaker, increasing the risk of breaks such as hip fractures, which are problems we rarely see in young people. Muscles also become weaker, which explains why champion athletes are invariably young.

Third, at the cellular and molecular levels, response to hormones decreases with age. For example, high insulin (a fat- and glucose-storing hormone) or thyroid hormone levels won’t benefit you much if your cells no longer respond to those hormones. Mitochondria, the important cellular components that produce energy and are commonly known as the “powerhouse of the cell,” become less efficient and less able to produce energy. The declining efficiency of an aging body results in higher rates of illness and disease.

Increasing age exponentially increases the risk for disease and death. Heart attacks, for example, are virtually absent in children but common in the elderly. Aging is not a disease itself, but it increases the chances of developing diseases, which makes it the best target to stop or reverse chronic diseases. Age, in chronological years, is a river—irreversible and flowing in a single direction. But aging, in physiological years, is not. Many factors contribute to aging and disease, and in this book, we primarily consider the aspects that are influenced by diet.

Given the overall functional decline, why do organisms age at all? In short, aging is the accumulation of damage. Young animals, including humans, have a high capacity for repairing the damage of everyday life, such as when children scrape their knees. Species’ survival depends on the ability to repair this damage: for example, in healing wounds or broken bones. With age, this ability to repair damage diminishes in all respects—whether it is to fight infections, clear arteries, or kill cancer cells. But this decline is not a natural, foregone conclusion. Nutrition and lifestyle determine much of the speed and extent of the aging process. Long-lived, healthy populations around the world that eat few processed foods show us the possibility of slowing the aging process.

Hippocrates, the ancient Greek father of modern medicine, long ago acknowledged nutrition as the cornerstone of health and longevity. Famine is one of the Four Horsemen of the Apocalypse, but the modern problems of obesity, insulin resistance, and diabetes are equally deadly. In both cases, the foods we eat play an important part in promoting or preventing all these issues.

One important damage-repair mechanism is called autophagy. (The fact that the 2016 Nobel Prize in Medicine was awarded to Yoshinori Ohsumi for his “discoveries of mechanisms for autophagy” underscores how vital this process is.) In autophagy, cellular parts called organelles are broken down and recycled periodically as part of a wide-ranging quality control system. Just as a car needs regular replacement of oil, filters, and belts, a cell must replace its organelles regularly to maintain normal function. As cellular organelles pass their expiration dates, the body ensures that old organelles are removed and replaced with new ones so that no residual damage impedes function. One of the key discoveries of the last quarter century is that the foods we eat heavily influence these damage control procedures.

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Evolution Doesn’t Care Whether You Age

You might think that evolution would perfect our damage control responses, allowing us to live forever. But evolution doesn’t care if you age or even if you survive. It ensures the survival of the species, not the individual. Once you’ve had children, your genes will survive even if you don’t, so there is no natural selection toward longer-lived species. This reasoning is behind the theory of aging known as antagonistic pleiotropy. Despite its name, the theory is relatively simple.

Evolution by natural selection works at the level of genes rather than for individual organisms. We all carry thousands of different genes and pass them to our children. Genes best suited to the individual’s environment survive better and enable the individual to produce more offspring. Over time, these beneficial genes become more widespread in the population. Age plays a large role in determining the effect of a gene on the population.

A gene that is fatal at age 10 (before a person has children) is rapidly eliminated from the population because the person bearing that gene is unable to pass it on. A gene that is fatal at age 30 will still be eliminated (albeit more slowly) because people without that gene have more children. A gene that is fatal at age 70 might never be eliminated because the gene will have passed into the next generation long before it manifests its deadly effects.

Antagonistic pleiotropy suggests that genes have different effects at different stages of life. For example, a gene that increases growth and fertility but also increases the risk of cancer in old age means more children but a shorter life span. This gene would still spread in a given population because evolution favors survival of the gene, not the longevity of an individual life. One gene might have two different, unrelated effects (pleiotropy) that are seemingly at odds with one another (antagonistic). Survival of the gene is always given priority over longevity of the individual.

This particular gene described codes for a protein known as insulin-like growth factor 1 (IGF-1). High levels of IGF-1 promote growth, allowing organisms to grow larger, reproduce faster, and weather wounds better. That’s a huge advantage in the competition to survive in order to have children. However, in old age, high IGF-1 contributes to cancer, heart disease, and early death, and by that time, the gene has already passed into the next generation. When growth/reproduction comes up against longevity, evolution favors reproduction and high IGF-1 levels. This is the fundamental and natural balance between growth and longevity.

Viewed in this manner, the fight against the ravages of aging is a fight against nature itself. Aging is completely natural, although the extent and speed are variable. Living and eating completely in tune with nature does not prevent aging. Nature and evolution do not “care” about your longevity; your genes’ survival is the only concern. In a sense, we must look beyond nature to slow or prevent aging.

Aging and Disease

Shockingly, and almost without precedent in human history, children today might have shorter life spans than their parents.1 The twentieth century witnessed huge and steady advances in medicine and public health that significantly increased average life expectancy. But recently, an epidemic of chronic diseases is threatening to reverse that enviable record.

Before the modern industrial era, with its advances in sanitation and medicine, infectious diseases were the main natural causes of death. In the United States in 1900, life expectancy at birth was 46 years for a man and 48 years for a woman, due largely to high infant and childhood mortality.2 But those who survived childhood had a good chance of surviving to older age. The top three causes of death in 1900 were all infectious diseases: pneumonia, tuberculosis, and gastrointestinal infections.3 These infectious diseases can affect people at any age, although children and the elderly are especially vulnerable.

Today’s situation is different. The top two causes of death are cardiovascular disease and cancer, and both diseases correlate tightly to age. Cardiovascular disease, which includes heart disease and stroke, is the number-one cause of death in the United States, accounting for one in four deaths, and its incidence increases dramatically with age.4 Children rarely suffer heart attacks, but by age 65, the majority of us have developed some form of cardiovascular disease.

The story is the same for cancer. Children and young adults each account for only about 1 percent of new cancer cases each year.5 Adults aged 25 to 49 account for about another 10 percent, whereas people aged 50 and older account for around 89 percent of all new cancer cases. Other diseases with clear links to aging include cataracts, osteoporosis, type 2 diabetes, Alzheimer’s, and Parkinson’s. These diseases of aging are responsible for approximately two-thirds of the roughly 150,000 deaths that occur around the world every single day. These are diseases that affect hardly anyone younger than the age of 40. In the industrialized West, the proportion of people who die from aging-caused diseases approaches 90 percent.6

As modern medicine conquered infectious diseases like smallpox, one consequence of this success is an aging population with its inherently higher risk of chronic diseases. But that’s not the whole story. The seemingly unstoppable and unparalleled obesity epidemic is putting our health at increasing risk of cancer and heart disease. There are many dietary and lifestyle modifications that you can adopt to reverse this risk of chronic disease.

Aging is the slow accumulation of cellular damage due to a decreasing ability to repair it. The result is a low level of inflammation, which is so characteristic of aging that it’s been termed inflammaging. Oxidative stress, a condition in which free radicals (highly reactive molecules with an unpaired electron) overpower the body’s internal antioxidant system, rises with age. However, you can make lifestyle changes that can increase your odds of healthy aging. You can increase not just your life span, but your “health span.” Nobody wants to spend their last years frail, sick, and in a nursing home. The prevention of aging is about more years of healthy life during which you’re free of disease and other drawbacks of old age, you feel vigorous and energetic, and you have an enthusiasm for living. Longevity means extending youth, not extending old age.

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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.

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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.



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.




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.




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.




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.


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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.”

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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

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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 pounds 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.

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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.



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.



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.


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



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.

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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

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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 of 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.

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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.


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

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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.

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Fig. 3.2: High nutrient availability

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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 animal 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.

Growth hormone is the main stimulant to IGF-1. Both are highest in growing children and adolescents and decline into adulthood and old age, reflecting the different priorities of each stage of life. Childhood and early adulthood are periods in which growth is the priority, so GH and IGF-1 are high. Later in life, though, these high levels of GH and IGF-1 become detrimental to longevity. Studies of centenarians have revealed that less growth hormone and IGF-1 are associated with better health and longer life.

Interestingly, though, GH levels are significantly elevated during fasting. Huh? Why would the body increase GH when no nutrients are available? The reason GH increases during fasting is that fasting induces a state of “GH resistance.” This is caused by activation of fibroblast growth factor 21 (FGF-21), which reduces IGF-1 and increases liver expression of IGF-1 binding protein 1 to blunt GH signaling.41 Thus, while GH may be higher during fasting, there is actually less growth and more repair.

Dietary protein increases levels of both GH and IGF-1, which may be good or bad, depending on your stage in life. When we are young, protein helps us mature, ensures that all systems are healthy and strong, and readies us for conceiving, bearing, and caring for children. In an adult, too much protein might promote cancer, heart disease, and other ills of aging. Considered in this new light, many of the diseases that affect adults are diseases of “too much growth.”

For example, atherosclerosis is the underlying process of “hardening of the arteries” that causes heart attacks and strokes. Initially thought to be a disease of cholesterol blocking the arteries, it is now known to be a disease of excessive smooth muscle proliferation and inflammation that blocks the arteries. “Too much growth” in the blood vessels leads to blockages. Cancer is a disease of “too much growth” that is uncontrolled. Obesity, with its related metabolic diseases, is a disease of “too much growth.”

Reining in this epidemic of “too much growth” depends on decreasing growth pathways. The key to reaping the antiaging, antidisease benefits of calorie restriction is getting the right amount and balance of dietary protein appropriate to your stage of life and lifestyle.

It All Comes Down to Protein

Longevity is not just about calories.42 (Is it ever?!) Protein restriction plays a large role in extending life span43 by slowing growth (and aging). Manipulation of dietary protein is potentially easier than restricting calories or fasting, but it has similar benefits.44 Even as early as the 1930s, animal studies showed that protein restriction can double life span.45 Mice live longest with a diet of just 5 percent protein; at that level, they also have lower rates of cancer46 and lower cholesterol.47 One specific essential amino acid, methionine, may be especially important.48 Plant-based diets are not only lower in protein but often low in methionine specifically.

Low-protein diets might reduce cancer and mortality in humans.49 Customizing our diets—specifically our protein intake—could stave off disease and promote longer life. The key to longevity might already be in your hands. It’s not a magical berry from a far-off land. It’s not even a stringent low-calorie diet. It starts with simply optimizing your protein intake.

Is Aging Just a Program We Can Update?

The master program that drives growth, mTOR, doesn’t magically turn off when we’re older. It also drives aging. This growth versus longevity paradox means that the mTOR so necessary for early life may also lead to early death. But perhaps there are ways to reprogram our cells to slow aging.50 Perhaps all we need is an update in our software.

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Restricting dietary protein might promote longevity, but if taken too far, it will also inhibit normal growth and cause malnutrition. Protein deficiency can occur in isolation, or it can occur as part of a general lack of food. Overall starvation, with not only protein deficiency but also fat deficiency, is called marasmus. People become skeletally thin, with no body fat and wasting of muscle. In other situations, people get sufficient calories but very little protein.

This issue of getting enough calories without enough protein typically occurs in children in the war-torn nations of sub-Saharan Africa that rely on food aid. These people receive mostly refined carbohydrates (which are cheap) but almost no protein (which is expensive). Food donation by First World countries typically is refined carbohydrates (sugar, flour, rice, corn), which provide calories at a fraction of the cost of protein and, importantly, do not require refrigeration during the long trip. The 1970s and 1980s saw many cases of isolated protein deficiency called kwashiorkor. African children had swollen feet, thin arms and legs (due to loss of muscle), hair loss, poor immune function, and a swollen fatty liver (due to excess carbohydrates).

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Kwashiorkor affects mostly children because of the importance of dietary protein for proper growth in infancy and childhood. Adults may break down their own protein and recycle the amino acids, but children must eat sufficient protein to grow. In developed nations, kwashiorkor is virtually absent, so we rarely see severe protein deficiency in these areas.

As humans move into middle age, growth is no longer necessary, and it’s possibly detrimental to longevity. Low protein intake is associated with a reduction in IGF-1, as well as a reduction in cancer and overall mortality in people 65 or younger, but not in those older than 65.1

As we age (especially as we pass the age of 65), too little protein can be detrimental, as we typically lose muscle over time. Of all human tissue, muscle burns the most energy. Muscle wasting, or atrophy, can start at as early as 30 years of age. On average, people lose 10 percent of their muscle mass per decade of life. By age 80, the typical person may have lost a full 50 percent of muscle mass. (See Figure 4.1.) Loss of muscle, known as sarcopenia, has dire consequences, including the inability to perform simple tasks of daily living, such as getting out of a chair or even standing. Lack of exercise likely plays a large role in sarcopenia, as studies of traditional societies with an active lifestyle have shown that those individuals maintain muscle mass and strength. However, in Western societies, we tend to become more sedentary with age, and we might need more protein due to a phenomenon known as anabolic resistance.

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Fig. 4.1: Muscle mass and aging

Anabolic resistance is the phenomenon in which sufficient dietary protein, and particularly the amino acid leucine, results in less muscle growth (anabolism) in older people than in the young. Most tissues of the body, including muscle and bone, are in a constant state of breakdown and repair. For example, cells called osteoclasts break down bone tissue, whereas other cells called osteoblasts lay down new bone. Sometimes this renewal cycle moves slowly, and sometimes it can be accelerated, as with fasting.

Fasting decreases insulin and mTOR and activates the breakdown of protein. The body has some amino acids in the bloodstream at all times, and when eating is resumed, the high growth hormone levels help rebuild muscle to replace that which was lost. If you are doing exercise, then the muscle is rebuilt to carry more weight. We should emphasize that this cycle involves small amounts of muscle. You are not in danger of losing much, if any, muscle mass through periodic short-term (i.e., 24-hour) fasting. This renewal cycle is similar to autophagy, which happens at a subcellular level and involves organelles and mitochondria. In older people, anabolic resistance means more protein is necessary for this cycle of muscle breakdown and growth. Eating more protein can help older people overcome this phenomenon.

Restricting calories is not the same as restricting protein. Members of the Calorie Restriction Society (CRS), which was founded in 1993, deliberately restrict calories for longevity and wellness. They don’t follow a low-protein diet, however. Scientific studies found their protein intake rather high at 1.7 grams per kilogram of body weight per day compared to 1.2 grams on a typical Western diet and only 0.8 gram on a vegan diet. The CRS group’s IGF-1 levels were not much different compared to a standard Western diet.2 Only the vegan group showed decreased IGF-1. When some of the CRS group decreased their protein intake to 0.95 gram, their IGF-1 levels dropped by 22 percent and measured only slightly higher than the vegan group. Protein intake is critically important for IGF-1 levels in humans, despite calorie restriction. The vegan group in the study consumed more calories but less protein than the CRS group. And the protein they consumed was only plant protein. So lowering IGF-1 seems to have more to do with protein restriction than calorie restriction.

While the decrease in IGF-1 that’s observed with lower protein intake appears encouraging, the relation between IGF-1 and longevity is still unproven. Yet the Laron dwarfs we mentioned in Chapter 2 are an example of the importance of low IGF-1 levels for cancer and other diseases of aging.

Aging and Amino Acids

Proteins are composed of individual amino acids, and certain amino acids are worth discussing in more detail.



The nonessential amino acid cysteine is crucial for the formation of glutathione (the body’s internal antioxidant), which tends to decline with age. When the body is depleted of glutathione, it’s less able to handle oxidative stress, and eating more cysteine may help solve this problem. The close association among aging, oxidative stress, and cysteine has even led some scientists to deem aging a “cysteine deficiency syndrome”; ensuring an adequate supply of cysteine might go a long way toward ameliorating the maladies of aging. Cysteine is in most high-protein foods; for example, meat, dairy, onions, broccoli, Brussels sprouts, and oats are high in cysteine.



The amino acid leucine plays a key role as a signaling molecule in muscle growth and critical processes such as autophagy. Together, leucine, isoleucine, and valine are known as branched-chain amino acids (BCAAs). All three BCAAs are essential amino acids and are important for building muscle.

Specific situations in which more BCAAs are useful include those situations in which a great deal of growth is desired. Bodybuilders often take whey supplements, which contain large amounts of leucine. Burn victims often lose massive amounts of protein, and supplementing with leucine might be a useful strategy to increase growth of new tissue.3 Whey also can be useful for the elderly and ill due to its growth-promoting effects on mTOR.



The amino acid methionine is one of the nine essential amino acids. Restricting methionine, even without overall caloric restriction, has the astounding ability to increase life span in certain species, including the fruit fly and mouse.4 Methionine-restricted animals have less body fat and better insulin sensitivity and metabolism. Methionine is in meat, eggs, fish, some nuts, seeds, and cereal grains. Fruits and vegetables, including legumes, although otherwise protein dense, contain little methionine. This offers the tantalizing possibility that dietary changes could extend human life span. However, since methionine is an essential amino acid, you cannot eliminate it from the diet entirely. (Remember, essential amino acids are the type of amino acids that your body cannot make.)



Glycine is the most important nonessential amino acid. It represents 11.5 percent of the total amino acids in the body and is an important precursor for vital proteins such creatine (in muscle), glutathione (an antioxidant), and heme (in blood). Glycine supplementation appears to be particularly unique, as it may afford protection against dietary fructose in animal models.5 And considering that the typical American consumes around 50 pounds of fructose per year, the protective potential of glycine supplementation is advantageous.

Glycine is also important for the skin and joints. Gelatin, such as that found in Jell-O brand desserts, is a particularly rich source of glycine. It is produced by boiling the bones and skins of cows and pigs. Bone broth is also a good dietary source of glycine. Horses’ hooves, despite the popular myth, do not contain sufficient collagen, the connective tissue around the joints, to be used in the production of gelatin. In Asia, tendons, high in glycine, are prized delicacies.

Methionine lowers glycine levels by reducing absorption and increasing excretion. Some of the benefits of methionine restriction might be due to higher glycine levels. Glycine might mimic methionine restriction by changing amino acid metabolism. Increasing the glycine content of diets might offer an easy way to obtain the effects of methionine restriction and, thus, life extension.

All these amino acids play a role in normal human metabolism. We must get enough protein to stay healthy, but the million-dollar question is how much protein is too little, and how much protein is too much?

How Much Protein Is Too Little?

The Institute of Medicine of the National Academy of Sciences set the Recommended Daily Allowance (RDA) for protein to be 0.8 gram per kilogram of body weight. For the average man, that amounts to about 56 grams of protein a day; for the average woman, it’s about 46 grams. This is not the same as 46 to 56 grams of meat, because protein makes up only about 16 to 25 percent of the weight of meat, depending upon the type and the leanness. If you eat 56 grams of steak, you’re not getting a full 56 grams of protein. You require about six times more by weight (approximately) to offset the portion of the steak that’s not protein. How did the Institute of Medicine come up with this RDA of 0.8?

You can estimate the amount of protein you need from the amount your body loses on a daily basis, assuming you are maintaining weight rather than losing or gaining it. Protein losses can be measured by checking nitrogen losses in the urine and stool. Carbohydrates and fat are composed mainly of carbon and hydrogen, whereas protein is the major source of nitrogen in the body. In 1985, the World Health Organization found that daily losses of protein averaged 0.61 gram per kilogram per day. Presumably, then, a person’s diet should replace (roughly) this 0.61 gram per kilogram per day that’s lost. This average is for normal healthy people, not for people who are losing muscle or otherwise are sick.

To build in a margin of safety against protein deficiency, the World Health Organization added 25 percent (two standard deviations) more than the 0.61 gram per kilogram per day value, which is approximately 0.8 gram per kilogram per day. Based on the original calculations, 97.5 percent of the healthy general population was eating less than 0.8 gram per kilogram per day of amino acids. This value is not a low standard. This is a very high standard of sufficient protein intake, and the value was calculated on the assumption that excess dietary protein is not dangerous.

Even at this high level, the average man still required only 56 grams of protein and the average woman only 46 grams. For reference, the USDA in 1985 determined that in the United States, 14 to 18 percent of calories came from protein, and the average consumption was 90 to 110 grams per day for men and 70 grams per day for women. Americans, being one of the wealthiest populations on Earth, were eating much more protein than the average inhabitants of this planet. The average American male was eating twice the recommended daily amount, which itself is already a high estimate of our actual needs. This happens day after day. Week after week. Year after year.

Furthermore, in adults, our bodies continuously degrade and resynthesize intrinsic body proteins. Old proteins are broken down, and the amino acids are reabsorbed to be built into new proteins. The amount of turnover is several times larger than the amount of amino acids we eat daily. However, some amino acids do get lost in the process, predominantly in the stool and urine. During periods of low protein intake, the amount of nitrogen lost in the stool and urine can drop to a very low level, which explains how adults in sub-Saharan Africa largely avoided kwashiorkor despite extremely low protein intake. Their bodies were recycling their own amino acids to build new proteins. So, the lower limit of protein needed to maintain health is largely still unknown, but it might be far lower than 0.61 gram per kilogram per day.

Protein intake is best calculated using grams per kilogram of lean body mass because fat tissue requires little to no protein for maintenance. Online body fat calculators can provide a reasonable estimate of your lean body mass using gender, weight, and waist circumference.6 For example, if someone weighs 200 pounds and has 25 percent body fat, that would imply 75 percent lean mass. Total lean mass is then simply calculated like so:

200 pounds x 0.75 = 150 pounds (68 kilograms) of lean mass

If that person ate 68 grams of protein per day, he would consume 1.0 gram per kilogram of lean mass.

These recommendations differ due to individual differences and the type of protein consumed. Animal protein is a more digestible and complete source of protein, so we likely require less. We likely require more plant proteins (such as from soy or legumes) because of its lower absorption (bioavailability).

So, should you worry about protein deficiency? Not really. In the United States, the average person eats approximately twice the RDA, which itself is designed to be higher than a healthy person needs. If we start seeing a North American outbreak of kwashiorkor, we’ll start worrying. So, this brings us to the opposite question.

How Much Protein Is Too Much?

Excess protein, beyond what you need to maintain structural tissues such as muscle, is metabolized for energy or stored as glycogen or fat. Like excess carbohydrate or sugar, excess protein might lead to metabolic problems like obesity and type 2 diabetes. A low-carbohydrate diet might resolve many of these problems, such as insulin resistance and obesity, by allowing fat to be used preferentially as an energy source; low-protein diets might be beneficial in the same way.7

The answer is highly dependent on the situation. If you are trying to build muscle, as in body building, you need to eat more protein to sustain muscle growth. Pregnancy, breastfeeding, and typical growth in children are situations in which growth is normal, and more protein is required.

On the other hand, if you are trying to lose weight, then you should eat less protein than the 0.61 gram per kilogram per day estimate. Overweight and obese people not only have more body fat but also an estimated 20 to 50 percent more protein than a lean person. Different types of protein loss need to happen along with fat loss—skin, connective tissue, capillaries, blood vessels, and so on. All this protein needs to be catabolized (burned up and not replaced). You often hear about how surgeons must remove 20 to 30 pounds of excess skin and tissue after significant weight loss. Yes, that’s all protein that should have been catabolized.

Some people argue that protein builds muscle. Hmm. Eating protein without exercise builds muscle? Right. Dream on. If that were true, we would not have an obesity epidemic; we’d have a muscle epidemic. Americans eat more protein than most of the rest of the world, and the cover of Time magazine has never posed the question, “Is America too muscular?” Although adequate protein is necessary for good health, more is not always better. Some of the antiaging benefits of calorie restriction are due to less protein but likely also less refined carbohydrates. However, too little protein may lead to sarcopenia and frailty. Longevity requires a happy medium.

Dietary protein, through mTOR, stops autophagy, which declines with age; the result is the accumulation of damaged molecules.8 The amino acid leucine, which is in virtually all proteins, is a key regulator of autophagy; when leucine levels in the bloodstream rise, autophagy quickly drops, and vice versa. Conversely, intermittent fasting promotes autophagy.

The role of leucine means that you don’t need to lower your protein intake much, if at all, to get the benefits of increased autophagy (although you might need to lower overall protein to get the benefits of reduced IGF-1). Decreased meal frequency, such as eating only once a day or eating only during a restricted feeding “window,” such as an eight-hour period daily, may activate autophagy without reducing calories or protein overall.

Longer periods of fasting, coupled with lower protein intake, have a pronounced antiaging effect through the renewal of immune system cells.9 Other diets that mimic fasting might have some benefit, too.10

Lower protein intake over a period of hours to days can have many benefits. Resuming normal protein intake then stimulates muscle to renew itself. This system of protein cycling could promote life extension while preventing muscle loss.

Based on these physiologic principles, a low-carbohydrate, adequate-protein diet would produce many of the benefits of calorie restriction. Carbohydrates, particularly refined carbs, stimulate both insulin and mTOR, which turns off autophagy. A diet low in carbohydrates and only moderate in protein would involve eating lots of natural fats, which are not to be feared. Dietary fat does not stimulate insulin, mTOR, or IGF-1. Indeed, early research confirmed that a high-fat, adequate protein, low-carb diet dramatically improved biomarkers of aging, such as improvements in body weight, leptin, fasting glucose, insulin, and triglycerides.11 As a side benefit, subjects lost an average of 8 kilograms (17.6 pounds) in body weight. Specific restriction of the dietary amino acid methionine decreased mitochondrial damage. The subjects were counseled to limit their protein intake to 1.0 gram per kilogram of lean body mass; those subjects who exercised were told to increase the quantity to 1.25 grams. Lose weight and increase longevity? Sounds like a plan.

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Jordan Peterson, a professor at the University of Toronto and bestselling author, and his daughter, Mikhaila, have both followed in recent years a carnivorous diet, consisting of meat, salt, and little else. Mikhaila had been diagnosed with juvenile rheumatoid arthritis, depression, and idiopathic hypersomnia. All that disappeared when she switched to eating meat only. They eat 100 percent animal foods. Vegans, on the other hand, eat no animal products, so they eat 100 percent plant foods. Major food chains have added vegan choices including meatless burgers. Guinness, the famous Irish beer, stopped using fish bladders in its brewing process after more than 200 years. According to the newspaper the Guardian, we are witnessing the “unstoppable rise of veganism: how a fringe movement went mainstream.”1 Members of each group feel terrific on either all plant or all animal foods. Who is correct? Which proteins are optimal for health—animal or plant? What does the science tell us?

We often associate the word protein with animal foods. However, vegetables also contain protein in varying amounts. Tofu, chickpeas, lentils, beans, wheat (gluten is a protein), nuts, and seeds are sources of plant proteins. We rarely see serious protein deficiency in North America, except perhaps in alcoholics. So, a largely vegetarian diet is not necessarily deficient in protein. Instead, the main culprit that could lead to inadequate protein intake is the consumption of highly processed foodlike substances such as soda, candy, chips, and pretzels. These drinks and foods contain mostly carbohydrates and refined fats such as vegetable oils, and they’re generally very low in protein.


All plants contain protein because they need it for proper structure and function. Animals ultimately get their protein (essential amino acids, to be precise) from plants, either by eating them directly or by eating other animals that eat plants. Still, plant protein differs from animal protein in many ways that have significant health implications, particularly for aging and life span.

The Difference Between Plant and Animal Protein

The simple word protein gives little away of its complexity. Carbohydrates are chains of sugar molecules, sometimes long and sometimes short. Fats (triglycerides) consist of three chains of fatty acids linked to a glycerol molecule. Proteins, however, can be of virtually any size and composition and contain different amounts and types of amino acids. They range from two amino acids linked together to chains that stretch hundreds of amino acids long.

Plants must synthesize all of their necessary amino acids, whereas animals eat plants to obtain the essential amino acids they cannot produce themselves. Except in very limited amounts, humans do not store protein or amino acids. Small amounts of amino acids exist in our bloodstreams at all times due to normal turnover of protein. Old tissues can be broken down into component amino acids, which can be recycled into newly built proteins. Cells are continually being degraded and rebuilt to rejuvenate tissues. Red blood cells, for example, survive for only about three months before being replaced. Nerve cells (neurons) often live for decades, which is why nerve injuries heal so slowly. Skin cells are replaced every few days.

Protein, either from diet or breakdown of tissue, is used for two main purposes:

• To build (or rebuild) tissues

• To be burned or stored as fuel (glycogen or body fat)

Because of the many different proteins in our bodies, we require specific types of amino acids in the right quantities. Because the body can’t store amino acids, except in very limited amounts, we must eat the right amount and proportion of amino acids when we need them. This system seems precarious because nature does not email us a handy daily list of which proteins to eat. Anyway, most of the foods we want to eat (either animal or plant) might not be available at our convenience. During the turnover of proteins, most of the amino acid components can be recycled and used to build new proteins, so we don’t have to obtain all of them through diet alone.

Some proteins are easier for us to use than others. This concept is known as the biological value of proteins, and it’s expressed as a number from 0 to 100. A protein with a biological value of 100 contains all the amino acids in the right proportions for humans to use. Egg protein has a value of 100; gluten, the protein found in wheat, has a value of 64.

If you eat eggs, you can use 100 percent of its protein. If you eat wheat, you can use only 64 percent of its protein. Plant proteins generally have lower biological values than a