Preface to Cracking the Aging Code
by Josh Mitteldorf and Dorion Sagan
Flatiron Press, June 2016
During the twentieth century, medical technology took enormous strides toward the conquest of infectious disease and recovery from trauma. With hygiene and sanitation, then antibiotics in the 1930s and an ever-expanding arsenal of vaccines, many plagues of the past have been banished; tuberculosis, polio, syphilis, whooping cough, diphtheria, and cholera were once feared as a death sentence, and now they are footnotes in the mortality statistics. The diseases that remain are all associated with aging; diabetes, arthritis, and osteoporosis are growing, and the Big Three killers are cardiovascular disease, cancer, and Alzheimer’s. Tens of billions of dollars have been spent on medical research over several de cades trying to conquer these diseases with the same approach that succeeded so well for infectious disease.
That approach has been to work with the body, to stimulate the body’s growth and inborn strength, to buttress its natural defenses. Even the reductionist tradition of Western, allopathic medicine has been influenced by the philosophy of natural medicine, working with the body instead of attempting to overpower it with technology or drugs. But what the doctors do not yet realize is that they are working with a suicidal patient.
You run to the railing and throw him a lifeline. If only you can get the buoy within his reach, you might pull him back to safety . . .
Good toss! The life preserver is right in front of him, but he is not taking it. Is he just too weak? Has he lost the will to live? You call to him. “Go away,” he answers. “Leave me alone!” And now your understanding of his situation is changed.
He didn’t fall off the boat–he flung himself into the sea. To save a man from drowning is one thing; to dissuade him from suicide will require a different approach. In the immediacy of the crisis, you might take advantage of his exhaustion, jump in the water, overpower him, and carry him forcibly to safety. But next week, he might make another attempt. To help this man, you will have to get to know him, learn what is important to him, understand why he wants to kill himself, and convince him to choose life.
Doctors today are trying to help a body that does not want to be helped. Efforts to restore the body’s natural balance won’t work, because as we age, the body’s natural metabolism is bent on self-destruction. Attempts to bolster the body’s natural defenses are doomed to failure because the natural defenses are slowly being shut down with age.
Progress can be made against the Big Three diseases, and aging itself can be abated, but a different approach is required. We must be willing not just to assist the body but to coax, cajole, and even fight with it when appropriate. We must learn more about hormones and the signaling language that regulates metabolism. We must whisper the word “youth” in the body’s own native language of biochemistry, a language as yet still somewhat foreign to us. But this is the language in which the entire life plan is spelled out, from development in the womb to aging and death.
The central idea of this book is that aging is built into our bodies. Aging doesn’t just happen but is regulated and controlled by our genes. Our self-destruction is scheduled as much as is our development in childhood or our sexual development at puberty. Growth, puberty, and aging all unfold on a schedule programmed into the regulatory segments of our DNA.
But to an evolutionist, these things are not the same at all. A strong body helps us to survive and preserve ourselves. Sexual development is necessary for reproduction. These things are good for us, good for the prospects of our genes. They help our genes to be passed along, to prevail, and to spread in succeeding generations. This fits well with the idea of natural se lection, the fundamental premise of Darwinian evolution. It is easy to understand how genes for growth and sexual development evolved. They are “selfish genes,” because they help the body, their vehicle, and so they help themselves.
But aging is about weakening and dying. It cannot be good for the body. Genes may cause aging, but aging cannot promote the prospects of those genes; quite the contrary, aging ends the careers of the very genes that cause it. This does not make sense from the prevailing evolutionary perspective. Why would selfish genes kill their bodies? But in fact multiple lines of evidence suggest that is exactly what they are doing. As we get older, our genes turn against us, killing healthy nerve cells and muscle cells, permitting the thymus gland to wither away, which undermines our immune system. We consider this self-destruction normal, but in fact, it doesn’t apply to all species. There are a few animals and many plants that do not age. And although selfish gene theory cannot explain why our bodies do this, another theory–the Demographic Theory described in Chapter 8–does. The self-destruction we take for granted is in fact under evolutionary control. These evolutionary “suicidal tendencies,” while they do not make us as individuals “live long and prosper,” turn out to have a vital evolutionary function.
These suicide genes are the opposite of selfish genes. In the course of evolution, genes for aging must have fought an uphill battle against natural se lection. How could aging have evolved?
This is a question that has been asked over and over since Darwin first skirted the issue 150 years ago. In fact, there was no mention at all of life span or aging in the first edition of On the Origin of Species (1859). Skeptics confronted him with the great range of life spans in nature. Why have life spans not evolved ever longer? Isn’t that what we should expect from your theory? Darwin’s answer in later editions was uncharacteristically vague and unconvincing. Although many volumes and thousands of articles have been written on the subject ever since, there are really only three kinds of answers.
Three Evolutionary Stories About Aging
Answer number one is that there really is no aging in nature. Animals in the wild do not live long enough to die of old age, because they die of other things first. It’s a highly competitive world out there, “red in tooth and claw.”* Organisms are ever at risk from predators, accidents, and starvation. We are aware of aging when we look at domesticated animals protected from their natural enemies, and of course civilization has afforded humans a safety that is completely uncharacteristic of our evolutionary history. Aging is an artifact of protected environments, and in the natural world where evolution runs its course, aging doesn’t exist-so there is nothing to explain.
Answer number two is that natural se lection encounters trade- offs and makes compromises. The body is doing its best to repair itself and forestall damage, but there are other priorities that keep it from doing a perfect job. In youth, the body allows itself to gradually accumulate damage, even though this eventually will prove fatal, because neglecting the infrastructure frees up resources for survival and reproduction.
Answer number three is that even though aging is bad for the individual, it is important for the community. Aging creates opportunities for the young and thus it promotes population turnover for adaptive change. Another communal benefit of aging is the stabilization of populations. Aging levels the death rate so individuals don’t all die at once, as in famines and epidemics.
Answer number one (aging is an artifact of protected environments) has been thoroughly discredited by population studies of animals in the wild. It has been established that, indeed, animals in nature live long enough for aging to matter. Answer number two (trade- offs and compromises) depends crucially on the assumption that the body can only do a good job of one thing at a time. Although this seems to be true in par tic u lar cases, there is no reason to think that a strengthening in one area must always come at the expense of a weakening in another, and indeed there are abundant counterexamples. There is a lot of genetic and experimental evidence in favor of answer number three (communal benefit), but deeply entrenched evolutionary theory has created a strong prejudice against it.
This prejudice is a deep vein in our culture of individual competition. In economics, it is the myth of free markets. Socially, it is the conceit that status is a reward for talent and hard work. In health, it is the belief that “nature knows best.” And in the academic study of evolution, the prejudice is echoed as an assumption that natural se lection takes place only between individuals, never between teams or groups or communities. As these pages unfold, I hope to show you that these are prejudices, not science, and that the evolutionary prejudice is related historically to discredited economic and social ideas.
Breeding animals is an ancient art. Dogs were domesticated long before recorded history. But in the 1980s, the breeder’s art took a big step closer to being a quantitative science as techniques were developed to analyze small differences in DNA, to see exactly what genes were being bred. Tom Johnson, working at UC- Irvine, was onto the advantages of studying aging in the lab worm Caenorhabditis elegans. These worms are happy growing on a petri dish, they live just a couple of weeks, and their aging is remarkably flexible in response to feeding, temperature, and genes. Johnson grew worms with a defective gene, which he named AGE-1 after he discovered that worms without it lived half again as long as normal worms. No one had ever imagined that a single gene could have such an effect on life span. In fact, the best experts in evolution had theorized that “everything ought to wear out at once,” so that no single gene could have any noticeable effect. Johnson’s discovery was the more remarkable because longer life required nothing new but rather the deletion of an existing gene. This implied that the effect of the AGE-1 gene was to cut the worm’s life short. What was it doing in the genome? How did it get there? And why did natural se lection put up with it?
Johnson had a ready explanation. He believed (and still believes, I believe) in the conventional explanation for evolution of aging, answer number two in the section above (trade- offs and compromises). The worms without AGE-1 laid only a quarter as many eggs as other worms. It was easy to see how they had been losers in Darwin’s struggle. In fact, Johnson’s finding looked like a dramatic confirmation of the theory that aging was a side effect of genes for greater fertility, greater individual fitness. Aging had not evolved directly, selected for its own sake, but as a cost of greater fertility, so the paradox was avoided.
But a few years later, this story unraveled, and what had been confirmation of theory number two became a direct contradiction. Johnson discovered that his mutant worms actually had two genes that were different. In addition to AGE-1, there was another, unrelated gene defect (FER-15) on a separate chromosome. By crossbreeding, he was able to separate the two. Worms with the FER-15 mutation had impaired fertility without extended life spans. Worms with the AGE-1 mutation had extended life spans with unimpaired fertility. This was a full- fledged Darwinian paradox: the AGE-1 gene found in nature was the one that gave the worm a short life span. It was the “defective” gene that caused the worm to live longer. AGE-1 looked not like a selfish gene but an aging gene. It was just the kind of gene that natural selection ought to eliminate handily. How had this gene survived, and what was it doing in the worm genome?
AGE-1 was only the first case of an aging gene in worms. There are now hundreds of genes known that lengthen life span when they are deleted. In other words, these genes, when present, have the effect of shortening life span. Some of them tend to improve fertility; some don’t. Some have other beneficial side effects, but about half the known life-shortening genes offer nothing in return, or at least nothing that has yet been identified. This is direct evidence in favor of answer number three, the answer that defies conventional evolutionary theory.
Aging genes have been discovered in other lab animals as well as worms. The other pop lar species for aging scientists to study have been yeast cells, fruit flies, and mice. These four species come from very different branches of the evolutionary tree. Nonetheless, they share common ancestors, going back hundreds of millions of years ago to the first eukaryotes (complex cells with nuclei and certain other organelles). You and I and the mouse and the worm and the fly and the yeast cell are all eukaryotes, and there are some genes–including deleterious ones–that we share. Why? Why has nature conserved life- shortening, “killer” genes?
The answer must reflect the unity of life. There are certain core functions of the cell that arose in the distant past and have been conserved through aeons of evolution. We all transcribe our genes into proteins using the same gene tic code, we all burn sugar for energy using the Krebs cycle, and we all reproduce sexually using a style of cell combination and division known as meiosis. We all age and die.
It is remarkable that aging is one of these core life functions that almost all eukaryotes share. There are genes that modulate aging in yeast cells that are close cousins of aging genes in worms, in flies, and in mammals, including you and me. Despite the fact that aging is a disaster for the individual, evolution seems to have guarded and preserved the genes for aging as though they were the crown jewels. This is a dead giveaway that aging must have an essential biological function.
There is a natural analogy between population cycles in ecology and the economic cycles of boom and bust that appear in the brand of capitalism embraced by America and the West.
In the wake of the 1929 economic collapse, the Roosevelt administration was able to pass a broad program of government oversight and regulation of business practices. There followed forty years of unprecedented growth and the rise of an American middle class, the first time in history that any economic system had supported a majority of its citizens in comfort and security. But in 1980 began the Reagan backlash, deregulation, and the return of unbridled economic competition. Capitalism became predatory, the middle class began to shrink, business cycles deepened, and a growing rift now separates a wealthy elite from the struggling majority. There have been three major stock market crashes in the thirty years since deregulation, each followed by painful unemployment and economic stagnation.
Without regulation, competition becomes destructive. The idea that stability and a broad prosperity can emerge from pure competition is thoroughly discredited in practice, but it is a useful myth for the 1 percent who profit mightily when there are no rules and no regulators. If they told the truth about their motives, the rapacious corporate giants could never sell deregulation to an enlightened democracy. So they promote the dogma of a ” free market,” not because they believe in this or any ideology but because it supports the freedom of the largest and the strongest to pillage everyone else.
Historically, an important part of the argument for the benignity of free markets comes from the analogy with evolution. (Just look at the marvels nature hath wrought using only the chisel of bare- knuckled competition!) This is social Darwinism, the doctrine that the rich and successful not only contribute more to society than you and I but that they have better genes to boot. It is a perversion of Darwin’s ideas, but from the very beginning, his sound biological theory has been linked to an elitist social ideology. During the early years of the twentieth century, social Darwinism played a crucial role in shaping the version of evolutionary theory that emerged and predominates to this day.
People are rich and powerful because their parents were rich and powerful — nothing remotely fair or just about it. But social Darwinism promotes the fiction that there is a natural order in the predominance of an elite hereditary class. Like the “invisible hand” of Adam Smith a century earlier, Darwin’s “struggle for existence” has been caricatured to support the myth that pure, unrestrained competition can be magically transmuted into a harmonious society. The truth is that “tooth and claw” competition doesn’t work in economics, and it doesn’t work in ecology. Competition is vital, but it must be regulated, or it poses a fatal risk of instability for the whole system.
Darwin himself was of the British aristocracy, and he had some trouble acknowledging the huge evolutionary significance of cooperation. Yet in his later work The Descent of Man, Darwin spoke explicitly of a group that could have an evolutionary advantage distinct from the sum of its individuals.
By the mid-twentieth century, the existence of cooperation was denied utterly by the mainstream of evolutionary theory. We live now in an age of hyperindividualism, and it is no accident that, in our culture, the dominant version of Darwin’s theory is based on pure selfishness.
Where This Book Is Headed
Aging is the very antithesis of what Darwin called “fitness”- the competitive vigor and reproductive potential of organisms. If aging is governed by genes that cause us to become frail, to lose our fertility, and to die, then how did those genes prevail in evolutionary competition? How could aging have evolved?
That is a central question in this book. The answer is that natural selection is not just the life and death of individuals but also the rise and collapse of local populations and of entire ecosystems. Evolution is about cooperation as well as selfishness, and aging has evolved as part of the dues owed by an individual for participating in a stable ecosystem. Evolution and ecology have inscribed a death sentence in our genes. We literally pay with our lives to protect ecosystems, as increased death rate via aging prevents the sort of wild overgrowth that presages wholesale population collapse.
Aging appears to be caused by an explicit genetic program. One consequence of this is that medical science will have to approach the diseases of old age with a different attitude. We can’t use “natural medicine.” We can’t help the body to heal, because the body isn’t trying to heal-it’s trying to destroy itself. Instead, we must decode the signals that trigger self-destruction and replace them artificially with the signals of youthful vitality.
Another consequence is that the selfish gene version of evolutionary theory is not the whole story. Mothers teach their children to take care of themselves. What mother wants her child to be indifferent to the welfare of others? Mother Nature, like all mothers, has counseled her children against excessive selfishness. She wants them to take care of themselves to be sure, but because she wants them to get along in the world, she has tempered selfishness with altruism.
This seems to be an intuitive truth, easy to grasp for anyone who does not have an advanced degree in evolutionary biology (and to their credit, not a few professional evolutionists have figured out that the selfish gene version they learned in school was a tortured picture of reality).
Ripe for Scientific Revolution
The science of aging is a very active field, expanding in scope, with new labs, new techniques, and an influx of creative young talent. The field is not at all moribund, but it is flailing. At meetings and in journal articles, the puzzling mismatch between experimental results and theoretical expectations is everywhere apparent. Some researchers try to paper it over, and their explanations come out as incoherent or obviously flawed. But most are presenting the data with an honest admission, appending such comments as:
We don’t understand why this happens.
There is some kind of dysregulation here, a failure of the body to do the right thing.
It’s strange that the damage the body suffers seems completely avoidable, and yet . . .
What they are seeing–or refusing to see–is the body destroying itself on a schedule.
Evolutionary theorists have tried to understand aging within the framework of the theory as they learned it. They have done a workman like job of extending and modifying the theory as each new result comes in, carving out exceptions and elaborations on the basic themes. But specialists in the field tend toward myopia, and few have stepped back to look at the big picture, to see the signs that the basic principles of the theory no longer match the basic observations.
The essential problem is that the theory has been built from the bottom up, taking the individual animal and its individual success to be primary. (Darwin did not make this error; it came into the field only later, in the twentieth century.) Neglected are all the ways in which a community functions as a collective, with logic that cannot be understood simply as the sum of individuals. The limited perspective of the selfish gene is very much the standard today. Evolutionary scientists are quite aware that their paradigm is based on individuals to the exclusion of communal adaptation, and they have their reasons for this strong bias in favor of the individual over the group. Such reasons include an overreaction to an earlier excess in the opposite direction, when naturalists spoke too glibly about “the good of the species.” But although the bio-mathematicians’ skepticism of group se lection was understandable, it is clear now that they are wrong. I* am in the minority, but I am not alone in saying this. Many smart people, including Nobel laureates and experts on the edge of the field, have recognized that evolutionary science today is missing something basic. Perhaps you have sensed this already; if not, I think that you will come to see it in the chapters that follow.
Why Should It Matter If Evolutionary Competition Is Individual or Communal?
And What Does All This Have to Do with Aging?
Having a fixed life span–dying on a schedule–is bad for the individual, but it has advantages for the community. To understand what aging is and how it came to be, it is necessary to adopt a communal perspective for evolution. Aging is a paradox if your paradigm is confined to selfish genes, but it is possible to understand aging if you imagine natural se lection in a broader context, with cooperative groups competing in a classical Darwinian struggle. The fashion in evolutionary theory these last fifty years has been to think exclusively in terms of individual competition, to disallow group competition. This has been the root of the scientific community’s failure to understand aging.
I have said all this in scientific forums and on the pages of biology journals, and now I am going over the heads of the experts to appeal to your good sense. For eighteen years, I have been watching the response of the academic community to ideas about communal evolution, including my own ideas. It has been both deeply gratifying and intensely frustrating for me–gratifying because the scientific world is moving in the right direction, frustrating because the movement is so slow. There is still a great deal of unthinking bias against “group se lection.” Lab scientists still report their results in terms of the failed theories.
A few years ago, I was visiting my mother (now ninety-three years old and sharp as a tack) when I complained about the conservatism of the scientific community. I had wanted to initiate a scientific dialogue, and I was frustrated. “Take your case to the people,” she said. “Write a book.” That project proceeded in fits and starts for two years. Then I hit the jackpot and found an ally in Dorion Sagan. He quickly understood my ideas about aging and was able to help me both put them in the context of broader evidence-based evolutionary theory and make them more accessible. This book is our first collaboration.
* From an 1849 poem by Alfred, Lord Tennyson, poet laureate of Great Britain and Ireland, in memory of his friend Arthur Henry Hallam.