With The Longevity Seekers, science writer Ted Anton takes readers inside this tale that began with worms and branched out to snare innovative minds from California to Crete, investments from big biotech, and endorsements from TV personalities like Oprah and Dr. Oz. Some of the research was remarkable, such as the discovery of an enzyme in humans that stops cells from aging. And some, like an oft-cited study touting the compound resveratrol, found in red wine—proved highly controversial, igniting a science war over truth, credit, and potential profit. As the pace of discovery accelerated, so too did powerful personal rivalries and public fascination, driven by the hope that a longer, healthier life was right around the corner. Anton has spent years interviewing and working with the scientists at the frontier of longevity science, and this book offers a behind-the-scenes look at the state-of-the-art research and the impact it might have on global public health, society, and even our friends and family.
With spectacular science and an unforgettable cast of characters, The Longevity Seekers has all the elements of a great story and sheds light on discoveriesthat could fundamentally reshape human life.
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THE LONGEVITY SEEKERS
Science, Business, and the Fountain of Youth
By TED ANTON
THE UNIVERSITY OF CHICAGO PRESSCopyright © 2013 Ted Anton
All rights reserved.
"Greater Than the Double Helix Itself": 1980–1990
In all our exploration of longevity, going to the beginning of language and latest of human follies, lies a bargain. To overcome aging and death, most of us would give almost anything. That slinking wish lies at the foundation of much of our storytelling and many of our founding mythologies. The fear of death is so unbearable we traveled the world seeking a fountain of youth.
Partly for that reason, scientists have insisted that the processes of aging were random and uncontrollable. In 1825, the British actuary Benjamin Gompertz went so far as to quantify the depressing inevitability of our decline. He calculated that after puberty, the human death rate doubles every eight years. The older you get, the more likely you are to die. Some theory. There was no fountain of youth nor the possibility of a fountain of youth.
In the early years of the twentieth century, however, scientists applied the power of Darwin's theory of natural selection to the question of aging. They saw that the influence of natural selection fades over a lifetime, affecting only the hormones and behaviors that contribute best to an organism's chance to survive long enough to reproduce. Youth hormones like estrogen in women and testosterone in men are favored, because they grant reproductive fitness even though they may harm us later in life. By the middle of the twentieth century, this trade-off idea between youth and age had a name: "antagonistic pleiotropy." Pleiotropy means that one gene has many effects. Antagonistic pleiotropy means that virility or fertility genes that trigger youth hormones to keep us vigorous and attractive can later cause us to age more rapidly.
The discovery of such hormones led to a wave of early charlatans who transplanted goat and monkey testicles into their patients, preying on the eternal insecurities of potency in all of us. In the 1920s, the Viennese-born doctor Eugene Steinach promised that vasectomies would increase male longevity. Austria's leading scientist, Sigmund Freud, and America's biggest cynic, H. L. Mencken, both got themselves "Steinached." The Kansas-born John Brinkley, who twice ran for state governor, made a fortune by implanting goat testicles right beside the natural ones of his patients. Brinkley was so successful with his dangerous surgeries that he single-handedly gave life to the fledgling American Medical Association as it tried to stop him. When they did so, he took his radio personality to Mexico and founded the first of the great border-blasting broadcasters that gave the world rock and roll.
But what exactly causes aging? Several twentieth-century ideas sprang up to explain it. The genetic mutation accumulation theory suggested that it was unrepaired damage to DNA. Another idea, the error catastrophe theory, offered that cellular mistakes build until they reach a tipping point of disaster. Yet another theory, called hormesis, offered that a little stress improves longevity. The free radical theory of aging, which claimed that the reactive waste molecules of oxidation cause the body to break down when they bind to other compounds in the cell, became a widely accepted idea. But the main scientific point, driven home by serious research in order to counteract all the quackery, was that aging processes are always chaotic, disconnected, and uncontrollable.
Most researchers were influenced by evolutionary biologist George Williams, who in 1957 said that the processes of aging had to be random, "never due largely to the changes in a single system." His idea made the scientific quest for longevity unsavory. "This conclusion banishes the 'fountain of youth' to the limbo," Williams concluded, "of scientific impossibilities."
The discovery in 1965 by biologist Leonard Hayflick at Philadelphia's Wistar Institute that normal human cells in a cell culture divide only fifty-two times, never more, confirmed the inevitable limit to human life span. The discovery was even called the Hayflick limit. Scientists like Williams and Hayflick pounded out a jeremiad against the pop science of longevity. Their thought generated overwhelming doubt, which made studying the biology of aging an uphill battle for serious researchers.
There was one discovery, however, that tantalized the later generation of aging researchers. In the Depression, a Cornell University veterinary professor concerned about diet observed that when he trimmed back the feed of his animals, they actually lived longer than normal. In the era of soup lines and hunger, Clive McCay found that rats and mice lived 40 percent longer if you cut their feed by 30 percent. McCay published his longevity findings in 1934 in a respected journal and went on a long publicity tour. But he was not in the mainstream of aging research at the time. Some of the mice were sterile and many of rats showed reduced litters, so it was thought they had sacrificed reproduction for lengthened life. The assumption, quite reasonably, was that the long-lived, half-starved animals had a lower metabolism or a loss of fat.
A charismatic character who described himself as a "bit of a Bolshevik," McCay was a biochemist and professor of animal husbandry who planned the meal rations for America's World War II soldiers. He got himself a lot of publicity, but his caloric restriction idea languished. Few serious scientists wanted to pursue it.
By the 1960s, a contrary, ascetic mathematician and immunologist named Roy Walford latched onto caloric restriction in a best-selling book called Maximum Life Span. At UCLA, Walford became a low- calorie diet champion and practitioner who influenced millions, attracting followers like Timothy Leary and inspiring significant new researchers to enter the field. His work led to a cascade of scientific papers on caloric restriction in mice, rats, monkeys, and even humans, sparking the founding of the Calorie Restriction Society International in, appropriately, Las Vegas in 1994. But his best-selling books were often reviled by experts in gerontology. Walford passed away at the age of seventy-four, a gaunt figure permanently damaged by poor atmospheric conditions in his biosphere experiment in the Arizona desert. Still, he found that the biospherans' restricted diet had lowered their cholesterol, blood pressure, and blood glucose levels. He and his followers promoted the healthful effects of caloric restriction with science studies and popular books, and a following across the world came to include some important new biologists of aging.
Policy makers were thinking about aging, though, because they had to. By the end of the twentieth century, the percentage of Americans over the age of sixty-five was projected to grow from 20 percent to 41 percent of the total population. In 1974, Congress created the National Institute on Aging (NIA) as a new division of the National Institutes of Health in a nation suddenly aware that it was graying fast. How would the members of a developed country fare in a world that half a century earlier would have considered them lucky to make it to fifty-five? The American NIA pushed academic science to take on the big but unsavory biomedical quest to improve the quality of aging. The main concerns were the rising rates of cancer, heart disease, and dementia. The incidence of Alzheimer's disease, which got its name just ten years before, was expected to increase fourfold, up to sixteen million sufferers, by 2030.
In the late 1970s, a few academic conferences on the genetics of aging had sprung up. "If we found one thing, a trick say, that led to the mechanism by which longevity is achieved in mammalian species," said National Center for Toxicological Research biologist Ron Hart in the first wave of genetic idealism, "it would probably have a greater effect than the discovery of the double helix itself."
On a February night in 1977, a biologist named Tom Kirkwood was thinking about some of these issues, especially the trade-off theory of aging called antagonistic pleiotropy, while sitting in the bath in his northern England apartment. Kirkwood wondered how cells had made the same proteins unbelievably accurately for hundreds of millions of years. Cells in principle can be as accurate as they want, he reasoned, but at a cost of expending great chemical energy. Kirkwood loved thinking about big questions. In his bath, he asked himself a big question: How do we age?
As he sat in the steaming water, Kirkwood realized that the replication of seed cells like sperm and egg requires tremendous accuracy, but not so much the soma, or body cells. Sooner or later the body decays, so it does not need to be perfect. The most efficient way of assuring survival, then, was to devote super care to the seed cells and maintain the soma until the animal reproduces. The body was disposable. Eureka! He leaped out of the tub with the "disposable soma" theory of aging, soma being the Greek word for "body."
What Kirkwood hinted at was the difference between aging, commonly understood as the random breakdown of body tissues and organs over time, and life span or longevity, which could have some degree of genetic influence. Of longevity, even the noted scholar Leonard Hayflick admitted a few years later, "Evidence for the proposition that longevity is somehow determined by genetic events is overwhelming."
Such was the idealism of the first wave of researchers, utopian and generous but lacking much science, or money, to back it up. The problem was how to test any of these theories in an actual living being. Our many breakdowns, graying hair, weakening bones, and fading memory seemed too confusing to study scientifically, like the shifting eddies of a mountain stream. Were such breakdowns causes or effects? How would you ever separate the two? For that reason, the magnificent theories of aging or longevity amounted to little more than educated guesses more or less before 1980. To study them meaningfully required a short-lived, free-living, clear, beautiful, near-ubiquitous, voracious tiny animal. Enter the worm.
The "Gang of Cryptographers"
It all began with a tiny worm. The nematode lives virtually everywhere on earth, from mountaintops to deserts. In backyard mulch heaps and in the crevices of Antarctic mountains, in the stomachs of many large animals, nematodes are overwhelmingly the most numerous animals we know. They parasitize almost everything we eat, from sheep and steers to the cores of carrots and coffee beans. Four-fifths of all the visible life forms on earth are members of the nematode family, which counts among its branches an elegant, free-living curlicue named Caenorhabditis elegans, so elegant scientists made it part of its Latin name. Transparent, fluted, and graceful, it has a head and digestive and nervous systems, and yet is the size of the period at the end of this sentence. If you stare at one long enough through a microscope, you will see one of its 959 cells divide, which is, as one postdoctoral fellow once observed to me, "like seeing God." When the Columbia shuttle incinerated and crashed to earth, the only thing to survive were the C. elegans in silver-clad lab containers; they were found in a Texas field. To nab one with a pick under a microscope and move it from one plate to another, as I have done a few times, is a thrill of science.
In the 1970s at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, England, a group led by Nobel Prize winner Sydney Brenner picked C. elegans as the model for a quest to study the way the nervous system affects behavior. Brenner, a short, fast-talking, thick-browed South African, had helped to discover messenger RNA and the code for the body's twenty amino acids. His dream of understanding the nervous system never panned out, but his choice of the worm as a lab model helped give birth to a new field in developmental biology. He inspired young researchers, recalled John White, professor of anatomy and molecular biology at the University of Wisconsin, "by talking nonstop about how he was going to transform science. Sydney never stopped smoking. My head was reeling." The molecular biologist Joshua Lederberg called them "the gang of cryptographers."
By the end of the 1970s, the group completed a remarkable timeline of every cell division in a worm's development from embryo to adult, work that brought the Nobel to Brenner and his colleagues Robert Horvitz, who went on to MIT, and John Sulston, who went to direct England's Human Genome Project. Horvitz discovered the genes involved in programmed cell death, or apoptosis (from the Greek for "falling away"), which offered a hint that genes timed the processes of life and death. Their timeline helped create a revolution in biological focus from "fixed entities" like genes, University of Illinois researcher Carl Woese wrote, to "fluid processes" like the translation of genes into proteins. Their gene analysis of the worm paved the way for the human genome race.
More than that, they shared an ethos. "We were an evangelical sect," Brenner said, "preaching to the heathen." New ideas and data were shared immediately in a free mimeographed journal called the Worm Breeder's Gazette, modeled on an English gardening magazine. One early cover featured a giant worm staring down through a microscope at a plate of tiny terrified scientists. At night they met at pubs like the Green Man in the town of Grantchester. On weekends they discussed politics at the Cambridge bookstore. They believed in research "as an unending argument between a great multitude of voices," the physicist Freeman Dyson later wrote, "in a continuing exploration of mysteries."
Their main discovery, already heralded by fly researchers, was of a small number of shared developmental genes that built similar body components in vastly different animals. No one expected that life followed such a unified, timed blueprint. The finding laid the groundwork for a new understanding of growth, Brenner aid, as a "flow of information through a biological system."
The key to that flow of information is DNA, specifically, the protein switches that can work to unravel its tightly wound threads, process the information they contain, and translate that information into other proteins that do the real work of life. The longevity gene story is really a story of switches that give cells their work assignments. It is a switch that instructs a cell to become part of a nerve, or heart, or intestine. Without such gene switches, a body could not take shape from a two-celled embryo. Controlled by triggers that sense the environment, these gene switches instruct the cell as to which of tens of thousands of proteins to make and when to make them.
The process is hard to visualize and infinitely fascinating: Sticky and clear, easy for school children to extract with a cheek swab, DNA is easiest to visualize as a child's model. Two tubular strands run up the sides of a string of DNA with ladder rungs between them. When one strand separates from the other, a messenger makes a perfect copy of the original and rolls this template out to the ribosome of the cell. The ribosome in turn uses the template to make the proteins. The methods, triggers, and schedules of these tiny molecular switches unwinding DNA strands are the keys to the revolution in the biology of aging. DNA held the blueprint, but the instructors reading the blueprint proved to be the real keys to longevity. To understand that, an outsider needed to step in.
In Marinette, Wisconsin, north of Green Bay, Michael Klass grew up as the son of a telephone lineman. At the age of seventeen, he sat frozen through the famous Cowboy–Packer NFL Ice Bowl championship game. After studying engineering for a while at Michigan Technological University, he transferred to the University of Wisconsin–Madison in 1971, while the campus was in the midst of revolt against the war in Vietnam, where he wandered into the lab of early aging researcher Joan Smith Sonneborn.
One of the first researchers to use a simple lab animal to explore DNA's life-extending capacities, Sonneborn was studying aging in the paramecium. After sex, a one-celled paramecium near death will be reinvigorated into an entire second youth. Her research detonated an early Santa Barbara, California, aging conference, an observer noted, "like a neutron bomb."
Klass was fascinated. "Aging just seemed to me to be an illogical process, like a deleterious form of development," he said to me from his office at Abbott Labs in Chicago. "I wanted to know why life allowed it to happen." He went off for a postdoctoral position at the University of Colorado in Boulder to study longevity in the worm C. elegans. Working with the researcher David Hirsh, he focused on the worm's unique state of suspended animation called dauer, German for durable. At two days old or so, early in their development, juvenile worms face a turning point: when food is plentiful, they mature and have babies. But if food is lacking, signaled by powerful chemicals called pheromones, then growth stops and they enter the dauer state. In this suspended state, the worm can survive for up to two months. It can curl into a tiny ball, stick up its end to try to catch a passing bird, and wait to be transferred to a site with more food.
Hirsh won an early NIA grant as he and Klass discovered that worms live longer when you lowered the temperature. More important, when the animals came out of suspended animation, they lived a normal life span. The dauer state thus made a cosmic time-out from the aging process. The discovery landed them with a paper in Nature. But they did not get much response.
Klass wondered whether genes controlled life span. Gene mutations certainly limited life span. "If there was a mutation in a vital gene it could cause the death of the organism," he recalled, "but could you get mutations that would lengthen life span—and what would those genes look like?"
Excerpted from THE LONGEVITY SEEKERS by TED ANTON. Copyright © 2013 by Ted Anton. Excerpted by permission of THE UNIVERSITY OF CHICAGO PRESS.
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Table of ContentsA Note on Purpose
Part 1. From Obscurity, 1980–2005
1 “Greater Than the Double Helix Itself,” 1980–1990
2 The Grim Reaper, 1991–1993
3 Sorcerer’s Apprentices, 1991–1996
4 Race for a Master Switch, 1989–2000
5 Money to Burn, 2000–2003
6 Longevity Noir, 2003- 2004
7 Betting the Trifecta, 2005–2006
Part 2. Defying Gravity: The Battle to Find a Drug for Extending Health, 2005–2013
8 Sex, Power and the Wild: The Evolution of Aging, 2001–2008
9 The Rush and Crisis, 2008–2010
10 Live Long and Prosper, 2009–2011
11 Centenarians in the Making, 2011–2013
12 Fountains of Youth, 2013–
13 Reimagining Age
Longevity Gene Timeline
List of Longevity Genes
About the Author