THE LONGEVITY SEEKERS

Science, Business, and the Fountain of Youth

By TED ANTON

THE UNIVERSITY OF CHICAGO PRESS

Copyright © 2013 Ted Anton
All rights reserved.
ISBN: 978-0-226-02093-8

Contents

A Note on Purpose………………………………………………….ixPreface…………………………………………………………..xiPART 1. FROM OBSCURITY, 1980–2005……………………………………11 “Greater Than the Double Helix Itself,” 1980–1990……………………32 The Grim Reaper, 1991–1993………………………………………..143 Sorcerer’s Apprentices, 1991–1996………………………………….234 Race for a Master Switch, 1989–2000………………………………..335 Money to Burn, 2000–2003………………………………………….446 Longevity Noir, 2003–2004…………………………………………577 Betting the Trifecta, 2005–2006……………………………………73PART 2. DEFYING GRAVITY: THE BATTLE TO FIND A DRUG FOR EXTENDING HEALTH,
2005–2013…………………………………………………………858 Sex, Power and the Wild: The Evolution of Aging, 2001–2008……………879 The Rush and Crisis, 2008–2010…………………………………….10010 Live Long and Prosper, 2009–2011………………………………….11311 Centenarians in the Making, 2011–2013……………………………..12812 Fountains of Youth, 2013–………………………………………..14113 Reimagining Age…………………………………………………156Epilogue………………………………………………………….171Acknowledgments……………………………………………………177Longevity Gene Timeline…………………………………………….179List of Longevity Genes…………………………………………….181Notes…………………………………………………………….183About the Author…………………………………………………..213Index…………………………………………………………….215

CHAPTER 1

“Greater Than the Double HelixItself”: 1980–1990

In all our exploration of longevity, going to the beginning of languageand latest of human follies, lies a bargain. To overcome aging anddeath, most of us would give almost anything. That slinking wish liesat the foundation of much of our storytelling and many of our foundingmythologies. The fear of death is so unbearable we traveled theworld seeking a fountain of youth.

Partly for that reason, scientists have insisted that the processesof aging were random and uncontrollable. In 1825, the British actuaryBenjamin Gompertz went so far as to quantify the depressing inevitabilityof our decline. He calculated that after puberty, the human deathrate doubles every eight years. The older you get, the more likely youare to die. Some theory. There was no fountain of youth nor the possibilityof a fountain of youth.

In the early years of the twentieth century, however, scientists appliedthe power of Darwin’s theory of natural selection to the questionof aging. They saw that the influence of natural selection fades overa lifetime, affecting only the hormones and behaviors that contributebest to an organism’s chance to survive long enough to reproduce.Youth hormones like estrogen in women and testosterone in men arefavored, because they grant reproductive fitness even though theymay harm us later in life. By the middle of the twentieth century, thistrade-off idea between youth and age had a name: “antagonistic pleiotropy.”Pleiotropy means that one gene has many effects. Antagonisticpleiotropy means that virility or fertility genes that trigger youth hormonesto keep us vigorous and attractive can later cause us to age morerapidly.

The discovery of such hormones led to a wave of early charlatanswho transplanted goat and monkey testicles into their patients, preyingon the eternal insecurities of potency in all of us. In the 1920s,the Viennese-born doctor Eugene Steinach promised that vasectomieswould increase male longevity. Austria’s leading scientist, SigmundFreud, and America’s biggest cynic, H. L. Mencken, both got themselves”Steinached.” The Kansas-born John Brinkley, who twice ran for stategovernor, made a fortune by implanting goat testicles right besidethe natural ones of his patients. Brinkley was so successful with hisdangerous surgeries that he single-handedly gave life to the fledglingAmerican Medical Association as it tried to stop him. When they didso, he took his radio personality to Mexico and founded the first of thegreat border-blasting broadcasters that gave the world rock and roll.

But what exactly causes aging? Several twentieth-century ideassprang up to explain it. The genetic mutation accumulation theorysuggested that it was unrepaired damage to DNA. Another idea, theerror catastrophe theory, offered that cellular mistakes build until theyreach a tipping point of disaster. Yet another theory, called hormesis,offered that a little stress improves longevity. The free radical theoryof aging, which claimed that the reactive waste molecules of oxidationcause the body to break down when they bind to other compounds inthe 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, anduncontrollable.

Most researchers were influenced by evolutionary biologist GeorgeWilliams, who in 1957 said that the processes of aging had to be random,”never due largely to the changes in a single system.” His ideamade the scientific quest for longevity unsavory. “This conclusion banishesthe ‘fountain of youth’ to the limbo,” Williams concluded, “of scientificimpossibilities.”

The discovery in 1965 by biologist Leonard Hayflick at Philadelphia’sWistar Institute that normal human cells in a cell culture divide onlyfifty-two times, never more, confirmed the inevitable limit to humanlife span. The discovery was even called the Hayflick limit. Scientistslike Williams and Hayflick pounded out a jeremiad against the popscience of longevity. Their thought generated overwhelming doubt,which made studying the biology of aging an uphill battle for seriousresearchers.

There was one discovery, however, that tantalized the later generationof aging researchers. In the Depression, a Cornell University veterinaryprofessor concerned about diet observed that when he trimmedback the feed of his animals, they actually lived longer than normal.In the era of soup lines and hunger, Clive McCay found that rats andmice lived 40 percent longer if you cut their feed by 30 percent. McCaypublished his longevity findings in 1934 in a respected journal andwent on a long publicity tour. But he was not in the mainstream ofaging research at the time. Some of the mice were sterile and many ofrats showed reduced litters, so it was thought they had sacrificed reproductionfor lengthened life. The assumption, quite reasonably, wasthat the long-lived, half-starved animals had a lower metabolism or aloss of fat.

A charismatic character who described himself as a “bit of a Bolshevik,”McCay was a biochemist and professor of animal husbandry whoplanned the meal rations for America’s World War II soldiers. He gothimself 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 immunologistnamed Roy Walford latched onto caloric restriction in a best-sellingbook called Maximum Life Span. At UCLA, Walford became a low- caloriediet champion and practitioner who influenced millions, attractingfollowers like Timothy Leary and inspiring significant new researchersto enter the field. His work led to a cascade of scientific papers on caloricrestriction in mice, rats, monkeys, and even humans, sparking thefounding of the Calorie Restriction Society International in, appropriately,Las Vegas in 1994. But his best-selling books were often reviled byexperts in gerontology. Walford passed away at the age of seventy-four,a gaunt figure permanently damaged by poor atmospheric conditionsin his biosphere experiment in the Arizona desert. Still, he found thatthe biospherans’ restricted diet had lowered their cholesterol, bloodpressure, and blood glucose levels. He and his followers promoted thehealthful effects of caloric restriction with science studies and popularbooks, and a following across the world came to include some importantnew biologists of aging.

Policy makers were thinking about aging, though, because they hadto. By the end of the twentieth century, the percentage of Americansover the age of sixty-five was projected to grow from 20 percent to41 percent of the total population. In 1974, Congress created the NationalInstitute on Aging (NIA) as a new division of the National Institutesof Health in a nation suddenly aware that it was graying fast.How would the members of a developed country fare in a world thathalf a century earlier would have considered them lucky to make it tofifty-five? The American NIA pushed academic science to take on thebig but unsavory biomedical quest to improve the quality of aging. Themain concerns were the rising rates of cancer, heart disease, and dementia.The incidence of Alzheimer’s disease, which got its name justten years before, was expected to increase fourfold, up to sixteen millionsufferers, by 2030.

In the late 1970s, a few academic conferences on the genetics of aginghad sprung up. “If we found one thing, a trick say, that led to themechanism by which longevity is achieved in mammalian species,”said National Center for Toxicological Research biologist Ron Hart inthe first wave of genetic idealism, “it would probably have a greater effectthan the discovery of the double helix itself.”

On a February night in 1977, a biologist named Tom Kirkwood wasthinking about some of these issues, especially the trade-off theory ofaging called antagonistic pleiotropy, while sitting in the bath in hisnorthern England apartment. Kirkwood wondered how cells had madethe same proteins unbelievably accurately for hundreds of millions ofyears. Cells in principle can be as accurate as they want, he reasoned,but at a cost of expending great chemical energy. Kirkwood lovedthinking 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 replicationof seed cells like sperm and egg requires tremendous accuracy, butnot so much the soma, or body cells. Sooner or later the body decays, soit 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 thesoma 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, commonlyunderstood as the random breakdown of body tissues and organsover time, and life span or longevity, which could have some degreeof genetic influence. Of longevity, even the noted scholar LeonardHayflick admitted a few years later, “Evidence for the proposition thatlongevity is somehow determined by genetic events is overwhelming.”

Such was the idealism of the first wave of researchers, utopian andgenerous but lacking much science, or money, to back it up. The problemwas how to test any of these theories in an actual living being. Ourmany breakdowns, graying hair, weakening bones, and fading memoryseemed too confusing to study scientifically, like the shifting eddiesof a mountain stream. Were such breakdowns causes or effects? Howwould you ever separate the two? For that reason, the magnificenttheories of aging or longevity amounted to little more than educatedguesses more or less before 1980. To study them meaningfully requireda short-lived, free-living, clear, beautiful, near-ubiquitous, voracioustiny animal. Enter the worm.

The “Gang of Cryptographers”

It all began with a tiny worm. The nematode lives virtually everywhereon earth, from mountaintops to deserts. In backyard mulch heaps andin the crevices of Antarctic mountains, in the stomachs of many largeanimals, nematodes are overwhelmingly the most numerous animalswe know. They parasitize almost everything we eat, from sheep andsteers to the cores of carrots and coffee beans. Four-fifths of all thevisible life forms on earth are members of the nematode family, whichcounts among its branches an elegant, free-living curlicue namedCaenorhabditis elegans, so elegant scientists made it part of its Latinname. Transparent, fluted, and graceful, it has a head and digestiveand nervous systems, and yet is the size of the period at the end of thissentence. If you stare at one long enough through a microscope, youwill see one of its 959 cells divide, which is, as one postdoctoral fellowonce observed to me, “like seeing God.” When the Columbia shuttleincinerated and crashed to earth, the only thing to survive were theC. 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 plateto another, as I have done a few times, is a thrill of science.

In the 1970s at the Medical Research Council’s Laboratory of MolecularBiology in Cambridge, England, a group led by Nobel Prize winnerSydney Brenner picked C. elegans as the model for a quest to study theway the nervous system affects behavior. Brenner, a short, fast-talking,thick-browed South African, had helped to discover messenger RNAand the code for the body’s twenty amino acids. His dream of understandingthe nervous system never panned out, but his choice of theworm as a lab model helped give birth to a new field in developmentalbiology. He inspired young researchers, recalled John White, professorof anatomy and molecular biology at the University of Wisconsin, “bytalking nonstop about how he was going to transform science. Sydneynever stopped smoking. My head was reeling.” The molecular biologistJoshua Lederberg called them “the gang of cryptographers.”

By the end of the 1970s, the group completed a remarkable timelineof every cell division in a worm’s development from embryo toadult, work that brought the Nobel to Brenner and his colleagues RobertHorvitz, who went on to MIT, and John Sulston, who went to directEngland’s Human Genome Project. Horvitz discovered the genesinvolved in programmed cell death, or apoptosis (from the Greek for”falling away”), which offered a hint that genes timed the processes oflife and death. Their timeline helped create a revolution in biologicalfocus from “fixed entities” like genes, University of Illinois researcherCarl Woese wrote, to “fluid processes” like the translation of genes intoproteins. Their gene analysis of the worm paved the way for the humangenome race.

More than that, they shared an ethos. “We were an evangelical sect,”Brenner said, “preaching to the heathen.” New ideas and data wereshared immediately in a free mimeographed journal called the WormBreeder’s Gazette, modeled on an English gardening magazine. One earlycover featured a giant worm staring down through a microscope at aplate of tiny terrified scientists. At night they met at pubs like the GreenMan in the town of Grantchester. On weekends they discussed politicsat the Cambridge bookstore. They believed in research “as an unendingargument between a great multitude of voices,” the physicist FreemanDyson later wrote, “in a continuing exploration of mysteries.”

Their main discovery, already heralded by fly researchers, was of asmall number of shared developmental genes that built similar bodycomponents in vastly different animals. No one expected that life followedsuch a unified, timed blueprint. The finding laid the groundworkfor a new understanding of growth, Brenner said, as a “flow of informationthrough a biological system.”

The key to that flow of information is DNA, specifically, the proteinswitches that can work to unravel its tightly wound threads, processthe information they contain, and translate that information intoother proteins that do the real work of life. The longevity gene story isreally a story of switches that give cells their work assignments. It is aswitch 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 atwo-celled embryo. Controlled by triggers that sense the environment,these gene switches instruct the cell as to which of tens of thousandsof proteins to make and when to make them.

The process is hard to visualize and infinitely fascinating: Stickyand clear, easy for school children to extract with a cheek swab, DNA iseasiest to visualize as a child’s model. Two tubular strands run up thesides of a string of DNA with ladder rungs between them. When onestrand separates from the other, a messenger makes a perfect copy ofthe original and rolls this template out to the ribosome of the cell. Theribosome in turn uses the template to make the proteins. The methods,triggers, and schedules of these tiny molecular switches unwindingDNA strands are the keys to the revolution in the biology of aging.DNA held the blueprint, but the instructors reading the blueprintproved to be the real keys to longevity. To understand that, an outsiderneeded to step in.

Gene Revolt

In Marinette, Wisconsin, north of Green Bay, Michael Klass grew upas the son of a telephone lineman. At the age of seventeen, he sat frozenthrough the famous Cowboy–Packer NFL Ice Bowl championshipgame. After studying engineering for a while at Michigan TechnologicalUniversity, he transferred to the University of Wisconsin–Madisonin 1971, while the campus was in the midst of revolt against the war inVietnam, where he wandered into the lab of early aging researcher JoanSmith Sonneborn.

One of the first researchers to use a simple lab animal to exploreDNA’s life-extending capacities, Sonneborn was studying aging in theparamecium. After sex, a one-celled paramecium near death will bereinvigorated into an entire second youth. Her research detonated anearly Santa Barbara, California, aging conference, an observer noted,”like a neutron bomb.”

Klass was fascinated. “Aging just seemed to me to be an illogicalprocess, like a deleterious form of development,” he said to me from hisoffice at Abbott Labs in Chicago. “I wanted to know why life allowed itto happen.” He went off for a postdoctoral position at the University ofColorado in Boulder to study longevity in the worm C. elegans. Workingwith the researcher David Hirsh, he focused on the worm’s unique stateof suspended animation called dauer, German for durable. At two daysold or so, early in their development, juvenile worms face a turningpoint: when food is plentiful, they mature and have babies. But if foodis lacking, signaled by powerful chemicals called pheromones, thengrowth 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 transferredto a site with more food.

Hirsh won an early NIA grant as he and Klass discovered that wormslive longer when you lowered the temperature. More important, whenthe animals came out of suspended animation, they lived a normal lifespan. The dauer state thus made a cosmic time-out from the aging process.The discovery landed them with a paper in Nature. But they didnot get much response.

Klass wondered whether genes controlled life span. Gene mutationscertainly limited life span. “If there was a mutation in a vital gene itcould cause the death of the organism,” he recalled, “but could youget mutations that would lengthen life span—and what would thosegenes look like?”
(Continues…)Excerpted from THE LONGEVITY SEEKERS by TED ANTON. Copyright © 2013 Ted Anton. Excerpted by permission of THE UNIVERSITY OF CHICAGO PRESS.
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