The Youth Pill

Malfroy and other Eukarion scientists took pains to disabuse reporters of the idea that the biotech planned to develop anti-aging drugs. Their goal had always been to treat diseases of aging, not to try tampering with the aging process.² In an interview with the British newspaper the Guardian, Susan Doctrow, Eukarion’s vice president of research, noted that “we’re not going to test our compounds for their effects on ageing. But if the effect of treating diseases of old age is to extend life, everyone’s going to be happy.”

Of course, only a small fraction of drugs that show promise in lower animals like worms prove safe and effective in people. But worm aging is surprisingly similar to human senescence. As nematodes get old, their muscles weaken, their motor activity declines, they lose their appetites, they take on a rough and lumpy appearance—they even get constipated. Thus, it wasn’t unreasonable to hope that medical science had just taken a giant step toward life-span extension. Even if Eukarion’s drugs failed to pass muster in clinical trials, it arguably would be only a matter of time—and probably not a very long time at that—before even better antioxidants worked anti-aging magic in people.

The free radical theory of aging is more than fifty years old, and the man who thought it up was almost forty when it occurred to him. After adding those numbers together, you wouldn’t expect to walk down a hall at a medical research center today and spot his name on one of the doors. But when I sought him out in mid-2008, I found Denham Harman, at ninety-two, still working at the University of Nebraska Medical Center in Omaha, where he had spent the past half-century. Though somewhat frail and hard of hearing, he was professorial and precise, casually natty in a white shirt, gray slacks, and maroon tie, and continuing to make history—or at least to nail down his place in it; when I dropped in, he was working on a paper about key milestones in the study of free radicals and aging. He insisted that I take the most comfortable chair in his office, and after I reluctantly accepted, it took me a while to stop marveling about the fact that I was interviewing an Authentic Historic Figure—it seemed a little like opening a door into the medical arm of the Twilight Zone and finding Louis Pasteur scribbling away on a germ-theory paper.

A native of San Francisco, Harman came of age during the Depression in a family whose fortunes rose and fell with the stuttering economy. During his high school years, his father, a gentlemanly, London-born accountant who had come to the United States in his early twenties, sometimes had trouble getting work, and for a while it seemed that college would be financially out of reach for Denham. Then a chance meeting at a Berkeley tennis club between his father and a fellow English expatriate, who happened to be the director of Shell Oil’s research arm, helped him land a job as a lab technician at the oil company’s research center in Emeryville, California. It paid sixty-five dollars a month, Harman recalled with characteristic exactitude, and after his years of peddling newspapers on street corners to help make ends meet, “that was a lot of money.” (One of his most vivid early memories was the time he gave in to the rare, guilty pleasure of spending some of his hard-earned newspaper money on a root beer on a sweltering summer day—a vignette right out of Norman Rockwell. He could still taste the cold, sweet, nose-prickling fizz nearly eighty years later.) Urged by his boss at Shell to pursue a career in chemistry, he soon saved up enough to enter the University of California at Berkeley. But he held on to his job at Shell for more than a decade while going to school, learning the ropes as an industrial chemist as he earned his Ph.D.

While America’s top physicists raced to build the atomic bomb during World War II, chemists at major universities like Berkeley found themselves swept up in military research that had the same damn-the-torpedoes urgency as the Manhattan Project. One of Berkeley’s promising young chemists, a classmate of Harman’s, lost his life in this behind-the-scenes war of the chem labs: “He was working with phosgene [a chemical-warfare agent], and one day he broke a flask, got a whiff, and just lay down,” Harman said. “He knew he was going to die, and he did.”

For his part, Harman took part in pioneering research during the 1940s on free radicals, which were increasingly recognized as key intermediaries in chemical reactions—the unstable molecules often flicker into existence as reactions unfold and speed up the chemical changes taking place. At Shell, he and colleagues sought to harness free radicals to help synthesize products such as pesticides and polymers. Harman racked up three dozen patents during his years at the company, mostly based on his free radical research.

By the end of the war, he seemed well on his way to becoming a distinguished industrial chemist. Then one evening in December 1945 his wife handed him a Ladies’ Home Journal article written by prominent New York Times science writer William L. Laurence, the official journalist of the Manhattan Project, titled “Tomorrow You May Be Younger.” The subject was a Russian scientist who claimed to have invented an anti-aging compound. In a memorably ghoulish twist, he reportedly extracted his elixir from the blood of horses injected with tissues from healthy, young humans who had died by accident. It was yet another example of the sensational silliness that drives mainstream gerontologists crazy, but it sparked Harman’s interest in aging and helped convince him, at thirty-three, to change directions and go to medical school.

Five years later, in 1954, Dr. Harman, M.D.-Ph.D., was hired as a research associate at Berkeley’s Donner Laboratory of Biophysics and Medical Physics. Its director, John Lawrence, known as the father of nuclear medicine, was pioneering the use of radioactive isotopes to treat cancer. Harman’s formal duties were light: He was required to spend a few hours each week examining cancer patients, which gave him time to launch a research project of his own devising. Going for broke, he decided to seek the fundamental cause of aging. He figured his unusual background in chemistry and medicine might let him see things that had eluded others.

“Everything dies,” he told me, “so I thought there had to be some common, basic cause. I sat at my desk for four solid months without getting anywhere. It was damn frustrating. Then, when I was just about ready to chuck the whole business, the phrase ‘free radicals’ crossed my mind one morning in November. I thought, ‘My god, have I got the answer?’ ”

I myself can’t hear the term free radical without picturing Abbie Hoffman attempting to levitate the Pentagon with psychic energy, but in chemistry it denotes a molecule with an unpaired electron. (Electrons, the negatively charged particles that buzz around the nuclei of atoms, are usually found in pairs, and things tend to get messy when only one of a pair is present.) To eliminate its electron deficiency, a free radical typically grabs an electron from a nearby molecule. Because electrons form bonds between atoms, the molecular victim of this act of violence can be severely deformed or even broken up by its loss of a key structural component. Worse, lacking one of its electrons, it, or one of its remnants, becomes a free radical that’s likely to steal an electron from another innocent bystander. Within microseconds, a chain reaction can erupt that creates a widening circle of damage to a cell’s proteins, lipid molecules, and DNA.

The most important free radicals in biology consist of oxygen bonded to hydrogen and other elements—scientists often refer to them as reactive oxygen species, or ROS, and to the harmful effect of run-amok mobs of free radicals as oxidative stress. The most dangerous one is the hydroxyl radical, an oxygen-hydrogen combination with a particularly ferocious appetite for electrons. Another key member of the ROS family is hydrogen peroxide, found in antiseptics and bleach. Although technically not a free radical, hydrogen peroxide is continually formed in cells from a free radical, called superoxide (a radicalized oxygen molecule), that’s released by the energy-producing oxidation of sugar. In fact, every breath we take engenders tiny puffs of the stuff of bottle blondes in our cells. That’s not usually a problem—peroxide by itself isn’t very reactive—but in the presence of metals like iron it breaks down to form the highly reactive hydroxyl radical. Not surprisingly, our cells handle iron atoms very gingerly, normally keeping them under wraps inside large protein “complexes,” such as one at the center of hemoglobin, the protein that carries oxygen in red blood cells.

Antioxidants are chemicals that can yield up electrons to free radicals without becoming greedy electron thieves themselves. Chemists call them chain-breakers, because their electron donations halt free radical chain reactions. Curiously, vitamin C actually turns into a free radical when it plays chain-breaker. But the arrangement of electrons in radicalized vitamin C molecules keeps them relatively stable, making them much less reactive than most free radicals. Vitamin E molecules act the same way. But they often don’t stay in free radical state long because vitamin C steps up to restore their lost electrons. This teamwork literally covers the waterfront inside our bodies. Because it’s fat-soluble, E plays chain-breaker in lipid-rich places, such as cell membranes and cholesterol molecules, while water-soluble C halts chain reactions in the surrounding watery realms.

Many of these free radical basics were known, or at least suspected, when Harman sat down to solve the mystery of aging. Six months before his aha moment, a team led by Rebeca Gerschman, a University of Rochester researcher investigating radiation injury under the auspices of the federal Atomic Energy Commission, had proposed that tissue damage from exposure to X-rays, or breathing pure oxygen (it’s much deadlier than tobacco smoke), stems from the release of free radicals in cells. A second prominent 1954 report on free radicals caught Harman’s attention: Researchers led by cell biologist Barry Commoner, who later won fame as an environmentalist, demonstrated that free radicals could be detected in cells using a technology akin to that in today’s MRI scanners. Before Commoner’s finding, the molecules’ fleeting existence had thwarted attempts to prove that they really do exist in living tissues.

But during the 1950s most scientists believed molecules as ephemeral as free radicals couldn’t possibly play important roles in biology. Thus, Harman’s conclusion that they were behind aging wasn’t at all obvious. In 1956 Harman first presented the theory to a wide audience in a succinct, two-page report in the Journal of Gerontology. (A version of it had appeared the previous year in his lab’s newsletter.) The paper, in retrospect, was amazingly prescient. Harman posited that the hydroxyl radical, generated in the course of normal metabolism, is probably a primary agent of our destruction; that DNA damage from free radicals might cause gene mutations that lead to cancer; that heart disease may result from free radical injury to cells of the circulatory system; and that free radical damage might impair cells’ “functional efficiency” and capacity for self-renewal. Each of these ideas is now supported by a mountain of data.

Like many ideas ahead of their time, Harman’s fell stillborn from the press, to use philosopher David Hume’s rueful phrase about his own magnum opus. At Donner Lab, Harman recalled, friendly colleagues told him that his theory was intriguing but too simple to explain aging. Elsewhere, “it was either ignored or ridiculed.” Harman began worrying that he wouldn’t be able to make a living solely doing research. Marked by the Depression, he was loath to waste anything, including his years of training to be a doctor. Soon after proposing his free radical theory, he cut back on his hours at Donner to complete residency requirements for practicing medicine. Then, after two of his physician acquaintances at the lab threw in the towel and returned to doctoring, he too dropped out of Donner’s illustrious rat race and in 1958 joined the faculty at the Nebraska medical center.

The morning I visited him happened to be fifty years to the day since he had set out for Omaha. “I hated to leave San Francisco,” he reflected, sitting beneath a large painting of wind-whipped Pacific waves hanging over his desk—the most striking personal effect in his office. Still, he apparently looked back on the beginning of his new life as a treasured memory. As I listened to him reminisce, it seemed like only yesterday that he was driving toward the rising sun with his wife, his three sons, and the family’s pet hamster.

It took more than a decade for Harman’s theory to get traction after its 1956 debut. The boost that started it rolling into biology’s foreground was provided by a Duke University biochemist named Irwin Fridovich and one of his graduate students, Joe M. McCord. In 1968 they isolated an intriguing blue-green protein, later dubbed superoxide dismutase, or SOD, from red blood cells of cattle. They knew it was an enzyme because, like all such catalytic proteins, it greatly accelerated a specific chemical reaction—in SOD’s case, the conversion of superoxide free radicals into hydrogen peroxide and oxygen. But the full import of the discovery didn’t become clear until they and other researchers investigated SOD’s role in living cells. Because the enzyme could be readily detected, it served as a kind of divining rod for will-o’-the-wisp free radicals. “We were like children with a new toy or like a craftsman with a new tool,” Fridovich wrote years later.

One of SOD’s most striking properties, they found, was its ability to eliminate superoxide at an almost impossibly fast rate, an indication that it was designed by evolution to handle surprisingly large amounts of the free radical in cells. Its ubiquity stood out too. SOD variants were found everywhere scientists looked, from bacteria to human cells. Gradually it became clear that free radicals are constantly churned out by cells’ oxygen-based energy systems, and that SOD is a key defense against their harmful effects.

But it also became apparent that superoxide isn’t always instantly disposed of, supporting Harman’s hypothesis that free radical damage can happen. For one thing, researchers discovered that white blood cells, like tiny dragons, spit superoxide at invading bacteria. And although superoxide isn’t terribly reactive as ROS go, it can team with hydrogen peroxide to produce the highly destructive hydroxyl radical. All in all it looked as if Harman had been right to finger free radicals as prime suspects in the great biochemical murder mystery of life.

Ironically, just as Harman’s theory was gaining credibility, he himself was having doubts about it. Between the late 1950s and late 1960s, he had put his theory to the acid test by feeding antioxidants to different strains of mice to see whether they lived longer than control animals. At first blush the results seemed promising. Some, but not all, of the compounds increased the “half-survival time”—the age at which half of a group of mice were still alive—by as much as a third in strains of short-lived, cancer-prone mice. However, it was entirely possible that the antioxidants had only delayed the appearance of tumors in the mice rather than retarded their aging process.

Mindful of that possibility, Harman next carried out similar experiments with male mice of the “LAF1” strain, which have relatively low tumor incidence. The results, reported in 1968, showed that 2-mercaptoethylamine, an antioxidant sometimes used as a treatment for radiation sickness, lengthened the rodents’ average life span by nearly 30 percent. Meanwhile, several other researchers were following in his footsteps. In 1971, Britain’s Alex Comfort reported that an antioxidant called ethoxyquin significantly boosted life span in one of the same strains of short-lived, cancer-prone mice Harman had used. Comfort’s colleague at University College London, Peter Medawar, the eminent immunologist who had shed light on the evolution of aging, was impressed by the mouse studies, and during his later years he took large daily doses of antioxidant vitamins C and E in hopes of extending his own life.

But the rodent studies still didn’t make a strong case for Harman’s theory. The data were mixed—scientists’ euphemism for “we really can’t tell what the hell’s going on.” Some kinds of mice didn’t live longer on any of the antioxidants that were tried. Some antioxidants that seemed to work did so only in certain mouse strains. A few of the compounds were downright toxic to the rodents at the applied doses. Further, the antioxidants that worked best in mice posed toxicity risks to humans and other animals. Ethoxyquin, for example, has been linked to kidney and liver toxicity in several species.

What most troubled Harman, however, was the fact that although antioxidants sometimes raised life expectancy, or average life span, they never increased maximum life span. That had the look of a killer issue. Harman acknowledged in a 2003 interview, “I had expected both of them, mean [average] and maximum life spans, to be increased [by antioxidants given to mice]. So I came to a halt for quite a while” to ponder two big questions: “Was the theory wrong? Did I miss something or what?”

To understand his crisis of confidence, consider the effect of installing a waterworks in a rural town in Africa that has long relied on a polluted community well. It’s likely that over time the life expectancy (reminder: that’s average life span) of the town’s inhabitants would rise, largely because of lower infant mortality from water-borne infections. (Such public-health measures were largely responsible for a rise in U.S. life expectancy by nearly thirty years between 1900 and 2000, from about age forty-seven to about age seventy-seven.) But drinking clean water wouldn’t make the people actually age slower and live longer than healthy people typically do in other places.

In contrast, if half of the people in the town were still sprightly at one hundred after taking long-term, daily doses of, say, a novel antioxidant, there would be little doubt that the compound had profoundly altered their aging process. There’s no other way their maximum life span could have risen so dramatically. (A commonly used proxy for maximum life span, by the way, is the average life span of the longest-lived 10 percent of a study group.) Thus, maximum life span is a much better indicator of anti-aging effects than life expectancy is.

So here’s the possibility that troubled Harman: Antioxidants’ consistent failure to extend rodents’ maximum life span suggested that the benefits they sometimes conferred may have resulted from amelioration of diseases, as providing clean water does, rather than slowed aging. This kind of ambiguity crops up surprisingly often in gerontology. One reason is that supposedly normal rodents used in studies on aging are often disease-prone and short-lived. Many strains of lab rodents were drafted for research precisely because they’re predisposed to life-shortening disorders of medical interest. And widely used strains of lab mice, like livestock, have been bred to mature fast and reproduce rapidly—in keeping with the idea that there’s a trade-off between fertility and longevity, they’re very fertile but may well age faster than their wild ancestors. That may make them ideal for studies on the fallout from modern lifestyles.³ But it can be hard to say whether a drug that boosts longevity in lab mice has slowed normal aging or has merely ameliorated life-shortening disorders peculiar to hothouse animals with idiosyncratic genomes.

Although taken aback by the murky antioxidant data, Harman wasn’t about to abandon his baby. In 1972, he proposed a second big idea about free radicals that both explained the troubling antioxidant results and pointed to a fertile new frontier in free radical research. His updated theory stressed that free radicals mainly arise inside mitochondria—power plants inside cells where oxidation of sugar releases energy. Mitochondria are crammed with delicate machinery that’s highly vulnerable to free radical damage. Each mitochondrion has its own set of thirty-seven genes separate from those in the cell nucleus, as well as lipid membranes and complex sets of energy-generating proteins—mitochondria are actually remnants of ancient bacteria that took up residence nearly two billion years ago as symbiotic organisms inside larger cells.

Cells’ native antioxidants, such as SOD, neutralize most of the free radicals spun off by their power plants. But some radicals elude the defenses and act like wrenches hurled into spinning dynamos. As a result, Harman suggested, mitochondria are the key sites of free radical injury behind the aging process. He compared them to “biologic clocks”—when the damage reaches a critical mass, they burn out in various key organs, and death ensues. It’s probable, he added, that membranes surrounding mitochondria, which fence them off from other parts of cells, block out antioxidants ingested in food or drugs, preventing them from reaching the key sites of free radical injury. That’s why feeding the compounds to mice didn’t extend their maximum life span.

But taking antioxidants might confer significant health benefits, he theorized, by blocking damage that occurs outside mitochondria. Research by other scientists has elucidated how such damage occurs. Free radicals outside mitochondria, for instance, have been shown to help foster “cross-linking” reactions in which sugar molecules react with proteins to form “advanced glycation end products,” or AGEs, in which the protein molecules are basically glued together in an irreversible way that stiffens and degrades them. AGEs engender yet more radicals, accelerating the sugary decay of proteins—this may well be one of the worst of the bad things that happen to us as we age. (Picture a bunch of stiff, old stuck-together rubber bands—those are your cross-linked proteins at age eighty.) Cross-links in collagen alone, an abundant protein in skin, cartilage, arteries, and tendons, are thought to underlie everything from high blood pressure to wrinkles.

Harman’s updated theory was later honed by other scientists, who postulated that damaged mitochondria, like aging engines belching smoke, tend to spew more free radicals, which causes yet more mitochondrial damage—killer positive feedback, in other words. According to a popular variant of this idea, the degradation of mitochondrial DNA is the main driver of a self-accelerating “vicious cycle” at the heart of aging.

During the 1980s and after, biologists found more and more to like about Harman’s matured brainchild. In 1988, Bruce Ames, a prominent biochemist at the University of California at Berkeley, added weight to the theory by reporting that signs of free radical damage in rats’ mitochondrial DNA increase as they age. A few years later Takayuki Ozawa and colleagues at the University of Nagoya in Japan showed that mitochondrial DNA damage rises exponentially with age in humans, just as mortality risk does. In 1992, Earl Stadtman at the National Institutes of Health marshaled evidence indicating that nearly half of the protein in elderly bodies is scarred by free radical damage. Other researchers reported that genetically altered fruit flies with bolstered antioxidant enzymes live longer than normal flies.

If any biotech company could claim to be on top of the rising wave of support for the free radical theory, it was Eukarion. Other biotechs were riding the wave: In 1994, Fridovich, the discoverer of SOD, cofounded Aeolus Pharmaceuticals to capitalize on his research. Garland Marshall, a biochemist at Washington University in St. Louis, formed MetaPhore Pharmaceuticals in 1998 to work on another set of SOD-like drugs. And in 1999, Berkeley’s Bruce Ames cofounded a company called Juvenon to sell dietary supplements designed to help protect mitochondria from free radicals. But Malfroy’s company had a head start, and a number of animal studies had suggested that its compounds might be able to ameliorate neurological diseases, heart attacks, and other old-age killers.

The idea of developing drugs that mimic the body’s own extremely potent free radical defenses dated from the discovery of SOD in 1968. For years after, researchers hoped to turn SOD itself into a medicine. The enzyme promised to do great things—as a free radical remover, SOD is to familiar antioxidants like vitamin C as an industrial vacuum cleaner is to a whisk broom. But the idea didn’t pan out. Given as medicine, SOD was eliminated too fast in the body, provoked immune reactions, and was formidably expensive.

When Malfroy founded Eukarion in 1991, researchers had mostly given up on SOD and turned to synthetic compounds that mimic its catalytic action. Unlike SOD, a large, fragile protein molecule, the new drug candidates were relatively durable, small molecules that were more likely to reach sites of free radical damage. The seed idea for Eukarion’s SOD mimetics sprang from regular bridge games Malfroy played with a software executive who lived in his neighborhood near Boston. One day the neighbor introduced him to a computer program for chemists whose training examples featured an industrial reagent that looked a bit like SOD. (To be precise, it resembled one of three kinds of SOD, called SOD2, that specializes in defending mitochondria.) Within a few months Malfroy had established that a version of the molecule showed promising SOD-like activity in the test tube.

He and Doctrow, who together led Eukarion’s research, later discovered that their prototype drug, EUK-8, is a dual-action antioxidant—it mimics the antioxidant functions of both SOD and catalase. That was a major stroke of luck. Drugs that boost only SOD, which turns superoxide into hydrogen peroxide, would potentially backfire by generating an excess of peroxide in cells. But with EUK-8, Eukarion could avoid the risk, because the compound would boost the activities of both catalase and SOD, and the revved-up catalase would then convert hydrogen peroxide to water and oxygen as fast as the boosted SOD churned out peroxide. One cold, dark day late in December 1993, Malfroy rigged up a simple but striking test of EUK- 8’s power: When he added a sample of the compound to a test tube full of hydrogen peroxide, bubbles of oxygen instantly fizzed up—a sign of the same kind of free radical neutralizing that happens in cells. He dubbed it the “champagne experiment.”

A CEO who preferred working in the lab to pursuing potential investors, Malfroy kept Eukarion small, making do with modest backing from wealthy “angel investors” and research grants from the National Institutes of Health rather than trying to turn the company into a glitzy, go-go biotech bankrolled by venture capitalists. The strategy arguably worked too well. Joining forces with dozens of academic collaborators, Eukarion consistently punched above its weight in the medical literature. In the late 1990s, its promising preclinical results inspired Glaxo Wellcome (now GlaxoSmithKline) to fund exploratory research on its compounds. But the collaboration failed to yield compounds that the big drug company deemed ready for clinical testing, and Glaxo walked away after two years, leaving Eukarion stuck in research-boutique mode with little means of support. Scraping by on a shoestring budget with a staff of ten, it couldn’t do extensive animal tests, which can cost millions of dollars, much less clinical trials, which can cost hundreds of millions. By the end of the decade, Malfroy found himself grappling with a biotech version of a Catch-22: To take the company to the next level, he needed a major cash infusion to pay for big-ticket studies. But to convince investors that Eukarion warranted a hefty cash infusion after nearly a decade without putting a drug into the clinic, he needed data from the kind of studies that his start-up had never been able to afford. “What allowed us to survive all those years was having a very lean operation,” Malfroy said. “But that also prevented us from succeeding. We realized that we had boxed ourselves in.”

Then the riveting worm study in Science appeared, seeming to hand him a solution to his Catch-22 problem. After it was published he got a call from a venture capitalist eager to discuss a major financing. Estée Lauder, the cosmetics giant, wanted to add Eukarion antioxidants to products that might slow skin aging. A Swiss biotech company, Modex Therapeutics, licensed one of Eukarion’s compounds and began testing it for preventing and treating skin burns from radiation therapy administered to cancer patients. Meanwhile, academic researchers launched a new wave of studies with its compounds.

In the end, though, it was Malfroy’s hopes, not his fiscal conundrum, that were crushed. The bursting of the dot-com bubble after 2000 caused massive collateral damage in other high-tech niches, and investor interest in biotechs like Eukarion shriveled a few weeks after Malfroy began talking with VCs about a major financing. Then the University of Southern California’s Rajindar Sohal, a big name in free radical research, reported in mid-2002 that Eukarion’s compounds failed to extend life span in houseflies. Six months later, researchers at University College London published a study indicating that EUK-8 actually shortened rather than lengthened nematodes’ life spans. The discouraging data didn’t prove that the earlier worm study in Science was wrong—differences in the methods used in the different labs, such as varying ways of administering Eukarion’s compounds, might have caused the different outcomes. But the back-to-back failures to confirm the earlier results dimmed Eukarion’s glow.

Still, Eukarion’s compounds continued to rack up encouraging data in studies based on animal models of human disease and aging. Few of the reports made the news, but some were arguably more provocative than the famous life-extension study. A 2003 mouse study, for instance, offered hope for quelling the senior-moments epidemic that’s sweeping the world as baby boomers turn gray: It showed that chronic doses of Eukarion’s experimental medicines almost completely reversed learning and memory deficits that normally afflict middle-aged mice. Overseen by University of Southern California neuroscientist Michel Baudry, who had helped Malfroy start Eukarion, the study showed that the mental sharpening afforded by the drugs closely tracked a reduction of oxidative stress in the rodents’ brains. Such stress is thought to be a major contributor to Alzheimer’s disease, brain damage from strokes, Parkinson’s disease, and many other brain disorders, as well as the normal decline of mental acuity with age.

But the heartening studies didn’t stop Eukarion from reaching a fiscal dead end. Ironically, the crunch came right after Estée Lauder licensed a Eukarion compound for use in skin-care products. One Friday in early April 2002, Malfroy traveled to the cosmetics company’s New York City headquarters for a meeting with its chairman, Leonard Lauder, son of the founder. Since Lauder’s scientists were enthused about Eukarion’s compounds, Malfroy recalled, “I had high hopes” the wealthy executive might personally invest in the struggling biotech. “But nothing happened at the meeting” to suggest he would—and he didn’t.

That evening Malfroy and his wife attended a Carnegie Hall concert commemorating cellist Mstislav Rostropovich’s seventy-fifth birthday. The performance had a valedictory aura—the old master, who died in 2007, had made his American debut in 1956 at Carnegie. Malfroy found himself especially attuned to the occasion’s farewell feeling: After walking away empty-handed from his audience with Lauder, “I decided that day the only possibility for Eukarion was to be acquired,” he said.

After winding down Eukarion’s operations, he sold it in late 2004 to one of its research partners, Proteome Systems of Sydney, Australia. The purchase price, according to the Boston Business Journal, was $1 million in stock and “a modest cash payment.” The deal also included possible future payments of more than $20 million that were contingent on achieving certain milestones with Eukarion’s drugs. Deeply frustrated but still hopeful, Malfroy and Doctrow stayed on at Proteome to lead research on their compounds. In 2005, a collaboration Doctrow had arranged with a colleague at the Medical College of Wisconsin led to a grant from the NIH, which selected the antioxidants to test as treatments for people exposed to radiation in terrorist attacks and industrial accidents. Three years later, however, Proteome terminated its drug-development work, including research on Eukarion’s compounds, in order to focus on diagnostics. Refusing to give up, both Doctrow, now at Boston University, and Malfroy, who founded a new company called MindSet-Rx, have continued to pursue development of the experimental drugs as therapies for people exposed to radiation and for patients with rare neurological diseases.

Eukarion wasn’t the only company that had trouble capitalizing on free radical science. In 2005, MetaPhore’s main drug candidate failed in two clinical trials, prompting the company to merge with another struggling biotech that later folded. After more than a decade of work, Aeolus, the biotech cofounded by Fridovich, had nearly run out of money, and in 2007 it announced that it would postpone trials on its primary drug candidate, conserving capital while the National Institutes of Health sponsored research on the drug as a treatment for mustard gas exposure.

By mid-decade it was clear that breakthrough antioxidant drugs, once gerontology’s most promising commercial prospect, weren’t imminent after all. Management missteps, bad luck, and the insanely high risk of drug development were partly to blame. But there was also a deeper problem: A new chapter in free radical science had opened, and one of its surprising twists is that antioxidants don’t always come off as good guys.

Early hints of the revisionism arose in a long-running debate about vitamin C. The controversy ignited in 1970 when two-time Nobel laureate chemist Linus Pauling claimed in a popular book that downing gobs of the vitamin could prevent or cure the common cold. Pauling advised taking more than 2 grams a day, more than twenty times the generally recommended daily dose (the current U.S. “reference daily intake” is 75 milligrams for women and 90 milligrams for men). He himself reportedly took up to 40 grams a day. In a series of books and technical reports after 1970, he argued that megadoses of vitamin C could ward off cancer and heart disease, boost mental alertness, and maybe extend a person’s life by decades. Pauling, who died from prostate cancer in 1994 at age ninety-three, believed that our mammalian ancestors got massive amounts of vitamin C in their plant-rich diets, and that we’re geared by evolution to need far more of it for optimal health than we get from modern diets.

No one disputes the critical importance of vitamin C as a dietary component. Identified in 1932, it’s a remarkably versatile nutrient—and not only as an antioxidant. Vitamin C is essential for making collagen. We also need it to make neurotransmitters that carry signals between nerve cells. It facilitates absorption of dietary iron, and without it anemia sets in. No wonder most animals can synthesize it in their bodies, hence aren’t reliant on dietary sources. The few oddballs that lost the ability to make vitamin C at some point in the evolutionary past include humans and other primates, guinea pigs, and fruit-eating bats. In Pauling’s view, the deletion of our ancestors’ ability to synthesize vitamin C was a very bad move by Mother Nature, making us vulnerable to a life-shortening deficit of the vitamin as we moved away from plant-heavy diets.

His view has some merit, as famously shown by the prevalence of scurvy on British navy ships before their sailors were issued citrus rations after 1795, hence their nickname, “Limeys.” (Scurvy, caused by getting less than about 10 milligrams of vitamin C a day, induces extreme fatigue, bleeding gums, swollen limbs, and, ultimately, heart failure.) But as Pauling’s critics have made abundantly clear, there’s no compelling clinical evidence that megadoses of vitamin C offer significant benefits. Some of his logic seems iffy too. For instance, evolution appears to have taken pains to prevent us from getting too much vitamin C, as if it were potentially harmful. In fact, when we ingest more than 60 milligrams a day, we begin excreting it in our urine, and the daily dose we can absorb tops out at about 400 milligrams. This is odd: After we lost the ability to make vitamin C, why wouldn’t evolution have geared us to sock it away in our tissues for a rainy day, especially if it’s as amazingly beneficial as Pauling insisted?

Free radical experts have suggested a shocking answer to this question: Vitamin C can abet free radical damage as well as prevent it. For instance, it can combine with iron and hydrogen peroxide to release the dynamitelike hydroxyl radical. That probably accounts for data suggesting that ingesting large doses of iron plus vitamin C induces free radical injury in the intestines, potentially increasing the risk of ulcers, cancer, and inflammatory bowel disease. Other troubling research indicates that large doses of vitamin C can attenuate the body’s natural antioxidant defenses.

This last downside looms large, for it probably isn’t specific to vitamin C. There’s evidence that taking large doses of potent antioxidants can discombobulate intricate mechanisms in cells whose function is to counteract oxidative stress. The case for this distressing conclusion rests partly on the fact that, as strange as it may seem, free radicals serve as chemical messengers within cells as well as agents of destruction. Indeed, since the 1970s, scientists have discovered that radical messengers help regulate blood pressure, stimulate immune cells to attack infectious microbes, and switch on self-destruct programs in deranged cells that might otherwise form tumors.

And here’s a very important related issue: When levels of free radicals within cells rise—which is thought to happen, for instance, when we exercise hard—they act as signals to boost SOD and other natural defenses against free radical damage. Thus, raining antioxidants down on cells may make them drop their overall guard against oxidative stress, leaving them open to damage that more than offsets the possible gain.

It should be noted that this is a controversial idea. But a number of studies in recent years indicate that large antioxidant doses are risky, and that interfering with free radical metabolism can backfire. In fact, researchers who assembled what may be the most comprehensive look at the issue cited such interference as the most plausible explanation of their troubling results. Reporting in the February 28, 2007, issue of the Journal of the American Medical Association, the European team pooled results from forty-seven high-quality clinical trials with 180,938 participants and found that taking five popular supplements—vitamins E, C, and A, beta-carotene, and selenium—was associated with a statistically significant 5 percent increase in the overall risk of death. The risk, they found, was mainly associated with vitamins E and A and beta-carotene.

While hotly debated—and clearly not the final word on antioxidants—the JAMA report was consistent with other studies that have raised doubts about the wisdom of taking heavy doses of antioxidant supplements.⁴ In 2005, four major clinical studies were published showing that vitamin E supplements not only failed to fend off killers such as cancer and heart disease but also appeared to slightly increase the risk of death from all causes. Mulling the spate of dismaying data, the Annals of Internal Medicine dubbed 2005 the “annus horribilis” for vitamin E.

All this has given skeptics about the prospects for life-span extension the best opportunity to say “I told you so” since the 1950s, when George Williams, the influential evolutionary biologist, seemed to permanently vanquish the search for anti-aging therapies to the junk-science heap. But it would be a mistake to dismiss companies like Eukarion as lost causes. As part of the first wave of scientifically credible companies to spring from research on aging, they were the Roald Amundsens and Robert Pearys of applied gerontology, firmly planting its flag in biotech’s forbidding landscape. Eukarion, in particular, helped stir commercial excitement about aging science. And it’s too early to write off Eukarion’s medicines, which may yet reach the market for diseases of aging. While it’s true that chronic, heavy-handed fiddling with free radical metabolism seems problematic in healthy people, judicious use of potent antioxidants like Eukarion’s might ameliorate diseases involving severe oxidative stress.

The companies also pioneered a business model that has been emulated by similar start-ups that followed. The model’s forte is to enable biotechs to benefit from buzz about aging science without getting lumped with the flaky, miracle-elixir crowd. The key is to grow orthodox drugs from the unorthodox seeds of anti-aging research. A true anti-aging drug should, almost by definition, avert or slow the progression of a wide array of degenerative diseases that arise late in life. That would give it colossal value, but not as a dubious youth preservative sold in health-food stores. Instead, its full value could be unlocked by developing it as a conventional prescription drug that could address a whole slew of major diseases—it would be akin to disease-preventing drugs that lower cholesterol and high blood pressure, only far more versatile. As we’ll see, Sirtris Pharmaceuticals—the biotech start-up cofounded by resveratrol researcher David Sinclair—decanted this idea into entrepreneurial rocket fuel.

The nifty business model also finessed a problem that had long suppressed drug-industry interest in gerontology: the fact that neither government regulators nor doctors see aging as a condition warranting treatment. But industry players might eagerly pursue a compound whose potential uses include, say, warding off diabetes, arthritis, cancer, and various neurodegenerative diseases—not unlikely for a medicine that truly retards aging. Such a drug might well be prescribed to hundreds of millions of people across the globe. Over time, that would mean a large swathe of the population would wind up aging slower as a side effect. In short, Eukarion and its ilk managed to devise a way, inadvertently, to foment an anti-aging revolution without making any claims at all about life-span extension.

The short answer is—well, unfortunately there is no short answer. The free radical theory is still very much alive, and in recent years it has undergone another major update by its current advocates—call it Denham Harman’s Big Idea, Version 3.0. The update posits that as we lose our lifelong war with free radicals, oxidative-stressed-out cells turn into catatonic zombies that drool toxins—biologists call this spread-the-hurt state the senescent phenotype. This version also postulates that free radical damage abets chronic, low-level inflammation in our arteries, brains, muscles, and other tissues. Such insidious inflammation is thought to help prepare the way for the onset of major killers—cancer, heart attacks, diabetes, Alzheimer’s disease—and then help them polish us off.

On the experimental front, however, the picture is murkier than ever. In 2005, University of Washington researchers reported that by genetically altering mice to produce extra catalase in their mitochondria—catalase, recall, is the antioxidant enzyme that eliminates hydrogen peroxide—they boosted the animals’ life expectancy by 17 percent and their maximum life span by 21 percent. But other scientists, most prominently Arlan Richardson at the University of Texas, have compiled lots of data suggesting just the opposite—boosting rodents’ native free radical defenses doesn’t extend their lives, and in some cases shortens it.

Still, even doubters about the free radical theory acknowledge that the damaging molecules may be coconspirators in aging, and that mitigating their damage might help avert diseases of aging. If taking loads of antioxidants isn’t the way to go, though, what is? That’s still an open question, but several lines of research have suggested safe ways to do it. One is calorie restriction, or CR, which we’ll take up later—as noted earlier, CR, which entails a drastic reduction in food intake, is the only intervention that has reliably retarded aging across many species. No source of insight on free radicals and aging, however, is more fascinating than the menagerie of weirdly long-lived animals that we’ll explore next.