Since partnering with GlaxoSmithKline, Sirtris has been formulating concentrated, synthetic compounds that target sirtuin pathways more effectively than resveratrol. The hope is that one or more of these proprietary molecules will end up in a pill form, sold at pharmacies as a human therapy. It won’t be labeled as an antiaging medication; aging is not classified as a disease, meaning the drug can’t be regulated for aging. Glaxo’s pill may, however, be packaged as a drug for other purposes, such as type 2 diabetes, psoriasis, or vascular disorders.
Even though they’re already touting the drug’s “potential to treat diseases associated with aging,” they won’t be allowed to market the drug as having antiaging benefits because advertising and promotional activities are limited to the drug’s approved usage only. That does not stop doctors and others from mentioning that it also “may have” antiaging benefits.1 Several of the compounds are in human trials, but are still a ways off from widespread availability. Regulatory approval usually takes close to a decade, and early results are mixed, at best.
On several occasions, Sinclair and Guarente’s findings were disputed by scientists at Pfizer and Amgen, rivals of GlaxoSmithKline’s. They found no evidence that resveratrol-mimics activate sirtuins. Then, one of GlaxoSmithKline’s own human trials was halted after several patients developed kidney failure. The press release made it clear that the patients were already ill, but the drugs caused nausea, vomiting, and diarrhea, which may have “exacerbated the development of the acute renal failure.” That particular compound, SRT501, which was plant-derived, has been shelved by the company, but other synthetic compounds including SRT2104 and SRT2379 are still being studied. In the summer of 2011, some hopeful findings were released confirming that the compounds do help obese mice live longer (meaning it may increase the health span of fat humans).
In the fall of 2011, Nature reported more negative news about sirtuins when scientists in London attempted to replicate Guarente and Sinclair’s experiments. “We have re-examined the key experiments linking sirtuin with longevity in animals and none seem to stand up to close scrutiny. Sirtuins, far from being a key to longevity, appear to have nothing to do with extending life,” concluded the report. The Bostoners took issue with the British takedown, and a transatlantic dispute opened up.
The New York Times published a number of articles following sirtuins, first with enthusiasm and then with increasing dubiousness. Headlines went from “Quest for a Long Life Gains Scientific Respect” to “Doubt on Anti-Aging Molecule as Resveratrol Trial Is Halted.” By 2011, Nicholas Wade, who’d been reporting on the saga dutifully for a number of years, characterized the hope that human aging might somehow be decelerated as “flickering.”
In January 2012, a prolific resveratrol researcher at the University of Connecticut named Dipak K. Das was charged with 145 cases of fabrication and falsification of data in work he’d published in peer-reviewed journals. Dr. Das’s work had been touted by a Las Vegas supplement maker called Longevinex as proof that resveratrol can turn a mortal heart attack in animals into a nonmortal event. Longevinex suggested that for this reason, people should take the company’s formulation daily. Das himself dubbed resveratrol “the next aspirin.”
In the fallout, it emerged that David Sinclair had himself at one time been a consultant for Longevinex. He also had a paid position on the Scientific Advisory Board of a company called Shaklee, who manufactured a syrup called the Vivix Cellular Anti-Aging Tonic, sold as “the world’s best anti-aging supplement.” The price for a one-month supply of the grape-flavored resveratrol concentrate was $100. Sinclair attended sales conferences for the tonic, in which he hyped salespeople. “Over a year ago, we set out together to do this,” he enthused, “to make a product so that you could actually activate these genetic pathways that can slow down aging.”
When reporters from the Wall Street Journal questioned him about the affiliation, Sinclair immediately stepped down from Shaklee’s scientific board and told journalists that his name had been “misused in connection with Vivix.” In their own statement, Shaklee declared, “Every implied product endorsement was in Dr. Sinclair’s own words and every Shaklee use of his name—whether in print or video—was pre-approved by him in keeping with our agreement.”
If that wasn’t suspicious enough, in the summer of 2010 it was revealed that executives from Sirtris were covertly selling their own formulations of resveratrol on the side. An outfit called the Healthy LifeSpan Institute, run by Christoph Westphal (who cofounded Sirtris alongside Sinclair and was the company’s CEO), was selling one-year supplies of resveratrol for $540. The day after the first reports surfaced, GlaxoSmithKline ordered Westphal to cease selling the dietary supplement.
During one of our many interviews, I asked Collins whether he’d take resveratrol.
“I already do take resveratrol,” he answered. Initially, he told me he bought Longevinex, but then later mentioned he used a confidential source. “I don’t see why I shouldn’t be taking it,” he confided. “If it does no harm, I think everybody will take it. For now, it’s like Pascal’s Wager. If I’m wrong, no problem. If I’m right, then great.”
“So taking sirtuin activators is like believing in God?” I retorted, marveling at the comparison. “Now there’s a declaration of faith, especially from a skeptical optimist.”
Our conversation turned to the difference between immortality and longevity. Did he think the distinction had become blurred?
“I’m not going to let you set me up for a false dichotomy here,” he replied tellingly. “One man’s longevity is another man’s immortality, perhaps. I don’t know. I don’t know.”
* * *
At the time of my visit, the Harvard Medical School found itself in an ethics quandary, with hundreds of students and faculty protesting the influence of Big Pharma in classrooms and labs. Earlier that year, the school had received an F grade from the American Medical Student Association for conflicts of interest raised by its openness to drug industry money. Just under 20 percent of the medical school’s professors and lecturers reported having “a financial interest in a business related to their teaching, research or clinical care.” A Senate investigation of several medical professors was under way.
“If a school like Harvard can’t behave itself, who can?” declared Dr. Marcia Angell, a Harvard faculty member and author deemed to be among the twenty-five most influential Americans by Time magazine. In another article, Dr. Angell wrote, “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.”
Why was there so much corruption in the biomedical community? A twelve-story answer to that question hovered inches away from the symposium, in the form of a giant Merck research facility. It looms over the Harvard Medical School’s New Research Building, two stories taller, seventy-five thousand square feet bigger, and all but rubbing up against its academic neighbor. The result of the Bayh-Dole Act, adopted in 1980 and intended to give American universities intellectual-property rights over their innovations, was the interpenetration of corporate and educational institutions. In Dr. Angell’s words, “The big drug companies bribed and corrupted the medical establishment so that we no longer know which drugs are effective or why our doctors prescribe them.”
The Glenn Symposium itself was being held in the Joseph B. Martin Conference Center, named after the former dean of the medical school, a booster for industry involvement in academia. During his tenure as dean, Martin concurrently sat on the board of Baxter International, a medical-products corporation, which paid him an extra $197,000 a year on top of his university salary. Martin appeared to have been aware of how such behavior would be perceived, having written papers about “the increasingly complex web of financial relationships between corporate sponsors of research and the investig
ators who perform laboratory research and clinical trials on their behalf.” He also noted that eradicating conflicts of interest would be impossible, and that a wiser goal was finding productive, collaborative ways to work with industry.
His successor, Dean Flier (who’d spoken that morning at the symposium), followed in Martin’s footsteps, noting (unassailably) that faculty collaboration with industry facilitates “scientific discoveries and clinical translation that will benefit the sick and suffering.” According to the New York Times, he had also been the recipient of a $500,000 research grant from Bristol-Myers Squibb.
* * *
When the talks ended, speakers and other VIPs gathered for a “mingle.” The hors d’oeuvres consisted of local Massachusetts cheeses, the sort a multimillion-dollar endowment buys. Strangely, given all the talk of resveratrol, there was no wine. One disappointed gray-haired attendee turned to another and said, “Maybe they’ll just give out pills.”
In a corner of the room, Dean Flier traded stock tips with Paul F. Glenn, who implored the dean to get rid of his US dollars. “Convert whatever you can, because they’re going to lose all their value,” Glenn intoned solemnly. The dean paid close attention, nodded, and said he’d be sure to call his broker.
Collins introduced me to a mustachioed, dark-haired man named Gary Ruvkun. He’d just authored an important new paper in Nature that said, “The secret of long life may lurk within the genetic activity profile of sex cells.” I told him I’d seen reports about the paper. He was pleased to know that it was generating nonspecialist interest.
“I didn’t get a chance to read the whole paper,” I explained, “but the discovery had something to do with sex, right?”
“What?” he said, and looked at me as though I were joking. “Sex?”
I grew a little uncomfortable, as though I’d made an embarrassing faux pas. “Well, as far as I recall, the title mentioned the word sex.”
He shook his head. “It’s got nothing to do with sex. Not unless the press release got it wrong.”
“Sex cells, then?”
“Oh! I see, the PR people called them sex cells. Germ cells, yes. The paper is about somatic cells in worms that have the ability to take on some of the attributes of germ cells—or sex cells.”
“So that means regular body cells can become germinal cells?”
“Essentially, yes, if you start hitting insulin in all sorts of directions, you see this ability to turn into a germ line, which is called totipotency. The idea that somatic cells maintain the potential to reacquire pathways lost during differentiation, or the generation of new cells, is a tantalizing prospect.”
When our conversation ended, I turned to David Finkelstein, a program director in the Division of Aging Biology at the National Institute on Aging, who told me that their recent studies suggested that rapamycin (a bacterium from Easter Island) appeared to have a greater effect upon aging than resveratrol. He also pointed out that no one has any idea how either of them delay aging. “The smartest longevity scientists in America are gathered here today,” he explained, “and none of them know how aging works.” As he spoke, he accidentally spat out a bit of couscous and then picked it off my jacket, apologizing.
When Mark Collins came over to schmooze with us, Finkelstein said, “Paul Glenn is the portrait of Dorian Gray—he hasn’t changed in seventeen years.”
Collins nodded significantly and enthusiastically. “How did you like the symposium?” he asked me. “Heavy stuff, isn’t it?”
“I understood it all,” I joked.
“Yes, it’s pretty technical,” he conceded.
“Do you even know what they’re talking about?” I asked.
“No.” He laughed. “Not at all, which is why I’m the perfect person to be helping fund such research.”
Leonard Guarente overheard us and mentioned how even he’d been having trouble understanding some of the lectures, in particular one speech on stem cells. “Just by looking at the speaker, it’s clear that he’s saying something really profound, but I don’t grasp the profundity of it,” Guarente admitted.
As Collins and Guarente chatted, I spoke with John Furber, whom Collins had pointed out earlier as an acolyte of Aubrey de Grey’s. I asked Furber if he thought it was possible we would live for five thousand years, as de Grey insists.
“Five thousand years is possible,” Furber answered. “If you don’t believe it’s possible, you wouldn’t work on it. But say it correctly: ‘There’s a fifty percent chance that—’”
“But what would you do if you could live for five thousand years?” I interrupted.
“I’d live one day at a time. I’m enjoying today. I’m sure I’ll enjoy tomorrow. I’m in no hurry to die. What would you do? Would you plan it out or would you take it one day at a time?”
“I don’t believe we’ll be here for five thousand years. So those questions aren’t really relevant in my case. I respect your beliefs, but in my belief system, reality means being here for a brief time. It also means dying.”
“Well!” Collins cut in. “I do agree that the merits of death deserve to be discussed, but perhaps another time? Adam, I’d like to introduce you to David Sinclair.”
Collins pulled both of us together so we could shake hands. “This is the guy I was telling you about,” Collins told Sinclair, “the one writing a book on the fountain of youth.”
“Ah, yes, we have to talk,” Sinclair said with a thick Australian accent. He was shorter and more boyish than I’d anticipated, with a pointy nose, a broad smile, and sideways-parted hair. Something about him was Russian looking. Just as Guarente did at the taco stand, Sinclair started telling me how indebted he was to the Glenn Foundation. “Without Paul none of us could’ve gone from yeast to mice. He’s an angel.”
Perhaps expecting further discussion of Glenn’s involvement in longevity research, he seemed taken aback when I asked how excited he’d been when he found out that GlaxoSmithKline had purchased Sirtris for $720 million.
His smile dropped immediately. “What do you mean?” he asked flatly.
“Well, were you excited? How did you react? Was it an exhilarating feeling?”
He had personally received over $8 million at the time Glaxo acquired Sirtris. As a consultant for the company, he also earned an annual salary of $297,000 (on top of his university salary). Without any expression whatsoever he said, “It’s a dream.”
I asked him where sirtuin research was at, and he said, “We’ll know in twelve months or twenty-four months. In a few years. The earliest that the molecule will be available is in three years.”
“Why is it that the media has been focusing on resveratrol and red wine rather than sirtuins?”
“I’m rather amused by that myself,” he said, a modicum of joviality returning. “It would be as if Alexander Fleming had discovered penicillin and the media said, ‘Drink mold juice.’ Now they’re saying, ‘Drink red wine.’ But the public is always five years behind discoveries.”
“So based on current discoveries, where will we, the public, be five years from now?”
He pondered it for a moment. “In five years, there will be a few diseases that our pill is being prescribed for. In fifteen years, like Lipitor, it’ll be a preventative. In a hundred years, it’ll be at the drugstore for a cent a pill, which is what it should be. Ideally it could be free. I like to think about the molecule being added to the water supply like fluoride.”
“Do you really mean that?”
“Well, I won’t go as far as saying it should be in the water supply,” he hastened to add.
“Would you like to go that far?” I pressed.
“No. Because I think people should have the choice.”
* * *
The first modern gerontologist2 was Charles-Édouard Brown-Séquard (1817–94). He taught at Harvard before becoming chair of physiology at the Collège de France. His work made the idea of comprehending—if not controlling—aging a respectable aim. The discipline’s beginnin
gs, however, were as suspicious as they were inauspicious. Brown-Séquard’s late-period research occupies one of the more bizarre footnotes in medical history: toward the end of a distinguished career, he stunned the scientific community by announcing that he’d found a glandular elixir of eternal youth.
His speech on June 1, 1889, at the assembly of Paris’s Société de Biologie, is widely considered to mark the commencement of gerontology. Most members of the society were in their seventies, as was the swarthy, six-foot-four, bushy-bearded gentleman onstage. In unscheduled introductory remarks, Brown-Séquard confessed that his natural vigor had declined considerably over the last decade.
At that time, many scientists felt that old age was not a natural phenomenon, so a murmur of commiseration rippled through the room. Those graying authorities knew full well what it meant to grow old, nodding as Brown-Séquard lamented his own chronic pain—the lassitude, the insomnia, and, most delicate of all, the decline of his manliness. He had a pretty young wife, he was rich, successful, accomplished—et quand même.
“I have always thought that the weakness of old men was partly due to the diminution of the function of their sexual glands,” Brown-Séquard explained. Shouldn’t there be a means of stimulating those tired old glands? To shock them back into action, he posited, would jump-start the entire system. (As we’ve seen, this concept was appropriated decades later during the “gland craze” of the interwar years.)
In Brown-Séquard’s time, the functioning of internal secretions, hormones, and our glandular organs was even less understood than it is today. The endocrine system remained an undiscovered enigma. Testicles were thought to produce a sort of vitalizing substance that dissipated with age. Contemporary science recognizes testosterone as an essential component of bodily function. Brown-Séquard believed it to be the fountain of youth.
For the past few months, he told the assembly, he had been performing auto-experimentation with liquefied extracts from various glands. Several weeks earlier, he’d opened up the scrotum of a puppy and removed the testicles. Cutting them up, he blended them with an aqueous solution, ran the liquid through a filtration device, and filled a syringe. He then administered injections of the extract into his own thigh. Guinea-pig testes worked just as well, he declared, having inoculated himself with them as well. The physiological effects were, he testified, most surprising. He’d regained his youthful vitality—in every way. Just before the lecture, in fact, he’d managed an elusive feat offering empirical proof. He had been able to “pay a visit” to his young wife.
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