I stared at him. “That’s a plant,” Collins pointed out jokingly.
We walked out to the immense backyard, which contained a collection of plants so vast and magnificent it could have been a botanical garden. Nasturtiums bloomed by the thousands, cycads burst with life, Aloe ferox plants were covered in bright red cones. A patch of coral-reef-type flowers resembled anemones and urchins. Flesh-colored brain plants looked like warty organs pulsating in the breeze. “I love blue-tinted plants,” said Glenn, pointing out a blue cactus called a monstrose. “In fact, some of my monstroses have turned green and that ticketh me off.”
The Euphorbia ingens he’d wanted me to see formed a group of surprisingly tall and spiny African cacti. “One of them nearly killed me while I was in the pool,” he disclosed. “It came down diagonally across the lanes and narrowly missed impaling me.”
As we walked into the Technicolor vegetation, mottled sunlight streamed through the leafy canopy. Glenn paused next to a Jacuzzi. “My exercise consists of climbing up these stairs, and then back down, after the session.”4
“Session? Is that what you call them?” Collins teased.
Glenn pointed out that, even though he never married or had children, he’d been with the same girlfriend for twenty-three years. He then patted the foliage of a small bunya tree. “I won’t be here to see this bunya mature,” he pontificated. “But Collins might be.”
“No, no,” chuckled Collins tightly.
“Collins is young for his age,” Glenn maintained, as we ambled along.
“It’s a nice thought,” Collins responded, “but I don’t think so.”
Glenn pointed at some seedpods and said they grew fast and died young. Collins joked about their having progeria. Coming to a pond, Glenn grumbled about raccoons eating his goldfish for canapés. We gazed into the pond, which didn’t seem to have any fish in it at all. “I need to buy a hundred more tomorrow,” he huffed.
I tried to steer the conversation toward immortality, asking Glenn about the foundation’s mission. He started explaining how he’d been interested in longevity since childhood, with a major turning point being an article he’d read in 1951. The reminiscence trailed off as we came to a rare type of agave whose central flower stalk jutted fifteen feet into the sky like a gargantuan asparagus. “That stem is called a mast,” he said, pointing at the magnificent totem. “When the flowers open, clouds of hummingbirds gather to drink the nectar.”
Here he elbowed Mark and said, “Your spike was bigger than that in its prime, wasn’t it?” They both laughed, and Mark winked at me.
We arrived at a tumescent, waist-high cactus tied to supporting props. “We call this one the Mark,” Glenn deadpanned. “It’s so big you have to strap it down to keep it under control.”
When I brought up some more questions about longevity, Glenn said they would be better directed toward the scientists they funded, particularly Leonard Guarente from MIT and David Sinclair from Harvard, both of whom researched sirtuins, which Glenn called “an unusual benediction.” Guarente was in town for a conference, and Collins could arrange a preliminary conversation.
Paul Glenn ended our garden tour with an aside about how getting into ending aging had been psychologically logical to him. It all started with the terrible deterioration he’d seen overtake his grandmother when he was still a child. “She lived past ninety, and at the end she could barely walk.” He sighed. “She was very ill and infirm. At that time, it struck me that aging was a terrible phenomenon. I thought, ‘Life is so beautiful—why does it have to end?’”
* * *
The meeting with Leonard Guarente took place at La Super-Rica Taqueria, a turquoise-and-white taco shack reputed to have been one of Julia Child’s favorite hangouts. I’d been instructed to await the end of a black-tie ceremony, at which point Collins and Guarente would skip out on the after-party to come meet me. While standing by, I flipped through Guarente’s autobiography, Ageless Quest: One Scientist’s Search for Genes That Prolong Youth.
The book described Guarente’s discovery of genetic aging mechanisms within yeast. Investigating why certain genes expressed themselves in long-lived mutants, he realized that enzymes called sirtuins (from SIR2s, itself an acronym of silent information regulators) play a role in cellular pathways affecting longevity. These SIRs silence the expressing of certain genetic regions in chromosomes; but when the SIRs are inhibited, peculiar behaviors start expressing themselves. Some of the yeast strains he was studying lived up to 50 percent longer than average. But these long-lived yeasts were also sterile, as well as hermaphroditic. The SIR-controlled pathways that allowed them to live longer also rendered them incapable of mating.
As his research deepened, Guarente found that SIR2-like genes exist in every free-living organism known to biology, from bacteria to humans. He started suspecting that they might be “the master regulators” of the survival mechanism. Their biochemical activity has proliferated for over two billion years, which suggests that they perform some crucially important function. Guarente felt certain that they were part of the mechanism that turns on during caloric restriction. He came to suspect that sirtuins evolved as a means of surviving periods of food scarcity. An adaptation that became hereditary, sirtuins are best understood as evolutionary remnants from organisms that made it through famine, drought, or other extended periods of stress. “Imagine, as an example, I had a gene to slow down the aging process during a famine and you didn’t. When the famine is over, and assuming I survived, I would likely remain young enough to reproduce and you would not. In that way, the gene which slowed down aging will predominate in subsequent generations.” Guarente also started imagining what it would be like if there was a way of targeting those regulators, to make their antiaging effects express themselves.
Ageless Quest, published in 2003, covered the years in which that notion caught on—while remaining shackled to the speculative. The book began with his reminiscing about early breakthroughs alongside graduate students. Their work accelerated upon the arrival of an Australian whiz kid named David Sinclair. The book ended by noting that a major goal remained: “convincing big pharma that there is a new area of human health and product development that they will need to be a part of.” That certainly became true five years later, when GlaxoSmithKline purchased Sirtris.
In that process, however, tensions mounted between Guarente and his protégé Sinclair. For a spell, they stopped talking, experiencing “a bitter dispute that crescendoed,” as Science magazine put it, “when the pair published dueling papers.” Guarente told media that their quarrel had run him “through so many emotions, some of which I didn’t know I had.” The mood settled subsequently, with the two of them ending up as cochairs of Sirtris’s scientific advisory board.
Collins called my cell phone just after my order for rajas tacos emerged from the kitchen. I ate about half my plate before he and Guarente arrived. They pulled up in a black town car, wearing tuxedos. Guarente, tall and bald, said he liked “the vibe” of La Super-Rica, and we had a brief, interesting chat.
I started out by telling him that I liked the title of his book, Ageless Quest, because it had a whiff of the popular to it, which made him laugh. Although his interest lay in longevity, not immortality, he acknowledged that both urges are innate and intertwined.
“And for you it began with yeast,” I said. “The same yeast that’s in beer and bread?”
“Yes,” he answered. “Yeast cultures actually consist of live, dividing cells, which makes them easy to study. The notion that understanding their life span would shed light onto human aging used to be deemed preposterous. Of course, that’s no longer the case.”
He described an evening when, leaving the lab, one of his grad students exclaimed, “You’re gonna win the Nobel Prize for this!” Possibly a tad smug, Guarente was nonetheless clearly brilliant. He spoke technically, with precision. A classic egghead.
He considered Paul Glenn his patron, describing the ways in which the found
ation had assisted him, particularly in providing the funding for his lab to start testing mice. “He helped me so much in chasing the dream of sirtuins, from worms to mammals,” Guarente said. “What he’s done for aging is deeply inspiring. Paul has also taught me so much about how best to spend this brief, little period we have on this earth.”
When Lenny excused himself to go to the bathroom, I asked Collins if he thought I’d be able to visit Guarente’s lab. “Sure,” he answered. “If you really want. But all labs look the same. They all have the same glasses-wearing postgrad students tinkering on the same sorts of tests in the same nondescript buildings—labs, including his, are pretty uninteresting.”
I wondered aloud if there was some better place I could visit to understand what was happening with sirtuins and other developments in scientific life extension. He suggested I come to Boston in June for the annual Glenn symposium on aging at Harvard. It would be a chance to meet all the most important biologists on aging alive today, he said, plus I’d get to sit in on presentations about where real longevity science is at.
* * *
1. Not long after our meeting, he started pasting QR-code stamps into the Bibles. They linked to his own website.
2. His divorce counselor had suggested he undergo a rite of passage into manhood, an idea Collins said made him feel “smeary.”
3. Curious whether it had something to do with that breast-implant company, I later asked Collins for details. He responded with characteristic brevity: “It was a company that failed to rise to the point of relevance to my story or yours.”
4. Alex Comfort, author of The Joy of Sex as well as a noted gerontologist, once wrote, “Probably the nearest approach to the fountain of youth is the Jacuzzi, or the California hot tub. These small, sociable, whirlpool baths don’t ‘rejuvenate,’ but they are stunning ice-breakers at any age. And they reveal the fact that many older people—since uncovered skin ages faster than covered skin—still have good bodies.”
24
The Harvard Symposium
Meryl Streep: “What is that?”
Isabella Rossellini: “What you came for. A touch of magic in this world obsessed with science. A tonic. A potion . . . It stops the aging process dead in its tracks and forces it into retreat. Drink that potion and you’ll never grow even one day older. Don’t drink it—and continue to watch yourself rot.”
Meryl Streep: “How much is it?”
—Death Becomes Her
And the mind
trips, numbering waves; eyes, sore from sea horizons,
run; and the flesh of water stuffs the ears.
—Joseph Brodsky, “Odysseus to Telemachus”
HOUSING A faculty of the world’s brightest doctors and biomedical scientists, Harvard Medical School’s warren of buildings spills off from a central green quadrangle. While many of the original nineteenth-century buildings radiate Grecian notes—Ionic pillars; marble façades; Parthenonical neoclassicism—the colossal New Research Building just down Avenue Louis Pasteur is a hypermodern, half-million-square-foot behemoth in reflective glass and shimmering steel.
On the morning of Harvard’s Paul F. Glenn Symposium on Aging, a gaggle of students stood smoking and gossiping about the age of their mice. Passing them, I walked into the auditorium and slid into a back-row seat. The symposium’s program guide listed all the speakers, ten longevity scientists who’d converged here from institutions around the country. The brochure contained an introductory note by David Sinclair, the Harvard-based sirtuins researcher and director of the university’s Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. “Because chronic illness in the elderly is a major medical cost,” Sinclair had written in his position statement, “enormous savings would be achieved if mortality and morbidity could be compressed within a shorter duration of time at the end of life.” As Collins would’ve said, unassailable.
The dean of Harvard med school, Jeffrey Flier, stood up to give the opening address. He spoke of a graying US population living longer and, as a result, spending more time in the throes of age-related illnesses. Most of us want to live as long as we can, he noted, but a side effect to extended lives is the burden of disability, chronic disease, and increased cost. Fortunately, developments already under way at Harvard, and at MIT, would soon help forestall disease. The speakers today were all making discoveries on the verge of being translated into therapies. He spoke of helping cerebral functioning in aged people, of trying to learn why stem-cell capacity decreases during aging, of the tantalizing possibility of finding a universal set of genes that regulates aging. Their greatest hope lay in the sirtuin work of Sinclair and Guarente. Potent activators of sirtuin genes had already gone into clinical trials, Flier noted, so even though the work remained embryonic, optimism abounded. And none of it would be possible without Paul F. Glenn, whom they were honored to have in attendance. “With your help we will continue to push the limits of human knowledge,” concluded the dean, thanking Glenn repeatedly for his generosity.
Glenn took to the podium, looking skinny in his suit and tie. “As I approach eighty,” he said, coughing a few times, “the symposia get closer and closer. I’m trying to find a way to increase the distance of time. We’re working on that right now.”
He got a polite laugh, then began to emphasize the importance of sirtuins. “There are fifteen diseases that may benefit from sirtuin research. And I must say, just in time, as we’re facing unprecedented numbers of the elderly from the baby boomer generation. Life expectancy appears to be growing by a year per decade. The work at Harvard is causing that to accelerate. Which means people will draw on Medicare for even longer. There’s only $35 trillion in health-care money to assist the seventy-five million boomers out there. Their entitlements may cost up to $120 trillion. All the total assets in the US are $40 to $50 trillion. Meaning we have no way to pay for them. In 2017, Social Security will be running in the red. By 2030, it will be empty.”
* * *
The symposium’s presentations were impenetrable to nonspecialists. The Salk Institute’s Andy Dillin explained how toxic jumbles of protein clumps are regulated by insulin/IGF-l signaling pathways. Harvard’s Bruce Yankner shared his investigations into the role of the presenilin proteins Notch and Wnt in neuronal signaling. A biologist from the Salk Institute named Leanne Jones described mechanisms regulating the size and maintenance of a stem-cell niche. She had had success tweaking a gene known as PGC-1, also found in human DNA, in the intestinal stem cells of fruit flies. Doing this delayed the aging of their intestines and extended their life spans by as much as 50 percent.
At one point, a lovably nerdy jokester named Dan Gottschling, from the Fred Hutchinson Cancer Research Center in Seattle, took the stage. He started out by directing our gaze to the rectangular table onstage. Completely draped in black fabric, the table was barren except for a basket of flowers. “Thank you,” he declared with faux solemnity, “for putting the end point on what we’re all studying with this wonderful casket here.” As everyone laughed, he discussed how he and his colleagues were aiming to research the opposite of that. He then spoke about cellular aging as well as genomic and chromosomal instability, explaining that he’d engineered mice to study promiscuous activity of telomerase. There were also new clues to be found in yeast.
The next biomolecular lecturer discussed ARFs and twixxits and other ways to fix life, something not broken yet apparently not quite right either. My attention lasted until he mentioned something called Mxi1-mSin3-HDAC1/2 and revealed that p53 suppresses tumorigenesis via activation of apoptosis in aberrantly cycling cells. He droned on, trying to persuade the audience of peers and financiers (the most important of whom, Paul Glenn, was by now snoring audibly a few rows over) that his variables were the ones to make all the colors in the universe come into focus. I snuck out and went for a walk.
When I returned, a woman in the lobby smiled at me wanly. “Yeah, I had to duck out, too,” she offered. “If I didn’t, I was going to be
sick or explode.”
I nodded a bit sheepishly.
“Why are you here?”
I told her I was researching longevity and immortality.
“Those are very powerful drives.” She nodded. “Everyone in that conference hall has been bitten.”
“Yes, and it seems like sirtuins are what they’re most excited about.”
“That’s for sure,” she half laughed. “I’m actually coauthoring a crash book about sirtuins with David Sinclair.”
I told her I’d love to know more about what’s happening within sirtuin research.
“What do you want to know?” she asked.
“To begin with, will it work?”
“Well, they sure hope it will. The only answer now is: no one knows for sure. They will once it completes human trials.”
As we spoke, people started trickling out of the auditorium. The last speaker had finished.
“Do you think it’s really going to work?” I asked.
She looked around, then pulled me by my shirt collar into a stairwell. “The FDA won’t approve it for longevity,” she whispered. “But it might have street value. It’s a huge cognitive enhancer, and it gives you the most incredible endurance. Athletes are already using it. You can’t write about sirtuins without mentioning doping.”
* * *
What one scientific journal termed “the roller coaster ride of yeast aging research” began when David Sinclair revealed that resveratrol, a compound found in red wine and certain plants, activates sirtuins. Ever since, red wine has been touted as having life-extending attributes. What most journalists neglect to mention is that, to get the beneficient effects of resveratrol from wine, one would need to drink hundreds or thousands of bottles a night.
Book of Immortality Page 41