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David Sinclair Can Dramatically Extend the Life Span of Yeast

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David Sinclair Can Dramatically Extend the Life Span of Yeast News Focus Lenny Guarente and his former postdoc David Sinclair can dramatically extend the life span of yeast. They’re battling over how this works, and competing head-to-head to grant extra years to humans Aging Research’s Family Feud BOSTON AND CAMBRIDGE,MASSACHUSETTS—At tenure-track spot on Harvard’s faculty in late share many traits common among successful 34, David Sinclair is a rising star. His spa- 1999. He then made clear that his old profes- scientists. Both are deeply ambitious, relent- cious ninth-floor office at Harvard Medical sor’s pet theories weren’t off limits. At a lessly competitive, and supremely self-confi- School boasts a panoramic Boston view. His meeting at Cold Spring Harbor Laboratory dent. Both savor the limelight. Both love sci- rapidly growing lab pulled off the feat of pub- in late 2002, Sinclair surprised Guarente by ence and show little interest in other pursuits. lishing in both Nature and Science last year, challenging him on how a key gene Guarente Still, they’ve retained something of the and it made headlines around the world with discovered extends life in yeast. That sparked parent-child relationship that can shape in- a study of the possible antiaging properties of a bitter dispute that crescendoed this winter, teractions between senior researchers and a molecule found in red wine. In a typical when the pair published dueling papers. their students. Like a father dismayed when day, he fields calls from a couple practicing a Researchers who study aging are finding his son joins a punk rock band, and then dis- radical diet to extend life span, and from an the quarrel both intellectually provocative and mayed further when it attracts devoted fans actor hunting for antiaging pills and the a lively source of gossip. And the reverbera- and favorable reviews, Guarente exhibits a chance to invest in Sinclair’s new company. tions extend well beyond that community. At mix of pride, anger, and disappointment There is, however, another side to this its core, the argument involves one of the when the conversation turns to his former glossy picture of success. Sinclair is engaged hottest topics in longevity research: how cut- postdoc. At the same time, Guarente ting calories may increase confesses that Sinclair’s choices aren’t alto- life span and how its ef- gether startling. “There’s a side of me that fects can be translated identifies with him,” he says. “The young into antiaging therapies. Lenny Guarente was not all that different.” But the dispute, which remains unresolved, Endurance involves molecular biolo- A native of Massachusetts, Guarente’s aca- gy so intricate that many demic life has revolved around two of the scientists are uncertain most high-powered institutions in the coun- how to assess it. It’s also try. He attended MIT as an undergraduate— not clear how it applies to where biology at first “felt squishy to me”— other organisms, such as and completed graduate and postgraduate mammals. work at Harvard. Then he moved two sub- Guarente and Sinclair way stops back up Massachusetts Avenue are also rivals in busi- and settled again into MIT, where he has re- ness. Both have bold mained ever since. ideas for translating yeast With tenure under his belt at 34, Guarente studies into ways to stall began thinking beyond the mainstream as- mammalian aging and signments to which he had gravitated early “They’re doing exactly what we’re doing, and it’s a race.” —David Sinclair in a tense and very public battle with his treat age-related diseases. Sinclair recently on, like studies of gene regulation. In the mentor, a renowned scientist based across the announced plans to launch a biotechnology early 1990s, two of his graduate students, Charles River at the Massachusetts Institute company that he says will compete directly Brian Kennedy and Nick Austriaco, sat down of Technology (MIT). Leonard Guarente, 51, with one co-founded by his mentor. with him to discuss a project they wanted to is an undisputed leader in the field of aging, “They’re doing exactly what we’re doing, pursue: dissecting the causes of aging. an author of major discoveries about genes and it’s a race,” says Sinclair, clearly relish- At the time, aging was considered fringe that prolong life. For 4 years, Sinclair all but ing the prospect. science, a topic few reputable researchers lived in Guarente’s lab as a postdoctoral fel- The two have spoken little since their Cold would touch. But “Lenny likes a challenge,” low, and the two grew extremely close. Spring Harbor falling-out. Some who know says Kennedy, now at the University of Thanks in part to a glowing recommenda- the pair say the clash is unsurprising; despite Washington, Seattle. “He said, ‘You’ve got a tion from Guarente, Sinclair nabbed a the generation gap, Guarente and Sinclair year to learn something.’ ” CREDIT: GRAHAM RAMSAY 1276 27 FEBRUARY 2004 VOL 303 SCIENCE www.sciencemag.org The clock ticking, Kennedy and Austri- Sinclair had studied genetic regulation in SIR2 wasn’t the only project stirring ex- aco focused on yeast, a single-celled organ- yeast—he and Guarente first met after a ge- citement in Guarente’s lab. A graduate stu- ism that lends itself to laboratory manipula- netics conference in Australia—and Sin- dent, David Lombard, had just cloned the tion. They began hunting for mutant yeast clair’s dissertation was the thickest in the mouse gene for Werner syndrome, a rare cells that lived abnormally long life spans, lab. And he had already earned a reputation disease that mimics accelerated aging. measured by the number of daughter cells for pushing limits. He racked up traffic vio- Along with postdoc Robert Marciniak, they produce. (A mother cell will typically lations in his red sports car, regularly skat- Lombard was trying to understand how the produce a daughter every 1 to 4 hours; an av- ing close to losing his license and once hav- Werner’s protein behaved in mouse cells. erage cell generates about 20 daughters.) In ing it confiscated altogether. “You’re al- “There were ideas and debates flying those early days, when Kennedy and Austria- lowed to get 12 points, and at one stage he through the air constantly,” says Brad John- co were testing hundreds of strains, they or- had 14,” recalls Geoff Kornfeld, the lab son of the University of Pennsylvania in ganized round-the-clock vigils to track their manager in Ian Dawes’s lab at New South Philadelphia, who was then a postdoc in the yeast cells; one of them was always there, Wales, where Sinclair studied. lab. Guarente, never one to coddle his stu- “This has run me through so many emotions, some of which I didn’t know I had.” —Lenny Guarente gazing at the cells under a microscope and The atmosphere in delicately counting off the daughters. Guarente’s lab when Sin- It quickly became obvious that some clair joined was electric. strains lived unusually long, which piqued Other students were Guarente’s interest. He hovered nearby, building on the yeast checking in with the students two or three work by Kennedy and times a day and grilling them on what they’d Austriaco, and they pin- found. The news was good: About 1 in 1000 pointed a specific SIR strains both produced an abundance of gene, called SIR2, that daughter cells and survived well under the could dramatically ex- stress of a chilly refrigerator, underscoring tend the cells’ life span. known links between longevity and stress Extra copies of SIR2 tolerance. Of these, one mutant caught their also enabled worms to attention. It was sterile—unable to mate live longer. with other yeast cells—and lived 50% Furthermore, Guar- longer than normal. ente’s lab had found that activity of the protein dents, pushed for results. Guarente canceled golf games with generated by SIR2, called SIR2p, was depend- Sinclair proved to be a brilliant and pro- Kennedy to spend more time in the lab. ent on an enzyme called NAD. All cells carry lific researcher, often the first to arrive, at Gradually, the group homed in on a trio of NAD, which helps govern metabolism. 8:00 a.m., and the last to leave, at 12:30 a.m., genes called SIR genes; deleting them SIR2p, it appeared, could sense the metabolic running to catch the final subway train of the seemed to shorten a yeast cell’s life. state of a yeast cell. night. He quickly became a favorite of Guar- It was around this time, in early 1996, This was significant because it dove- ente. But many lab members began regard- that 26-year-old David Sinclair boarded a tailed with what scientists had observed for ing him warily, especially after the 1997 pub- plane in his hometown of Sydney, Australia, decades in animals: Curtailing calories and lication of a Cell paper by Sinclair and Guar- and flew halfway around the world to Cam- altering metabolism dramatically extends ente. The paper reported that buildup of ribo- bridge. “Before I even knew I got the [post- life span. Biologists theorize that, in the face somal DNA, a kind of repetitive DNA se- doctoral] fellowship, I said to Lenny, ‘I’ll of scarce resources, organisms trade off re- quence, in yeast cells caused them to age take out a loan, I’ll sell my car’ ” to come to production, which is hindered by calorie re- (Science, 2 January 1998, p. 34). Although the lab, says Sinclair. His wife-to-be, a Ger- striction, for survival. No one knows, Sinclair had conducted the experiments him- man biologist, was moving to Australia on a though, precisely how a meager environ- self, Johnson had also proposed similar stud- fellowship of her own, but Sinclair couldn’t ment slows aging.
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