Matt Kaeberlein fermented a breakthrough in the genetics of yeast aging. His next feat: starting a biotech firm.

Biologist Matt Kaeberlein (pictured left) looks like he just got out of boot camp. He's tall, burly, has a crew cut, and exudes an air of self-confidence--not exactly the stereotypical nerdy scientist. "If you lined him up with a bunch of drill sergeants, ... he'd fit right in," says colleague Preston "Pete" Estep III, a geneticist and CEO of Longenity Inc., a small biotech start-up in Waltham, Massachusetts.

But appearance aside, Kaeberlein isn't the type to blend into the ranks. He completed his Ph.D. at the Massachusetts Institute of Technology (MIT) in a swift 4 years and 3 months, the first in his class to graduate. During that time, he helped pinpoint the central gene that controls aging in brewer's yeast. And at the ripe age of 31, he is now vice president, as well as a co-founder, of Longenity.

Kaeberlein has been an independent thinker since his childhood in Seattle, Washington. In the eighth grade, he skipped the confirmation ceremony at his Lutheran church, telling the pastor that some Lutheran teachings--for example, the premise that Christianity was the only religious faith that could secure him a place in heaven--were inconsistent with his own observations and interpretations of the world. And in high school, hoping to become a heavy-metal rock star, he took up the guitar, got his ear pierced, and grew his hair to the middle of his back. He also played on the school basketball team, whose coach did not appreciate his flowing tresses. "He was going to make me get my hair cut," Kaeberlein recalls. "So I wrote a letter to the school newspaper saying how unfair that was." The coach backed down, but he insisted that Kaeberlein tie his hair in a ponytail.

Kaeberlein got decent grades without trying. And although he didn't fully understand in high school what getting a Ph.D. involved, he figured he would get one someday because he knew it was "the highest you could go" in education, he says. But Kaeberlein was in no hurry: Despite his intention of going to college, he spent 3 years working for United Parcel Service on the 3 a.m. shift after graduating from high school. Uncertain of what he wanted to do with his life, he presumed he'd find something that grabbed him sooner or later: "I was just waiting for it to come and hit me over the head."

That head-clobbering epiphany--the one that compelled him to go into science--came in mid-1992. Earlier that year, ready to ease himself back into student life, Kaeberlein had begun taking classes at a community college during the day. In the defining moment, the enthusiastic instructor of his introductory biology course was discussing evolution and creationism, Kaeberlein recalls. "He said flat out, very emphatically, that you can believe what you want to believe, but science clearly says that evolution occurred." Suddenly, Kaeberlein says, he realized that science was a way of looking at life that fit with his analytical personality. "This teacher really was able to communicate to me that science is built on logic and critical thinking," says Kaeberlein. A couple of weeks after starting the course, "I pretty much made up my mind that I was going to go into science," he says.

Kaeberlein earned bachelor's degrees in both math and biochemistry from Western Washington University in Bellingham, 145 kilometers north of Seattle. In fall 1997, he and his future wife, Tammi Isaacson, who was pursuing a career in marine microbiology, moved to Boston for grad school--he to MIT and she to Northeastern University. After his first semester, Kaeberlein heard MIT molecular biologist Leonard Guarente give a seminar about his research on aging. Guarente explained how David Sinclair, a postdoc in his lab, had discovered that aging in Saccharomyces cerevisiae results from an accumulation of rDNA circles, loops of DNA that encode ribosomal RNA. The idea that a specific molecular mechanism could explain something as complex as aging, even in a simple organism such as brewer's yeast, captivated Kaeberlein. And the pie-in-the-sky possibility of using experiments with yeast to figure out why people age--and thereby to someday extend human longevity--was "extremely exciting," he says. Kaeberlein says he knew immediately that he wanted to work in Guarente's lab: "Maybe I'm somewhat impulsive about these major life decisions, but when something strikes me as feeling right, I do it and I don't look back."

He joined Guarente's group, where "he immediately became a star of the lab," says Sinclair, now a cell biologist at Harvard Medical School in Boston. "In group meetings, he would pipe up and offer great insights. He was superefficient. ... He was more of a postdoc than a grad student." Kaeberlein usually got to the lab at 7 a.m. and left at about 4 p.m., partly to avoid traffic--he and Tammi resided 24 kilometers north of MIT in Nahant, where they were live-in caretakers at Northeastern University's marine field station. Guarente remembers being puzzled about Kaeberlein's behavior during one period. On Fridays, they would discuss the experiments that Kaeberlein needed to do. "I wouldn't see him on the weekend, but then he would come in on Monday with the data," says Guarente. "So I became very worried about what might be going on." Kaeberlein, it turned out, had borrowed a microscope and set up his own lab at the field station. "He worked all weekend at home, generating data," Guarente says.

And those data were hot. The Guarente team had discovered that a group of related genes called SIR2, SIR3, and SIR4 influenced aging in yeast; when mutated, each shortened life-span. Most of the students and postdocs in the lab were scrutinizing SIR3 and SIR4, but in 1999, Kaeberlein, fellow grad student Mitch McVey (see "Beer and Aging"), and Guarente published a paper showing that overproduction of Sir2p prolonged life and that SIR2 was the key regulator of yeast longevity (see Kaeberlein Perspective). Kaeberlein's work was "terrific," says Guarente, whose lab now focuses almost entirely on SIR2 and its contribution to longevity in yeast, roundworms, mice, and human cells.

Kaeberlein also found time as a grad student to spearhead a SAGE KE project. He and his colleagues in Guarente's group cataloged the genes and interventions--such as calorie restriction and treatment with antioxidants--known to alter aging and organized them into an online database (see "Genes/Interventions Database"). After he graduated from MIT, SAGE KE's editors asked him to continue as curator of the database, and he still keeps the resource up to date.

Kaeberlein finished his Ph.D. in December 2001. Like many other students, however, he went through a phase of dissatisfaction in his last year of grad school because he was itching to move on. He was eager to call his own shots as a researcher, he says, and he was disenchanted with the prospect of doing a postdoc. "I really felt that I had learned enough: I knew how to design experiments, and I was basically doing everything that the postdocs in the lab were doing." Besides, the notion that any Ph.D. should work 50 to 60 hours a week for $35,000 a year struck him as "a raw deal."

Despite those feelings, Kaeberlein decided to stick with science after considering careers in patent law and science writing. He decided to seek a postdoc position exploring what intrigued him most: using DNA microarray analysis to study aging in higher organisms. "Unfortunately, at that time there wasn't really anybody who was doing that," he says. But Kaeberlein contacted Harvard Medical School geneticist George Church, a pioneer in genomics and bioinformatics, who invited Kaeberlein to give a talk to his lab members. Church, now a scientific adviser to Longenity, invited Estep--a former grad student--to the presentation.

Estep had just launched Longenity, and he recalls immediately being impressed by Kaeberlein's energy and ideas. "Most people, when they first meet Matt, are probably quite intimidated," says Estep. "Because he's very sure of himself--he'll say whatever is on his mind and not think twice about just laying things on the table. He wants to be part of what's going on. ... That's one of the things that I think is so valuable about him: He wants to make things happen." Soon afterward, Kaeberlein accepted Estep's invitation to join Longenity as a co-founder--no postdoc training required. Guarente told him it was a mistake. "My advice to him was to do a postdoctoral [fellowship] and follow the academic track," Guarente recounts. "But it was his call. ... I think whatever path he chooses for himself, he'll end up in a good place."

Kaeberlein has thrived in his foray into the biotech industry. "I love the extra responsibility; I love the intellectual freedom; I love the brainstorming we do," he says. Longenity is using functional genomics and bioinformatics tools to hunt for genes and interventions that can extend human life-span. Although the dismal U.S. economy of late has slowed the company's growth, it is about to add to its staff of seven full- and part-time scientists.

One big difference between research in biotech and academia, Kaeberlein says, is that industry scientists must keep an eye on the bottom line. That means that when you're designing experiments, "you do have to think about, 'Well, is this eventually going to lead to a product?' " he says. But so far, he hasn't bumped against constraints on his curiosity. "There are so many great, very exciting areas to study in the biology of aging. Maybe I won't be able to do one experiment that I want to do, but there are 10 others that I can do."

In his spare time, Kaeberlein enjoys reading science fiction, lifting weights, and pampering his Keeshond, Duchess, who often accompanies him to work. Last February, he and Tammi had a baby, Connor, who arrived 5 weeks premature and had to spend 12 days in an intensive-care unit. "Connor came through it fine and is a happy, healthy little man," says Kaeberlein. "I love just spending time with him and playing with him." As a proud new father in the Internet age, Kaeberlein has even designed a Web site for his son, complete with family photos and a first-person biography "written" by Connor. But, ever the scientist, Kaeberlein can't stop collecting and analyzing data even at home: The Web site features a graph charting Connor's growth.

* Ingfei Chen, a writer in Santa Cruz, California, is waiting for her own head-clobbering epiphany.