Ten years ago, geriatrician Thomas Perls couldn't understand why his 100-year-old patients were never in their rooms. He started looking into why, and he hasn't stopped since

Like most doctors, Thomas Perls was trained to accept the view that aging inevitably brings on a litany of chronic illnesses, leaving elderly people senile and decrepit. So in 1992, Perls was prepared for the worst when, as a fellow in geriatric medicine at Harvard Medical School in Boston, he heard that two of his patients were more than 100 years old. "I expected them to have every age-related disease under the sun and certainly be at death's doorstep and demented," says Perls, a 43-year-old with curly brown hair, a gentle manner, and a mellow and measured way of speaking.

But a funny thing happened: At the Hebrew Rehabilitation Center for Aged, where he worked, Perls could never find the two centenarians, Celia Bloom and Ed Fisher, to do their physical exams. "For 6 months, I'd be going by their rooms, and they were never there," he says. Eventually he tracked them down--and found that Bloom was always busy playing Chopin and Mozart on the piano for the other nursing home residents. "She was totally sharp, but she was 102," Perls recalls. "And Ed Fisher had been a tailor all his life, so he was out and about mending everybody's clothes. ... And when he wasn't doing that, he was robbing the cradle--dating his 85-year-old girlfriend!"

The discovery that centenarians could be so hale in mind and body took Perls by surprise, particularly because experts then believed that anyone over 100 would surely have Alzheimer's disease. But when he examined other centenarians at the center, a quarter of them showed no evidence of cognitive decline. Curious about how they were able to thrive to such an advanced age, he started the New England Centenarian Study (NECS), a survey of the very old that initially focused on people in eight towns around Boston. The study, now based at Boston University School of Medicine, has since grown into the largest comprehensive investigation of its kind anywhere--with data on 1000 centenarians from primarily the United States and Canada, as well as Germany, Japan, and Australia--and it has toppled a number of misconceptions about extremely old age.

Far from bolstering the widespread perception that the superannuated eke out their lives in illness and disability, Perls's work has revealed that some centenarians can stay remarkably healthy and functional for almost their entire lives, escaping ailments ranging from dementia to diabetes. Perls built "a new view, a new way to look at it," says geriatrician T. Franklin Williams of the University of Rochester School of Medicine and Dentistry in New York, who mentored Perls in medical school.

The NECS demonstrates that "in order to get to 100, you have to be among the strongest and most resilient--physically, mentally, socially," says Daniel Perry, executive director of the nonprofit Alliance for Aging Research in Washington, D.C., which funded some of the NECS work in the past (and which co-sponsors SAGE KE's sister Web site, SAGE Crossroads). "It sort of raises the bar and raises our vision of what healthy longevity can look like." Perls's investigations of these superachievers in longevity also suggest that genetics underlies exceptional life span in people.

Respecting His Elders

Born in Northern California, Perls became fascinated with nature and biology from an early age. His father, a German physicist who earned his Ph.D. at age 22, worked for the U.S. space program; that career took the family to Littleton, Colorado, when Perls was in third grade. There, Perls grew up on a lake where bird watching and fishing gave him an appreciation for living creatures, and he wanted to become a veterinarian. But around the age of 13, he began to change his mind. "I recall deciding I liked talking with people. I couldn't do that with the animals," he says with a chuckle.

So Perls considered going into medicine instead. To explore that notion, he worked as an orderly in nursing homes during the summers after 10th and 11th grades, and he found that he enjoyed striking up friendships with patients. But while applying for jobs, he also realized that some facilities mistreated the elderly by overmedicating them, putting them in "chemical straitjackets that controlled their behavior." Perceiving a huge gap between the medical care that some seniors received and the care that they deserved, Perls decided to become a doctor who looked after elderly people.

After graduating from Pitzer College in Claremont, California, in 1982, Perls went to the University of Rochester's medical school, one of only a handful that offered a geriatrics curriculum. Williams, who headed the geriatrics program, remembers how, as a second-year student, Perls sought him out. "He's the only student I've ever known who took it upon himself fairly early in his career to come and say, 'Look, I want to go into geriatrics,' " Williams says. In 1983, Williams left to become the second director of the National Institute on Aging in Baltimore, Maryland. Before departing, he agreed to rent his house to Perls on two conditions: "One was that I take care of his wife's garden," says Perls. "And the other was that I continue to be interested in geriatrics." Although for a time, he seriously considered becoming a surgeon, Perls kept his end of the bargain.

After finishing med school in 1986, he did his residency at the Harbor-UCLA Medical Center in Torrance, California, and in his third year he married Leslie Smoot, a pediatric cardiology resident. When Smoot secured a fellowship at Harvard, Perls also applied to the university and landed his clinical geriatrics fellowship there. But the couple deferred that training for a year to start a family and travel abroad. For the first 6 months, Perls worked in the student health center at the University of Southern California in Los Angeles while Smoot, pregnant, took time off and gave birth to their first daughter. Then the family headed for Australia, vacationing 1 month in New Zealand before settling into Melbourne, where the couple worked at different hospitals. Perls was a fellow at the Mount Royal Hospital, a medical center dedicated to geriatrics--a foreign concept by American standards. "It was an incredible experience for me, in a health care system that was completely different from that of the United States," says Perls.

After returning home in 1990, Perls began his Harvard fellowship and started treating patients at the Hebrew Rehabilitation Center for Aged, where he met Bloom and Fisher in his second year. In addition to having a personal affinity for senior citizens, Perls also recognized that geriatrics was a relatively unexplored field with wide-open research opportunities. "The world was kind of your oyster," he says. With funding from the federal Agency for Health Care Policy and Research (AHCPR), he arranged to stay on for a third fellowship year, doing geriatrics research at both Harvard and Brown University in Providence, Rhode Island, and he began hunting for a topic to investigate. After his initial encounters with the centenarians piqued his interest, a subsequent literature search confirmed his hunch that little was known about the very old. "Lo and behold, I found my research project," he says. "I was very lucky. I was in the right place at the right time, with a little curiosity."

Heeding the Lessons of Survivors

During his AHCPR fellowship, Perls surveyed the other centenarians at Hebrew Rehab. He wanted to tackle a population-based study of long-lived elderly, but he didn't know any epidemiology or statistics. So that same year, he earned a master's degree in quantitative methods from the Harvard School of Public Health. In 1994, he joined the Harvard faculty and began tracking down centenarians for his eight-town survey, first working out of New England Deaconess Hospital and, later, Beth Israel Hospital. (The two hospitals later merged to become the Beth Israel Deaconess Medical Center.) Last year, Perls moved across town to Boston University.

As his project was getting off the ground, Perls was inspired and guided by demographer James Vaupel of the Max Planck Institute for Demographic Research in Rostock, Germany, as well as other European researchers who were studying centenarians in France, Italy, and Denmark. At their invitation, in the mid-1990s, Perls began attending annual meetings of their organization, the Alliance for Research on Longevity and Survival, or ARLES--named after the French city that was home to the oldest human in recorded history, Jeanne Calment, who died at age 122. "It was otherwise quite lonely, and to be with others who have a tremendous interest in the same thing was a real morale booster," he says.

The NECS, which has been expanding ever since its inception, has been a gold mine of unexpected findings. For instance, Perls and his colleagues documented that one-fifth of women in their survey had babies after the age of 40--and that they were four times more likely to survive to 100 than were those who didn't bear children in middle age. The results suggested that centenarian women age slowly enough to preserve their reproductive health into their 40s. The scientists published their research in Nature. "It was just a one-page article. ... And suddenly me and a co-author were on the Today show, and it was 3 days of media madness," Perls says. The 1997 paper also grabbed the attention of the National Institute on Aging, making it easier to obtain grants for his research, he says.

Perls's team relied partly upon local newspapers to track down centenarians. One day, for example, the Quincy, Massachusetts, Patriot Ledger ran a front-page picture of a 108-year-old man blowing out candles on his birthday cake. It was a rare sight, because only 15% of centenarians are men. "But very amazingly, there was his 103-year-old sister looking on. And I had never seen anything like that before," says Perls. The scientists went to visit the duo--and learned that the siblings also had two living "baby" sisters, aged 102 and 99. What's more, two more sisters had died just 2 years earlier, both after passing 100. The investigators identified two other families elsewhere in the country that had several very long-lived members. That centenarians could cluster in families was a "heck of a revelation," suggesting that extremely long life span can run in the blood, Perls recalls. The data were "just screaming 'genetics,' " and he quickly found himself at the forefront of research into the genetics of exceptional longevity.

Working initially with Leonid Kruglyak, a geneticist at the nearby Whitehead Institute, Perls found that brothers and sisters of centenarians were four times more likely to reach the age of 91 than were members of the general population. Perls went on to collaborate with Louis Kunkel, a geneticist at Children's Hospital in Boston; Annibale Puca, a postdoc working with Kunkel; and other scientists at the Whitehead. After analyzing DNA from 137 sets of extremely old siblings in the NECS from across the United States, the scientists found that the centenarians share a stretch of DNA on chromosome 4 that might contain a gene for exceptional longevity (see Strauss Science Article).

A Biotech Gamble Exacts a Price

The region the researchers had defined was huge, spanning about 20 million "letters" in the DNA code. They knew that a hunt for the crucial gene would be both difficult and expensive--too costly and risky, they thought, for the National Institutes of Health to finance. Several venture capital (VC) firms had previously approached Perls and his hospital about starting a biotech company. "It seemed like if we could get the funding through a VC and get a company to do this work, it could go very fast," he says. The technology transfer offices at Beth Israel Deaconess and Children's were enthusiastic about the idea: "Then it was like rolling a snowball down a big mountain." In 2002, Perls, Kunkel, and Puca founded Centagenetix, which merged with Elixir Pharmaceuticals in January 2003 (see "Joining Forces").

Establishing the company permitted the scientists to do a tremendous amount of work on centenarian genetics; the project has already uncovered some major findings about the "longevity" region of chromosome 4, and a paper about the work is currently under review. But Perls says that some colleagues seemed to lose respect for him. "I think that there is a real negative connotation to not being a purist academically, and that the minute you delve into the commercial world, you've become a second-class citizen," he says. Some university scientists perceived that his collaboration with industry hindered him from publishing his research results or openly sharing them at meetings. "In many ways, it's a misperception," Perls says: The reality is that any scientist who has a hot finding won't publicize it before publishing it, for fear of getting scooped.

Spreading the Word on Extreme Longevity

Perls has clearly made his mark on biogerontology. Previously, says Perry of the Alliance for Aging Research, all that society could glean about the secrets to extra-long life were the personal prescriptions that centenarians might share with newspaper reporters on their birthdays--"anecdotal stories that ranged from reading the Bible every day to drinking a pint of whiskey every day." But thanks to the NECS, "we now have some real information about what are some of the qualities present in common among those [who] make it to such a long life," he says.

Perls's success arises in part from his thoroughness and imaginativeness as both a scientist and a clinician, says Williams: "He puts things together in new ways, and he's always asking new questions." Perls is also a team player who believes strongly in acknowledging the group effort that goes into his research. For instance, says Dellara Terry, a Boston University geriatrician who works on the NECS, when NBC Nightly News wanted to interview Perls shortly after she'd joined the project, he invited her to go along to do the interview. "I kind of looked at him, 'Why would they possibly want to interview me?' So we went and they filmed the two of us sitting together," she recalls. Terry didn't make the final cut: "All that you could see was my elbow," she says, laughing. "But Tom felt that what I was doing was important"--she had spent a month recruiting more than 100 participants into the study--"and he wanted to give me credit."

In their prime. Perls and tai chi instructor Murray Keller, 98, showed off some of their moves at a biogerontology conference in 2001. [Credit: Courtesy of Thomas Perls]

Perls also has a knack for communicating the message that extreme old age doesn't automatically equate with frailty and debilitation. Case in point: Five years ago, Perls received a 3-year Beeson scholarship, administered by the Alliance for Aging Research and the American Federation for Aging Research. When his grant ended in 2001, he presented his findings at the annual meeting of Beeson awardees, which was held in Florida that year. To demonstrate to the audience what exceptional longevity really looks like, Perls brought along Murray Keller, a 98-year-old Florida resident enrolled in the NECS who is known as the "Tai Chi Tiger" because he teaches the martial art. Keller and Perls got up on the stage and did tai chi moves together as the geriatrician explained his results. "Tom and the man dropped to the ground and started doing one-handed waves from the pushup position," Perry recalls.

Penning the Story of a 108-Year-Old Ghost

Getting to know centenarians has motivated Perls to start taking better care of himself. Their stories "really opened my eyes" to the high quality of life one can have beyond the age of 60, he says. He lost nearly 14 kilograms in the past couple of years by cutting back on ice cream, bagels, and chocolate. And he hopes to stick around long enough to enjoy not only his three kids and their future children, but also--maybe--his great-grandchildren. His genetics research would suggest that he has a chance: One of his great-grandmothers lived to 102.

On the home front, Perls and Smoot, now a pediatric cardiologist at Children's Hospital, juggle child-care duties with the help of a part-time nanny. Smoot is usually gone from 8 a.m. to 8 p.m., so Perls heads home at about 6 p.m. every day to cook dinner for the family. Smoot has been the most influential force in his life, offering a sounding board off of which he bounces his research ideas, Perls says. "She's been my most important devil's advocate and is very quick to tell me when she thinks I'm full of it versus when I'm on to something."

In his meager spare time, Perls has been dabbling in writing a screenplay about a curse put upon the Boston Red Sox by the ghost of Babe Ruth, who died in 1948 at the age of 53. The tale is inspired by the house next door to Perls's, which was once owned by Eddie Collins, who managed the Sox when the Babe played for them. In the screenplay, the neighbor's barn is haunted by the baseball legend's phantom. Perls hopes to finish the story soon. But in the meantime his primary fascination is with 100-year-olds who are still living and breathing.

* SAGE KE contributing editor Ingfei Chen is based in Santa Cruz, California. Her parents are in their 70s and can still cream her at tennis.