Sci. Aging Knowl. Environ., 5 February 2003
Listening to the Song of Senescence
Caleb Finch, a biogerontologist and bluegrass fiddler, has woven diverse themes into a research opus on aging
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/nf3 This article comes to you through a collaboration between SAGE KE and Science's career development Web site, Next Wave. The joint venture is supported by the AARP Andrus Foundation. In the late '60s at Rockefeller University in New York City, biology graduate student Caleb "Tuck" Finch gave a talk on his Ph.D. research, titled "Cellular Activities During Aging in Mammals." He recalls that afterward, pathologist Peyton Rous, who had recently won a Nobel Prize for discovering tumor-inducing viruses, challenged him about why he was going into such a research area. "Everybody knows aging is just about vascular disease and cancer," Finch recollects Rous saying.
Rous's view echoed the prevailing scientific sentiment on aging: Nothing was left to explain about growing old. Convinced, however, that there was in fact "a hell of a field" to build around gerontological science, Finch has spent the past 3 decades at the University of Southern California's (USC's) Leonard Davis School of Gerontology in Los Angeles seeking to understand the genomic control of senescence in the brain. Over the years, he has been influential in promoting the idea that mammalian aging is a regulated process that scientists can tease apart at the molecular level. "Many people still don't believe that," says Charles Mobbs, a neuroendocrinologist at Mount Sinai School of Medicine in New York City who did his Ph.D. work in Finch's lab. "... But Tuck gave me the faith that aging could be understood that way."
At 63, Finch projects a formidable presence: He's tall and balding with a bushy, grizzled beard and a "fierce look in his eyes," says Mobbs. "He looks like God: He looks like he came down from the Appalachians last week." Finch is an avid reader who wields an impressively large lexicon--"he doesn't suffer fools gladly," says Mobbs--and he plays traditional southern mountain music on the fiddle. As a man of words, ideas, and music--and a hearty, distinctive laugh--Finch stands out for his efforts to elicit harmony from current scientific knowledge about aging by weaving various lines of research into coherent compositions.
Genes for Science
Finch was born in England on 4 July 1939 to a couple with roots in colonial New England. His father, who worked for National City Bank of New York, had been assigned to the firm's London branch, but a month after Great Britain declared war on Germany in September 1939, Finch and his mother returned to New York City. His father came home 2 years later, and the family settled in Katonah, a small rural town 65 kilometers north of Manhattan. In 1945, Finch's father died of tuberculosis. His mother, who later became a schoolteacher, encouraged Finch's natural curiosity. He spent his childhood immersed in books and tinkering with a home chemistry set, now and then creating explosive mixtures: "The fire patrol came over more than once," he says.
Science ran in Finch's veins. His forebears include Benjamin Silliman, the first chemistry professor at Yale College in New Haven, Connecticut, whose teachings in the early 1800s helped popularize science education in the United States. And with an uncle and granduncle who were both engineers, Finch grew up surrounded by talk of science.
As it happened, Katonah was the home of the Hickrill Chemical Research Foundation, an outpost of Yale's chemistry department, and Finch found his way into the foundation's labs when he was 16. "I had a summer job washing lab glassware that put me in contact with a lot of really smart people, who found it amusing to try to answer questions from a kid who hadn't had high school chemistry."
He got into Yale on a scholarship in 1957. As a so-called bursary boy, in his first week on campus, he was sent to wait on tables in the upper-class dormitories. But the assignment did not sit well, Finch recalls. "I stormed into the bursary office and said, 'I didn't come to Yale to wait on tables. I came to learn to do science. I want to have a lab job, not a job in the dining room.' " A startled clerk handed him a directory of available research positions, and 15 minutes later, Finch was talking with Ernest Pollard, founder and head of Yale's then-new biophysics department. Pollard hired Finch as a lab assistant. "I was sort of taken in as a mascot by this group of tremendous minds who were coming from physics into biology and questioning everything. It was a marvelous formative opportunity," Finch says. Encouraged by his mentors, he decided to major in biophysics.
In 1958, microbiologist Carl Woese, an assistant professor at Yale who later identified the kingdom of Archaea bacteria at the University of Illinois, Urbana-Champaign, advised Finch to head into little-trodden scientific territory. They discussed developmental biology as an area ripe for discovery, but Finch recalls Woese suggesting, "Why not think about aging? That's even more mysterious." About a year later, Finch read British physician Alex Comfort's book, The Biology of Senescence, and found himself enthralled. Finch's interest in aging had been piqued, although it would lay dormant for a few years more.
Early Disaster Molds a Successful Career
After graduating from Yale in 1961, Finch moved to New York City so that he could do Ph.D. research at Rockefeller University. Working in the lab of biochemist and Nobel laureate Edward Tatum, Finch attempted to isolate nucleoproteins from the bread mold Neurospora. But the project "crashed and burned," Finch says, as a result of his "being too rigid and not realizing the technical limitations of the system." No one had ever isolated nuclei from Neurospora, let alone nuclear proteins. Unable to work out the difficulties, Finch abandoned the work: "It was devastating. I put in approximately 26 months of superheavy time and didn't get anything out of it."
Finch started again under the tutelage of Rockefeller biochemist Alfred Mirsky, a leading investigator on the chemistry of the nucleus, with whom he had often discussed his Neurospora project. With Mirsky's encouragement, Finch decided to tackle another risky project: deciphering the physiology of growing old. Although most scientists--including Rous--regarded research on senescence as a waste of time, Finch says he saw huge potential for developing rational strategies that would allow him to tease out underlying causes of aging.
The cellular functions that Finch studied for his "second Ph.D." included the activation of the gene that encodes tyrosine aminotransferase (TAT). In mammals, cold temperatures trigger the release of glucocorticoid stress hormones, which in turn crank up production of this enzyme in the liver. Finch showed that TAT gene expression is reduced in old mice relative to young mice; however, when he injected glucocorticoids directly into old and young rodents, he found no age-associated impairment in their responses.
The findings led Finch to a surprising conclusion--one that would form the bedrock of his entire career. At the time, a prevailing view on senescence was that cells die after a set number of divisions--a phenomenon known as the "Hayflick limit"--and that the physical infirmities of aging arise because cells simply stop operating as they reach this critical point (see "More Than a Sum of Our Cells"). Many researchers were hunting for intrinsic impairments in gene regulation with aging. But Finch's results suggested instead that cells and genes in aged mammals function no differently from those in younger animals, given the right physiological milieu--in this case, a sufficient dose of glucocorticoids. He speculated that hormonal abnormalities accompanying aging--specifically, those regulated by the nervous system--might drive the cellular changes associated with senescence. "It was a radical concept," he says of the so-called neuroendocrine hypothesis.
Striking the Right Chord
As Finch's science was beginning to pick up, he was exploring another passion: his gift for music. In elementary school, he had learned to play the trumpet, and even at that young age, he managed to syncopate his way into the local high school marching band. But the melodies that were ingrained on his soul were the strains of the traditional fiddle music that had permeated the square dances and town festivals of his childhood in Katonah. Years later, in college, Finch taught himself how to play the fiddle. "I was always drawn to the rustic roots of things," he says.
In New York City, he found a musical soul mate. Another grad student in the Mirsky lab, Eric Davidson, was a banjo player who had been making recordings of traditional mountain tunes from the southwestern Virginia Appalachians for the Smithsonian Institution. Finch joined Davidson on a number of field recording trips, and in 1963, they and a guitarist named Peggy Haine formed the Iron Mountain String Band. The group, which cut its first album in 1972, improvised on bluegrass and other traditional tunes, including laments about bad luck and hard times. Between experiments, Finch practiced the "drone" style of fiddling on two or three strings simultaneously, a technique that yields bagpipelike results that Scots-Irish settlers brought to the Appalachians in the 18th century. "I would take a break, fiddle a little bit, have a nap, and then go back for another 4 or 5 hours," he says.
Go West, Young Man
After completing his Ph.D. in 1969, Finch conducted independent research at Rockefeller as a postdoc while working as an assistant professor down the street at Cornell University Medical College. To further probe the links between the endocrine system and aging, he focused on the effects of hormones upon the brain. At Cornell, he studied the metabolism of neurotransmitters, including dopamine, in the noggins of aging mice.
In 1972, Finch made tracks for the West Coast. Davidson had taken a position at the California Institute of Technology in Pasadena, and the idea of reviving the String Band (albeit without Haine, who stayed in New York) was appealing. But even more enticing was a job offer from USC. With a donation from Leonard Davis, co-founder of the American Association of Retired Persons (now called simply AARP), the university was constructing a building that would house its future school of gerontology, the first of its kind in the nation. Unlike efforts elsewhere, USC was developing a program to study not just the sociological and psychological impact of aging but also the biology of senescence. The university's commitment and broad approach impressed Finch and has kept him there ever since.
In the decades that have followed, Finch has probed the neurobiology of senescence in his lab at the school's Ethel Percy Andrus Gerontology Center. Among their many contributions, he and his colleagues showed in the late '70s that, contrary to what previous reports had suggested, overall amounts of active messenger RNA in the rat brain do not decrease with aging, further bolstering the idea that mammalian gene expression remains largely normal into senescence. Research by Finch's team in the mid-'90s also led to a startling discovery in Alzheimer's research: In 1998, working with neuroscientists at Northwestern University in Evanston, Illinois, the group reported that amyloid--the insoluble protein that piles up in the Alzheimer's-afflicted brain--is also highly neurotoxic when it clusters into small but soluble oligomers, dubbed ADDLs.
Finch's ideas about senescence from his grad school days have also held up: The popularity of the Hayflick model has declined as other research questioned its relevance to aging in whole organisms, and recent studies in long-lived nematodes have confirmed Finch's hunch that brain hormones control aging (see Johnson Review). "The evidence has strongly shifted in favor of the neuroendocrine hypothesis," says Mobbs.
Meanwhile, tuning in to other research themes, Finch has delved into the comparative biology of aging, a topic he surveyed in detail in his 1990 book, Longevity, Senescence, and the Genome, a 922-page tome. "Some people refer to it as the bible on aging," says USC biochemist and biogerontologist Valter Longo, a former Finch postdoc. And every year or two since 1997, Finch has organized a symposium to highlight research on animals and plants that age slowly, including species of turtle and tern that display, in his terms, "negligible senescence" (see "Growing Old in Style").
Improvising a New Attitude on Aging
But Finch's most important role in gerontology, some colleagues say, has been as a deep thinker who has substantially cultivated gerontology's reputation as a field of credible science. Many theories on aging have come and gone over the decades, and "99% of them were bogus," says Mobbs. Starting with his Ph.D. work and continuing with his many reviews, essays, and books (see "A Short Course on Aging"), Finch is one of the first people to offer a convincing argument that senescence can and should be studied in the same way that other developmental processes are, Mobbs adds.
Much of Finch's persuasiveness stems from his talent for integrating the many different themes of gerontology research--from inflammatory brain processes to the biology of slowly aging creatures--into a sweeping view of the aging process. "He has encyclopedic knowledge of this area," says biodemographer James Carey of the University of California, Davis. "Tuck can talk about everything from the arcana of molecular genetics of aging to aging at the level of the whole organism, including ecological and evolutionary and demographic components." Recently, Finch even wrote a book with gerontologist Tom Kirkwood--called Chance, Development, and Aging--exploring how intrinsic random processes during development could explain why genetically identical creatures grown in the same environmental setting show a wide range of life-spans.
As a mentor, Finch is known for keeping his prot�g�s on their toes. "It's a continuous test," says Longo. Whenever members of two or three labs gather casually at a meeting, Longo says, at some point "he'll turn to you and he'll say, 'So Valter, why don't you connect this with your work?' or 'Tell us your opinion on this.' ... All of a sudden, you have this question, and you have maybe a second to decide what you're going to say." In the same way, Finch has even caught senior colleagues off-guard during public discussions at national conferences.
Finch's pop-quiz style of questioning is great training: "You get to the point where you're listening ... in every single meeting because you know you're going to get this question. It really prepares you for the conferences, the real world out there," says Longo. And by pulling others into a debate, Finch also taps into the expertise of whoever's in the audience. "It keeps everybody energized and engaged," says Carey. It's just one more way Finch fosters synergy in the field. "He's trying to bring in new people, fresh ideas at all levels," Carey adds.
Despite his busy research schedule, Finch devours books on topics far and wide. Says Longo, "I'm Italian, and he knows way more than I do about the Roman Empire and trade in the Middle Ages." Finch also still finds time for jamming with Davidson and guitarist Brooke Moyer in the Iron Mountain String Band. They've played all the major folk music festivals in Southern California, and they even performed the bluegrass score for The Dollmaker, a 1984 film starring Jane Fonda. The musicmaking is a high-speed feat of constantly anticipating, responding to, and melding with his partners' interpretations on a central theme, Finch says: "Each of us senses where the music is going at a given moment and puts it together so that it makes sense." Perhaps it's mere coincidence, but the same description could also apply to Finch's role in the science of senescence. Whether with intellectual ideas or with music, he's spun out one creative improvisation after another.
February 5, 2003
Ingfei Chen, a writer in Santa Cruz, California, is beginning to feel the song of senescence droning through her achy joints.
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Citation: I. Chen, Listening to the Song of Senescence. Science's SAGE KE (5 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/5/nf3
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