Sci. Aging Knowl. Environ., 23 July 2003
Funded Up and Raring to Go
The nonprofit American Federation for Aging Research has just announced its 2003 grant awardees, and four winners tell how they plan to use the money
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/29/nf14 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. On Friday the 13th last December, Daniel Herrera was running late. A psychiatrist-neurologist at Cornell University's Weill Medical College in New York City, Herrera was scrambling to submit a grant application to the American Federation for Aging Research (AFAR) by 5 p.m. "I thought I wasn't going to make it," he recalls. But despite the date, his luck held out. He hopped in a taxi to AFAR's headquarters in midtown Manhattan--squeaking through traffic to hand-deliver his application 30 minutes before the deadline.
The last-minute hustle was worth the effort. In June, Herrera learned that he was one of 130 scientists who won funding this year through 11 grant programs sponsored by AFAR. "In 2003 we are going to give away just over $7 million," says Odette van der Willik, director of grant programs for the nonprofit organization. AFAR aims to promote healthier aging by supporting research into the basic mechanisms of aging and age-related diseases. The outfit is particularly interested in bringing new scientists into the discipline. Since its creation in 1981, AFAR has distributed $71 million to more than 1800 investigators ranging from grad students to junior faculty. The competition is tough: The nonprofit received 130 proposals for its core program, the AFAR Research Grant Program, which provides up to $60,000 of support for 1 to 2 years to those in the first or second year of a junior faculty appointment. But it funded only 12, including Herrera's. Similarly, whereas 39 young scientists applied for the Ellison Medical Foundation/AFAR Senior Postdoctoral Fellows Research Program, only three won the 2-year, $100,000 fellowships that are meant to encourage M.D.s and Ph.D.s to study fundamental mechanisms of aging.
This year's AFAR-funded research projects span a spectrum of disciplines and ideas, from studies that probe the role of oxidative damage in aging in fruit flies to those that investigate the effect of kidney ailments on the development of heart disease in the elderly. But, as the examples below illustrate, the grant winners share one thing: The money is helping propel their investigations into fledgling interests or in new directions within the field of biogerontology. And in many cases, it is giving junior faculty members a boost toward independence.
A Toast to Protecting the Aging Mind
At Weill Medical College, Herrera's lab studies neural stem cell transplants and neurogenesis--the birth of new neurons--in the adult brain. With his AFAR money, the 39-year-old assistant professor is beginning to investigate how alcoholism influences neurogenesis as the noggin ages, through experiments with boozing rats.
The project arose from a confluence of Herrera's interests as a clinician and a research scientist. A native of Argentina, he earned his medical degree from the University of Buenos Aires in 1986. (In Argentina, medical school training begins after high school.) After moving to McGill University in Montreal, Canada, he completed a Ph.D. in pharmacology in 1993 by studying gene activity after brain injury. Starting in the mid-1990s, during a combined neurology and psychiatry residency at the New York Presbyterian Hospital-Cornell Medical Center in Manhattan, a number of observations got him thinking.
As a physician, he often dealt with elderly patients whose confusion and forgetfulness suggested dementia; but to confirm that diagnosis, he had to rule out alcoholism, because heavy drinking can also severely impair memory and learning. Scanning the scientific literature, Herrera learned that the brain region that controls these functions--the hippocampus--shrinks in longtime alcoholics. However, this decrease in size, along with the associated mental glitches, reverses with abstinence. The mechanism through which alcohol harms brain cells, however, was unknown. Meanwhile, in the late 1990s, other scientists began reporting that the adult brain can make new neurons in the hippocampus, contrary to the century-old dogma that neurogenesis ceases after early development (see Wise Perspective).
Herrera decided to explore whether high alcohol intake influences this process. In a study published in the June 24 issue of the Proceedings of the National Academy of Sciences, he and his colleagues plied young adult rats with ethanol for 6 weeks and found that the number of new neurons forming in the hippocampus plummeted by 66%, compared with sober controls. But this detrimental effect disappeared when the rodents also consumed a synthetic antioxidant called ebselen. The results support the notion that alcohol kills brain cells by enhancing the production of free radicals, unstable oxygen molecules that attack and injure DNA, proteins, and lipids.
Herrera is now using his 1-year, $60,000 AFAR grant to assess whether old rats are more vulnerable than young ones to alcohol's lethal effect on new neurons. He speculates that as the brain grows old, antioxidant therapy could protect even more dramatically against the toxic effects of chronic drinking. The grant is "perfect for this kind of project," says Herrera. "If we get good results, we can apply for NIH funding." From the clinical viewpoint, an effective antioxidant treatment could pay off for human tipplers: According to past studies, alcoholics--particularly elderly ones--in rehabilitation programs are more successful at kicking the habit if they have fewer cognitive impairments.
Going Batty Over Old Age
The last week of June found molecular biologist Andrej Podlutsky and his family driving from Connecticut to Moscow, Idaho. The 36-year-old was headed to a new postdoc position with evolutionary biologist Steven Austad (see "Taming Lions, Unleashing a Career") at the University of Idaho. Podlutsky brought along the family's Russian-speaking parakeet, a dozen pet catfish and cichlids in a 15-gallon picnic cooler--and $50,000 from the Glenn/AFAR Research Grant Program for Postdoctoral Fellows. "When you come to a new place and you bring some money, it's very good," he says. "It's like coming to a birthday party with a present."
Podlutsky plans to use the grant, which is sponsored by the nonprofit Glenn Foundation for Medical Research and administered by AFAR, to study aging in an order of mammals that are pros at growing old: bats. When it comes to studying senescence, "mice and rats are very convenient and affordable, but they are not designed for long life," he says. Mice live only 2 to 3 years in the lab--and they rarely age in the wild because few of them survive longer than a year. Natural populations of bats are quite the opposite; "almost all of them survive to old age," Podlutsky says.
He is focusing on the little brown bat, Myotis lucifugus, which lives more than 30 years in the wild, and the Mexican free-tailed bat, Tadarida brasiliensis, which has an 8-year life span. By comparing the two, he'll test the theory that damage caused by free radicals drives the process of aging (see "The Two Faces of Oxygen"). He plans to expose cultured bat embryonic skin cells to hydrogen peroxide or radiation, both of which trigger the formation of free radicals; then he'll measure how efficiently the cells activate protective genes such as the one that codes for manganese superoxide dismutase, an enzyme that sops up the toxic molecules. "You'd expect that short-lived animals will react much less efficiently than long-lived animals," he says. Previous work on birds by Austad's lab and collaborators has lent support to that idea: Their experiments suggest that budgies, which can survive more than 20 years, are more resistant to oxidative stress than quail, which chirp their last breath after about 4 years (see "Bye-bye Birdie").
Podlutsky has had bats on the brain since 1997, when he first learned of their long life spans by perusing Austad's book Why We Age. At the time, he was a junior guest researcher at the Karolinska Institute in Stockholm, Sweden, studying DNA mutation rates in mammalian cells. That work contributed to a Ph.D. in molecular biology in 1999 from the Institute of Theoretical and Experimental Biophysics in Pushchino, near Moscow, Russia. Podlutsky's dissertation showed that the rate of mutation was much higher in cells from old mice than in young ones and that a diet of antioxidants reduced the mutation frequency in the elderly rodents to the same level as that seen in the juveniles. After reading about bats, he wanted to investigate mutation rates in those animals, but the idea proved impractical because it would require far more blood cells than the small creatures could spare.
Podlutsky had to put his bat fancy on hold for a while, but he maintained his interest in aging. In 1999, he moved to the United States to pursue postdoctoral research on DNA repair at the National Institute on Aging in Baltimore, Maryland. Later he joined the lab of molecular biologist Nikki Holbrook and worked with colleagues to construct a DNA microarray chip of 1300 human genes involved in DNA repair, cell suicide, and responses to stress. When Holbrook moved to Yale University in New Haven, Connecticut, in 2001, Podlutsky followed and then proposed a research project on bat aging. But no one at the university had the comparative biology experience to tackle such an endeavor, he says. So Podlutsky contacted Austad, who agreed to take him on and helped him apply for the Glenn/AFAR grant; reviewers judge applications for the award not only on the postdoc's potential but also on the credentials and strengths of the supervising mentor.
Podlutsky recalls that when he first read Austad's book, he was flabbergasted to discover that there was a Moscow in Idaho. He now says with a chuckle, "I would never imagine at that time that [I would] end up working in Moscow, Idaho, myself."
Gaining Firmer Ground
Michael Irizarry, a neurologist and assistant professor at Harvard University who is studying an enzyme that might promote Alzheimer's disease, walked off with one of AFAR's choicest awards: He is now one of 11 new Paul Beeson Physician Faculty Scholars in Aging. These doctor-scientists, selected from a field of 40 applicants, will each receive up to $450,000 over 3 years. Given in honor of clinician, scientist, and teacher Paul Beeson, who chaired the first Institute of Medicine study on aging and medical education in 1978, the scholarships aim to nurture the development of future leaders in gerontology. According to van der Willik, "the goal of the Beeson program is to develop a cadre of physicians--promising junior faculty--who are committed to academic careers in aging research, teaching, and practice. ... A lot of the earlier Beeson scholars have already become leaders in their respective fields and have been able to put aging on their institutions' agendas."
Irizarry, 37, was born in Puerto Rico and grew up in northern Virginia. As an undergrad attending Georgetown University in Washington, D.C., he majored in math and minored in chemistry. But he wanted to devote himself to a career that would make a direct contribution to people's lives, so he went to medical school, also at Georgetown, graduating in 1990. The same analytical bent that provoked his interest in math ultimately led him into neurology, he says. The math classes he found most intriguing were number theory and abstract algebra, "where, to do proofs, you have to think analytically and also think of the little tricks you need to do to put things together." Irizarry says that the practice of neurology taps into a similar mode of thinking. "When you see a neurology patient, you take the clues from the neurologic exam and the history and try to figure out what part of the nervous system is not working. And then, [you] determine from there what particular problem is occurring in that part of the nervous system. Each patient ends up being a little different, and you end up learning more about the nervous system from each one."
After leaving Georgetown, Irizarry completed a neurology residency at Massachusetts General Hospital in Boston in 1994. He stayed for a combined clinical and research fellowship in the hospital and began studying the biochemical and neuropathological aspects of Alzheimer's disease with neurologist Bradley Hyman in the Alzheimer's Disease Research Unit. Later, in 2001, Irizarry set up his own lab in the newly opened Center for Aging, Genetics and Neurodegeneration at the hospital's campus in Charlestown.
He is currently scrutinizing the role of -secretase, an enzyme that helps makes -amyloid protein, which piles up into the plaques that characterize Alzheimer's disease (see "Detangling Alzheimer's Disease"). In a study published last September in the Archives of Neurology, Irizarry and his colleagues compared the quantity and activity of -secretase in brain samples from deceased Alzheimer's patients and others who didn't have the disease. In some parts of the Alzheimer's brain, amounts of -secretase remained the same as in the healthy brain, yet the enzyme's ability to produce amyloid increased. These findings suggest that structural changes in the protein could be to blame. Other ongoing experiments by Irizarry have found that the enzyme's activity similarly ramps up in the brain with aging--a shift that predisposes humans to the disease, the researchers speculate.
The Beeson scholarship will support him as he extracts the enzyme from human brain samples to determine which structural changes alter its functioning. Irizarry will also investigate whether any other proteins interact with -secretase and influence its activity, and he will explore ways of inhibiting the enzyme. The AFAR grant is "a big chunk of money," Irizarry says. "It significantly increases what my lab can do in terms of manpower--it funds, essentially, part of a technician and part of a research fellow for 3 years."
Flying Off in a New Direction
In December 2000, an article in Science caught the eye of molecular biologist Yih-Woei Fridell. The paper, by molecular geneticist Stephen Helfand's group at the University of Connecticut Health Center (UCHC) in Farmington, reported that mutations in a gene called Indy doubled the life span of fruit flies. Fridell was working in the biotech sector, but she wanted to return to academic science. Having studied fruit flies in grad school, she found Helfand's research intriguing. So she called him to find out if she could join his lab.
Today, Fridell, 38, is an instructor at UCHC and a recipient of a $60,000 AFAR/Pfizer Research Grant, a junior faculty award sponsored by the pharmaceutical giant for the study of metabolism and late life diseases. Working with Helfand, she, like Podlutsky, is investigating the nexus between free radicals and aging. Whereas many others are probing that link by focusing on antioxidants as a way to neutralize existing radicals, Fridell is exploring what happens to life span when production of the harmful molecules is squelched at their primary source in the mitochondria, the cell's fuel generators.
Fridell, a native of Taipei, Taiwan, began working with fruit flies as a grad student at the University of North Carolina (UNC), Chapel Hill. She earned her Ph.D. in 1992 by studying how the cell manages to make messenger RNA from an unusual gene, coding for brown eye color, that lacks a standard stretch of DNA (the TATA box) normally required to direct the production of messenger RNA. Fridell stayed at UNC to do postdoctoral research at the university's Lineberger Comprehensive Cancer Center, and she joined the National Cancer Institute in Bethesda, Maryland, as a staff scientist in 1997.
In 2000, she and her husband, a virologist, moved to the New Haven area in Connecticut when he took a job at Bristol-Myers Squibb. Fridell found a position at a small biotech firm that was developing a new DNA microarray technique, but she realized after a year that she was more jazzed up about using research tools than developing them. After hooking up with Helfand, who offered her temporary space in his lab, she joined UCHC in 2001 and has been working since then to develop her own funding.
The AFAR award is Fridell's first independent research grant. Her project tinkers with the biochemical reactions within the inner mitochondrial membrane. Normally, a buildup of protons on one side of the membrane creates pressure that drives them back across the barrier, fueling the production of ATP, the cell's energy carrier. This process, however, also generates free radicals. So-called uncoupling proteins (UCPs) undermine the pressure buildup because they allow protons to leak across the membrane (see "Bouncer at the Energy Bar"). Fridell theorizes that boosting the quantities of UCPs could drain protons and in turn crank down free radical output--and increase longevity--without completely disrupting ATP synthesis. In a pilot study, transgenic fruit flies that overproduced an uncoupling protein called UCP-2 lived 20% longer than normal. The new AFAR funding will allow her to conduct more experiments to solidify that finding, including measurements that will indicate whether the flies are making fewer free radicals.
Fridell commutes an hour each way to get to UCHC. The mother of three, she arrives at the lab by 6:30 a.m. and leaves by 4:15 p.m. to pick up her children from school and day care. "I know I have to work a little extra-hard so I can have both--family and my career. That's the extra price I have to pay, and I have no complaint whatsoever." In the near future, Fridell hopes to set up her own lab somewhere, and the AFAR grant is her first step toward roaming freely as an independent investigator.
July 23, 2003
Ingfei Chen, a SAGE KE contributing editor in Santa Cruz, California, would be thrilled to receive a grant to document her own aging process.
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