Forging a Palace for Research on Aging

Graphic: Cathleen Heard No one can escape one of the few risk factors common to neurodegenerative diseases, heart disease, and many cancers: age. Within the last decade or so, research on aging, once seen as unfeasible and impractical, has become the legitimate purview of many scientists who hope to prolong life, improve quality of later life, and delay humans' decay at the cellular and genetic level. By viewing aging as a fundamental root of other diseases, researchers studying the mechanisms

Feb 5, 2001
Eugene Russo

Graphic: Cathleen Heard
No one can escape one of the few risk factors common to neurodegenerative diseases, heart disease, and many cancers: age. Within the last decade or so, research on aging, once seen as unfeasible and impractical, has become the legitimate purview of many scientists who hope to prolong life, improve quality of later life, and delay humans' decay at the cellular and genetic level. By viewing aging as a fundamental root of other diseases, researchers studying the mechanisms of aging hope to have an impact not only a range of maladies, but on the average person's general health and well-being.

Yet most private and government funding continues to go toward treating diseases rather than aging per se, a philosophy that, according to some, ignores the real problem. "I think people are going to realize that just curing one disease after another isn't getting at the fundamental problem," says Arlan Richardson, director of the aging, research, and education center at the University of Texas Health Science Center (UTHSC) in San Antonio.

One helpful step in addressing this problem is the establishment of centers that focus exclusively on the basic mechanisms of aging. The National Institute on Aging (NIA), for example, recently renewed grants for four universities designated as Nathan Shock Centers of Excellence in Basic Biology of Aging. Named after the first director of the NIA, the centers are assigned the task of developing research techniques and model systems to enhance research into the basic biological processes of aging. The five-year grants of $4 million dollars each (the first set was given in 1995) have been awarded to the UTHSC, the University of Michigan in Ann Arbor, the University of Washington in Seattle, and the University of Rochester in N.Y.

 

Born of Fruit and Oil

To foster the sort of interdisciplinary study required in aging research, institutions may have to find ways to break down departmental boundaries. One unique effort currently under way is at the recently founded Buck Institute for Age Research in Novato, Calif. The institute, which opened in the summer of 1999, is the nation's first freestanding institute devoted to basic research on aging. Emphasizing an interdisciplinary environment that includes specialists in apoptosis, aging-related genes, neuronal degeneration, cancer, and bioinformatics, the institute fosters aging research including aging-related diseases. "It's unique in the sense that it's virtually the only setting ... outside of the NIA itself that is devoted essentially totally to research in aging," says T. Franklin Williams former NIA director, emeritus professor of medicine at the University of Rochester, and current Buck Institute trustee. He adds that more such centers are needed especially in light of an aging population composed of millions of soon-to-be retired baby boomers.

The Buck Institute came to fruition after a decade-long battle over the sizable bequest of Leonard and Beryl Buck to Marin County, Calif.1 The couple lived in the county for more than 40 years. Leonard, a pathologist at the University of California, San Francisco, died in the 1950s; his wife, who had trained as a nurse, died in the 1970s. Leonard's father Frank amassed the Buck family fortune through a fruit-shipping business and later through Bell Ridge Oil Co. Beryl left the money to Marin County, asking that it be used to satisfy the needs of county residents, including the aged.

Skyrocketing oil prices in 1976 turned $12 million into $330 million, and eventually into $1 billion by the late 1990s. In the end, a court set up the Marin Community Foundation that allocates 80 percent of the money for general applications and 20 percent for three major projects. The Buck Institute, one of those projects, will receive three-fourths of that 20 percent, or about $150 million. Other projects include an institute for education, and one for alcohol and drug rehabilitation.

Photograph ©2001 David Wakely

The Buck Institute's front entrance of the Research, Support & Education, and lab buildings.

Time, Money, and Technology

The Buck Institute has amenities the likes of which few universities or other institutes can offer. As part of phase one of the project, two of a planned five buildings have been completed; 100 employees (including 14 principal investigators) of a planned 550 have been hired. Set on 488 scenic wooded acres only 5 percent of which will ever be developed (it's not unusual to see wild turkey and deer roaming the grounds), the Institute boasts state-of-the art laboratory facilities situated in artful buildings designed by renowned architect I.M. Pei. Each floor has 38 lab benches and includes a circular, paneled library.

Other more practical amenities serve to facilitate the research and make Buck investigators' jobs easier. Employing a framework not unlike the La Jolla, Calif.-based Burnham and Scripps institutes, the Buck Institute supplies its scientists with lab start-up funds (used for pilot studies, supplies, and postdoc salaries at the scientist's discretion), benefits, and a salary based on each individual's external grants. According to Christopher Benz, Buck's director of cancer and developmental therapeutics, the supplemental salary cuts down on time-consuming grant writing. He recently left UCSF after 20 years and turned down a senior-level position at the National Cancer Institute to come to the Buck Institute. Benz is not sour on the university, but he notes its limitations. "At UCSF, I never got a dime," says Benz, who's still an adjunct professor at UCSF. "They kept the lights on and the heat on. I basically paid my own way with the grants I got."

Simon Melov, an assistant professor at the Institute, enjoys his freedom from the teaching duties that would be required of him at a university. He notes that some of his colleagues who spent decades working in academia are literally "giddy" about the amount of time freed up by the lack of administrative tasks. Melov has also benefited from company collaboration rules that are more lax than most universities. He's currently conducting longevity studies in Caenorhabditis elegans and mice in conjunction with Eukarion, a biopharmaceutical company in Bedford, Mass.

In deciding whether to come to an institute like the Buck, says Benz, academic investigators consider two major factors: the ease with which they'll be able to carry out their research, and the quality of the personnel. "I didn't want to come here unless I was going to work with absolutely excellent people," he remarks. Dale Bredesen, Buck Institute president and CEO, also lauds the freedom from the agenda of a bureaucracy-laden university, though he does acknowledge a couple of drawbacks of independence and the lack of a clinical center: no grateful patients or alumni willing to donate money to support research. Funds from the trust currently compose 40 percent of the research budget.

To make better its capacity for clinically related research and to increase access to valuable software and databases, the Buck is actually currently looking to establish an affiliation with a nearby university. Still, the institute's scientists, says Bredesen, will retain their independence.

Courtesy Simon Melov

Buck Institute assistant professor Simon Melov was able to triple the life span of nematodes treated with a strong antioxidant. Researchers think a loss of internal water pressure causes wrinkles in older nematodes like the one shown above.

Tackling the Aging Problem

Of course, the advantages of time, money, and high-tech facilities only go so far in the complex realm of aging research. Bredesen identifies three complementary areas through which Buck carries out its mission: the first focuses on the aging process itself and how scientists might extend human beings' maximum life span; the second focuses on age-associated diseases such as cancer, in which disease incidence skyrockets with age; and the third centers on technology--applying proteomics and genomics know-how to aging research problems.

Melov's work on the aging process attracted considerable media attention last fall. Working with Eukarion, he used strong, synthetic, catalytic antioxidants to extend the mean life span of a nematode by 50 percent.2 It's the first time a drug has been used to extend the life span of a wild type organism (versus genetic mutants in which most lifespan increases have been reported). He and his colleagues are now using the same drugs in mice.

Bredesen headed up a team of researchers that recently reported fundamental findings about cell death that could some day have implications for neurodegenerative diseases.3 They characterized a new form of programmed cell death (PCD) other than apoptosis--the term that's actually often suggested to be synonymous with PCD. Paraptosis, they contend, is distinct from apoptosis based on criteria of morphology, biochemistry, and response to apoptosis inhibitors. Thus far, they believe it occurs during brain development and in some cases of neurodegeneration; they have yet to determine whether it occurs during other processes.

Other investigators had previously suspected alternate forms of cell death but had not suggested they were programmed nor had they characterized the molecules involved. "There are companies out there spending millions of dollars to develop modulators of apoptosis," explains Bredesen. "But if these are worthless for other forms of cell death, then we had better develop modulators that affect other programs as well."

 

Cancer and Aging

Though seemingly disparate, Benz's research on cancer involves some contributing factors similar to the study of neurodegenerative disease--most noticeably the age factor. He sums up his work in a quote he often cites: "Age is the most important demographic risk factor for most of our life-threatening human malignancies." Benz uses breast cancer as a model to study how aging affects cancer. Two-thirds of all breast cancer cases arise after age 65, three-fourths after age 50. "We have no molecular or cellular explanation for this," says Benz, adding that it could have to do with the accumulation of carcinogenic insults, or the diminishment of host defenses.

Reasoning that cancer biology is different in old versus young persons, Benz has recently studied breast tumor markers--partly in preparation for his arrival at the institute. He's discovered that the estrogen receptors, the target of antiestrogen breast cancer therapies like tamoxifen, are much more highly expressed in women over age 65 as compared with women under 40. In contrast, the overexpression of the well-known receptor and therapeutic target HER2/ErbB2, is at least twice as frequent in women under 40 as compared to women over 65. "This was not previously established and is not being taken into account clinically now," Benz contends. "We only have sort of gross averages over populations." Other fundamental questions he hopes to address include whether older, more differentiated tissues are actually more resistant to carcinogenesis, and how the biology of cancer in older persons differs from that seen in younger persons.

Ideally, research areas including cancer and apoptosis will cross-fertilize and foster new ideas in ways only possible at a setting such as the Buck Institute. "At the subcellular level, many of these mechanisms are the same," says Benz. "We speak the same molecular language. We can talk about programmed cell death. We can talk about gene programs. The pathways are all the same, they're just wired differently."

Eugene Russo can be contacted at erusso@the-scientist.com.

References

1. R. Brylawski, "Buck Trust to Finance Aging Center," The Scientist, 1[23]:7, Oct. 19, 1987.

2. S. Melov et al., "Extension of life-span with superoxide dismutase/catalase mimetics," Science, 289:1567-69, 2000.

3. S. Sperandio et al., "An alternative, nonapoptotic form of programmed cell death," Proceedings of the National Academy of Sciences, 97:14376-81, 2000.

The Basics of Research on Aging

Traditionally, clinically-oriented aging research has received relatively little attention from government and private funders compared to basic, mechanism-based aging research. In the last 20 years, though, scientific breakthroughs and an aging population have sparked interest from scientists, the public, and Congress. As a result, the field has gained recognition, resulting in new research centers and grants. But is it enough? And is the money in the right place?

Examples of new efforts are many: In 2000, the NIA renewed a second round of five-year, $4 million grants at four universities to fund so-called Nathan Shock Centers for basic research on aging. Universities including the University of Texas Health Science Center at San Antonio are devoting significant resources toward basic research on aging. UTHSC, already a designated Nathan Shock Center, plans to build a new university-affiliated center for longevity and aging studies. Tentatively slated to open within two to three years depending on funding, the $25 million center would focus on aging-related genes in models ranging from single cells to nematodes to rodents to humans.

In 1998, a nonprofit foundation called the Ellison Medical Foundation (www.ellisonfoundation.org) was created to support basic biological and biomedical research on aging. "There was a feeling that this is an area that right now, from a scientific point of view, is poised on a moment of real opportunity," says Richard l. Sprott, executive director of Ellison and former NIA investigator. Claiming to be the largest private foundation source of its kind, Ellison provides $20 million per year in grant funds for aging-related basic research on areas that include the telomeres and telomerase, mechanisms of free-radical induced cell aging, and approaches to age-modulated disease mechanisms.

But research on aging continues to mean different things to different people. Sprott, for example, cautions that research on using strong antioxidants to extend animals' lifespan has been over-hyped in the media with errant suggestions of the discovery of biomarkers for aging. And disease-related aging research has gotten an inordinate amount of attention. "Funding agencies, and even funding from private sources, are more oriented to disease-based type models," says Arlan Richardson, director of the aging, research, and education center at UTHSC. Richardson, like Sprott, emphasizes the importance of differentiating research on the basic processes of aging from research on aging-dependent diseases. Says Sprott, "Aging isn't a disease."

University of California, San Francisco professor of anatomy Leonard Hayflick suggests that even programs such the NIA's Shock Centers are too disease-oriented and are completely missing the point. Hayflick is known for having demonstrated something dubbed the "Hayflick limit," where normal cells in culture go through a limited number of rounds of division before they senesce. He claims that authentic basic research on aging must answer the question: Why are old cells more vulnerable to disease than new ones?1

Hayflick contends that policy makers and some scientists have failed to appreciate that the resolution of diseases including Alzheimer's (AD) and cancer will not actually advance scientists' knowledge of the fundamental biology of aging, a field that he feels has been horribly neglected. T. Franklin Williams, former National Institute on Aging (NIA) director and emeritus professor of medicine at the University of Rochester, notes that AD research was severely underfunded prior to the tenure of NIA's founding director Robert Butler. But now, with half of the NIA's budget devoted to the disease, some suggest that there's been a severe overcorrection and that areas of basic research have suffered.2

"The public and the politicians have all been sold a bill of goods," Hayflick comments, adding that research on disease treatments may extend life expectation a few years, but it will elucidate little about the process of aging. He draws an analogy with the treatment of conditions like polio-myelitis and iron deficiency anemia: Just as cures for those conditions did not advance scientists' understanding of childhood development, the resolution of diseases of old age will not advance investigators' knowledge of aging itself.

--Eugene Russo

References

1. L. Hayflick, "The future of aging," Nature, 408:267-9, 2000.

2. S. Benowitz, "To target or not to target," The Scientist, 10[4]:1, Feb. 19, 1996.