Sci. Aging Knowl. Environ., 17 July 2002
"Gero-Tech" Sprouts, But Will It Bloom?
Scientists hope to turn academic observations into marketable interventions
R. John Davenport, and Jennifer Toyhttp://sageke.sciencemag.org/cgi/content/full/sageke;2002/28/ns6
Abstract: Companies are betting that studies of aging will reveal new routes to life-enhancing pharmaceuticals. Antiaging pills are a distant dream, in part because testing a drug for its effect on life-span is a practical impossibility and scientists haven't yet come up with a substitute measure of aging. But research on aging might yield novel ways to treat age-related disease. Along the way, private ventures are offering new resources and a variety of experiences to academic scientists.
Siegfried Hekimi never thought he'd start a company. But when the McGill University biologist made a splash in 1998 after discovering genes that appear to control aging in nematodes, university officials and private investors approached him about turning his academic discovery into a commercial venture. The resulting company, Chronogen in Montreal, Quebec, is part of a new breed of biotechnology companies founded on the premise that research on the underlying causes of aging will lead to promising drugs.
"Understanding and affecting the aging process at a fundamental level of biology is likely to become one of the organizing principles of biotech," says Daniel Perry, director of the Alliance for Aging Research (A4AR), a nonprofit organization based in Washington, D.C. Don't expect your doctor to dispense antiaging tonics any time soon, however. Imagine a 50-year clinical trial to see if a treatment increases life-span, tracking patients from when they first encounter the intervention until they die. This kind of undertaking would be expensive and logistically complicated--scientists would need to extend their own life-spans to see a trial to its completion--and the data produced might not even yield definitive results. Yet researchers haven't agreed on any other measurable characteristic that accurately gauges aging.
For now, only hucksters who dispense cure-alls on the Web will be selling "antiaging" tonics. But as entrepreneurs apply scientific brainpower and venture capital to the challenge of aging, their efforts could produce novel ways to treat age-related diseases that would otherwise escape traditional drug-discovery approaches. In the meantime, companies that are trying to combat aging are providing career and research opportunities that academic scientists would otherwise miss.
In a year 2000 review of U.S. and Canadian biotech firms, A4AR coined the term "gero-tech" for what it described as a boom in companies that are fueled by the scientific literature on the biology of aging. Many drug companies already target human diseases--such as cancer, Alzheimer's disease, and heart disease--whose risk escalates with advancing years. For instance, Indianapolis, Indiana-based Eli Lilly and Co. doesn't call itself an "aging" company, but it sells Evista, a synthetic estrogen substitute, for osteoporosis, and CEO Sidney Taurel delivered a speech entitled "The Future of Aging" in fall 2001 at Cornell University in Ithaca, New York. Novartis markets drugs for Parkinson's disease, Alzheimer's disease, and osteoporosis. And Wyeth peddles a variety of hormone formulations for postmenopausal women. But unlike established companies that aim at a particular disease, the new gero-techs (see table) follow an innovative strategy: targeting the processes that might underlie aging itself, such as hormone signaling or mitochondrial damage (see "Aging Research Grows Up").
"[Drug] programs [for diseases] are of enormous value, but the diseases don't cause aging," says Ed Cannon, CEO of Elixir Pharmaceuticals in Cambridge, Massachusetts. "It's the aging that causes the diseases. We're going to discover the pathways that lead to these diseases." Launched in 2001, Elixir builds on the academic research of its scientific founders, molecular geneticists Cynthia Kenyon of the University of California, San Francisco, and Leonard Guarente of the Massachusetts Institute of Technology (MIT) in Cambridge. These researchers have discovered mutations that more than double life-span in Caenorhabditis elegans and Saccharomyces cerevisiae. Elixir is putting money on the idea that similar genetic pathways control aging in people. The company's founders want to identify the human pathways and then screen for compounds that will mimic the effects of the age-retarding mutations found in animals. Other companies' advisers--including Chronogen's--have anted up at the same table, placing bets on similar advances in understanding how model organisms age.
Whether any of the companies will collect on their wagers remains to be seen, and some researchers are skeptical. "You take a concept of something you know is true in yeast and worms, then build a company around that," says molecular biologist Judith Campisi of Lawrence Berkeley National Laboratory (LBNL) in California. "The odds of success are better than the lottery, but it is a gamble."
Although risky, the idea is sound enough to attract money. "With a single hit, you could have a product that would be valuable for treatment of cardiovascular disease, diabetes, degenerative disease--all the problems associated with aging," says Cindy Bayley, a venture capitalist who co-founded Elixir on behalf of ARCH Venture Partners in Chicago. "That would absolutely be a tremendous benefit." The promise of such a jackpot is attracting mainstream investors who "are looking for the big breakthrough, the big opportunity, the big problem to be solved," says Bayley. "Aging offers all of that."
Testing, Testing, 1, 2, 3
If a company does come up with a promising compound, it will face a conundrum: how to test the drug in humans. A clinical trial assessing life-span in people would be impracticably expensive and lengthy. Instead, scientists will measure the ability of potential drugs to reduce the incidence or severity of age-related diseases, says Guarente. Bone density, skin elasticity, or immune function might also serve as markers for a drug's ability to stall a person's demise, but whether such measures could be used to assess aging is still unproven (see Miller Perspective). For now, therefore, marketing a true antiaging pharmaceutical is out of the question. With no system to review or approve such treatments, the Food and Drug Administration (FDA) "would throw your application out if you applied for a drug that claimed to slow or reverse the process of aging," says A4AR's Perry. So companies are using knowledge of basic aging pathways to identify drug targets, and then they will gauge the effect of promising compounds on particular age-related diseases that fit into the existing drug-approval system.
End runs around the FDA do exist, however. Although drugs require FDA approval, companies can sell vitamins, herbs, and other nutritional supplements without such federal blessing, thanks to the 1994 Dietary Supplement Health and Education Act. Most companies offering such supplements imply miracle cures yet don't do any research to back their statements. But some firms strive for hard data.
Biochemist Bruce Ames of the University of California, Berkeley, for instance, founded a company called Juvenon to test two compounds--acetyl-L-carnitine and -lipoic acid--that he says can rejuvenate old rats (see "Young Again?"). He wondered whether they work similarly in people, he says, but the expense kept him from carrying out clinical trials in his academic lab. So, along with Tory Hagen, a biochemist at Oregon State University in Corvallis, he created Juvenon in 1999 to conduct that work.
Juvenon scientists have wrapped up the first study, which assessed the effect of acetyl-L-carnitine and -lipoic acid on general fitness in a small group of elderly men. Based on the promising results and on demand from consumers, the company went to market in June, says CEO Allan Prager: The Juvenon "Energy Formula" is already available through the company's Web site and toll-free hotline. Researchers have also embarked on a second trial, which measures the risk of heart disease, and they plan eventually to test mental function. Once the researchers figure out how people might benefit from such supplements, they intend to optimize the dosage and formulation.
"One could just put them in pills and sell them without any clinical trials," says Ames. "But there's so much hype out there that the only way I was going to do this was if the company was really a proper scientific company. We're doing FDA-style clinical trials even though the FDA doesn't require it." Without an objective body to assess those trials or others like them, however, consumers will have to judge for themselves whose claims are backed up by science and whose are pure marketing.
Other research-oriented companies in the aging arena are moving toward selling products. Senetek in Napa, California, already licenses kinetin--a plant hormone--to cosmetic and pharmaceutical companies, based on studies suggesting that it reduces radiation damage to skin. And Eukarion in Bedford, Massachusetts, has developed reactive oxygen quenching compounds that have shown promise in extending rodents' lives and sharpening their wits (see "Drugs Protect Mice From Pernicious Forms of Oxygen"). They expect to start testing their compounds in humans this year.
Learn From Your Elders
The challenges of producing life-extending therapeutics begin long before drug testing, however, as demonstrated by the experiences of Jouvence Pharmaceuticals of San Diego, California. Jouvence began in 1995 as a genomics company striving to capitalize on the genetic regulation of aging in yeast, mice, worms, and flies. In the short term, says co-founder and mouse geneticist David Harrison of the Jackson Laboratory in Bar Harbor, Maine, the goal was to keep the company afloat by selling a product such as an antioxidant. In the long term, Jouvence's leaders strove to patent genes from model systems and then look for drugs that alter the function of the genes' products. But after 3 years, Jouvence failed to come up with a product or continue to attract investors, and it floundered. The company was reborn in 1998 as HealthSpan Sciences when current president and CEO Bryant Villeponteau, the former head of the Molecular Discovery Department of Geron Corp. in Menlo Park, California, stepped in. Villeponteau brought with him his own patent for an antioxidant and concentrated the company's efforts on launching over-the-counter nutritional supplements. The HealthSpan Sciences management still intends to channel profits from the supplement line toward research into the underlying causes of aging, Harrison says.
Geron has similarly balanced lofty goals with down-to-earth reality. In the early 1990s, the company rose to fame as the first biotech outfit that zeroed in on aging. The firm grew out of research on telomerase, an enzyme that controls the length of the caps that protect chromosome ends. At the time, many scientists thought that telomere length indicates an organism's age. The structures shorten each time a cell divides, until they reach a critical length. At that point, the cell stops splitting and enters a state known as senescence. Because telomerase lengthens telomeres, Geron scientists proposed that manipulating telomerase activity would inhibit cellular senescence and hinder aging.
But the link between telomere length and organismal aging turned out to be convoluted (see "More Than a Sum of Our Cells"), and thus far, Geron has failed to transform telomerase into a therapeutic that slows aging. With the discovery that telomerase activation likely promotes the formation of tumors (see "Dangerous Liaisons"), the company shifted its research agenda to cancer, says Geron consultant Woodring Wright of the University of Texas Southwestern Medical Center in Dallas.
Not everyone thinks that telomerase is dead as an age retardant, however. William Andrews, former director of molecular biology at Geron, started Reno, Nevada-based Sierra Sciences to investigate how cells control the telomerase gene and then to find small molecules that perturb the process. "I felt that Geron was deemphasizing aging and focusing more on cancer," he says. "I have a passionate interest in aging."
For some researchers, putting the brakes on aging isn't just about extending life-span; it also involves keeping organs youthful. In addition to cancer, Geron is now stirring headlines for its work in organ regeneration and stem cell applications. Having a handle on stem cells--foundations of the body that can morph into many different cell types--might provide researchers with the tools to rebuild tissues, such as brain, bone, and heart, that are scarred by age. Geron founder Michael West left Geron in 1998 to take the reins of Advanced Cell Technology (ACT), based in Worcester, Massachusetts, and pursue that idea. ACT has received front-page attention for its attempts to clone cattle and endangered species--and for its controversial announcement in November 2001 that it had created human embryos for so-called therapeutic cloning, in which stem cells could be extracted from embryos for tissue regeneration. Although promising, the approach is controversial: Politicians, theologians, and others debate the ethics of collecting embryonic stem cells, and research has yet to demonstrate that stem cells can live up to their promise.
Taking the Leap
Launching a company that aims to beat aging is a risky venture, and most scientists are not dropping their academic positions to go commercial (see "Wearing Two Hats"). But industry can offer otherwise unavailable opportunities and resources. "Academic labs are traditionally pretty lousy at bringing stuff to fruition, but small companies can develop something further," says LBNL's Campisi. By prioritizing product development, companies take research beyond what's possible in an academic setting. "I can't screen 1000 compounds in my [university] lab," says MIT's Guarente. But Elixir gives him the resources to do exactly that.
Likewise, hunting for aging genes is a massive undertaking for academic researchers. Scientists at Centagenetix in Cambridge, Massachusetts, say they hope the company will aid their quest for human longevity genes. Last fall, geneticists Louis Kunkel and Annibale Puca and geriatrician Thomas Perls of Harvard University isolated a chromosomal region that might contain one or more genes that give centenarians an edge over the rest of us (see "Hints of a 'Master Gene' for Extreme Old Age"). The trio founded Centagenetix to speed the search for those genes, an enterprise that faces considerable peril. "The next steps are going to take so much money and so much risk," says Centagenetix chief operating officer Carl Weissman. Company scientists are striving to develop treatments that mimic the effects of the yet-to-be-identified longevity genes as well as to market a database of the centenarian genome to pharmaceutical companies. "Celera has the human genome," says Weissman, "but centenarians have the ideal genome."
Many scientists embark on commercial ventures at advanced career stages, but companies can offer unique opportunities to young researchers as well. After finishing a Ph.D. in Guarente's lab at MIT, Matt Kaeberlein passed up multiple postdoctoral offers at Harvard University to co-found Longenity, a company based in Medford, Massachusetts, that is taking a genomics approach to studying aging in people. "If I had stayed in academia, I would have spent the next 3 to 5 years doing essentially the same things I did as a grad student," says Kaeberlein. "In industry, I still get to do benchwork, but I also get to learn a whole new set of business and managerial skills."
Whether gero-tech will explode or merely simmer will depend on the success of the current crop of companies. But researchers in the field of aging will likely continue to expand ties to industry partners in the hopes of developing applications from their academic work. Translating knowledge into practice could be the ultimate validation for decades of intellectual inquiry. Says Chronogen's Hekimi, "If you can apply academic concepts to the world, then to some extent you must have gotten things correct."
July 17, 2002
R. John Davenport is a Santa Cruz, California-based associate editor of SAGE KE. He's hoping to bottle the antiaging secrets of local octogenarian surfers. Jennifer Toy is a former SAGE KE intern who now works at an arboretum in Chicago. Having dabbled in echinacea, she's now placing her bets on biotech.Citation: R. J. Davenport, J. Toy, "Gero-Tech" Sprouts, But Will It Bloom? Science's SAGE KE (17 July 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/28/ns6
Science of Aging Knowledge Environment. ISSN 1539-6150