Magic Markers?

The quest to measure how fast individuals age has proven far more complicated than originally thought. Because such methods could yield more definitive tests for antiaging medicines, though, some researchers refuse to give up.

Not all 70-year-olds are the same age. If that sounds like a contradiction, witness the spry septuagenarian who plays tennis twice a week and jogs on weekends. Then compare her to a more feeble contemporary who has been felled by arthritis and finds it difficult to get in and out of bed unaided. Chronologically, both are 70, but biologically they might be decades apart.

The distinction is an important one. People don't age at the same rate, and researchers currently know of no way to measure the biological age of an individual. They'd very much like to find one: Such a technique would allow scientists or physicians to better predict how long a particular person might expect to live. To aid in the development of such a tool, researchers hope to identify biological markers--"biomarkers" for short--that track with biological age. These biomarkers could serve as a proxy for the biological age in an individual organism.

To date, scientists have yet to turn up any biomarkers--and some even question whether they exist. In a 2001 essay published in Science's SAGE KE, gerontologist Richard Miller of the University of Michigan, Ann Arbor, observed that some scientists consider biomarkers "as fanciful a construct as the weight of a goblin, in that both goblins and aging are imaginary items for which metrics cannot be expected or condoned." Such critics say that aging is not a unified, coherent process but instead represents a willy-nilly accumulation of largely unrelated pathologies over time. That being the case, these thinkers can't imagine what, if anything, a biomarker would measure.

This schism in the research community has big ramifications for scientists working to understand the mechanisms that drive the aging process. In 1988, the National Institute on Aging (NIA) launched a decade-long research initiative that failed to identify a reliable battery of biomarkers. The question facing those who fund aging research is "Does this line of inquiry deserve another chance?" The topic is the subject of this month's SAGE Crossroads Webcast debate, "Biomarkers of Aging: Roadmap or Roadblock on the Way to the Fountain of Youth?" In the pro-biomarker camp, physiological geneticist David Harrison of the Jackson Laboratory in Bar Harbor, Maine, says he sees "some hints that aging might be regulated, might be timed, by fairly simple processes." To Harrison, this regulation suggests that scientists might someday dig out biomarkers that reflect these processes in action. But on the pessimistic side, Roderick Bronson, a pathologist at Harvard Medical School in Boston, argues that aging represents the decline of various bodily systems in a roughly parallel, but nevertheless chaotic, fashion. Given the disorder inherent in this process, he says, "to think there is any crossover from one system to another is completely foolish."

The ability to identify and measure biomarkers would allow researchers to track aging in an individual--and to analyze interventions that might interfere with that process. To prove that a medicine or treatment slows aging, Miller says, "you have to be able to measure how rapidly aging is going." Barring such measurements, the only definitive means of testing antiaging medicines is to wait until all the test subjects have died. Researchers would then determine whether the patients receiving the treatment lived longer than those who did not--an approach that obviously holds little appeal for research scientists, their funding agencies, or the individuals who volunteer for such studies.

But with a reliable group of biomarkers, scientists could measure, in real time, how rapidly their patients were aging. They could then assess whether a particular therapy puts the brakes on aging. The process could take a matter of years rather than a lifetime. And it would allow scientists to measure aging on a person-by-person basis, something that is now beyond their reach. To date, the regimens that have been shown to postpone aging have been judged by their effect on populations. Take, for example, calorie restriction. When researchers report that this intervention retards aging in rats, they're talking about a population--not any individual rat, says Edward Masoro, a physiologist and professor emeritus at the University of Texas Health Science Center in San Antonio. Yet to know if a drug has benefited a particular person, doctors will need to put a finger on the pulse of aging in that individual. "If you're going to be able to study aging in the individual, and not aging of a population, you have to have a biomarker," says Masoro.

Definition Problems

At the heart of the biomarker debate lies a problem of definition. What exactly is a biomarker? "It has become a very trendy word and has lost much of its original meaning," says behavioral geneticist Richard Sprott, who oversaw NIA's biomarker initiative and now serves as executive director of the Ellison Medical Foundation in Bethesda, Maryland. To some researchers, a biomarker is simply a trait that accompanies aging--gray hair or wrinkled skin, for example. But such characteristics could be mere byproducts of aging, notes a 2000 report on biomarkers from the International Longevity Center-USA (ILC-USA). So researchers such as Miller have set their sights on something far more elusive: They hope to identify a panel of attributes that can collectively serve as a surrogate indicator for the process of aging itself--much, writes Miller, as the stock market serves as an indicator for the overall state of the economy. By this definition, a good biomarker might be a molecule whose concentration or activity changes with age in a reliable and predictable manner. Potential biomarkers include human growth hormone, whose concentration declines with age, or oxidative damage, which accumulates with age.

And if definition problems bedevil biomarker research, philosophical rifts concerning the very definition of aging cause even more headaches. The debate is rooted in the evolutionary theory of aging. As renowned evolutionary biologists such as Peter Medawar and George Williams argued, natural selection, which privileges only traits that in some way improve reproductive fitness, has provided humans with the genes they need to survive through reproductive age. "Our genes were only selected to be good enough to get the job done, which is to have kids," says Bronson. Once these "selfish genes" have made their way to the next generation, the vehicles they used to transport them--our bodies--can be discarded.

The theory defines "aging" as what happens when organisms enter that postreproductive period in which their genes are no longer optimized to preserve them. But no one knows whether there is any order to the process of bodily deterioration. Here's where the biomarker supporters and detractors part company. "Aging is chaos," argues Bronson, in which case the search for biomarkers capable of tying together the various aspects of the aging process stands little chance of success. Rather than looking for definitive biomarkers, Bronson supports attempts to understand the mechanisms behind age-related traits--including gray hair and wrinkled skin. "I want that kind of stuff done, and then we'll make progress in understanding aging," he says.

Harrison views the postreproductive years a different way. "Why do dogs age seven times faster than people, why do mice age 30 times faster than people, and yet, we get basically the same types of pathologies?" he asks. Dogs, mice, and humans all get cancer as they age, for instance. Such evidence, says Harrison, suggests that at least some aspects of aging might be subject to coordinated or overarching genetic control. Perhaps one or a few master switches tell our genes when they no longer need to preserve our bodies for reproduction--or allow deleterious genes to kick in later in life, once the time for reproduction has passed. "I'm suggesting that there's some biological signal that tells genes when it's late," Harrison says. Presumably, if such a control process exists, the right biomarkers could tap into it.

Off the Mark?

Researchers who think that biomarkers might exist have some ideas about why NIA spent 10 years and $20 million searching but failed to identify them. The first problem was coordination. "It was a lot harder to get 15 to 20 investigators to work toward the same objective for a decade than we'd guessed," says Sprott. NIA selected a nationally distributed group of researchers with different specialties (among them Harvard's Bronson) and provided each with groups of genetically identical rats and mice, half of which had been subjected to calorie restriction. The research teams each set out to identify and measure key physical differences between the young and old animals--and the treated and untreated animals. These differences, the thinking went, should have led researchers to the much sought-after biomarkers.

Perhaps the search was too ambitious. NIA charged the researchers with finding a panel of measurable traits that could be used to predict an individual organism's life span and that would work consistently in a range of different species. In addition, the initiative sought only those biomarkers that could be identified without killing the organism in question and that could be measured in a time period that represented only a small portion of the organism's life. These criteria would be key if biomarkers were to be used to evaluate the effectiveness of potential antiaging medicines in humans. "If you're going to use [biomarkers] to help design clinical tests, you obviously aren't going to be able to kill people," notes Miller.

Then again, perhaps no quest for biomarkers, at least in the strictest sense of the term, could have succeeded. If these biomarkers don't exist, as Bronson and others suggest, there would have been nothing for NIA to find, no matter how diligently its research teams pursued the search.

What Now?

Because of this humbling failure, NIA is unlikely to try a similar tack again--certainly not at such a grand scale. "We knew then it was a one-shot deal," says Sprott. Huber Warner, associate director of the Biology of Aging program at NIA, agrees: "There's no chance that we're going to, in the near future, mount the same level of attack on this that we did almost 15 years ago."

Still, Warner says, new knowledge could help direct future biomarker research. In the past few years, scientists have uncovered a battery of genetic changes capable of slowing aging in organisms such as flies, mice, and worms. Focusing on these genetic pathways could provide a more direct pathway to biomarkers, says Warner. And new technologies, such as DNA microarrays, could provide new tools for digging them out. Although NIA won't attempt another "frontal assault" on the biomarker problem anytime soon, Warner says, the agency might support studies that pursue these promising new leads.

Some doubt that will be enough. Unfortunately, NIA's much-publicized failure had led to a sense of "buyer's remorse" about biomarker research, writes Miller. For this reason, future biomarker research might require "a nontraditional long-term source of funding," notes ILC-USA's biomarkers report. Such alternative funding could include "commercial or philanthropic sources of support."

For Miller, who is examining the mouse immune system as a possible predictor of longevity, the future of biomarker studies comes down to a question of priorities. "Biomarker research, in essence, is a tool development," he says. "Once you have the tool, then you can use it to ask other interesting questions." This particular tool, if discovered--and that's still a big if--would have an immense impact on researchers' ability to study and evaluate antiaging medicines. Those who hold the purse strings in the field of aging research will have to bear this in mind as they try to decide whether biomarker research deserves another shot.

Chris Mooney (www.chriscmooney.com) is a freelance writer living in Palo Alto, California. He hopes his biological age doesn't overtake his chronological age anytime soon.