By Alison Ramsey
Forget about gorging on antioxidant-rich “superfoods.” Mutant roundworms are boring a hole through one of aging’s most enduring concepts.
Anyone with even a passing interest in nutrition has heard that antioxidants fight aging. Since the idea was first proposed over 50 years ago, it has become widely accepted that oxidants are toxic, contributing to the aging process by damaging the molecular constituents of robust cells. The popular press loudly touts the latest antioxidant “superfood” — be it açai berries, pomegranates or pinto beans.
Recently, a new idea wormed its way in. Literally.
For the past decade, McGill biology professor Siegfried Hekimi has been breeding roundworms (nematodes of species Caenorhabditis elegans) with a surplus of oxidants, free radicals that are also called reactive oxygen species (ROS). If the antioxidant theory held true, then the mutant C. elegans should have been shorter lived. Instead, they lived longer.
“We can sometimes completely uncouple oxidative stress from how long an animal lives,” asserts the Swissborn scientist.
Similar experiments with mice further bolstered his results, and gave rise to Hekimi’s own theory, that ROS are produced as a stress response to the damage caused by aging. In study after study, published in journals including Genetics, Science, Developmental Cell, Aging, Cell, PLoS Genetics and most recently in the December issue of PLoS Biology, Hekimi’s work further erodes oxidative stress theory while leaving the door open to his own theory. (A new paper is currently being revised.)
The oxidative stress theory, first posited in 1954, is largely based on the observation that ROS gradually increase with age. It proposes that aging is caused by ROS damage to macromolecules, including proteins, nucleic acids, amino acids, lipids and DNA base. But the theory fails to explain recent scientific observations, including Hekimi’s: there are no clear correlations between ROS production and longevity in some species. Some mutations of C. elegans live dramatically long lives despite high ROS production and high oxidative damage.
Hekimi does not dispute the basic observation that ROS increase with age. Nor does he dispute scientific research showing a link between increased ROS and age dependent diseases such as cancer, heart disease and diabetes. He does, however, have a different interpretation of those facts.
“There is mounting evidence,” he notes, “that ROS can stimulate beneficial responses to cellular stresses produced by aging.” It may act as a signal in young mutants that triggers changes of gene expression that help prevent or delay the effects of aging. To a point: Over time, ever higher ROS levels may eventually overwhelm those beneficial responses, now harming where once they helped. Hekimi, a fit 54-year-old, describes his work with dynamic energy indicative of the professional athlete he once was. Before earning his PhD in biology at the University of Geneva, he cycled professionally full-time for more than six years, competing in the Tour de France and the Giro d’Italia. Slowly, however, he concluded that “professional sport is not a sport, it’s a profession. After awhile it became not fun. The professional mentality is: what counts is success, whatever the means, and not whether the path is interesting or pleasurable.” Hekimi’s current path is interesting, and something more. “Scientific research is like a shock wave,” he says. “You always feel lost, everything is always new. But if it were not like that, it would not be science. Of course,” he shrugs, “it makes you suffer. You feel like you don’t know what you’re doing all the time.”
Hekimi had no clue that unseating a tenet of aging was in store when he was a post-doc at the government-run Laboratory of Molecular Biology in Cambridge, England, in the late 1980s. While attempting to find new mutants that affect nervous system development in C. elegans, he noticed one clone with a modified clk-1 gene behaving oddly.
“I saw worms that should have been adult, but they were tiny,” he says. “I thought, ‘Oh, they’re terribly sick and probably will never grow up.’” Yet, a few days later, the runts were healthy adults. He was stunned.
His curiosity piqued, Hekimi began studying those aspects of the worms that normally followed a strictly structured timetable. There were many. “They defecate every 50 seconds — ping!” he describes. Egg-laying, wiggling, pumping — each has its timetable that produces a classic, bell-shaped distribution curve.
The clk-1 mutants, however, broke the rules. Though perfectly healthy, some took two or even three times longer to develop. “They gave a completely flat distribution, which is completely weird. There was no peak, no favoured length of development time, which makes no sense whatsoever.” Clk-1 mutations in both worms and mice, he observed, have increased ROS levels, yet the animals live longer: a direct contradiction of the oxidative stress theory of aging.
But do tests on worms and mice unhinge the theory of how oxidative stress affects humans? Hekimi responds vigorously: “The oxidative stress theory proposes that oxidative stress is the cause of aging” in organisms, regardless of species. “You can’t say, ‘Oh, there’s an exception for your mutant.’” Don’t expect to see nutritionists recanting anytime soon, however. The oxidative stress theory has become too well entrenched, in both the scientific community and the public consciousness.
“It has become like a dogma in a religion,” explains Hekimi. Not to mention a huge industry comprising food, supplements and cosmetics.
“It’s a reasonable theory based on plausibility, and the human brain cannot help but love those,” explains Hekimi. “The sun comes up every morning, therefore the sun goes around the Earth, right? There’s a big pile of correlative data on oxidative stress. When a theory appears to be supported by a big pile of data, and you want to say that the data is right but the theory is wrong, people find it hard to believe you.”
Having realized that he “can’t pursue every question,” Hekimi is focusing on two. The first question is: If ROS can lengthen lifespan, how does it do it? “By what pathway? What other genes are involved that transmit the signal? There’s a business end to this mechanism we don’t know about yet.” The implications of decoding that business end? “Everything!” says Hekimi. “We don’t really know what causes aging. Finding out how ROS can moderate the rate of aging could allow us to do the same in a medical context.”
One thing he is certain of is that neither his nor anyone else’s research will suddenly create extremely long-lived people.
“In the past 300 years, average lifespan has increased three-fold, but not due to genetic research, vaccinations or medicine,” he says. It’s thanks to better sanitation, more abundant food, and generally having an easier life. Even 300 years ago, he adds, some people were long-lived. “We’re not living any longer, it’s just that now, everyone does! We have a limit. In theory, we could intervene on this limit. Maybe in a couple of centuries, we’ll live a bit longer… There will be no big step, and to propose it is quackery.”
Having nipped a hole in oxidative stress theory, Hekimi’s second question takes on another medical principle of mythic size: that inflammation is bad for you.
“Scientists believe that everything going wrong in us is inflammation gone awry, and it certainly is the source of some types of pain and maybe aspects of heart disease and cancer. But I believe that it could be that it is mostly good for you. It can get out of hand sometimes, but most of the time, it’s good.” His preliminary research indicates that aging biomarkers are reduced in mice with elevated immune system function.
Hekimi has made one other discovery in the past 27 years. Science isn’t anything like professional cycling. It’s a more lasting kind of fun.
Siegfried Hekimi is the Robert Archibald and Catherine Louise Campbell Chair in Developmental Biology. His laboratory receives funding from the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI) and the Canadian Cancer Society Research Institute.