Web edition: April 13, 2011
WASHINGTON, D.C. New mouse data suggest that even among seemingly identical sugars, how they are delivered can exert subtle metabolic differences with long-term impacts on vitality -- and lifespan.
It’s comparatively easy to identify a substance that is acutely toxic, causing immediate sickness or death. More challenging – but also important – is recognizing whether dietary or environmental exposures compromise long-term health and fitness. Scientists at the University of Utah in Salt Lake City have developed a mouse assay to probe for such chronic risks, ones that might diminish lifespan or an animal’s ability to win a mate.
Instead of caging one or more similarly exposed animals, James Ruff, Wayne Potts and their Utah colleagues release animals with different exposures together within a semi-natural ecosystem. It’s a huge well-lit enclosure with a few mouse houses that offer dark seclusion. Within this environment, the animals eat at will, mate at will, fight at will or do whatever coexisting communities of mice do.
And with minimal interference from their minders. Electronic tags identify each animal so that off-site scientists can keep track digitally of where the rodents eat or sleep.
In the most recent experiment, the Utah biologists began feeding newly weaned, three-week-old mice a diet of healthy chow to which they added simple sugars. Overall, 25 percent of the rodents’ diet traced to these sugars.
Half of the mice received their sweets as sucrose, or table sugar – a molecule made of equal parts fructose and glucose. The other animals got their sugar as a mix of unbound fructose and glucose. After three months, five males and 10 females from each group were released together into each large enclosure for 200 days – essentially until the rodents were well into old age.
Female mice that had been reared on the unbound simple sugars experienced high rates of mortality, beginning 50 to 80 days after entering the enclosure. Their death rate was about triple that of sucrose-treated females, James Ruff and his colleagues reported April 11 at the Experimental Biology meeting.
The experiment was repeated five times, each time with the same result. What impaired the females' survival remains unknown, Ruff says. Autopsies didn’t reveal much, he adds, because his team generally enters an enclosure only about once every five weeks. So if a mouse died in one of the little community houses, of which there were four scattered around the enclosure, it could be days or even weeks before they were seen and retrieved for analysis. By then, serious decomposition would have masked markers of stress, hormone imbalances or other clues to their untimely demise.
But Ruff says one thing is suspicious. These early deaths started to occur in the females fed fructose-plus-glucose at about the time they were pregnant with their second litter. This was also just after they started to nurse their first babies. “So they’re under acute metabolic stress,” Ruff observes. And it appears that something about the separated-sugars diet compromised the moms’ vigor, relative to sucrose-reared neighbors.
That’s concerning, he adds, because the dual delivery of simple sugars in their diet somewhat mirrors the delivery of carbohydrates inhigh-fructose corn syrup (aka corn sugar), where its component sugars are delivered individually, Ruff says, not as sucrose with a little fructose bonus.
In a second experiment, Ruff and his colleagues fed their weanling mice a diet of the two simple sugars or an equal-calorie quantity of corn starch. After three months, these two groups of mice were united in the big enclosures for 200 days.
Here too, females that had been reared on the simple sugars experienced triple the rate of mortality seen in the other moms.
But in this experiment, sugar-fed males also suffered a disadvantage. They had a more difficult time fighting off competitors to win control of prime real estate – a little mouse house where their eventual family would be able to nest in comfortable darkness. The fallout from this: Sugar-reared males fathered only half as many babies, largely because most females rejected the non-dominant males as a potential mate.
Says Ruff, this suggests that being raised for the human equivalent of adolescence through early middle age on a diet of simple sugars may subtly impair health or behavior relative to diets comprised of more complex carbohydrates.
“Successful reproduction is the raison d'être for mice,” explains Potts. The enclosure-ecosystem assays that his group is pioneering allow scientists to identify “sensitive measures of toxicity,” he says, because these test environments “integrate the impacts of multiple physiological changes.” For instance, he notes, if some exposure renders one house hunter unable to take the proverbial keys to a secluded villa, his family will be forced out into the open where they’ll be vulnerable to predators. It’s in competition with other mice – especially ones that might have grown up under different conditions – that a house hunter proves his mettle.
If the novel community-enclosure systems reveal an apparent reproductive vulnerability, the next step will be to home in on the cause through more conventional toxicological testing, Ruff says.
“I think it’s an interesting approach,” says John Vandenbergh, the former head of biology at North Carolina State University in Raleigh. This assay does “sort of give a global response – an end measure to a whole long series of physiological and behavioral adaptations to these diets.”
However, he adds, data acquired from such a system are unlikely to impress regulators, like risk-assessment analysts with the Food and Drug Administration. And the reason: “it’s just an end measurement – where the animals either die or they don’t breed.” Understanding the cause of health impacts is what really sways regulators, Vandenbergh says. But as an early screening test for possible adverse effects, he says, the new enclosure-system assay do hold interesting possibilities.
J.S. Ruff, . . . and W.K. Potts. Health consequences of a moderate fructose diet revealed by organismal performance assays. Abstract: 766.11. Experimental Biology 2011, April 11, Washington, D.C.