AgBioResearch

Every year, the World Health Organization estimates that between 250,000 and 500,000 people are killed by seasonal influenza, or flu, epidemics, with another 3 million to 5 million developing severe cases that warrant hospitalization. Though the virus cuts across every demographic, the very young, elderly and chronically ill remain at the greatest risk. Making matters worse, common flu vaccines lack the same effectiveness in those at-risk groups compared with other segments of the population. In a continued effort to reduce the common disease’s impact, Michigan State University (MSU) AgBioResearch nutritional immunologist Elizabeth Gardner is developing a novel approach: during flu season, slacken dietary restrictions and eat a few more calories.

In 1558, Venetian nobleman Luigi Cornaro first wrote about the virtues of dietary restriction as a means of improving health and increasing lifespan. In the intervening centuries, many scientists have investigated this claim, which has lately reemerged as “calorie restriction.” As a nutritional paradigm, calorie restriction has been shown to improve the health and longevity of animals in a laboratory setting. In this scenario, calories are simultaneously reduced while significant amounts of key nutrients are delivered through vitamin and mineral supplements. Experiments conducted on numerous species, from drosophila fruit flies to non-human
primates, have shown continual support for the method. A 2-year human trial is in progress. Recent findings, however, have shown that calorie restriction does not affect all parameters of health positively.

The aging benefits of calorie restriction have largely been shown to be linked to its ability to increase immunity. Mice under a calorie-restricted diet show significantly less incidence of tumors and respond better to other age-related problems. It was also reported that calorie restriction improved the immune response to the flu vaccine.

“We had the hypothesis that calorie restriction could be a simple dietary intervention to improve the immune response to flu,” Gardner said. “Back in 1996, I started a study that took both young and aged mice and infected them with flu virus. To my surprise and dismay, we found that the calorie-restricted animals died within four to six days after infection, which was about half the time of the non-restricted animals. In every circumstance, there wasn’t a calorie-restricted animal that lived longer.”

Troubled by the results, Gardner began investigating the cause. The four- to six-day window during which the mice succumbed constituted the time during which the body’s primary immune response — the general response, before the body develops a pathogen-specific counterattack — is battling the illness. During this phase, the body’s primary defense against the virus is the natural killer (NK) cells, a type of white blood cell that can identify and target infections without the presence of antibodies. Gardner discovered that, in mice under calorie restriction, both the numbers and the functionality of NK cells are diminished. This loss was correlated to diminishing body mass brought on by one of the flu’s most common symptoms, anorexia.

Though most commonly associated with the eating disorder anorexia nervosa, anorexia generally refers to any decreased sensation of appetite. Loss of appetite is a common symptom of the flu, and mice are no exception. Shortly after infection, the mice stopped eating. Both calorie-restricted and non-restricted mice lost body weight as a result, but the non-restricted mice had enough mass initially to hang on and eventually begin fighting the infection. The calorie-restricted mice, having less mass to start with, simply lost too much. For older mice, mortality came even more quickly.

“We started to look at how we could address this from a nutritional perspective,” Gardner said. “This finding had particular implications for human health because a lot of the patients who are hospitalized with the flu are older, thinner people. Someone with less body mass is much more susceptible to the worst effects of the flu.”

With support from the National Institute on Aging, Gardner and her lab have been conducting studies on mitigating the effects of the flu on calorie-restricted subjects. For the next round of experiments, they fed calorie-restricted mice a higher calorie diet for two weeks prior to inoculating them with the flu virus. NK cells are known to perform poorly under reduced-caloric conditions, and Gardner hoped that by increasing calorie intake, she could bolster their effectiveness.

The findings were starkly different from those of the original experiment. The mice that were given more expansive diets prior to infection showed NK cells in higher numbers and with greater efficacy to allow
them to survive.

Though increasing calorie intake immediately before contracting the flu was shown to improve the chances of recovering, that approach isn’t practical.

“Unlike in the experiment, we have no idea when precisely we’ll get the flu,” Gardner said. “We do, however, know when flu season is. If you are on a calorie-restricted diet, bumping up your calorie intake by about 10 percent during the four months of flu season ensures that you have adequate caloric stores to maintain your ability to fight the disease.”