Despite its occasional detractors and debate about how it works (at both global and molecular levels), biogerontologists generally consider calorie restriction (CR) to be A Good Thing™.

CR, as the catechism goes, is the only intervention that significantly increases lifespan in every organism studied. This strict dietary regimen also has other benefits, e.g., modifying adipocyte (fat cell) gene expression to increase insulin sensitivity and thereby fend off late-onset insulin-resistant diabetes.

At the immunological level, too, CR shows great promise, apparently slowing immune system aging by delaying clonal senescence and increasing the effectiveness of response to both previously encountered and novel pathogens.

All the more surprising, then, is the finding that CR increases susceptibility to certain types of infection. Deborah Kristan has demonstrated that chronically food-limited mice are less capable of fighting off a nematode parasite, despite their higher immunoglobulin and eosinophil responses to the infection.

Contrary to predictions, CR mice had more worms than ad libitum-fed mice and the worms from CR mice produced more eggs than worms from ad libitum-fed mice. These data indicate that, despite the evidence that long-term CR enhances traditional measures of immune function, CR may actually increase susceptibility to intact parasite infection.

In other words, despite prior reasons to believe that CR would boost immunity, and evidence from this very study supporting the theory (i.e., the increased immune response), the ultimate result turned out exactly the opposite: CR mice had a higher parasite load, at least in this particular model of infection.

This outcome demonstrates the importance of continuing to drive a field toward the best answers by asking the best questions. “Does CR enhance the immune system?” is a good question, but it’s not as good as “Does it do so in a manner that is functionally relevant?” Kristan didn’t stop at what some would have considered the finish line, but pushed ahead to ask the next question — one whose answer casts quite a different light on CR.

Skepticism, the healthy tendency to test the corollaries of past findings rather than lean back and contently predict them, has great value in science — perhaps even more so in the face of an emerging consensus. While no one (at least, no one responsible) has claimed that CR is a panacea for all ills, it is crucial to temper our enthusiasm about its growing list of benefits (from longevity to diabetes and beyond) by keeping in mind its potential shortcomings, from bone loss to depression and now potentially immunological compromise.

While it’s unlikely that large swaths of the population will ever voluntarily restrict their caloric intake, it seems increasingly likely that CR mimetics will someday be a reality. Knowledge about the pitfalls of CR, and whether a given downside can be uncoupled from its benefits, will dramatically influence drug design, clinical indications for the use of mimetics, and strategies for long-term care of the end users.