Using a mix of clinical and animal studies, researchers at Yale University have identified an enzyme whose decreased activity appears to be behind some of the beneficial effects of caloric restriction. They published their work in the February 11, 2022, issue of Science.

In principle, the key to living longer is simple. Caloric restriction of about 40% increases the lifespan of all species that have been subjected to it to date.

There have been no studies demonstrating such an effect on lifespan in humans, owing both to our long lifespan and the rigors of the approach. But it stands to reason that for the few who are able to pull it off long-term, less food would translate into more years.

However, research studies have shown that caloric restriction's effects may not be all desirable. Long-term severe caloric restriction damages the immune system in multiple ways in animal models, making the animals more susceptible to viral and parasitic infections and more likely to die from sepsis.

That immune compromise seems to be due to both direct and indirect effects. Immune cell functioning takes a lot of energy at baseline, and energy requirements are further increased when cells rapidly proliferate in response to microbial invaders. In calorie-restricted mice, T-cell production in the thymus declined more rapidly than in age-matched controls, hampering one of the major defense systems of the adaptive immune system.

Studies have also shown that severe caloric restriction raises stress hormones, which also have immunosuppressive effects.

Those stress hormones illustrate another issue with caloric restriction. In a way, it really doesn't matter what the effects in humans would be – because barring an eating disorder, 40% caloric restriction is next to impossible.

Bodies are evolutionarily wired to care about the short-term effects of famine, not the long-term effects of feasts, and caloric restriction will set off massive alarm bells and compensatory mechanisms. There is a cornucopia of studies showing that prolonged caloric restriction, aka dieting, has multiple negative effects on quality of life, libido, mood and eating patterns.

In an editorial accompanying the Science paper, the authors spelled out the logical conclusion.

"The real potential [of caloric restriction] lies in understanding the mechanisms and translating them. By identifying critical factors and processes that are causal in the beneficial effects of CR, it could be possible to learn what is creating vulnerability and what might be targeted to change the pace of functional decline," they wrote. "In taking the leap from observations in humans to experiments with transgenic mouse models, [the investigators] provide new insight into the biology of PLA2G7 and its important role in immunometabolic regulation and systemic homeostasis."

CALERIE

The studies now published in Science started with the question of what the effects of milder, and perhaps more sustainable, caloric restriction would be on the human immune system.

The team first imaged the thymus of individuals who had taken part in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE 2) clinical trial, a randomized controlled trial designed to explore sustainable caloric restriction and its effects on the body. CALERIE 2 recruited individuals whose body mass index was between 22 and 28.5, and attempted to subject them to 25% caloric restriction – an amount the investigators of the trial deemed "a compromise between the attainment of optimal physiological adaptations and perceived feasibility."

Over the course of the CALERIE 2 trial, it turned out that 25% was still too high to be sustainable. However, trial participants did reduce their caloric intake by an average of 12%.

In the work now published in Science, senior author Vishwa Deep Dixit, Waldemar Von Zedtwitz Professor of Pathology, Immunobiology, and Comparative Medicine at Yale University School of Medicine, and his colleagues looked at immune markers in CALERIE 2 participants.

The team found that caloric restriction led to increased thymic mass and greater numbers of circulating T cells.

"The fact that this organ can be rejuvenated is, in my view, stunning because there is very little evidence of that happening in humans," Dixit said in a prepared statement. "That this is even possible is very exciting."

RNA sequencing of those cells showed no differences between caloric restricters and the control group. Instead the difference was in fat cells, where caloric restriction affected the levels of multiple proteins.

Dixit and his colleagues focused on group VII A platelet activating factor acetylhydrolase (PLA2G7), which is expressed in macrophages. PLAG27 levels are increased in a slew of disorders, but to date, little had been known about its function. Dixit and his colleagues showed that in mice, knocking out the enzyme prevented diet-induced weight gain and reduced levels of immune cells and proinflammatory cytokines in fat tissue.