Everybody knows: You are what you eat. But new research suggests, if your wish is to live longer, what matters most is how much you eat.

Scientists have known that — at least when it comes to lab animals — that cutting calories leads to a lengthening in lifespan: in worms, rodents; even in monkeys. The first study on calorie restriction to promote longevity in animals dates back to the 1930s. Despite this glut of research whether the approach works for humans has yet to be determined.

This new study, published in Cell on Thursday, brings us one step closer, by helping to elucidate the underlying mechanisms behind this phenomenon.

Researchers from the United States and China put rats on a calorie-restricted diet and found ignited a number of anti-aging effects. This included protection against cellular aging, reversing age-related immune dysfunction, and alleviating chronic inflammation. These results suggest that caloric restriction has the propensity to rewire the physiological aging process.

“The effect of caloric restriction on extending healthspan and lifespan suggests that aging is reversible and druggable,” co-author Guang-Hui Liu, a professor at the Chinese Academy of Sciences, tells Inverse. “We hope that we can identify the intervention target to mimic the beneficial effect of caloric restriction in the future.”

Calories and cellular aging

Researchers pitted two groups of rats against one another: One group received 30 percent fewer calories versus the other group, who were kept on a normal diet. The researchers followed the rats over the course of nine months, from age 18 months (middle-aged for a rat) to 27 months, deliberately choosing older rats as this is when potential clinical applications would prove most effective. The rats’ ages were comparable in humans to about the ages 50 through 70.

"The effect of caloric restriction on extending healthspan and lifespan suggests that aging is reversible and druggable."

They found that the rats who were subjected to calorie restriction didn’t display almost 60 percent of the age-related changes in cell composition that occurred in the rats on a normal diet.

Older rats on a calorie-restricted diet were also found to share similarities in tissue and cell composition with young rats on a normal diet, suggesting that older rats maintained similar physiology to rats much their junior.

The future of "aging" science

The build-up of pro-inflammatory cells in the tissues of the rats — a process associated with aging — was found to be repressed thanks to calorie restriction. This finding lends weight to the theory that many chronic illnesses are closely linked to age-related inflammation, including cancer, diabetes, and Alzheimer’s disease.

They used single-cell genetic sequencing to look at the effects of calorie restriction on the activity levels of certain genes when comparing the cells of the rats from the start of the experiment to the end. They found that the expression levels of many anti-inflammatory genes were reverted to those seen in young animals in the older rats on a diet.

When asked if he thinks the results of the study could one day be translated to humans, Liu says it’s possible. When it comes to humans, caloric restriction is defined as reducing average daily caloric intake below what is habitual, without malnutrition or deprivation of essential nutrients.

Liu acknowledges that the study was conducted in rats – not humans – and therefore, its clinical applications may be a ways away. “A lot of interesting things discovered here need to be tested carefully in the human context,” he tells Inverse, and that “more tests and cautions are needed” before that can happen.

For now, the study has uncovered new biomarkers that could be used in humans “to predict our biological ages” – something he says is “urgently needed in the aging research field”.

Eat less, live longer? Perhaps. Eating less (but still respecting your hunger and eating enough to get the nutrients you need) may or may not extend human life, but research is pointing in that direction.

Longevity Hacks is a regular series from Inverse on the science-backed strategies to live better, healthier, and longer without medicine.

HOW THIS AFFECTS LONGEVITY — This study on rats found that a calorie-restricted diet ignited a number of anti-aging effects, including protecting against cellular aging, reversing age-related immune dysfunction, and alleviating chronic inflammation.

WHY IT’S A HACK — Studies conducted on animals since the 1930s suggest that cutting calories can lengthen a lifespan. However, this hasn’t been definitively proven in humans — and scientists aren’t exactly sure why it can help in the first place. This study suggests caloric restriction can rewire the physiological aging process.

SCIENCE IN ACTION — The study authors note that this study needs to be replicated in a trial conducted on humans. However, they are hopeful that caloric restriction — defined as reducing one’s average daily caloric intake without depriving oneself of essential nutrients — can help people live longer.

HACK SCORE OUT OF 10 — 🐀🐀🐀🐀🐀 (5/10 rats)

Abstract: Aging causes a functional decline in tissues throughout the body that may be delayed by caloric restriction (CR). However, the cellular profiles and signatures of aging, as well as those ameliorated by CR, remain unclear. Here, we built comprehensive single-cell/single-nucleus transcriptomic atlases across various rat tissues undergoing aging and CR. CR attenuated aging-related changes in cell-type composition, gene expression, and core transcriptional regulatory networks. Immune cells were increased during aging, and CR favorably reversed the aging-disturbed immune ecosystem. Computational prediction revealed that the abnormal cell communication patterns observed during aging, including the excessive proinflammatory ligand-receptor interplay, were reversed by CR. Our work provides the multi-tissue single-cell transcriptional landscapes associated with aging and CR in a mammal, enhances our understanding of the robustness of CR as a geroprotective intervention, and uncovers how metabolic interventions can act upon the immune system to modify the process of aging.