Anti-aging mechanism of calorie restriction identified in Yale study

New findings indicate long-term calorie restriction inhibits the activity of a protein known to increase inflammation
New findings indicate long-term calorie restriction inhibits the activity of a protein known to increase inflammation


Animal studies have consistently demonstrated calorie-controlled diets lead to better health and longer lifespans. Human trials testing different dietary regimes have established calorie restriction as an effective way to lose weight, but it hasn’t been clear if long-term calorie restricted diets generate the same systemic health benefits in humans as seen in animal studies.

The researchers leveraged data from a landmark clinical trial conducted a few years ago called CALERIE (Comprehensive Assessment of Long term Effects of Reducing Intake of Energy). The trial recruited more than 200 healthy non-obese subjects and tasked half with reducing their caloric intake by 25 percent.

The trial ran for two years, allowing for unique insights into the long-term effects of caloric restriction across a number of physiological biomarkers. In the end, the interventional cohort achieved a consistent calorie reduction of 14 percent from their baseline intake at the beginning of the study.

“Because we know that chronic low-grade inflammation in humans is a major trigger of many chronic diseases and, therefore, has a negative effect on life span,” said Dixit. “Here we’re asking: What is calorie restriction doing to the immune and metabolic systems and if it is indeed beneficial, how can we harness the endogenous pathways that mimic its effects in humans?”

The first discovery came when the researchers examined MRI data focused on the thymus gland. The thymus produces immune T-cells and is known to age much more rapidly than other organs in the body. Age-related thymus dysfunction is one of the reasons immune responses in the elderly are weak.

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

Zooming in on gene expression changes in fat tissue, the researchers were most interested in one significant alteration. A gene that codes for a protein known as PLA2G7 was strongly inhibited in the cohort eating a calorie restricted diet for two years.

High circulating volumes of PLA2G7 have long been associated with metabolic and immune diseases, including diabetes, cardiovascular disease and some cancers. But it hasn’t been clear exactly how this protein may be contributing to chronic disease.

Knocking out the PLA2G7 gene in mice led to a number of intriguing effects that resembled what is seen with caloric restriction. The PLA2G7-inhibited mice were somewhat resistant to diet-induced weight gain, displayed less age-related thymus dysfunction, and showed lower levels of circulating pro-inflammatory biomarkers.

“These findings demonstrate that PLA2G7 is one of the drivers of the effects of calorie restriction,” Dixit said. “Identifying these drivers helps us understand how the metabolic system and the immune system talk to each other, which can point us to potential targets that can improve immune function, reduce inflammation, and potentially even enhance healthy lifespan.”

“Although there has been interest in CR [calorie restriction] as a lifestyle recommendation for humans, the real potential lies in understanding the mechanisms and translating them,” wrote Rhodes and Anderson. “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. Poised at the intersection of metabolism and immunity, PLA2G7 could be a valuable target for correction of immuno-metabolic dysfunction.”

This is certainly not the first time PLA2G7 has come to the attention of scientists. In the early 2000s, researchers discovered a distinct correlation between elevated PLA2G7 levels and atherosclerosis.

A drug to inhibit PLA2G7 production was developed and large-scale clinical trials on patients with acute coronary syndrome were conducted. While the drug, called Darapladib, was found to be safe, it was also found to be ineffective at reducing the risk of heart disease compared to placebo across two Phase 3 trials encompassing over 25,000 subjects.

It is clear there is a long road ahead before this discovery yields any anti-aging therapy. But Dixit is optimistic about his team’s findings, and indicates they inform how caloric restriction can lead to long-term health benefits in humans.

There may be ongoing debate over what kind of diet is best, Dixit says, but the most immediate takeaway is that simply eating less can be enough to generate notable health benefits.

“There’s so much debate about what type of diet is better – low carbohydrates or fat, increased protein, intermittent fasting, etc. – and I think time will tell which of these are important,” Dixit said. “But CALERIE is a very well-controlled study that shows a simple reduction in calories, and no specific diet, has a remarkable effect in terms of biology and shifting the immuno-metabolic state in a direction that’s protective of human health. So from a public health standpoint, I think it gives hope.”

The new study was published in the journal Science.

Source: Yale University