Anti-aging mechanism of calorie restriction identified in Yale study

Animal studies have consistently demonstrated calorie controlled diets lead to better health Y longer lives. human trials trying different dietary regimens have established caloric restriction as effective way to lose weightbut it has not been clear whether long-term calorie-restricted diets lead to the same systemic health benefits in humans as those seen in animal studies.

This new study, led by scientists at Yale University, offers some of the strongest research ever conducted on the long-term health effects of calorie-restricted diets in humans. The results have focused on a protein that appears to play a key role in age-related immune dysfunction, and the researchers hypothesize that it could be a therapeutic target to extend lifespan in humans.

The researchers took advantage of data from a landmark clinical trial conducted a few years ago called CALERIA (Comprehensive evaluation of the long-term effects of reducing energy consumption). The trial recruited more than 200 healthy, non-obese subjects and tasked half with reducing their caloric intake by 25 percent.

The trial lasted two years, providing unique insights into the long-term effects of calorie restriction on a range of physiological biomarkers. In the end, the intervention cohort achieved a consistent calorie reduction of 14 percent of their initial intake at the start of the study.

Lead author of the new study, Vishwa Deep Dixit, says this investigation of the CALERIE data focused on how long-term calorie restriction in humans influenced immune response and inflammation.

“Because we know that low-grade chronic inflammation in humans is a major trigger for many chronic diseases and therefore has a negative effect on life,” Dixit said. “Here we ask: What is calorie restriction doing to the immune and metabolic systems, and if it is indeed beneficial, how can we harness 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 faster than other organs in the body. Age-related thymic dysfunction is one of the reasons why immune responses in the elderly are weak.

Incredibly, the researchers found that two years of calorie restriction appeared to increase the functional volume of the thymus gland compared to data collected at the start of the trial. A reduction in fat around the gland was also detected, compared to little change in the control group without dietary restriction. Dixit says this indicates that the thymus was producing more T cells after two years of calorie restriction than it was at the start of the trial.

“From my point of view, the fact that this organ can be rejuvenated is surprising because there is very little evidence that this happens in humans,” said Dixit. “That this is possible is very exciting.”

By focusing on gene expression changes in adipose tissue, the researchers were more interested in significant alteration. A gene that codes for a protein known as PLA2G7 was strongly downregulated in the cohort that ate 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 has not been clear exactly how this protein may be contributing to chronic disease.

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

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

In addition to identifying one of the ways that calorie-restricted diets can improve human health, the really exciting result of the findings is a potential new therapeutic target for general age-related decline in health. Commenting on new findingsResearchers Timothy Rhodes and Rozalyn Anderson said the study sheds light on how fat-derived molecules can broadly modulate overall health. And PLA2G7 therapies could hypothetically be developed to slow the pace of age-related metabolic and immune decline.

“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,” Rhodes and Anderson wrote. “By identifying the critical factors and processes that are causal in the beneficial effects of CR, it might be possible to learn what is creating vulnerability and what might be targeted to change the pace of functional decline. Positioned at the intersection of metabolism and immunity, PLA2G7 could be a valuable target for correcting immunometabolic dysfunction.”

Certainly, this is not the first time that PLA2G7 has come to the attention of scientists. In the early 2000s, the researchers discovered a clear correlation between elevated levels of PLA2G7 and atherosclerosis.

A drug to inhibit the production of PLA2G7 was developed and large-scale clinical trials were conducted in patients with acute coronary syndrome. While the drug, called darapladib, was found to be safe, it was also ineffective in reducing the risk of heart disease compared to placebo in two phase 3 trials involving more than 25,000 subjects.

It is clear that there is a long way to go before this discovery produces an anti-aging therapy. But Dixit is optimistic about his team’s findings, saying they inform how calorie restriction can lead to long-term health benefits in humans.

There may be an ongoing debate about which type of diet is best, says Dixit, but the most immediate conclusion is that simply eating less may be enough to generate remarkable health benefits.

“There is a lot of debate about which type of diet is best (low carb or fat, higher protein, intermittent fasting, etc.) and I think time will tell which ones are important,” Dixit said. “But CALERIE is a very well-controlled study that shows that a simple reduction in calories, without a specific diet, has a remarkable effect in terms of biology and changes the immunometabolic state in a direction that protects human health. So from a public health standpoint, I think it gives hope.”

The new study was published in the journal Sciences.

Fountain: Yale University