by Aditya Misra and Shreya Mathur
figures by Wei Wu and Jovana Andrejevic

117 million U.S. adults have one or more preventable chronic diseases related to diet, such as cardiovascular disease, high blood pressure, and type 2 diabetes. In an effort to prevent this outcome for themselves, an estimated 45 million Americans try to be healthier by taking up a diet and spending upwards of a combined $33 billion on weight-loss products. Some even go as far as to eat nothing but meat. However, perhaps the simplest and cheapest diet involves simply reducing portion sizes and the calories consumed at each meal. This so-called calorie-restriction diet was first proposed in 1917, and subsequent research in 1935 demonstrated that reducing the number of calories eaten every day while still consuming essential nutrients can extend one’s lifespan. Unlike fad diets that often have questionable medical outcomes, clinical studies have found that calorie restriction provides a number of benefits over time, including reducing blood cholesterol, blood pressure, and blood glucose levels. These changes can help prevent future chronic diseases from developing, including atherosclerosis (linked to heart attack and stroke) and diabetes (linked to blindness and limb amputation). 

However, exactly why calorie restriction can provide these health benefits still remains a mystery. While the most straightforward answer might be that eating fewer calories leads to consuming fewer sugars and fats, recent studies have found that the body responds to calorie restriction in ways that we are only just beginning to understand. Perhaps surprisingly, researchers recently discovered that calorie restriction helps the key defender of our bodies: the immune system.

The immune system: a double-edged sword

Our bodies are constantly under attack by bacteria, viruses and parasites trying to get in. If an invader does get in, the immune system tries to fight back and protect the body through a process called inflammation. For example, imagine for a moment what a bee sting feels like – ouch! Right after the stinger pierces the skin, the damage from the puncture wound and venom alert the immune system to respond to these external threats and initiate inflammation. Immune cells release proinflammatory compounds that dilate blood vessels in the harmed area, causing the familiar redness and painful swelling that recruits more immune cells to rush in (Figure 1). The proinflammatory immune cells at the site of damage and inflammation then fight off the venom from the bee sting and any other germs that may have also penetrated into the area. 

Figure 1. Immune cells are in either a proinflammatory state (left) or anti-inflammatory state (right) while combating threats like pathogenic bacteria and viruses. Although inflammation is important to defend against these threats, it is equally important for the body to stop inflammation and enter the anti-inflammatory state once these threats are dealt with.

As the immune cells release chemicals at the site of inflammation to fight germs, these chemicals unfortunately also destroy the healthy cells around them. This is the double-edged sword of the immune system: while we need inflammation to fight invaders, our healthy tissues are also damaged as a byproduct. Therefore, to prevent further damage, once the threat is contained, anti-inflammatory signals shut down the attacking immune cells and allow the swelling to go away as the wound heals. 

Depending on the needs of the tissue, the body must balance the proinflammatory processes that combat germs and the anti-inflammatory processes that subsequently heal the tissue. As people age, however, this balance is skewed as more immune cells become proinflammatory at baseline, which can lead to diseases such as rheumatoid arthritis and chronic pain. Studies have shown that calorie restriction may reduce inflammation and the risk of cardiovascular diseases, which typically develop as we age. Given these hints of a dynamic interaction between the immune system and calorie restriction during aging, researchers at the Salk Institute and the Chinese Academy of Sciences decided to put rats on a diet in order to figure out what exactly was going on.

Eating less – for immune health!

For their study, the researchers took middle-aged rats (18 months old, which corresponds to 50 human years) and provided them with either a normal-calorie diet or a calorie-restricted diet comprising 30% fewer calories (Figure 2). Once the rats reached 27 months of age (equivalent to 70 human years), the researchers looked at how the two groups differed. They focused on analyzing organs in the body often impacted by age-related diseases, such as fatty tissue, the aorta, kidney, liver, skin, and bone marrow. 

The researchers found that rats on a normal diet had high numbers of proinflammatory immune cells in fat, liver, and kidney tissue, which could possibly potentiate diseases developing in those organs. Surprisingly, however, they found that rats on the calorie-restricted diet had fewer immune cells present in these tissues overall, and that these immune cells were predominantly in an anti-inflammatory state. However, the scientists did not yet have an answer to why calorie restriction reduced the number of inflammatory immune cells in the first place. 

Figure 2. Researchers found and investigated why rats on a lower calorie diet (left) have less aging-associated tissue inflammation than those on a normal calorie diet (right).

Ybx1 – a restrictor of aging

The researchers decided to take a closer look at how the cells in different tissues changed after calorie restriction. They were surprised to find significant changes in a little-known gene called Ybx1, which produces a type of protein whose function is to control the levels of other genes. The researchers discovered that the rats that had been fed a calorie-restricted diet had higher production of Ybx1 in multiple organs than the rats that were fed a normal diet. With this phenomena occurring in many different cell types, particularly in tissues vulnerable to numerous age-related diseases, the researchers were motivated to figure out what Ybx1 was doing in these cells.

Researchers next artificially reduced levels of Ybx1 to mimic what occurs during normal aging. They discovered that reduction of Ybx1 resulted in more proinflammatory signals and a decrease in overall cell growth. This finding suggested that Ybx1 functions to encourage an anti-inflammatory state; therefore its decline during aging results in greater inflammation. This discovery finally explained why calorie restriction can reduce inflammation: calorie restriction reduces normal Ybx1 loss, which protects against aging-associated inflammation (Figure 3). 

Figure 3. On a normal diet, scientists observed that levels of the gene Ybx1 decreased, and these rats had signs of tissue inflammation (top). In contrast, rats on a calorie-restricted diet (bottom) had higher Ybx1 and lower levels of tissue inflammation, suggesting that Ybx1 reduces aging-associated inflammation.

For the first time, scientists now understand some of the biology behind the health benefits associated with a calorie-restriction diet down to the cellular level. Even more exciting, this study also reported many other unknown genes associated with the protective benefits of calorie restriction that could be further explored. Moreover, while both groups of rats in this study ate the same type of food, future work may uncover how our food choices (such as eating processed foods vs. fresh foods) affect our cells over time. By further investigating the changes our cells undergo as a result of our diets, scientists might one day be able to create drugs or dietary supplements that induce similar anti-inflammatory and anti-aging protection as calorie restriction. We need revolutionary new therapies to improve the quality of life for our aging population, allowing our elderly loved ones to engage more actively with their families and live longer, fuller lives. These potential new treatments, along with new knowledge with which to make informed decisions on how we eat, would bolster our fight against debilitating inflammation- and age-related chronic diseases. 

---

Aditya Misra is a second-year Medical Engineering and Medical Physics Ph.D. student in the Health Sciences and Technology program at MIT.

Shreya Mathur is a first-year MD student at the UCLA David Geffen School of Medicine.

Wei Wu is a first year graduate student in the Design Studies program at Harvard University Graduate School of Design. Her concentration is Art, Design and the Public domain.

Jovana Andrejevic is a fourth-year Applied Physics Ph.D. student in the School of Engineering and Applied Sciences at Harvard University. 

For More Information:

• To read the primary research described in this article, see this article published in the journal Cell.
• For more information about calorie restriction, check out the NIH website.
• For more commentary from the original researchers, check out their press release.
• For more studies linking caloric restriction and immunity, see this article and this article.