Calorie Restriction Acts via p38 to Reduce Inflammation due to Innate Immune Activity

The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining optimal micronutrient intake, slows aging in most species tested to date. The effect on life span is much larger in short-lived species than in long-lived species, but the short-term health benefits are similar in mice and humans, even though mice live up to 40% longer when calorie restricted, and humans clearly do not. One component of the beneficial response to calorie restriction is a reduction in inflammation, particularly important given the prominent role that chronic inflammation plays in the aging process. In later life the immune system falls into an inflammatory, overly active, but ineffective state, a combination of the states known as inflammaging and immunosenescence. This disrupts tissue maintenance and accelerates the progression of all of the most common age-related diseases. Control over inflammation is a very desirable goal for older individuals.

Researchers have found that caloric restriction reduces levels of innate immunity by decreasing the activity of a regulatory protein called p38, triggering a chain reaction effect ending in a reduced immune response. Innate immunity is like the security guard of the body, keeping an eye out for any unwelcome bacteria or viruses. If the innate immune system spots something, it activates an acute immune response. We need some degree of both kinds of immunity to stay healthy, but an overactive innate immune system - which occurs more often as we age - means constant low-grade inflammation, which can lead to myriad health issues.

The research was conducted in the microscopic nematode worm C. elegans. The most fundamental genes and regulatory mechanisms found in these worms are typically simpler versions of those present in humans, making them a good model for studying human aging, genetics, and disease. Researchers analyzed the levels of proteins and actions of genetic pathways during periods of caloric restriction. They were able to zero in on a particular genetic pathway that was regulated by the p38 protein. They saw that when p38 was totally inactive, caloric restriction failed and had no impact on innate immunity. When it was active, but at lower levels than normal, it triggered the genetic pathways that turned down the innate immune response to an optimal level.

After making this discovery, the researchers were curious to know if the well-known longevity mechanism of reduced IGF1 signaling also acted on the immune system. For over 20 years, study after study in many different organisms have confirmed that lower levels of IGF1 signaling contributes to a longer lifespan. This is thought to be due to the activation of protective factors by a protein called FOXO (called DAF-16 in C. elegans). A reduction in the activity of the FOXO-like gene seems to tell the worms that they are in a fasting-like state, and that nutrients may be scarce. This directs the worms to conserve energy, leading to a reduction in food intake. This self-imposed caloric restriction then leads to the lowering of the innate immune response.


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