How are inflammation, aging and diet related?  Describe the systemic regulatory network for the first time

How are inflammation, aging and diet related? Describe the systemic regulatory network for the first time

Dietary restriction (DR) can interrupt the feedback loop that keeps the aging-related state of inflammation (inflammation) going. Credit: FLI/F. Neri & M. Rasa

Mild and persistent inflammation in tissues is a biological feature of the aging process in humans – and at the same time a risk factor for diseases such as Alzheimer’s disease or cancer. Professor Francesco Neri and Dr. Mehdi Rasa of the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena have succeeded for the first time in describing the regulatory network that drives the general multi-organ inflammatory response at the molecular level. Furthermore, they were able to demonstrate that dietary restriction can affect this regulatory circuit, thereby inhibiting inflammation.

Inflammation is the body’s immune response, and it is, in and of itself, beneficial: our immune system uses it to fight pathogens or to remove damaged cells from tissues. As soon as the immune cells do their job, the inflammation subsides: the infection ends, the wound heals. In contrast to these acute infections, age-related chronic inflammation is not localized. The innate immune system generally increases its activity, resulting in chronic low-grade inflammation. This aging-related inflammation is also known as inflammation.

Inflammation is bad for health

This primary inflammation has consequences for health. “If you have constant activation of immune cells, this can lead to their depletion, which in turn leads to problems when infection occurs. And immune cells may not respond properly. Inflammation is also linked to the development of cancer – because it is in inflamed tissues,” explains Professor Francesco Neri, who headed the group Research “Epigenetics of Aging” at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena until the end of 2021, shows that we see an increase in cell proliferation.” Conducting research at the University of Turin, Italy.

How do aging, inflammation and diet interact?

Together with Dr. Mehdi Rasa and other FLI colleagues, Professor Neri conducted a study in mice to investigate how chronic aging-associated inflammation is regulated and maintained by genes – and whether dietary restriction can affect this regulatory network and prevent inflammation. In fact, studies over the past two decades have shown that many animals — from flies to worms to rodents to monkeys — live longer when fed a calorie-reducing diet.

For example, when rats were fed 30% less food, they were fitter and more active, and lived three to four months longer – equivalent to a 10% to 15% increase in life span. Improved health has also been observed in people who follow calorie-restricted diets. It is also known that inflammatory responses can be reduced through this dietary approach. However, the ways in which inflammation, aging and dietary restrictions are regulated in detail at the molecular level, as well as how they relate to each other, are not yet understood.

Inflammation feedback loop

About their current study that was recently published in the journal cell reportsThe FLI researchers first compared four-month-old mice with older mice (22 months old). In contrast to previous studies, gene activity was measured not just in one organ, but in multiple tissues in parallel: blood, brain, heart, kidney, liver, lung, muscle and skin.

“The priority was to study the pathways that were affected in all tissues to understand inflammation at the systemic level,” Neri explains. “What we found is that the inflammatory phase in older mice was marked by the infusion of a specific set of genes that encode the receptors for the innate immune system. This downregulation leads to the activation of a set of interferon-regulating genes. These genes then the activation of other genes that produce inflammatory cytokines, as well as the activation of Stat1,” It is a key transcription factor for the regulation of genes related to inflammation. This whole process is like a positive feedback loop that keeps the inflammatory state going.” Genea researchers are thus the first to describe the regulatory network across organs and thus systemic. But can this cycle be stopped by reducing calories?

To answer this question, Neri and Rasa studied genetic activity in members of two additional groups of rodents: mice that were given 30% less food for nearly their entire life (4 to 22 months) and mice that were kept under these for only two months at the end of their lives. Whether the calorie restriction was short or long-term, the diet in general had a positive effect on all organs studied, with the exception of the heart.

The systemic regulatory network is the starting point for interventions

Through their work, the two researchers also provide starting points for future drug therapies for chronic inflammation associated with aging. “Within this regulatory network we describe, one important and well-studied component is, for example, TLR4, a gene that encodes the receptor for the innate immune system,” explains Dr. Rasa, who performed the genetic analyzes as part of his Ph.D. .Dr. hypothesis. “The receptor acts like an SOS signal that we don’t need when there are no pathogens to combat it. If we can downregulate TLR4, we will be able to reduce the chronic inflammatory response in old age.”

Another much-discussed possibility of intervention is the administration of nutritional supplements such as vitamins or probiotics with the aim of influencing the composition of the microorganisms in the gastrointestinal tract. “Dietary restriction appears to alter the microbiome, resulting in reduced inflammation. If the gut flora of the microbiome can be altered through supplementation, the same beneficial effects can be achieved without the need for a restrictive diet.” Professor Neri admits that this is still speculation. “First we need to have a better understanding of the processes involved.”

Reducing calories reduces protein associated with the aging process

more information:
Syed Muhammad Mahdi Rasa et al., Inflammation is caused by upregulation of innate immune receptors and systemic interferon signaling and is attenuated by dietary restriction, cell reports (2022). DOI: 10.1016 / j.celrep.2022.111017

Provided by the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)

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