Raised SIGIRR Levels May Mediate Reduced Chronic Inflammation via Calorie Restriction
Here researchers investigate some of the mechanisms involved in the relationship between calorie restriction (CR) and inflammation. The practice of calorie restriction is known to reduce inflammation in the short term, and over the long term it also reduces the growth in chronic inflammation that occurs with aging and which contributes to the development of many age-related conditions. Given that excess visceral fat tissue provides a potent contribution to inflammation, it is tempting to think that the effects of calorie restriction in this case result from practitioners becoming lean. However lack of visceral fat is never the whole story in anything relating to calorie restriction; a lot of other changes take place in cellular biochemistry in response to reduced nutrient intake:
Much of the aging phenotype, including immunosenescence, can be explained by an imbalance between inflammatory and anti-inflammatory networks, resulting in a chronic low-grade pro-inflammatory status. In previous studies, CR has been shown to play a significant role in the anti-inflamm-aging process by decreasing the levels of inflammatory markers in aging tissues. However, thus far, the anti-inflammatory effects of CR have only been superficially examined, and the underlying mechanism has not yet been elucidated. The present study is for the first time to demonstrate the possible regulatory mechanism by which CR induces anti-inflamm-aging and to explore the expression of the upstream and downstream molecules.Toll-like receptor (TLR) 4 is a type of pattern recognition receptor (PRR) that recognizes molecules that are broadly shared by pathogens but distinguishable from host molecules; collectively, these molecules are referred to as pathogen-associated molecular patterns (PAMPs). TLRs, together with the interleukin-1 (IL-1) receptor (IL-1R), form a receptor superfamily known as the 'IL-1R/TLR superfamily'; all of the members of this family have a so-called Toll/IL-1R (TIR) domain in common. TLRs recognize PAMPs and initiate an intracellular kinase cascade to trigger an immediate defense response.
Fisher 344 rats in a CR group were fed an amount of food corresponding to 60% of that fed to an ad libitum-fed (AL) group for 8 months. Biochemical analyses and renal pathological grading were used to analyze physiological status. Important signaling molecules in the Toll-like receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/NF-κB) pathway were also analyzed. Compared with AL feeding, CR decreased aging-mediated increases in both biochemical marker levels and renal pathological grading. Single immunoglobulin IL-1 (IL-1)-related receptor (SIGIRR) expression decreased with increasing age, but CR led to overexpression. The expression of TLR4 was significantly higher in the CR group than in the AL group. SIGIRR overexpression decreased the expression of the adaptor molecules myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinase 4 (IRAK4) and tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of the inflammatory markers phospho-IκBα and phospho-NF-κB p65 decreased in the CR group.
We conclude that the inflammatory response might be alleviated by SIGIRR via blockade of the TLR4/NF-κB signaling pathway. Therefore, CR can decrease inflammation via SIGIRR overexpression, and SIGIRR might be a new target to delay aging.