Caloric restriction and chronic inflammatory diseases

Abstract

A reduction in calorie intake [caloric restriction (CR)] appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by CR has generated interest in finding molecular targets that could be modulated by CR mimetics. This review describes the general concepts of CR and CR mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of CR on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, CR mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.

© 2011 John Wiley & Sons A/S.

Figures

Figure 1. Calorie intake levels and inflammation

The normal balance between the production of oxidative stress (Reactive oxygen -ROS, and Nitrogen-RNS species) and the antioxidant enzymatic system (superoxide dismutase-SOD, glutathione-GSH, and thioredoxin-TRX) observed during a normal/healthy caloric intake (A), is lost with either higher levels of calorie intake commonly observed in obesity or during aging, which leads to the accumulation of oxidative stress and production of inflammatory molecules and mediators (B). Caloric restriction would compensate the balance by reducing production of oxidative stress and inflammation as well as enhancing the production and activity of anti-oxidant enzymes and anti-inflammatory mediators.

Figure 2. Molecular targets for caloric restriction mimetics

Normally, the target of rapamycin (TOR) pathway is activated by nutrients (Glucose and amino acids), growth factors and insulin, which enhances the activation downstream of the transcription factor nuclear factor kappa B (NFκB) that is critical regulator of the pro-inflammatory gene expression. TOR is directly inhibited by rapamycin, and indirectly by the oral anti-diabetic drug metformin and resveratrol, which activate AMPK, an important inhibitor of TOR. The histone deacetylase, Sirtuin-1, considered a master metabolic regulator (involved in Cholesterol and fat metabolism, and glucose homeostasis), exhibits ability to modulate and control numerous transcription factors including de-acetylating (inactivation) of NFκB with the consequent reduction in the transcription of pro-inflammatory genes. Resveratrol also enhances activation of Sirtuin-1 (negative regulator of NFκB) and inhibits PI3K and S6K (positive regulators of NFκB). The levels of nutrients and insulin are reduced during caloric restriction which decreases activation of TOR pathway. IGF-1R: Insulin growth factor type 1 receptor; IRS-1: Insulin receptor substrate-1; PI3K: Phosphoinositide 3-kinase; PTEN: Phosphatase and tensin homolog; Akt: Serine-threonine protein kinase; S6K: 70KDa protein kinase; ATP: Adenosine triphosphate; AMP: Adenosine monophosphate; AMPK: 5’ adenosine monophosphate-activated protein kinase.

Figure 3

Collection of gingival crevicular fluid (GCF) from the periodontal pocket of Rhesus monkeys using Periopaper absorbent strips.

Figure 4

Effect of caloric restriction on inflammatory mediators and IgA/IgG levels in gingival crevicular fluid (GCF) during ligature-induced periodontitis in nonhuman primates. CON: Control, CR: Caloric restriction.

Figure 4

Effect of caloric restriction on inflammatory mediators and IgA/IgG levels in gingival crevicular fluid (GCF) during ligature-induced periodontitis in nonhuman primates. CON: Control, CR: Caloric restriction.

Figure 5

Effect of gender on inflammatory mediators levels in gingival crevicular fluid (GCF) during ligature-induced periodontitis in nonhuman primates under caloric restriction. F: Female, M: Male.