Elevated Muscle TLR4 Expression and Metabolic Endotoxemia in Human Aging

Abstract

Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia.

Microbial translocation and skeletal muscle in young and old vervet monkeys

“…However, Rodriguez-Miguelez et al reported that TLR4 levels dropped 50 % in overweight, older participants following a low-intensity vibration-platform-based exercise intervention. In the study by Ghosh et al (Ghosh et al, 2014), circulating LBP-1 concentrations were close to double those in young people, as were muscle TLR4 receptor levels. In our study of vervet monkeys, increased LBP-1 levels per se were not associated with age, but the combination of being old and sedentary resulted in ninefold greater LBP-1 concentrations.…”

“…Intestinal Bleakiness^occurs with advancing age across many species (Ma et al, 1992;Rera et al, 2012;Tran and Greenwood-Van Meerveld, 2013;Ghosh et al, 2014), but only recently has become recognized as an important mediator of healthspan, lifespan, and insulin signaling in invertebrates (Rera et al, 2012;Ulgherait et al, 2014). A Bleaky^mucosa allows greater translocation of microbial antigens into the intestinal wall and portal circulation, inciting inflammation both locally and remotely.…”

“…Means with standard errors of the mean presented in parentheses are shown Stehle et al reported that greater MT was associated with worsening physical function in older people and that this relationship was also independent of inflammatory cytokines (Stehle et al, 2012), consistent with results from the current study. To date, only two exercise intervention trials in older people have been published with opposing results on muscle toll-like receptor 4 (TLR4) levels, which like LBP-1 reflects MT burden (Ghosh et al, 2014;Rodriguez-Miguelez et al, 2015). Ghosh et al found than an intense exercise program did not reduce muscle levels of TLR4 in a US population of sedentary, normal-weight, aged individuals.…”

“…For example, fruit flies with impaired intestinal barrier function have reduced physical activity, and their loss of intestinal barrier function predicted imminent death (Rera et al, 2012). Recent studies have documented that aged people also have greater MT (Ghosh et al, 2014), and that even in healthy older people, MT specifically relates to physical function indices (Stehle et al, 2012). Function of the intestinal barrier declines with aging-an effectsuggests that aging effects, not diet, may primarily drive intestinal leakiness and MT.…”

“…In rodent experiments where age was controlled, increasing TLR-mediated inflammation in peripheral tissues by multiple methods (e.g., infusing LPS, dietinduced endotoxemia, or microbiomic alterations) all caused reduced insulin sensitivity (Cani et al, 2007(Cani et al, , 2008. Evidence from a few clinical studies shows that MT increases with age (Reiner et al, 2013;Ghosh et al, 2015). Thus, we hypothesized that aging monkeys would have higher MT rates than younger counterparts.…”