Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term "senoinflammation", that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.

Ginsenoside Rd is a primary constituent of the ginseng rhizome and has been shown to participate in the regulation of diabetes and in tumor formation. Reports also show that ginsenoside Rd exerts anti-oxidative effects by activating anti-oxidant enzymes. Treatment with ginsenoside Rd decreased nitric oxide and prostaglandin E2 (PGE2) in lipopolysaccharides (LPS)-challenged RAW264.7 cells and in ICR mouse livers (5 mg/kg LPS; LPS + ginsenoside Rd [2, 10, and 50 mg/kg]). Furthermore, these decreases were associated with the down-regulations of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and of nuclear factor (NF)-κB activity in vitro and in vivo. Our results indicate that ginsenoside Rd treatment decreases; 1) nitric oxide production (40% inhibition); 2) PGE2 synthesis (69% to 93% inhibition); 3) NF-κB activity; and 4) the NF-κB-regulated expressions of iNOS and COX-2. Taken together, our results suggest that the anti-inflammatory effects of ginsenoside Rd are due to the down-regulation of NF-κB and the consequent expressional suppressions of iNOS and COX-2.

FoxO has been proposed to play a role in the promotion of insulin resistance, and inflammation. FoxO is a pro-inflammatory transcription factor that is a key mediator of generation of inflammatory cytokines such as IL-1β in the liver. However, the detailed association of FoxO6 with insulin resistance and age-related inflammation has not been fully documented. Here, we showed that FoxO6 was elevated in the livers of aging rats and obese mice that exhibited insulin resistance. In addition, virus-mediated FoxO6 activation led to insulin resistance in mice with a notable increase in PAR2 and inflammatory signaling in the liver. On the other hand, FoxO6-KO mice showed reduced PAR2 signaling with a decrease in inflammatory cytokine expression and elevated insulin signaling. Because FoxO6 is closely associated with abnormal production of IL-1β in the liver, we focused on the FoxO6/IL-1β/PAR2 axis to further examine mechanisms underlying FoxO6-mediated insulin resistance and inflammation in the liver. In vitro experiments showed that FoxO6 directly binds to and elevates IL-1β expression. In turn, IL-1β treatment elevated the protein levels of PAR2 with a significant decrease in hepatic insulin signaling, whereas PAR2-siRNA treatment abolished these effects. However, PAR2-siRNA treatment had no effect on IL-1β expression induced by FoxO6, indicating that IL-1β may not be downstream of PAR2. Taken together, we assume that FoxO6-mediated IL-1β is involved in hepatic inflammation and insulin resistance via TF/PAR2 pathway in the liver.