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.

Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor (PPAR) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPAR and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPAR protein expression associated with increased expression of PPAR-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPAR expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF--induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPAR mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPAR signaling during aging aggravates renal fibrosis development, and targeting PPAR is useful for preventing age-associated CKD.

β-Hydroxybutyrate, a ketone body that is used as an energy source in organs such as the brain, muscle, and heart when blood glucose is low, is produced by fatty acid oxidation in the liver under the fasting state. Endoplasmic reticulum (ER) stress is linked with the generation of intracellular reactive oxygen species and the accumulation of misfolded protein in the ER. ER stress is known to induce the NOD-like receptor protein 3 inflammasome, which mediates activation of the proinflammatory cytokine interleukin-1β, whose maturation is caspase-1-dependent. We investigated whether β-hydroxybutyrate modulates ER stress, inflammasome formation, and insulin signaling. Sprague Dawley rats (6 and 24 months of age) that were starved for 3 d and rats treated with β-hydroxybutyrate (200 mg·kg−1·d−1 i.p., for 5 d) were used for in vivo investigations, whereas human hepatoma HepG2 cells were used for in vitro studies. Overexpression of AMPK in cultured cells was performed to elucidate the molecular mechanism. The starvation resulted in increased serum β-hydroxybutyrate levels with decreased ER stress (PERK, IRE1, and ATF6α) and inflammasome (ASC, caspase-1, and NLRP3) formation compared with non-fasted 24-month-old rats. In addition, β-hydroxybutyrate suppressed the increase of ER stress- and inflammasome-related marker proteins. Furthermore, β-hydroxybutyrate treatment increased the expression of manganese superoxide dismutase and catalase via the AMP-activated protein kinase-forkhead box protein O3α transcription factor pathway both in vivo and in vitro. The significance of the current study was the discovery of the potential therapeutic role of β-hydroxybutyrate in suppressing ER-stress-induced inflammasome formation.

Chronic inflammation is a major risk factor underlying aging and the associated diseases of aging; of particular interest is insulin resistance during aging. Chronic inflammation impairs normal lipid accumulation, adipose tissue function, mitochondrial function, and causes endoplasmic reticulum (ER) stress, which lead to insulin resistance. However, some studies show that insulin resistance itself amplifies chronic inflammation. The activity of the insulin-dependent Akt signaling pathway is highlighted because of its decrease in insulin-sensitive organs, like liver and muscle, which may underlie insulin resistance and hyperinsulinemia, and its increased levels in non-metabolic organs, such as kidney and aorta. In that the prevalence of obesity has increased substantially for all age groups in recent years, our review summarizes the data showing the involvement of chronic inflammation in obesity-induced insulin resistance, which perpetuates reciprocal interactions between the chronic inflammatory process and increased adiposity, thereby accelerating the aging process.