Age-related inflammation and insulin resistance: a review of their intricate interdependency

Abstract

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.

Fig. 1

Signaling pathways downstream of NIK and Akt activation. Extracellular receptors bind to their ligands and signal via NF-κB inducing kinase (NIK) or Akt molecules. This leads to phosphorylation of the IκB kinase (IKK) subunits and the subsequent phosphorylation of IκBα, which leads to its ubiquitination and proteasomal degradation. Inflammasome activation also triggers signaling through nuclear factor-κB (NF-κB) and Interleukin-1β (IL-1β). NF-κB is then released into the nucleus where it acts as a transcription factor and stimulates inflammatory responses

Fig. 2

Obesity is determined by increasing both, the size and number of adipocytes. Adipogenesis can lead to a large number of new adipocytes (hyperplasia) which produce more adiponectin and less inflammatory adipokines. Conversely, hypertrophied adipocytes produce less adiponectin and more inflammatory adipokines. The prevalence of hypertrophied adipocytes in adipose tissue leads to a reduction in blood flow with subsequent hypoxia and macrophage infiltration. In addition, cytokines produced by macrophages inhibit adipogenesis

Fig. 3

Crosstalk between insulin resistance in metabolic organs and molecular inflammation in non-metabolic organs. The serum insulin concentration is up regulated in an insulin resistance state. Insulin resistance-induced hyperinsulinemia stimulates inflammatory responses in non-metabolic organs such as kidney by activating the Akt/IκB kinase (IKK) signaling pathway