IGF Binding Protein-5 Induces Cell Senescence

Abstract

Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5) with the induction of the tumor suppressor p53 is upregulated during cellular senescence. This mechanism mediates interleukin-6/gp130-induced premature senescence in human fibroblasts, irradiation-induced premature senescence in human endothelial cells (ECs), and replicative senescence in human ECs independent of insulin-like growth factor I (IGF-I) and IGF-II. Additionally, a link between IGFBP-5, hyper-coagulation, and inflammation, which occur with age, has been implicated. Thus, IGFBP-5 seems to play decisive roles in controlling cell senescence and cell inflammation. In this review, we describe the accumulating evidence for this role of IGFBP-5 including our new finding.

Keywords: IGF binding protein-5; age-related disease; cell senescence; coagulation system; inflammation.

Figure 1

Source of “inflammaging.” Among the main causes of inflammaging, the accumulation of pro-coagulation factors, cell senescence, cell debris such as circulating mitochondrial DNA (cmtDNA), gut dysbiosis, and immune senescence are the main causes of inflammaging. Pro-coagulation factors also cause cell senescence. Inflammaging can also be influenced by many other factors, including age, reactive oxygen species, and those not directly related to inflammation, such as microRNAs (miRs) and agalactosylated N-glycans. SASP, senescence-associated secretory phenotype.

Figure 2

Activation of the pro-coagulation cascade and interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT3) pathway induce cell senescence and persistent inflammation through IGF binding protein-5 (IGFBP-5). ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.