1.5 Chronic Inflammation During Aging: Inflammaging

Senescence is the phenomenon in which cells enter a permanent state of non-proliferation in response to stress (e.g., telomere shortening), developing some characteristic phenotypic changes. These characteristics include changes in the organization of chromatin, alteration of gene expression and secretion of several pro-inflammatory cytokines, chemokines, growth factors and proteases, dependent on stress factors (CAMPISI; D’ADDA DI FAGAGNA, 2007).

‌ It is assumed that cell senescence contributes to ageing, as its amount increases with ageing (BAKER et al., 2016; VAN DEURSEN, 2014). Such accumulation may reflect either an increase in the rate of generation of senescent cells or a decrease in their removal rate, as a consequence of an attenuated immune response. This balance requires an efficient cell replacement system that involves, simultaneously, the removal of senescent cells and the mobilization of progenitors to reestablish cell numbers. In elderly organisms, this system can become inefficient since the regenerative capacity of the progenitor cells can be exhausted and, eventually, result in the accumulation of senescent cells (STAHL; BROWN, 2015).

‌ Senescent cells manifest alterations in their secretome, called senescence-associated secretory phenotype (SASP), in which they are particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases (MMPs) ((KUILMAN et al., 2010), (RODIER; CAMPISI, 2011)). SASP has paracrine activities involved in the recruitment of leukocytes and the migration of innate immune cells to the vicinity of tumour regions (MANTOVANI; ALLAVENA; SICA, 2004), (XUE et al., 2007)). In addition, the production of growth factors promotes cell proliferation through GROs (growth-regulated oncogenes) and AREG (amphiregulin) proteins, as well as the formation of new blood vessels through proteins such as VEGF (vascular endothelial growth factor) (COPPE). et al., 2008). This suggests that cellular senescence and SASP may contribute not only to - suppressing cancer development but also to promoting repair of damaged tissue.

‌ If SASP secretion becomes chronic, harmful phenotypes characteristic of ageing can develop. An example of this is the case of the biphasic SFRP1 (secreted frizzled-related protein 1) modulator, which can stimulate or inhibit Wnt signalling depending on the physiological context (ELZI et al., 2012). Chronic Wnt signalling can induce both stem cells and differentiated cells to senescence (LIU et al, 2007).

‌ Components of SASP also regulate multiple aspects of inflammation. The cytokines IL-6 and IL-8 ((COPPÉ et al., 2008); (

[[1]](#1)

); (KUILMAN et al., 2010)), some varieties of MCPs (monocyte chemoattractant proteins), MIPs ( macrophage inflammatory proteins), and GM-CSF (granulocyte/macrophage colony-stimulating factor), can promote chronic inflammation (ADAMS et al, 2009; (COPPÉ et al., 2010); (FREUND et al., 2010); ( DAVALOS et al., 2010); TCHKINIA et al, 2010). Chronic inflammation is the cause, or at least an important contributor to many of the diseases related to ageing, both degenerative and hyperplastic, characterizing the phenomenon called Inflammaging (FULOP et al., 2017).

‌ It should be noted that senescence is not a generalized property of all tissues in older organisms (WANG et al., 2009), furthermore, recent work indicates that immunosenescence is not accompanied by an inevitable and progressive deterioration of immune function, but rather, it is a complex process involving a series of changes in reorganization and development, in which some characteristics of the immune function are reduced, others increased, and others even untouched (COPPÉ et al., 2010).