AgingGenes

Through the expression profile of the AgingGenes (Figures 4.8 A and B), two important moments can be seen during life, in which transcriptional alterations occur in all classes. The first phase refers to the ages between 30-36 years old, when the first changes appear, even if subtle. These changes are continually intensifying and around 45-55 years, a second phase, all AgingGenes classes undergo alterations again in their expression profile, but more intense. There are also large transcriptional changes after the age of 89 years. However, they may reflect both authentic biological changes that happen at advanced ages and technical artefacts caused by the low number of samples from individuals of these ages. For this reason, the changes observed in individuals aged over 89 years were disregarded.

‌ A notable feature in the AgingGenes' behaviour is the apparent agreement between the period in life where the first state changes, first stage, occur with the abrupt change in the mortality projection given by the Gompertz–Makeham law (illustrated in Figure 1.1), which indicates that the human mortality rate increases exponentially soon after maturation, around 30 years. This rate is composed of two mortality functions, representing age-independent factors, such as deaths triggered by accidents, and dependent ones, such as natural death. The change to an exponential state at this rate may be caused by age-dependent factors and may be related to physiological disturbances that occur early in life, such as damage accumulation, changes in homeostasis and infections, leading to concomitant transcriptional disturbances of various systems of the human body, including the immune system, and triggering the loss of function and protection observed in the elderly.

‌ The second notable feature in the AgingGenes expression profile is the apparent inflexion of expression of all AgingGenes classes during the second phase, between the ages of 55 and 65 years, and probably triggered by the various state changes that occurred for all classes of AgingGenes since 46 years old. This characteristic was also noted in (IRIZAR et al., 2015), where this inflexion was verified around the age of 54 years and it was suggested that the period between 49.3 and 55.6 years may be critical during life.

‌ In general, the first changes to appear among AgingGenes during the first phase are mainly related to problems in signal transduction pathways, such as NOTCH1 signalling, Tumor Necrosis Factor (TNF), PI3K/Akt and growth factors. The first pathway to be altered (neg) is related to NOTCH1 signalling, which regulates the expression of genes with important roles in the development of T lymphocytes and is involved in the suppressor function of regulatory cells, where the overexpression of their ligands can induce T cells regulatory bodies (Tregs) to exercise their suppressive functions (NAKAMURA; KITANI; STROBER, 2001)). These suppressive functions are mediated by TGF-β, in which they are secreted and presented in the membrane, inhibiting the function of APCs, the main focus of Treg-mediated suppression ((DU et al., 2006; GREGG et al., 2004; HUBER) et al., 2004)). Furthermore, TGF-β can induce the differentiation of naïve CD4+ cells into Tregs, facilitating the expansion of peripheral Treg populations ((DU et al., 2006; GREGG et al., 2004; HUBER et al., 2004)). The neg class is also enriched for entry pathways into the stationary (S) phase of the cell cycle, which, with its negative trend with age, indicates an increase in cell replication. This fact is corroborated by the micC class, which has a positive trend with age and major changes around 60 years of age. It is related to cell proliferation through mitotic pathways, epithelial growth factor (EGFR) and fibroblast (FGFR) signalling and, together with the pos class, also to aberrant CD28-dependent PI3K/Akt signalling and PI3K signalling in cancer. Akt regulates cell growth, contributing to cell proliferation through phosphorylation of p21 and p27 inhibitors and its signalling cascade is activated by B cell receptors, T cells, cytokines, among others, which induce the production of PIP3 by PI3K. Imbalances in growth factor pathways and PI3k/Akt signalling can lead to the development of autoimmune diseases (PATEL; MOHAN, 2005).

‌ Disturbances in TNF signalling pathways, enriched in the micB class, can also lead to increased cell proliferation and angiogenesis. This class has more subtle downward trends in expression during life and is related to signalling pathways by both TNFR1 and TNFR2 involved in cytokine signalling through the activation of NF-kB via the non-canonical pathway. TNF plays a regulatory role on immune cells, triggering the transcription of genes responsible for inflammation, proliferation, differentiation and apoptosis. To fight an infection, for example, TNF facilitates the proliferation of immune cell clones, stimulates the differentiation and recruitment of naïve immune cells, and once the infection is cleared, orchestrates the destruction of superfluous immune clones to reduce inflammation and damage. tissue. However, during the development of autoimmunity, abnormal T cell progenitors, and other cell types, proliferate and begin maturation in the thymus, and a variety of defects in the TNFR2/NFkB signalling pathway are found in these diseases (FAUSTMAN; DAVIS, 2013). These defects include polymorphisms and upregulation in the TNFR2 gene, as well as a decrease in TNFR2 receptors (FAUSTMAN; DAVIS, 2013). TNFR2 signalling appears to offer protective roles in several diseases, including autoimmune diseases, heart disease, neurodegenerative and demyelinating diseases, and infectious diseases (FAUSTMAN; DAVIS, 2013). Activation of NFkB via the classical pathway reverts to non-canonical in situations where TRAF2/3 or IAP are blocked. Together, TNF and TRAF3 are important in activated T cells, and TNF-induced NF-kB is important in inflammation since NF-kB is a global transactivator of numerous pro-inflammatory cytokines, chemokines and their receptors, and a critical regulator of leukocyte activation and function.

‌ The micA class has the profile that suffers the most abrupt falls during life, being enriched for telomere maintenance pathways, such as telomere terminal packing, and mainly enriched for the senescence induction pathway due to telomere-related stresses and DNA damage, which may be a reflection of the large cell proliferation mentioned above.

‌ The general enrichment of AgingGenes leads us to believe that there is a dysregulation in the signal transduction processes that start soon after the age of 30 and intensify around the age of 55, related to T lymphocyte signalling, especially in the regulation of Treg activity. This can lead to increased cell proliferation of damaged and self-reactive cells and induction of senescent cells due to malfunctioning telomere maintenance. Poor Treg signalling can lead to an accumulation of lymphocytes and other superfluous immune cells in the body, which can trigger disease