3. 2. Inflammaging and immunosenescence
Recently, chronic inflammation has been identified as one of the hallmarks of aging (Schmauck-Medina et al., 2022) and a strong connection to most ARDs, including those involving cognitive decline. The term “inflammaging” has been coined to describe the low-grade systemic inflammation caused by modifications in the immune cells over time, known as immunosenescence. All immune cell subsets are affected, but T cells experience a significant impact. One notable change is a reduced responsiveness to new antigens, which is caused by the reduction in the naïve T cell pool. This reduction is caused by the combination of thymic involution and the increase in the memory compartment due to continuous exposure to a myriad of antigens since birth (Aiello et al., 2019; Mittelbrunn & Kroemer, 2021). The accumulation of terminally differentiated T cells leads to the loss of co-stimulatory molecules CD28 and CD27, which occurs upon clonal expansion, and upregulation of CD57 and killer cell lectin-like receptor subfamily G member 1 (KLRG1) cytotoxic markers (Aiello et al., 2019; Rodriguez et al., 2020). Altogether, this senescent T cell pool is antigen-independent and highly differentiated, which is the perfect trigger to the release of the pro-inflammatory cytokines (IFNγ, TNF-α, IL-2 and IL-6) that characterizes the inflammaging status (Mittelbrunn & Kroemer, 2021; Rodriguez et al., 2020). Moreover, the senescence-associated secretory phenotype (SASP) adopted by immune and non-immune cells in older organisms further promotes inflammation through the release of cytokines and chemokines such as IL-6, IL-8 or IL-1β, which boost the action of innate cells, and Th1 and Th17 populations (Rea, Gibson, McGilligan, McNerlan, Alexander & Ross, 2018). Morover, exhausted T cells become poor cytokine producers, an extensive profiling study revealed the existence of a distinct age-related CD8+ T cell secreting high levels of granzyme K. Such environment exacerbates the SASP from senescent cells, perpetuating the inflammaging status (Mogilenko et al., 2021).