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).