Immunosenescence

Immunosenescence refers to the aging-associated progressive decline of the immune system affecting both natural and acquired immunity. ^{[1] [2]} It is characterized by a decrease in cell-mediated immune function together with reduced humoral immune responses. ^[3] Thymic involution, an imbalance in the naive-to-memory cell ratio, dysregulated metabolism, and epigenetic alterations are striking features of immunosenescence. ^[4]

Thymic involution impairs the immune system's capacity to react to novel antigens by reducing thymopoiesis and shifting the repertoire toward memory T cells. ^[5] Disturbed T-cell pools and chronic antigen stimulation drive premature senescence of immune cells, which then develop a proinflammatory senescence-associated secretory phenotype. ^[4] Immunosenescence is associated with dysregulated signaling pathways, including overactivation of the NF-κB signaling pathway. ^[6] Aging myeloid cells sustain a low-grade, sterile, and chronic inflammatory state while accumulating aged T cells and B cells. ^[7]

The immune system plays a central role in the onset of age-related diseases. ^[8] Immunosenescence contributes to the pathogenesis of aging-related diseases including cancer, infections, dementia, and neurodegenerative disorders. ^[1] The age-related decline in immune function is partially responsible for the increased prevalence and severity of infectious diseases and the low efficacy of vaccination in elderly persons. ^[3] In predisposed individuals, immune aging can lead to frank autoimmune disease manifesting with chronic inflammation and irreversible tissue damage. ^[7]

Potential interventions to mitigate immunosenescence include reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions. ^[6] Senotherapeutic agents that modulate the senescence process are being considered to prolong the healthy lifespan of the immune system and minimize the secondary effects of immunosenescence. ^[9] Proposed countermeasures against immunosenescence include intervention at cellular senescence and metabolic-epigenetic axes. ^[4]