The diseased kidney: aging and senescent immunology

Abstract

Immunosenescence is the deterioration of the innate and adaptive immune systems associated with aging and is primarily characterized by a reduction in T cell production and accumulation of atypical subsets. Age-related immunological dysfunction leads to impaired immune protection and persistent low-grade chronic inflammation, resulting in a decreased vaccination response and increased vulnerability to infection, cancer, cardiovascular disease, and autoimmune disease in the elderly. As the elderly constitute a growing proportion of the population with renal disease, immunosenescence is a normal aging process that is prevalent among older people. In addition, immunosenescence seems to be more pronounced in patients with kidney diseases than in healthy controls, as shown by severe chronic inflammation, accumulation of immune cells with the senescent phenotype (CD28^- T cells, CD14⁺CD16⁺ monocytes), and proinflammatory cytokine production. Immunosenescence inhibits immunological clearance and renal tissue regeneration, thereby increasing the risk of permanent renal damage, infection, and cardiovascular events in patients with kidney disease, lowering the prognosis, and even influencing the efficacy of renal replacement treatment. Biological drugs (senomorphics and senolytics) target the aging immune system and exert renoprotective effects. This review aims to emphasize the features of immunosenescence and its influence on kidney diseases and immunotherapy, highlighting the future directions of kidney disease treatment using senescence-focused techniques.

Keywords: Aging; Immunosenescence; Immunotherapy; Inflammaging; Kidney diseases.

Fig. 1

Characteristics of immunosenescence in innate and adaptive immunity. Many immune cell subpopulations are altered during immunosenescence. The mature CD56^dim natural killer (NK) cell subsets with high cytotoxic activity are decreased, diminishing the ability to recognize and clear viral infection and tumor cells. Antigen processing and presentation capabilities of macrophages and APCs are also diminished. Declined naïve T cells output of the thymus and decreased antigen stimulation presented by APCs lead to declining T cell response. Fewer naïve B cells are stimulated and transform into plasma cells, thus humoral immunity is impaired. However, the number of memory T and B cells increases

Fig. 2

Senescent TECs accumulation after AKI drives the progression of CKD. Acute kidney injury induces cellular damage and DNA degradation in TECs. Maladaptive repair after AKI leads to TECs senescence. Senescent TECs accumulates in kidney with SASP, which mainly includes proinflammatory cytokines, growth factors, chemokines, and matrix remodeling enzymes. These proinflammatory and profibrotic molecules aggravate immune cells infiltration and tubular cell injury, leading to persistent tubulointerstitial inflammation, proliferation of fibroblasts, and excessive deposition of extracellular matrix, which leads to the exacerbation of renal injury and drives AKI to CKD. Senescent immune cells such as CD28⁻ T cells, CD14⁺CD16⁺ monocytes also aggravate chronic inflammation and ROS production in kidney, which promotes the progression of CKD