Cellular Senescence and Immune System Aging as Causes of Chronic Kidney Disease

There is a great deal of interest in cellular senescence these days. The accumulation of senescent cells in later life is robustly demonstrated to be an important mechanism of aging, and one that can be reversed via the application of what have come to be called senolytic therapies. In mice, the application of senolytics extends life and reverses the progression of numerous age-related conditions. Senescent cells are harmful, even though their numbers are never very large, because they secrete a mix of signals that provoke inflammation, tissue remodeling, and changes in cell activity. Sustained over the long term, this contributes meaningfully to age-related declines and diseases.

Chronic kidney disease is one such condition. Treatment options are limited, while the inexorable loss of kidney function in patients produces increasingly serious downstream issues throughout the body. Evidence has accumulated for cellular senescence to be a major contributing cause of chronic kidney disease. It is widely recognized in the research community that senolytic therapies are a promising new approach to treatment of the condition. An ongoing clinical trial, watched with interest, is using the senolytic combination of dasatinib and quercetin in chronic kidney disease patients, with preliminary results reported last year indicating that this does in fact remove senescent cells. We will have to wait and see for the rest of the data.

Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease

Age-related pathologies are a major global disease burden, with potentially half of all morbidities being attributable to aging. Inflammation (or "inflammaging") is one of the main causative factors contributing to disease progression, and has been described in various age-related pathologies, including type 2 diabetes (T2D) and cardiovascular disease. While being beneficial in the acute stages of an insult, inflammation increasingly fails to resolve with age, leading to changes in both cellular phenotypes and immune system composition. Senescence pathways are induced by, as well as potentiate, chronic inflammation, with increased cellular senescence being observed in various age-related diseases. Cellular senescence is characterized by a stable growth arrest and a proinflammatory secretome, which potentiates low grade chronic inflammation, thereby building a positive feedback loop, gradually exacerbating its effects on the body.

With a prevalence of approximately 44% in the elderly population (of 65 years and older), chronic kidney disease (CKD) presents a major disease burden in an aging population. Therapies for late stage CKD including dialysis and renal transplantation carry a significant burden for patients, and the outcome is often poor; therefore, there is a significant need for early diagnosis and novel therapies targeting mechanisms driving the disease. CKD is associated with chronic inflammation, elevated levels of cellular senescence, as well as immune system dysfunction.

Senescent cells may both be a phenotype of age-related inflammatory disease, as well as the cause for disease progression. Thereby two models of disease progression exist: One in which senescent cells arise from local tissue injury, promoting senescence in neighboring cells in a paracrine manner. Alternatively, immune clearance may be impaired, thereby allowing the accumulation of senescent cells. Distinguishing between these two models becomes pivotal when exploring potential new treatments of CKD.

Much of the immune dysregulation is governed by the presence of proinflammatory cytokines, and uremia, or by pre-existing comorbidities such as high blood pressure or diabetes. In addition to the levels of inflammatory markers, an elevated white blood cell count is predictive of CKD development. This suggests various modes of pathogenesis, with the immune system, senescence, and inflammation at its core. Cellular senescence and immunosurveillance occur in conjunction, increased cellular senescence due to chronic inflammation increases the demand for immune clearance; however, as described above, uremia and inflammation lead to dysfunction of the immune system, thereby establishing a positive feedback loop in which more senescent cells drive inflammation and immune dysregulation which, in turn, cause more senescence.