Chronic kidney disease is largely age-related, though can occur in younger people under some circumstances. It is one of a number of conditions in which research strongly implicates cellular senescence in its onset, progression, and pathology. Senescent cells accumulate in tissues with age. Cells become senescent throughout life, both on reaching the Hayflick limit to replication and in response to stress or damage. A senescent cell ceases replication, grows in size, and generates pro-inflammatory, pro-growth signaling that attracts the immune system and alters the behavior of surrounding cells. In the short term, this signaling is helpful. In youth, senescent cells are cleared efficiently by the immune system, but in later life this clearance falters allowing senescent cells to accumulate in number. Sustained senescent cell signaling contributes to chronic inflammation and disruption of tissue structure and function.
Today's open access paper reviews what is known of cellular senescence in kidney aging versus chronic kidney disease, and notes the arguments for and against considering chronic kidney disease to be a form of accelerated kidney aging. Either way, kidney disease and dysfunction is fairly high on the list of conditions that may be treated earlier rather than later in the development of senotherapeutic drugs that either selectively destroy senescent cells or modulate their behavior to be less harmful. The diabetic form of kidney disease is one of the few conditions for which an initial clinical trial using first generation senolytic drugs has taken place. The similarities between kidney aging and kidney disease might provide hope that low-cost senotherapeutics can meaningfully reduce the burden of dysfunction in older individuals.
Chronic Kidney Disease and Cellular Senescence
As individuals age, kidney function naturally declines, with the decrease in estimated glomular filtration rate (eGFR) starting at around age 30 at a rate of 0.7-0.9 mL/min/1.73 m2 per year in healthy individuals. With age, the kidney undergoes a series of changes that resemble those observed in chronic kidney disease (CKD), including a reduction in the number and size of nephrons, glomerulosclerosis, tubular atrophy, inflammation, dyslipidemia, interstitial fibrosis, and an increase in the prevalence of vascular rarefaction and arteriosclerosis. Furthermore, aging kidneys, similarly to kidneys in CKD, are susceptible to injury, oxidative stress, inflammation, and fibrosis and often struggle to regenerate and recover. However, these changes are typically milder during normal aging than in CKD. Therefore, in many ways, CKD may be likened to a state of premature or accelerated renal aging.
This resemblance partly reflects the unique physiological context of the kidney, where high metabolic activity, chronic exposure to circulating toxins, susceptibility to hypoxia, and limited regenerative capacity of key cell populations amplify stress responses and promote the accumulation of senescent cells. At the cellular level, typical features of premature aging include the accumulation of senescent cells and stem cell exhaustion. Disruption or dysregulation of critical signaling pathways, such as DNA damage, oxidative stress, telomere shortening, loss of Klotho, and oncogene activation, can lead to premature aging. Recent proteomic and transcriptomic studies provide evidence that cellular senescence contributes to CKD progression rather than solely reflecting aging.
CKD patients can be stratified into senescence-based endotypes (sendotypes), where a high-senescence signature dominated by TNF, NF-κB, and MAPK signaling is associated with worse renal function and faster eGFR decline. These senescence-associated pathways were further validated in human CKD biopsies and kidney organoid injury models, confirming their involvement at the tissue level. These findings suggest that CKD is biologically heterogeneous with respect to senescence signaling. The sendotype framework may therefore provide a basis for precision senotherapeutic strategies, where therapies targeting specific inflammatory or senescence pathways (e.g., NF-κB or MAPK signaling) could be applied to patient subgroups most likely to benefit.
The literature highlights cellular senescence as a central mechanism driving both kidney aging and CKD. Nevertheless, determining whether renal senescence serves as a catalyst or an outcome of CKD remains challenging, as current evidence suggests a bidirectional relationship in which kidney injury promotes senescence, while senescent cells further promote inflammation and fibrosis, thereby contributing to disease progression.
View the full article at FightAging
