Senescent Cells

Over half a century ago, Hayflick and Moorhead observed that human diploid fibroblasts lose their ability to proliferate after undergoing multiple divisions, while remaining metabolically active. They named this loss of proliferative capacity “cellular senescence(definition).”1 The senescent cells exhibited distinct morphology, behavior, and responses to endogenous and exogenous stimuli, compared with actively dividing cells. It is now understood that senescence arises not only from telomere(definition) shortening (replicative senescence), but also from DNA damage, mitochondrial dysfunction(definition), and oxidative stress—conditions that are exacerbated during vascular remodeling and CKD. Senescence is recognized as a double-edged sword in the context of CKD vasculature, playing both protective and detrimental roles. In the short term, senescence can protect against vascular proliferative diseases, such as atherosclerosis and restenosis. However, cells with a senescence-associated secretory phenotype (SASP) release proinflammatory factors, growth factors, and proteases, contributing to tissue fibrosis, endothelial dysfunction, and proliferation of neighboring cells. Arteriovenous fistulas (AVFs), created by connecting a vein to a nearby artery in the arm, are the preferred vascular access for patients undergoing chronic hemodialysis. After AVF creation, the vein undergoes a recovery process from surgical trauma and adapts to extreme hemodynamic conditions and the higher oxygen tension of arterial circulation by thickening its wall in a process known as remodeling. Vein remodeling can result in either outward remodeling (thickening with a large lumen), which supports successful maturation, or inward remodeling (thickening with a narrowed lumen), leading to access failure in approximately 40% of newly created fistulas. The cellular and molecular mechanisms driving these divergent outcomes are poorly understood, contributing to the lack of success in clinical trials aimed at preventing inward remodeling. Consequently, there is an urgent clinical need to identify novel therapeutic targets to improve AVF outcomes. In this issue of Kidney360, Nath et al.2 expanded on their earlier studies3 to investigate the onset of senescence after AVF anastomosis in rats. The SASP, characterized by cytokine accumulation, cell-cycle inhibitors (p16CDKN2A, p21CDKN1A), and senescence-associated β-galactosidase, was prominently observed in both arterial and venous limbs shortly after anastomosis. Over time, senescence diminished as the fistula remodeled and adapted to arterial circulation, mirroring early senescence observed in other vascular remodeling models.4 Pharmacological intervention with fisetin, a senolytic drug designed to selectively eliminate senescent cells, along with the prosenescent agent hemin, further demonstrated the detrimental effects of SASP on the remodeling of the fistula wall. These findings highlight the critical role of senescence and SASP in vascular remodeling and suggest new therapeutic opportunities, such as fisetin, to improve AVF outcomes in patients undergoing hemodialysis. This insightful study by Nath et al.2 underscores the importance of “holding the tension of paradox” when addressing conflicting perspectives on a biological event that deepens our understanding of mechanisms impeding fistula maturation. The paradox lies in the observation that early and extensive cellular growth arrest exacerbates fistula outcomes, despite traditionally being associated with vascular proliferative diseases. The paradox is resolved by considering that cell migration of cell-cycle–competent cells and extracellular matrix production, rather than proliferation of resident cells, are primary drivers of inward remodeling. This hypothesis has gained traction through recent clinical observational studies demonstrating minimal association between histological intimal hyperplasia and fistula failure.5 Alternatively, it is plausible to hypothesize that clonal expansion of local cells after anastomosis is the primary source of cells populating the fistula wall. The clonal theory has previously been used to explain the expansion of arterial intimal hyperplasia after balloon angioplasty.6 The triggers of postoperative senescence after fistula creation must be identified for a better understanding of the pathophysiological mechanisms leading to maturation or failure. Aging, CKD, diabetes, and hypertension are known to increase the accumulation of senescent cells. However, the lack of preexisting senescence in the contralateral veins and the acute appearance of senescence point to the aberrant hemodynamic conditions in the fistula as the main trigger for postoperative vascular senescence. The Hemodialysis Fistula Maturation Consortium recently provided compelling evidence of a cause-and-effect relationship between disturbed flow and AVF maturation failure.7 Similarly, studies have demonstrated that disturbed flow induced by partial carotid artery ligation in mice leads to the expression of senescence markers.8 Elevated wall shear stress imposes substantial strain on endothelial cells, potentially causing telomere shortening through mechanisms involving telomeric repeat-binding factor 2–interacting protein.9 Concurrently, oxidative stress resulting from wall overstretching during flow-mediated dilation increases the likelihood of SASP development in fibroblasts and smooth muscle cells. These proinflammatory senescent cells may delay the resolution of inflammation, promoting fibrosis, intimal hyperplasia, and the progression of stenosis. Nath et al.2 have also laid the foundation for the use of senolytic drugs as promaturation agents after fistula creation. This emerging class of drugs may selectively eliminate senescent cells from the fistula vasculature, promoting improved outward remodeling. Senolytic drugs also have the potential to reduce inflammation, attenuate progenitor cell exhaustion, decrease fibrosis, and alleviate mitochondrial