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The Enormous Clinical Potential of Senotherapeutics for the Treatment of Chronic Kidney Disease


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Posted 20 January 2021 - 08:21 PM


Today's open access review paper is a high level look at what the newfound realization of the importance of senescent cells to aging and age-related disease means for the treatment of chronic kidney disease. At present there are few good options for treatment, and those therapies that are widely used can only slow the progression towards kidney failure. The kidneys filter waste and regulate many of the chemical and other characteristics of blood. Correct function of the kidneys is vital to the correct function of many other organs in the body, including heart, vascular system, and brain. As the kidneys decline, so too does heart function and cognitive function, among other vital processes.

The evidence from animal studies of cellular senescence in recent years demonstrates that the age-related accumulation of senescent cells is important in the onset and progression of chronic kidney disease. The targeted destruction of senescent cells via senolytic drugs has been shown to reverse aspects of kidney aging and damage, an otherwise challenging goal. Lingering senescent cells actively maintain a degraded state of tissue function via inflammatory and other secretions, the senescence-associated secretory phenotype (SASP). Remove the senescent cells and the SASP, and tissues quite quickly revert to a more youthful behavior. An early senolytic treatment for chronic kidney disease is presently being trialed in humans, and more such trials will follow from the numerous biotech companies working on novel senolytic therapies.

Implication of cellular senescence in the progression of chronic kidney disease and the treatment potencies

The prevalence of chronic kidney disease (CKD) has reached epidemic proportions, with approximately 10% of the total population show declined kidney function. Actually, during the disease progression, the majority of lesions develop into the end-stage renal disease (ESRD), a devastating condition that requires renal replacement treatment, including kidney transplant and dialysis. Remarkably, CKD not only shares numerous phenotypic similarities with kidney ageing, such as glomerular sclerosis, interstitial fibrosis, tubular atrophy, loss of repair capability, and vascular rarefaction, but also exhibits systemic geriatric phenotypes, for instance vascular calcification, persistent uraemic inflammation, cognitive dysfunction, muscle wasting, osteoporosis, and frailty.

The most common markers applied to identify cellular senescence include the overexpression of cyclin-dependent kinase (CDK) inhibitors such as p16ink4a and p21. Interestingly, the expression levels of p16ink4a and the activity of SA-β-gal are elevated in different stages of CKD and some kinds of original kidney diseases. These unexpected alternations indicate that cellular senescence may play important roles in the progression of CKD. The precise roles of cellular senescence in CKD are not fully understood currently. Nonetheless, it is proposed that targeting senescent cells in the kidney might serve as a novel therapeutic strategy for CKD treatment.

Numerous studies have demonstrated that the selectively elimination of senescent cells contributes to the improvement of healthy lifespan and benefits the outcomes of a wide range of age-related diseases. Some of them have shown significant potentials in reversing renal ageing. For example, the combination of dasatinib and quercetin, referred as "D + Q", is an effective senolytic and reduces the overall senescent cell burden in chronologically aged mice. Actually, D + Q has been tested in ageing diabetic kidney disease patients, and the administration of D + Q showed reduced adipose tissue p16ink4a and p21 expression, SA-β-gal activity, and circulating SASP-acquisition factors. Other senolytic molecules, such as Flavonoids (e.g., apigenin and kaempferol) have been proved to strongly inhibit the SASP acquisition in the kidney of aged rats. These findings have opened an exciting new therapeutic avenue for the treatment of CKD and its complications via selectively targeting senescent cells.


View the full article at FightAging




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