Targeting Senescent Cells to Reverse the Aging of the Kidneys

Senescent cells accumulate with age and cause a wide range of pathologies. They contribute in some way to near all of the common, ultimately fatal age-related conditions. Senescent cells secrete a mix of signals that produces chronic inflammation, disrupts tissue maintenance to encourage fibrosis, and changes the behavior of other cells for the worse in numerous ways. It is the signaling that allows the comparatively small fraction of senescent cells in any given aged tissue to cause such widespread harm.

Destroying senescent cells in a targeted fashion via the use of senolytic therapies has shown great promise in animal studies, and early human trials have show that at least some of those therapies can also destroy senescent cells in human patients. While scores of age-related conditions have been reversed in mice, and life span extended, via the use of senolytics, the clinical research community is initially focused on establishing efficacy for only a few conditions in human trials.

One of those conditions is chronic kidney disease, characterized by fibrosis, inflammation, and other effects likely caused in large part by senescent cells. Today's open access paper is a discussion of the science underlying this portion of the field.

Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials

Kidneys from elderly are associated with structural changes as the loss in renal mass, glomerulosclerosis, glomerular basement membrane thickening, tubular atrophy, interstitial fibrosis, and the arteriosclerosis. Furthermore, aged kidneys are characterized by functional impairments as reduced glomerular filtration rate (GFR), decrease in urine concentration, plasma flow, and sodium resorption. In healthy aging conditions, despite the gradual but constant drop in GFR (5-10% per decade after the age of 35 years), renal function can be preserved by compensatory mechanisms as hypertrophy of unaffected nephrons or by vasodilatory prostaglandins that can moderate excessive vasoconstriction.

However, beyond their functional reserve capacity, aged kidneys exhibit an increased susceptibility to "a second hit" damage as during acute kidney injury (AKI) occurrence, such as after a nephrotoxic drugs treatment (i.e., contrast agents) or during a bacterial induced systemic inflammatory response (i.e., sepsis or other infections). In the last few years, it has become extremely clear that maladaptive repair after an AKI episode can predispose to chronic kidney disease (CKD), and ultimately, depending on genetic, immunological, and environmental factors, to end-stage renal disease (ESRD).

The central mechanism underlying renal physiological and pathological aging is characterized by cellular senescence. Cellular senescence refers to a complex program that can be initiated by various cellular stresses and is characterized by cycle arrest despite the presence of growth stimuli. In renal aging-related diseases, senescent cells chronically accumulate in renal parenchyma, leading to tissue deterioration and to an aberrant signaling activation to different types of populations.

In the last few years, the development of compounds able to directly eliminate senescent cells or to target the effects of senescent cells has found a vivid interest in the complex field of age-related pathologies. Senotherapeutic agents hold promise for the utilization in treating disorders related to senescent cell accumulation such as neurodegenerative diseases, atherosclerosis, cancers, kidney injury, chronic obstructive lung disease, idiopathic pulmonary fibrosis, diabetes, as well as complications of organ transplantation, radiation, and chemotherapy. The term "senotherapeutic drugs" includes different molecules as the senolytics (compounds that kill senescent cells selectively), senomorphics (i.e., molecules that can inhibit SASP, modulate functions and morphology of senescence cells, or delay the progression of young cells to senescent cells), and senoinflammatory mediators (that are immune-system effectors of the clearance of senescent cells).

Senescent cell viability is strictly dependent on apoptosis resistance and anti-apoptotic signaling thus leading researchers in nephrology to extend the application of senotherapeutic strategies adopted in oncology also to prevent the complications of kidney aging.


Interestingly, this report discusses flavenoids as senolytic agents, but it focuses exclusively on Qurecetin (alone and in combination with Dasatinib, Resveratrol, etc.) Fisetin is not mentioned at all. I wonder why? It's my understanding the Fisetin has been shown to be a much more powerful senolytic than Quercetin.

Posted by: John G Cramer at May 29th, 2021 11:28 AM

Fisetin is and it's similar in form to quercetin. Absolutely I recommend Fisetin over quercetin.

Posted by: David at May 29th, 2021 4:57 PM
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