The Potential of Senolytic Therapies to Treat Chronic Kidney Disease

Senescent cells are a cause of aging. While near all senescent cells are destroyed shortly after entering that state, either by their own programmed cell death processes or by the immune system, the few that linger accumulate over the years to cause considerable harm. While it is true that even in late life senescent cells are far outnumbered by non-senescent, functional cells, senescent cells secrete a potent mix of inflammatory and other signals known as the senescence-associated secretory phenotype (SASP). The SASP disrupts tissue function, encourages nearby cells to also become senescent, and produce a state of chronic inflammation that accelerates many age-related conditions.

On the bright side, this means that near all age-related conditions can be turned back to some degree by the targeted removal of senescent cells, using senolytic therapies. The more such cells that are destroyed by a treatment, the larger the benefit. Since this produces such a broad range of beneficial effects, and there are only so many scientists in the world, the research community has yet to fully investigate even all of the most compelling, urgent uses of senolytic treatments to reverse specific age-related disease, let alone all of the other, lesser opportunities.

Today's open access paper on the prospects for senolytic therapies to effectively treat chronic kidney disease is an example of the sort of work we'll be seeing on a regular basis in the years ahead. Research teams will make slow inroads on assessing the use of senolytics as a rejuvenation therapy that can benefit patients with age-related condition A, B, or C, and so forth through a long, long list of diseases. It is a measure of just how new this field is, assessed in the grand scheme of things, that even the most widespread and severe conditions such as chronic kidney disease, those with no good therapeutic options at present, and wherein senolytic treatments might plausibly turn back much of the disease, are still not well investigated.

Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools

Chronic kidney disease (CKD) is defined by the persistent loss of kidney function and currently affects approximately 13.4% of the global population. The progressive nature of CKD often leads to end-stage renal disease (ESRD), requiring renal replacement therapy. To date, there are no curative therapeutic options for CKD/ESRD. An as yet untreatable final common pathway irrespective of the etiology in CKD is kidney fibrosis, characterized histologically by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Numerous compounds directly targeting factors involved in fibrosis driving pathways are currently being studied with varying results. Apart from the use of the renin-angiotensin-aldosteron pathway interfering agents such as ACE inhibitors or angiotensin receptor blockers to reduce the progressive remodeling of renal parenchyma, no therapeutics addressing pathophysiological mechanisms underlying CKD are used clinically. However, increasing effort is currently put into investigating the efficacy of targeting senescent cells during renal disease.

Aging is associated with the decline of kidney function. During aging, increased renal p16 expression is most notably seen in tubular epithelium and to a lesser extent in glomerular (podocytes and parietal epithelium) and interstitial cells. Changes in p16 were more pronounced in the cortex compared to the medulla. In rodents, the amount of senescent proximal tubular cells increases with age, whereas no increase of senescent cells is seen in the glomeruli. Renal tubular cell senescence correlates with tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Furthermore, the removal of senescent tubular cells leads to decreased glomerulosclerosis.

Eliminating senescent cells through transgenic depletion and pharmaceutical inhibition reduces kidney dysfunction and long-term kidney injury in experimental models of kidney damage, obesity-induced metabolic dysfunction, and during aging. These promising results have spurred interest in the development of clinically applicable therapeutic compounds that target senescence-associated pathways. Eliminating senescent cells (dubbed as senolysis) is just one of the various potential interventional approaches to target the adverse effects of cellular senescence (so-called "senotherapy"), including the prevention of senescence, modulation of SASP (termed senomorphics), and stimulation of immune system-mediated clearance of senescent cells.

The removal of senescent cells with so-called "senolytics" may be the most feasible and most attractive approach for clinical application, as the prevention of senescence and modulation of SASP would require chronic treatment with prolonged exposure to therapeutics. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated.

Research regarding senescence in the kidney has pointed to the proximal tubular epithelium as the culprit, and the removal of senescent tubular epithelial cells is therefore a promising approach to the attenuation of fibrosis in CKD. Due to the specific nature of proximal tubular epithelium, several specific targeting options are available, by which therapeutic drug efficacy can be potentiated and side effects can be reduced. Repurposing senolytic drugs that have been tested in clinical trials for other, mostly oncological, indications by functionalization for targeted delivery is a promising method to make a fast translation to clinical nephrology practice.

Comments

Is there likely to be a senolytic treatment that works in all tissues simultaneously, or will we need to administer numerous different therapies to get body wide effects?

Posted by: Ben at August 7th, 2019 5:42 PM

@Ben
If we are talking about small molecules than it is rather the second. Later generations might be universal

Posted by: Cuberat at August 7th, 2019 8:01 PM

Thanks for the response. That's disappointing. Seems likely that it will sill be some time before older generations are getting the full benefits, in that case.

Posted by: Ben at August 7th, 2019 11:43 PM

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