A Proof of Concept Attempt to Assess the Impact of First Generation Senolytic Drugs by Looking at Past Usage – Innovita Research

A Proof of Concept Attempt to Assess the Impact of First Generation Senolytic Drugs by Looking at Past Usage

Senolytic drugs are those capable of selectively destroying senescent cells. A range of such therapies are at various stages of development, including those that have reached initial human clinical trials.

Senescent cell accumulation is an important cause of degenerative aging, and the removal of such cells via senolytic treatments has been shown to produce rejuvenation and extension of life in animal models of age-related disease. Senescent cells, while never very large in numbers relative to other cells in the body, secrete a potent mix of molecules that spurs chronic inflammation and degrades tissue structure and function. The more senescent cells, the worse the outcome.

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At present assessment of senolytics in human medicine is still at a comparatively early, albeit promising, stage. Data will emerge at the usual glacial pace characteristic of the highly regulated medical industry. It may be possible to extract some data on the performance of first generation senolytic drugs in advance of clinical trials, however. Many of these drugs have been widely used for years in patient populations, as treatments for various age-related conditions, and all of that data still exists, there to be analyzed.

The primary challenge here is that most such first generation senolytic drugs are chemotherapeutics. Firstly the patients in question were not in good shape at all, exhibiting significant mortality and loss of function due to cancer and its complications, making it hard to pick out benefits to health. Secondly chemotherapeutic doses are higher and more sustained than senolytic doses, causing significant additional cell death and dysfunction. Is it possible to work around these issues by picking a comparatively isolated part of the body, such as the retina, as is the case in today's open access paper? Maybe, but I think that there remain sizable issues that would need to be addressed before one could take any such data at face value. Particularly given the very small sample size used here as a proof of concept for the ability to gather and analyze a broader range of data. For now, this is an interesting idea, perhaps worthy of further exploration.

Evaluating the neuroprotective impact of senolytic drugs on human vision

Based on neuropathological similarities of glaucoma with other age-related neurodegenerative diseases such as Alzheimer's and the involvement of the ubiquitin-proteasome and chaperone systems, researchers have hypothesized a cellular senescence contribution to glaucoma pathogenesis. Preclinical evidence has supported the cellular senescence hypothesis as a contributor to glaucoma pathogenesis. Senescent cells secrete a plethora of molecules known as senescence associated secretory proteins (SASP), which affect surrounding cells by inducing either apoptosis or senescence, thus propagating the phenotype. There are several senolytic drugs that are able to specifically target senescent cells to overcome the apoptosis block to remove them, presenting an attractive hypothesis for potential treatment of glaucoma.

Indeed, our recent study has shown that targeting senescent retinal ganglion cells (RGCs) in a mouse model of glaucoma using the senolytic drug dasatinib protected the remaining RGCs and visual function from glaucomatous injury. These data are also supported by evidence from human studies, as a bioinformatics analysis of genes associated with primary open angle glaucoma suggested senescence as a key factor in pathogenesis.

Little is known about the neuroprotective effects or safety of senolytic drugs on vision in human patients, however. Clinical management of glaucoma involves acquisition of extensive longitudinal data including visual acuity, intraocular pressure (IOP), visual field sensitivity, and retinal nerve fiber thickness. Compared to other neurodegenerative diseases that often lack objective standardized metrics of clinical progression, some of these ophthalmic data are readily available and amenable to investigations of novel therapeutics, including senolytic drugs. To this end, we performed a retrospective analysis of existing clinical data to evaluate the effect of senolytics on vision and glaucoma progression. For the current study, we queried the electronic health record (EHR) system of a large academic medical center to identify glaucoma and glaucoma suspect patients exposed to at least one senolytic drug and conducted several analyses of visual data.

Senolytic exposure was not associated with decreased visual acuity, elevated intraocular pressure, or documentation of senolytic-related adverse ocular effects by treating ophthalmologists. Additionally, patients exposed to senolytics (n = 9) did not exhibit faster progression of glaucomatous visual field damage compared to matched glaucoma patients (n = 26) without senolytic exposure. These results suggest that senolytic drugs do not carry significant ocular toxicity and provide further support for additional evaluation of the potential neuroprotective effects of senolytics on glaucoma and other neurodegenerative diseases.

Source: Fight Aging!