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.

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 (nā€‰=ā€‰9) did not exhibit faster progression of glaucomatous visual field damage compared to matched glaucoma patients (nā€‰=ā€‰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.


Anyone want to give an educated guess when we could start seeing senolytic treatments for the general public? I'm hoping not more than 10 years, but just a guess.

Posted by: Robert at December 21st, 2020 7:44 PM

If oneskin's stuff has no surprises, then we're already there.

Also on reading the paper, on average the people exposed to senolytics had better visual acuity despite their age after the exposure than before. The p-value is 0.38, which isn't great, but I'm surprised that the abstract doesn't seem to mention this and just goes with the safe "no evidence of damage" pitch.

Posted by: Mircea at December 22nd, 2020 2:12 AM

Robert, Oisin biotechnology https://www.oisinbio.com/ Should have treatments for removing senescent cells in about five years. Looking at these old cancer drugs sounds like a good idea. We have Dasatinib and Quercetin right now and Dasatinib has lost patent protection in Europe so is now much cheaper.

Posted by: Tj Green at December 22nd, 2020 4:58 AM

@Tj Green
Oisin is too silent. They had senolytics for at least two years and since then there were no real news.

We have to define what means to have treatments. Some experimental proof of concept mouse model, or phase II medical study, for example...

Posted by: Cuberat at December 22nd, 2020 9:07 AM

Treatments may start soon(ish). The real question is effectiveness in garden variety humans vs efficacy in lab rats. Unfortunately, the vast majority of new drugs - or tweaked / repurposed old molecules - offer only marginal improvements in the outcomes of whatever problem they aim to treat.
On top of that, effectiveness can only be measured by surrogate outcomes.
So my guess is that we won't have a good idea of how far along we are in controlling aging for a couple of decades, because even if multiple drugs with multiple targets came to market within the next 5 years, it would take three times as long to run a sufficient number of randomised controlled trials of all the various permutations to figure where we stand with respect to mortality.

Posted by: Barbara T. at December 22nd, 2020 11:03 AM

it depends on the effect size. If the effect is strong enough we can see increased life expectancy as soon as we have widely used senolytics. But if the effect is that large, then it can be obvious even in small studies which for the moment we cannot witness

Posted by: Cuberat at December 22nd, 2020 3:01 PM

Exactly. My skepticism derives from the historical effectiveness of repurposed / tweaked drugs (barely detectable at best) and the unlikeliness that one or two new senolytic agents will mop up enough senescent cells, at a systemic level, to make enough of a difference to enough organs.
I am not saying that it won't happen - I am saying that it will take many years before we develop effective drugs, find out the right combinations, dosages etc.
Ironically, we may already have everything we need to extend life significantly (just think about the serendipitous discovery of the epigenetic effect of the hGH, metformin, and DHEA combo) without knowing what these drugs are and how to use them.
It could be different if there were some major breakthrough in AI and deep learning, but I barely know what these things are so have no idea of where we are at with them.

Posted by: Barbara T. at December 22nd, 2020 4:21 PM

Why would we need to wait for decades to see if someone got younger?
Tools to measure someone biological age are getting better and we can see if they look younger.

If this works we would probably notice it in a matter of months.

Posted by: concerned90 at December 22nd, 2020 4:33 PM

Because, as i said, I can't imagine the development of one or two interventions that will make someone look many years younger in the near future.
My opinion is based on the fact that no matter how sophisticated the new drug (nanoparticle, engineered T-cell etc.) and whatever the disease, nothing that has been developed over the past few decades has managed to confer more than small, incremental improvements on the status quo. So far, this applies to senolytics too, and radical life extension will need a wide array of tools and drugs. To figure out how these tools and drugs work in unison, you need trials.
1. In order to impact looks to any discernible degree you must target different mechanisms, not just senescence. And if damage does indeed correlate with aging (= mortality), then getting rid of 50% of it in each relevant category (a massive feat) will only make you look about eight years younger. Botox does it already, which means that someone suddenly looking younger in a non-news.
2. There won't be scores of people taking multiple anti-aging drugs on their own volition: what would they combine what with? There are signs to heed that more is less and certain combinations may be toxic.
3. Anecdotes are good for the Daily Mail.
And conmen.
Epigenetic clocks may help, but again, you need to measure methylation in more than just the odd biohacker that has managed to scoff down a smattering of experimental molecules without offing himself in the process.

Posted by: Barbara T. at December 22nd, 2020 6:16 PM

@Robert: In the last interview of AdG (this week) he said 50% chance of reaching escape velocity in 15 years.

Posted by: Antonio at December 23rd, 2020 1:46 AM

Thanks Antonio,

I try to look for latest comments from AdG and Ray K regarding aging. I realize Ray is an optimistic, but his insights are helpful:)

Again, thanks for that bit of info. I just got done reading the list of companies working with senolytics, the more, the better, IMO:)

Also, looking forward to Reasons yearly review of accomplishments in the anti-aging field.


Posted by: Robert at December 23rd, 2020 3:34 AM
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