Long Term Weekly Dosage of Senolytic Dasatinib and Quercetin Reduces Disc Degeneration in Mice

The combination of dasatinib and quercetin was the first practical senolytic therapy explored in mice and human trials. Treatments tended to be one-time (a few doses a few days apart) or weekly over a period of a few months. Here, researchers try a longer term approach, weekly intervals for much of the adult life of mice.

Senolytic therapies produce rejuvenation in animal studies by selectively destroying senescent cells, which cause pathology as they accumulate in tissues. Present thinking is that this accumulation is more a matter of increased creation and slowed clearance rather than individual senescent cells lingering for the long term. Is the best dosing strategy a frequent one or an infrequent one. Or does it not much matter, so long as cells are periodically cleared?

That the study here shows greater benefits in terms of slowed disc degeneration when the senolytic treatement is started earlier in adult life suggests a few things. Firstly that some forms of structural damage do not tend to recover, even when their causes are removed. Secondly that senescent cells are causing some degree of harm earlier in adult life than we might otherwise have suspected. Assessments of the burden of cellular senescence by age do exist, but are not yet robust. Results like this might cause some reassessment of the ideal strategy for those who would like to take advantage of the existence of readily available senolytic drugs.

Studies of human tissues and mouse models have shown an increased incidence of senescent cells during intervertebral disc aging and degeneration. Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice.

We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, p19ARF, and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types.

Our results show that the D + Q combination could target senescence in the mouse disc, and these results provide proof of principle that senolytics may be useful in mitigating age-dependent disc degeneration by decreasing local senescence status, fibrosis and matrix degradation, while promoting cell viability, healthy matrix deposition and lower levels of systemic inflammation.

Link: https://doi.org/10.1038/s41467-021-25453-2

Comments

The DQ was injected. I wonder what the reasoning was for that. My guess is the decision to inject was motivated by marketing strategy concerns

Posted by: JohnD at September 14th, 2021 2:03 PM

Reason, when would you say the people currently doing calorie restriction to improve lev chances could stop doing it? CR mimetics in the future will probably capture only some of the benefits and be inferior to the real thing. So are we talking close to 22nd century because then we could be pretty sure we achieved lev because there are unknown types of damage beyond first therapies?

Posted by: Red at September 14th, 2021 2:14 PM

Hmmm, This makes me think that Life Extensions weekly dosed phytosome senolytic activator may be the way to go. The quercitin is correctly absorbable- fisetin is good, I just wonder how good a Dasatinib substitute the black tea theaflavins really are.
This seems to be based on 2017 study published in Free Radical Biology & Medicine Journal that showed that theaflavins, derived from black tea, significantly inhibited the accumulation of senescence cells. I drink decaf black tea all day every day - would adding a supplement be too much? Right now I'm drinking tea daily and popping 8 bioavailable fisetin capsules and a coupe quercetins each week. I already take apigenin daily to help recycle NAD.
I can't see myself popping a Dasatinib every week, that's for sure.

Posted by: august33 at September 14th, 2021 2:44 PM

To all self-experimenting pioneers. Please note that this is a single study and frequent application of Dasatinib , and even high doses of quercetin alone, could be quite harmful. I am leaning towards periodic administration of senolytics until other studies confirm the benefit of more frequent use, especially if there is no apparent inflammation.

Posted by: Cuberat at September 14th, 2021 3:56 PM

@cuberat, Are D and Q available OTC, or would you need a prescription?

Posted by: Robert at September 14th, 2021 4:16 PM

@JohnD
with mice it is easier to control what you inject than what they eat. And absorption could vary from case to case. As for marketing.. Dasatinib is quite expensive even for oral use, so injections wouldn't change that much, in fact would eat into profits.

Posted by: Cuberat at September 14th, 2021 5:49 PM

@Red
Extreme CR currently gives the best , albeit not perfect, results. It is extremely hard to follow it, though and too easy to fall from the wagon.

Posted by: Cuberat at September 14th, 2021 5:51 PM

@Robert
Quercetin is widely available as supplement and can be cheap too if bought in bulk. Dasatinib is a prescription drug not available OTC in most , if any, places. Also , human grade D can be 200 USD per pill. I have seen adds for "research" grade dasatinib as low as 1 USD per gram if bought in bulk( say 200-300 USD per package) . I cannot know how good it is, though. On the other hand fisetin is much cheaper than dasatinib and is not regulated. In some cases it could be as good senolytic as D+Q combo. And is much safer too.

Dasatinib as far as I know, has nasty side effects , so I would avoid taking it without a good reason. In some jurisdictions it might be illegal to self medicate with prescription drugs (for example body builders' steroids can get you a criminal record in some states). Of course, if there was a good and proven human protocol neither cost nor the legal status would stop many people .

The real problem is that we still don't have a good protocol. Still more studies are needed. And the information from the self experimenting crowd is very subjective and hardly scientifically rigorous.

And one final point . D+Q are a first generation senolytics. The second generation are more targeted ones like pro drug conjoining an existing chemodrug with galactose to be released near senescent cells where there are high levels of beta galactosidase. Those are highly targeted and more promising. You need a good lab and good chemists to get those, though. Still very experimental . And a few years before they become accessible to determined lay people. If you can wait a bit those are safer and effective.

https://www.fightaging.org/archives/2020/05/another-example-of-a-galactose-conjugated-senolytic-prodrug/

Posted by: Cuberat at September 14th, 2021 7:33 PM

@Cuberate,

Thanks for the information and thoughts on this.

I was taking Fesitin but felt it to be more of a supplement than of making a real difference in getting rid of the senescent. Yea, I realize it could be 5+ years before we have more clarity on better ways to rid ourselves of the accumulation of these zombie cells, but I want to take a preemptive strike against the possibility of most age related diseases sooner..

Take care

Posted by: Robert at September 14th, 2021 11:40 PM

If one were interested in taking Fisetin, any suggestions for the dosage?

I'm 150 lbs...

Posted by: GREGORY S SCHULTE at September 15th, 2021 11:16 AM

@robert and gregory. Most people, including myself, taking Fisetin for senolytic reasons binge It intermittently, roughly 2g a month all at once. Of course you would want to start with a low dose as a test per chance you have a bad reaction to it

Thanks Cuberat

Posted by: JohnD at September 15th, 2021 12:36 PM

At G, I buy Dr's Best, but yes, 20 100mg pills at a time. I do it on an empty stomach, just seems logical, i have no data to support that procedure. To Adjust what I said previously, I only do it once every 2 months, not every month.

Posted by: JohnD at September 15th, 2021 8:53 PM

I've tried Fisetin using the JL Kirkland protocol to be used in his Mayo Clinic studies (which for some weird reason are still in state: 'recruiting' after 3 or so years). 20mg Fisetin/kg bodyweight on 2 consecutive days, reapeated a month later. I've done this twice/year. For two years now.

I guess if I were a mouse, the results would have been stellar or at least some study would report my stellar results. But… I have to report no results that I would be able to discern.

Posted by: Jones at September 16th, 2021 2:06 AM

Probably a good read for the commenters.

https://forbetterscience.com/2021/09/15/send-in-the-senolytics/

'The idea is: all you have to do to cure those diseases is to remove the evil senescent cells, i.e. to dissolve them with senolytics. Pharmacologically, senolytics are drugs which are deemed to be inhibitors of various proteins related to cell cycle control and cell survival. Problem is that too often the same scientists who make the groundbreaking discoveries about senolytics and the dangers of cellular senescence are also active businesspeople seeking to monetize their research papers. They found their own biotech startups, or sit on the board of pharma giants.'

Posted by: Jones at September 16th, 2021 2:18 AM

@Cuberate @Robert @Jones,

I've been using Fisetin 1100g-2100g/day (started at the lowest recommended I could find that should have effect but bumped it up through trial). I don't really notice much though unless I add long pepper (6 x .5 g "4x" extract) and fenugreek (1 gm) to it. I also like to add turmeric, CBD and bromalin and 1g NAC and fiber to help with absorption.

3-5 days, once a quarter/half year. I'm not deep tracking all the indicators like some, but my hair is noticeably darker about 50/50 dark grey, than at the start of covid. When I started all this I was just grey. Age 60.

Those send gen ones are slick and out of reach. Also, They now know that your blood chemistry changes, for the worse at 30, 60 and 80. So I'm looking to clear as many crown ceils as possible since I'm on the cusp. So looking at Dasatinib (probably will start about 60mg) and Q, F or Q+F.

Any thoughts?

Posted by: djswarm at October 23rd, 2021 10:00 PM

@Red,

There was a newish study that recently showed that at least with mice, extreme calorie restriction wasn't needed. Instead, eating time restriction did the same job.

As I recall, they had mice with food available 24/7, ones calorie restricted, and ones that could eat what they wanted, but only for a restricted time period each day. The time restricted ones seem to fair the best.

Posted by: djswarm at October 23rd, 2021 10:10 PM
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