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Initial Evidence for the Antibiotics Azithromycin and Roxithromycin to be Senolytic

Researchers here report on two new senolytic compounds identified in the existing library of approved drugs, based on screening work in cell cultures. It is worth bearing in mind that drug candidates that demonstrate good results in cell culture quite often fail to show promise when tested in animals, so it is wise to be patient as new senolytics work their way through the research and development pipeline.

There will be a lot more of this sort of thing in the years ahead, as ever greater amounts of funding pour into finding new ways to selectively destroy senescent cells. Any senolytic approach that removes a significant fraction of these cells will produce a degree of rejuvenation in older patients, and so the hunt for mechanisms has taken on something of the air of a gold rush. So far at least four different mechanisms for prompting the self-destruction of senescent cells are targeted by a dozen or more drug candidates, while immunotherapy and suicide gene therapy approaches also exist. This will be a very busy industry a few years from now, and that bodes well for the future of our health and longevity.

Senescence is a clear hallmark of normal chronological aging. Senescence involves potentially irreversible cell cycle arrest, via the induction of CDK-inhibitors, such as p16-INK4A, p19-ARF, p21-WAF and p27-KIP1, as well as the onset of the SASP (senescence-associated secretory phenotype), and the induction of key lysosomal enzymes (e.g., Beta-Galactosidase) and Lipofuscin, an established aging-pigment. Interestingly, SASP results in the secretion of a wide array of inflammatory cytokines, such as IL-1-beta and IL-6, allowing senescent cells to "contagiously" spread the senescence phenotype from one cell type to another, systemically throughout the body, via chronic inflammation. Such chronic inflammation can also promote the onset of cancer, as well as drive tumor recurrence and metastasis.

Using the promoter of p16-IN4KA as a transgenic probe to detect and mark senescent cells, several research groups have now created murine models of aging in which senescent cells can be genetically eliminated in a real-time temporal fashion. Although this cannot be used as an anti-aging therapy, it can give us an indication whether the removal of senescent cells can potentially have therapeutic benefits to the organism. Results to date show great promise, indicating that the genetic removal of senescent cells can indeed prolong healthspan and lifespan.

As a consequence of this exciting genetic data, a large number of pharmaceutical companies are now actively engaged in the discovery of "senolytic" drugs that can target senescent cells. However, we believe that many FDA-approved drugs may also possess senolytic activity and this would dramatically accelerate the clinical use of these senolytic drugs in any anti-aging drug trials. Here, we have used controlled DNA-damage as a tool to induce senescence in human fibroblasts, which then can be employed as an efficient platform for drug screening.

Using this approach, we now report the identification of two macrolide antibiotics of the Erythromycin family, specifically Azithromycin and Roxithromycin, as new clinically-approved senolytic drugs. In direct support of the high specificity of these complex interactions, the parent macrolide compound - Erythromycin itself - has no senolytic activity in our assay system. Interestingly, Azithromycin is used clinically to chronically treat patients with cystic fibrosis, a genetic disease of the chloride-transporter, that generates a hyper-inflammatory state in lung tissue. Azithromycin extends patient lifespan by acting as an anti-inflammatory drug that prevents the onset of lung fibrosis by targeting and somehow eliminating "pro-inflammatory" lung fibroblasts. Therefore, the efficacy of Azithromycin in cystic fibrosis patients provides supporting clinical evidence for our current findings, as these lung fibroblasts are pro-inflammatory most likely because they are senescent.

Link: https://doi.org/10.18632/aging.101633

Comments

Haven more senolitic, albeit weak can give more options if using a cocktail of weak but mostly harmless senolitics. Even if on its own they are not very effective they could bring a synergetic effect when combined with something else. Like quercetin, for example, be which is not very effective alone...

It also interesting to see how the senolitics interest with stress response promoters like rapamycin, which should ideally let the cells repair themselves. Logically speaking, if we have one drug enjoying, say p16 or p21 and the other hindering them to have the effects cancel reach other. Or probably cycle promotion and suppression...

Posted by: Cuberat at November 16th, 2018 12:12 PM

I have been self-prescribing low-dose azithromycin for years as part of a multi abx combo and believe it has slowed my aging.

Posted by: Lee at November 16th, 2018 4:06 PM

@lee I recently ordered Injectable Ceftriaxone to experiment with, non life extention related. Is that in you combo? My thought process is that injectable abx are less detrimental to the microbiome, do you agree?, and how do you mitigate microbiome stress?

Posted by: JohnD at November 17th, 2018 11:27 AM

I don't understand why they used the word "chronological" in that article. Senescence is a hallmark of biological aging, not "chronological" aging.

Posted by: Nathan at November 18th, 2018 12:41 PM

@JohnD
My microbiome had issues in the first place so I am not concerned with that. Actually I feel it has been helpful.

Re: Injectable versus oral abx; The injectable are excreted in urine or through the gut so this layman can't see that it makes much of a difference.

My latest pulsed combo (not all at the same time)of Tinidazole, clindamycin, ciprofloxacin and azithromycin has been for fighting a weird persistent infection and I have noticed what I think is slowed aging as a nice byproduct.

Posted by: Lee at November 18th, 2018 4:42 PM

I have been taking Berberine ( which activates the same pathways as Metformin), and Fisetin. No negative side effects to report. I feel much younger and also look younger. Permanent injuries on my feet began to heal since starting on Berberine.

Posted by: Craig Paardekooper at November 18th, 2018 5:37 PM

I am currently taking Berberine and Fisetin twice a day.
I have ordered some Azithromycin and it should arrive soon.

Posted by: Craig Paardekooper at November 21st, 2018 6:57 AM

What would a low dose of Azithromycin be? How often would you take it?
Did the Z Pack I took for a cold last month eliminate most of my scenecent cells?

Posted by: August at December 2nd, 2018 5:32 PM

@August: That people are using this fairly widely, and have been for 20 years, argues strongly against it being meaningfully senolytic in humans, at least at the doses commonly used. It would have been noticed.

Posted by: Reason at December 2nd, 2018 5:44 PM

Azithfomyci is lipophilic and hence soluble in oils. 75 mg of azithfomyci added to 1 litre of olive oil is the required concentration to match the experimental concentration of 100 micro molar.

If this oil based solution is rubbed into the skin it will remove senescent cells and reduce inflammation. However it will also remove all the bacteria because azithfomyci is an antibiotic.

Posted by: Craig Paardekoopet at December 4th, 2018 11:43 AM

Azithromycin is lipophilic and hence soluble in oils. 75 mg of azithromycin added to 1 litre of olive oil is the required concentration to match the experimental concentration of 100 micro molar.

If this oil based solution is rubbed into the skin it will remove senescent cells and reduce inflammation. However it will also remove all the bacteria because azithromycin is an antibiotic.

So I would recommend that you test the solution on a small area of skin first.

I would not recommend that you take azithromycin orally because it is a strong antibiotic and will cause stomach upset and the runs. This is because the drug kills all the bacteria your intestines that you need for normal digestion. If you do take it orally then you should have a bottle if milk of magnesia to hand to neutralise the inevitable stomach aches.

I took it orally. But will not be repeating that. Taking it topically as a skin lotion is safer and will possibly regenerate your skin by removing senescent cells.

Posted by: Craig Paardekoopet at December 4th, 2018 1:35 PM

I tested out a solution of 750ml of extra virgin olive oil mixed with 200 mg of azithromycin. I applied the solution to my whole body. After 8 hours, I noticed that I developed itchy areas, and rash areas on my face. I was told this might happen because azithromycin kills all the skin bacteria - the good and the bad - leaving the skin vulnerable to re-invasion by bad bacteria. Normally the good bacteria keeps the bad at bay.

I will carry on testing, but will reduce the concentration and restrict the dosing area to my hands.

If we had a lypophilic senolytic that was not an antibacterial agent, that would be ideal.

Posted by: Craig Paardekooper at December 5th, 2018 12:11 PM

I was prescribed Azithromycin (250 mg three times a week) some months ago for my occasionally-severe asthma attacks. Within a week the severity of the asthma was reduced significantly. I went off it for a fortnight and the severe attacks returned, now back on it. This is the first time I've had real success with a pharmaceutical drug. Thanks to my Pulmonary Clinician for thinking in and out of the box(es).

PS I have sarcoid tissue in the lungs probably for decades which doesn't seem to be going anywhere, thank goodness. (determined by biopsy).

Posted by: Peter Brett at December 6th, 2018 7:09 AM

I identified a supplier in China for azithromycin. It costs $265 for 1 kg + $50 for postage
5 day delivery

I am also buying a 1mg balance to measure out the molarity of the azithromycin accurately - costs about $50

My experiment will be to dissolve the azithromycin in olive oil and apply to a small area of skin daily for about 1 month. The aim of the experiment is not to remove senescent cells but simply to see if there are any adverse reactions at different concentrations. Ie does dry skin develop? Does a rash develop?

If there are no negative side effects then stage2 will be to measure the regeneration caused by removal if senescent cells. I will do this by .easuring changes in skin elasticity using a skin elastometer. This step will take much longer depending on the rate of turnover if skin cells

Posted by: Craig Paardekooper at December 6th, 2018 7:52 AM

Craig,Please keep us updated on your results!

Posted by: August at December 13th, 2018 1:16 PM

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