Professor Michael Lisanti of Salford University highlights the potential application of senolytic drugs in combating COVID-19.
Professor Michael P Lisanti, Chair in Translational Medicine at the University of Salford, has been an active research scientist for more than 30 years and is an expert in the field of cellular senescence. He tells HEQ about the potential of readily available, low cost, MHRA- and FDA-approved drugs to possibly treat and prevent the spread of COVID-19.
What are the key characteristics and potential applications of senolytic drugs?
Senolytic drugs can be used to prevent or reverse ageing. There have been studies in mice that have shown that if you use a genetic trick, you can reverse ageing-associated disease characteristics – but the problem is you can’t do that in humans, so you would need a drug. We set out to identify drugs that would selectively kill senescent cells, but not harm normal cells; for this purpose, we developed a drug screen where we looked at various agents which prohibit cancer stem cell activity and we came across azithromycin, which selectively killed senescent cells with efficiency of nearly 97% and did not harm the normal cells. When we looked at the literature, we saw that patients with cystic fibrosis had been treated with azithromycin – cystic fibrosis is similar to accelerated ageing as a disease, because there’s a huge amount of inflammation and fibrosis – and it dramatically increased their lifespan and their survival rates.
Fibrosis is normally an ageing-associated disease characteristic: it’s what kills patients with cystic fibrosis, because their lungs become stiff and can no longer expand and contract, in order to breathe. The azithromycin was also behaving as an antifibrotic, removing or preventing the formation of senescent myofibroblast cells; so we actually had proof In previous studies that our drug was actually a senolytic. If you reread the literature with ‘senolytic glasses’, you realise that the proof of its efficacy in humans is already there.
Another study in Japan looked at azithromycin based on its activity in cystic fibrosis patients and then applied these finding to patients with idiopathic pulmonary fibrosis. The control group survival rate in that paper was 25%, but on azithromycin it was nearly 80%. There is evidence in the published literature that it’s either preventing or removing fibrosis which is consistent with our data, but nobody thought about cystic fibrosis or about idiopathic pulmonary fibrosis as diseases of senescence: they thought it was preventing the formation of the myofibroblasts, but we believe it was killing the myofibroblasts, which are now known to be senescent cells.
The reason you want to get rid of the senescent cells is because they are actually contagious. They secrete IL-6, which is an inflammatory mediator; and they make other cells senescent by diffusion of the inflammatory mediators, which explains why as you get older you accumulate more and more senescent cells. By the time you’re 40 or 50 years old, you have aches and pains and you feel stiffness: these are a symptom that you are beginning to accumulate senescent cells.
All of this is very reminiscent of what happens in patients with COVID-19. Fatality rates are much higher in older patients and in patients with ageing-associated diseases, such as diabetes or coronary artery disease. IL-6 levels have been shown to be the best predictor for whether or not a patient will to wind up on a respirator – and these patients may die from inflammation in the lung and the resulting fibrosis. It all sounds similar to a very acute episode of either cystic fibrosis or of idiopathic pulmonary fibrosis.
What is the relationship between COVID-19 and senescence?
The virus has something called a host receptor, which allows the virus to bind the surface of the cells and then get internalised. For COVID-19, there are two proposed host receptors: one is CD-26, which is a marker of senescence; and the other one is ACE-2, which is also increased during senescence. This would suggest that the virus is preferentially targeting cells with markers of senescence.
We think of senescent cells as old and not very energetic, but they have to secrete a lot of inflammatory mediators, like IL-6, so they actually have very active protein metabolism and they do a lot of protein synthesis – IL-6 is a protein – and they produce inflammatory mediators of the senescence associated secretory phenotype (SASP). Therefore, the virus would want to invade a cell that is better at protein synthesis in order to make more copies of itself and the necessary viral spiked glycoproteins, to package the viral RNA or DNA for viral replication. This virus is seeking out the cells that are the best at making protein, to make more copies of itself, so it gets in the cell and takes over.
The predilection for fatalities in patients with advanced chronological age suggests there is a connection with senescence; and azithromycin, which appears to be working in clinical trials, is a senolytic and an antifibrotic. Certain antibiotics of the azithromycin class – of which there are many – are inhibitors of protein synthesis. The same is true of tetracyclines like doxycycline. These drugs would inhibit protein synthesis, so they would block IL-6 production and also block viral replication. Azithromycin has been shown to inhibit Zika virus and Ebola virus replication; and doxycycline has been shown to inhibit Dengue virus replication. Any drug which is a protein synthesis inhibitor, like certain classes of antibiotics, would also inhibit viral replication – not because of any characteristics specific to the virus, but because it’s inhibiting protein synthesis, which is required for their viral replication.
The question, then, is why we can’t use these drugs now in the clinic. In the United States, if a drug is prescribed off-label, it’s perfectly legal: the FDA approves a drug after Phase 1, Phase 2 and Phase 3 clinical trials for a particular indication. Then because the drug already went through Phase 1, which is a safety trial, it can be legally prescribed for any other disease indication off-label. The FDA will not actually have to directly approve doxycycline or azithromycin for treatment of COVID-19, because doctors can already prescribe it.
In a time of crisis, we need to practise what people are calling ‘battlefield medicine’, where we think outside the box. There’s already evidence in the published literature that these antibiotics have the protein synthesis inhibition ‘side effect’ and have already been shown to inhibit viral replication. The problem in this country is people are – rightfully – afraid of antibiotic resistance. It’s the kind of thing that has been ingrained in the mindset of doctors in the UK. However, I think we need to rethink the whole use of antibiotics to target viral infections. In fact, if you look in the literature for herpes virus (HSV), it’s already been shown that erythromycin, which is another protein synthesis inhibitor, is used either orally or as a cream to treat herpes outbreaks.
Is it possible senolytic-based treatment could help limit the spread of the disease, by reducing viral load?
If we could give NHS workers either doxycycline or azithromycin prophylactically, the viral load would likely be gone or severely diminished. This would prevent the spread of the virus from one person to another, protecting clinicians against people who come to the hospital; and could also be used to treat patients. But, I think the key here is to avoid the fibrosis and the inflammation, which starts with the fever. When a patient comes down with a fever, they should immediately give them the doxycycline or the azithromycin, which will shut down IL-6 production and shut down the viral replication; so the patient is less likely to transmit the disease to healthcare workers.
All these drugs are very inexpensive – the cost of doxycycline is 10 pence a day; azithromycin is also very cheap, because it came off patent in 2017 – so these drugs could be used for prophylaxis and for treatment. Then potentially we could relax some of the social distancing and we could all go back to work. The problem is we’re not going to have vaccines for another 12 to 24 months, so we need something now that’s already safe, that’s MHRA- or FDA-approved for at least one indication. It may be something that can be used in conjunction with social distancing: some people don’t have extra space in their house where they can really isolate, so then they could take an antibiotic like doxycycline or azithromycin to reduce viral loads. This would reduce the stress on the healthcare system, because if you treat people in the early stages and it works, they won’t get to the ventilator stage – and the problem is when you get to the ventilator stage, the patient’s lungs have effectively turned to cement from all the fibrosis, so the chances of getting people off the ventilator is rather low. It’s very serious once you get to the ICU, so you want to prevent the onset of respiratory symptoms, by treating patients as soon as possible with an antibiotic that will shut down viral replication.
Doxycycline is the number one drug prescribed worldwide for any indication: it’s used for malaria, it’s mainly used for acne; and people will take it for six months at a time without any real issues, except maybe some stomach upset. People with acne rosacea take it for their whole life, especially in very disfiguring cases – usually they recommend a drug holiday for a week or two, every six months. Doxycycline was approved first in 1967. It’s not a senolytic, but it does inhibit IL-6 and it inhibits viral replication; and it has been shown by other people to be an anti-ageing drug as well. Both of these drugs are very cheap; and they should be in abundant supply worldwide.
Has research already been conducted into the use of senolytics or similar drugs in the treatment of other coronaviruses?
SARS-CoV-1, the precursor for COVID-19, shows the same pattern of infection. They conducted experiments in humans and mice and saw that, for example, young mice will become infected, but it doesn’t cause any real disease – there is no inflammation or fibrosis; and a very mild pneumonia – but if they use older mice aged 12 to 14 months, they see very severe inflammation, fibrosis and death. This is due to the induction of a very strong inflammatory response, which includes the IL-6. This original mouse model could be used to test this hypothesis regarding senolytics, but as these drugs are already FDA-approved, we can do that in parallel. The problem is it’s a question of time; and the longer we wait, the more people are infected, when we could just shut it down now. We could use patients already in hospital, you would have instant clinical trials. This is battlefield medicine. We should take advantage of the patient population with drugs that have very few side effects, and conduct clinical trials on a large scale.
I think people are in a state of helplessness. They don’t know what to do, and the solution could be right under our noses. What we’re doing is not working, for many patients, and we need to change something; and the first step would be propagate the idea of field clinical trials. We can record all the data from the treatment of the patients as it progresses – thousands of people have the disease and it could be a multicentre trial, the most important thing is to get something going now.
Much research into the treatment of COVID-19 is currently focused on the drugs chloroquine and azithromycin; and the FDA has granted an emergency licence for the use of chloroquine to treat COVID-19 patients. The European Medicines Agency has not yet followed suit, asserting that more research should be conducted; and some researchers have highlighted concerns over toxicity issues associated with chloroquine and its derivative, hydroxychloroquine.
Is the risk of chloroquine toxicity high enough to disqualify it from immediate medical use, in your opinion? Are there any significant risks associated with azithromycin?
Patients who are prescribed chloroquine or hydroxychloroquine normally would have to take a test for a glucose-6-phosphate dehydrogenase deficiency (G6PD) [an hereditary condition which increases the risk of haemolysis when chloroquine is administered]; and there are other issues with both chloroquine and hydroxychloroquine. I think the side effects may outweigh the benefits, because it’s not an inhibitor of viral replication; it’s an inhibitor of viral entry. If the patient is already sick, they already had the viral entry, then chloroquine will not necessarily shut down the viral replication. It only works for patients who have not already been infected.
In the clinical data from the French trial of hydroxychloroquine and azithromycin, the chloroquine did relatively little by itself – and that has been called into question in terms of the effects. The combination with azithromycin was much more effective, but they didn’t test azithromycin alone, which would probably be sufficient; because even if viral entry does occur, as long as the viral replication is inhibited, the virus will not propagate. We believe that the hydroxychloroquine isn’t necessary; and we can reduce the risk to older patients by eliminating the hydroxychloroquine.
Azithromycin has some very mild side effects, but they’re not very prevalent; if they had been prevalent the drug would have been pulled off the market. There was some controversy as to the reproducibility of the studies regarding its side effects: multiple studies were done and some are positive, some are negative, so there’s still a warning out there – but the side effects only really occur with high doses of azithromycin, which would not be needed in this case. If azithromycin did cause problems for a patient they could switch to doxycycline, or they could start with doxycycline in the first place. These are just two examples of classes of drugs; there are other drugs which inhibit protein synthesis: erythromycin is in the same class as azithromycin, and it inhibits protein synthesis. It doesn’t have the senolytic activity, but it would still inhibit the IL-6 and the viral replication.
The same is the case for the tetracyclines – these are classes of drugs which are relatively similar and interchangeable, so if we run out of doxycycline, we would still have minocycline, tetracycline and all these other variations which have a similar effect on protein synthesis. The main issue with doxycycline is patients can experience some stomach upset or some nausea, but this can be alleviated by using a probiotic.
Could these drugs be used in a preventive sense, to pre-emptively avert further contagion?
That would be the primary role of these drugs. Based on the results of clinical trials, the NHS could implement its usage. For example, ICU staff could receive it first, as they are in contact with patients that pose the most severe risk. Hospital staff right now are probably terrified of catching it, so why not take a prophylactic antibiotic, which has a chance of preventing infection? I’m sure they’re doing a great job taking care of the patients, but it is traumatic to be under all this stress constantly. It’s very stressful to be in such a high pressure situation, where you’re afraid for your own life, but you’re also trying to help other people at the same time. Then, you have your family at home and you don’t want to also make them sick either. Healthcare workers are the people who are at the greatest risk; and already we’ve seen a reduction in NHS staff levels – around one in four NHS staff are not at work, because they have either been infected or are isolating because they have symptoms.
We don’t want to lose too many of the doctors and nurses in this crisis, so this would be helpful for everyone – especially for preventing the further spread – to shut down viral replication and contagion. Anything that can be done to reduce the viral load will reduce the contagion. They can do trials with young healthy volunteers who are asymptomatic, but it would be better to do it with the NHS staff who would need it most as a preventative approach for prophylaxis. We have recently proposed and published this prophylaxis strategy in a Letter to the Editor at the British Medical Journal (BMJ), which is widely read by GPs and consultants in the UK.
1 Letter to the Editor, British Medical Journal: https://www.bmj.com/content/368/bmj.m1252/rr-20
2 Lisanti, Sotgia et al. (2020). Senescence, ageing and potential COVID-19 treatments. Aging-US. https://www.aging-us.com/article/103001/text
Professor Michael P Lisanti, MD-PhD, FRSA, FRSB
Chair in Translational Medicine
School of Science, Engineering & Environment
University of Salford
+44 (0)1612 950 240
This article is from issue 13 of Health Europa. Click here to get your free subscription today.
Sir, I have a question related to theoretical issues with doxycycline, which upregulates transcription of ZAP, but chelates zinc in metalloproteinases both viral and human, the latter catalysing collagen synthesis (? by polymerization of proline/hydroxyproline residues or ?cross-linking collagen polymers) which may contribute to pulmonary fibrosis. Dr. Marik in the USA suggests high dose steroids, intravenous ascorbic acid, heparin and Zinc for COVID-19. Is Zinc OK here, and can Doxycycline be added too?
Farooq Ali, MBBS