Senolytics: trials and judgements

In a previous post we considered the advantages of repurposing existing drugs to treat a new condition. The fact such treatments had already undergone safety testing and regulatory approval shortens the usually lengthy journey to the clinic. Such acceleration is particularly welcome during a gold rush. But don't visualise old prospectors sieving sand whilst cackling about them thar hills: in this story the old-timers involved are our senescent cells, and the gold rush is the race to discover senolytic drugs to remove them, potentially ameliorating multiple diseases of aging simultaneously.

Ignoring the major challenge of developing potential treatments, all candidate drugs must eventually undertake human trials. In January 2019, a small pilot study investigating the senolytic DQ (dasatinib plus quercetin) in idiopathic pulmonary fibrosis published results online. It is fair to characterise those results as modestly positive, showing clinically meaningful improvements in physical function, but inconclusive results in other areas. Other trials are in early stages, for example this investigation of the senolytic UBX0101 to treat osteoarthritis of the knee, or the AFFIRM study into the alleviation of frailty in older women. Since initial trials focus on safety and feasibility we should expect it to be some time before comprehensive results on efficacy are available. However, some tantalising research from the University of Salford has raised the prospect that certain senolytic treatments may already be in active use.

The Salford research considers the senolytic potential of pre-existing antibiotic compounds erythromycin, azithromycin and roxithromycin. The research used side-by-side MCR5 (human lung) cell samples, some of which were driven to senescence via controlled DNA damage, and some of which were left in normal state. The researchers found that erythromycin had no senolytic activity, but that both azithromycin and roxithromycin were senolytic, with azithromycin also being highly selective - preferentially destroying senescent cells while leaving normal cells unharmed. Azithromycin is established as an important drug for non-antibiotic reasons in the treatment of bronchial disease as summarised by a recent overview paper:

"[Azithromycin] has powerful immunomodulatory activity that initially reduces acute inflammation, and at a later stage helps resolve chronic inflammation by promoting long-term repair and healing. Because of these properties, azithromycin has been used in the treatment of a variety of chronic pulmonary diseases, including COPD, bronchiolitis obliterans, diffuse panbronchiolitis, asthma, and non-CF and CF bronchiectasis."

Bronchiectasis and azithromycin .
(Archivos de Bronconeumologia - Vol. 54. Num. 2.February 2018)

Since the University of Salford testing was conducted in vitro, the results cannot be automatically extrapolated to a living organism, however they remain of interest because azithromycin is an in-use medication, subject to human (in-vivo) use and research on an ongoing basis. The anti-inflammatory aspect of azithromycin has been noted for cystic-fibrosis patients, and it has been found to improve survival for both pulmonary fibrosis and pneumonia. There is some evidence that previously recorded effects of azithromycin are senolytic in nature. In treatment of chronic obstructive pulmonary disease (COPD), the efficacy of the treatment increased with age. In treatment of lung cancer, azithromycin was seen to reduce angiogenesis, i.e. the ability of a tumour to form a viable blood-supply. Previous research has shown senenscence drives angiogenesis in certain tissue types, for example with retinopathy and skin cancer. Finally, anticipated broad-spectrum senolytic effects might perhaps be evidenced by case reports of dental-bone regeneration. Given this, it is reasonable to ask whether the human trials of senolytics have been reporting for some time.

Of course this discussion is based on a selection of available research, so we should be cautious of cherry picking to support a particular position. The role of azithromycin will doubtless be re-examined in detail in research labs globally, and a scientific consensus on its applicability and modes of operation will be arrived at. Such consideration will necessarily include the substantial negatives around widening its use. In these days of antibiotic crisis, azithromycin has already been found to increase bacterial resistance. Also, macrolide antibiotics are known to increase the risk of ventricular arrhythmias and thus raise risk of sudden cardiac death. Adding to our no-free-lunch list, azithromycin has been found to increase risk of cancer relapse following donor stem-cell transplant. Oddly, this latter risk might also relate to the drug's senolytic properties, since the initial biological purpose of senescence is as an anti-cancer mechanism. This regulatory warning might therefore be a cogent reminder that the power of senolytics will require a comprehensive theoretical basis in order to wield safely.