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.