Lingering populations of senescent cells grow with age, and cause considerable harm via their inflammatory secretions. They are a tool to promote regeneration and resistance to cancer in the short term, but like many short term systems, they become damaging when left switched on for the long term. As I noted just yesterday, even looking at only the past year of studies of senolytic therapies to selectively destroy senescent cells, there is strong evidence in animal models for their ability to prevent or reverse a score of common age-related conditions, a broad range from Alzheimer’s disease and other forms of neurodegeneration to fibrosis of the heart and kidney. This is just a starting point. Senolytics have yet to be tested in earnest for many more conditions that could plausibly be reversed by the targeted removal of senescent cells; there is only so much funding, and only so many scientists.
As the study of senescent cells in the context of aging expands, with the continued influx of new funding driven by a growing interest in this part of the field, we should expect to see ever more examples such as the one I’ll note today. This is yet another age-related condition with poor treatment options in which animal models are shown for the first time to benefit from the application of senolytics.
In this case the condition is glaucoma, loss of vision caused by degeneration of retinal ganglion cells and the optic nerve. In most cases – but not all – this is caused by increased pressure in the eye, driven by hypertension and degeneration of fluid channels responsible for draining the eye. The precise nature of the relationship between risk factors such as pressure and mechanisms of neural degeneration in the eye has been far from clear, unfortunately. In this context, it is a ray of hope that the research here demonstrates cellular senescence as an important mediating mechanism, showing that removal of these cells prevents half of the retinal ganglion cell death that is produced in a model of raised pressure in the eye.
Glaucoma is comprised of progressive optic neuropathies characterized by degeneration of retinal ganglion cells (RGC) and resulting changes in the optic nerve. It is a complex disease where multiple genetic and environmental factors interact. Two of the leading risk factors, increased intraocular pressure (IOP) and age, are related to the extent and rate of RGC loss. Although lowering IOP is the only approved and effective treatment for slowing worsening of vision, many treated glaucoma patients continue to experience loss of vision and some eventually become blind. Several findings suggest that age-related physiological tissue changes contribute significantly to neurodegenerative defects that cause result in the loss of vision.
Mammalian aging is a complex process where distinct molecular processes contribute to age-related tissue dysfunction. It is notable that specific molecular processes underlying RGC damage in aging eyes are poorly understood. While no single defect defines aging, several lines of evidence suggest that activation of senescence is a vital contributor. In a mouse model of glaucoma/ischemic stress, we reported the effects of p16Ink4a on RGC death. Upon increased IOP, the expression of p16Ink4a was elevated, and this led to enhanced senescence in RGCs and their death. Such changes most likely cause further RGC death and directly cause loss of vision. Of particular note, a recent bioinformatic meta-analysis of a published set of genes associated with primary open-angle glaucoma (POAG) pointed at senescence and inflammation as key factors in RGC degeneration in glaucoma.
Glaucoma remains relatively asymptomatic until it is severe, and the number of affected individuals is much higher than the number diagnosed. Numerous clinical studies have shown that lowering IOP slows the disease progression. However, RGC and optic nerve damage are not halted despite lowered IOP, and deterioration of vision progresses in most treated patients. This suggests the possibility that an independent damaging agent or process persists even after the original insult (elevated IOP) has been ameliorated.
We hypothesized that early removal of senescent RGCs that secrete senescent associated secretory proteins (SASP) could protect remaining RGCs from senescence and death induced by IOP elevation. To test this hypothesis, we used an established transgenic p16-3MR mouse model in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells. We show that the early removal of p16Ink4+ cells has a strong protective effect on RGC survival and visual function. We confirm the efficiency of the method by showing the reduced level of p16INK4a expression and lower number of senescent β-galactosidase-positive cells after GCV treatment. Finally, we show that treatment of p16-3MR mice with a known senolytic drug (dasatinib) has a similar protective effect on RGCs as compared to GCV treatment in p16-3MR mice.