Arguing for Senolytics to Prevent or Slow Development of Macular Degeneration
In this short commentary on omics analysis of the aging retina, researchers make the point that the evidence suggests the use of senolytic therapies to prevent or slow the development of age-related macular degeneration. This condition is associated with an increased burden of senescent cells in the retina and nearby tissues. When present over the long term, the mix of signals secreted by senescent cells induce inflammation, maladaptive tissue remodeling, and other problematic changes in the behavior of other cells.
Senescent retinal pigment epithelium (RPE) was linked to the onset of age-related macular degeneration (AMD), with senolytic agents assessed as potential treatments for AMD. A fact that has been seldom considered among the plethora of processes that are affected and, in turn, effected by cellular senescence (an adaptive cell response to stressors effected by an inflammatory secretome) is that of intercellular communication. In the case of the RPE, its functional and anatomical ties to the choroid are as much, if not more so, functionally relevant as those with the neuroretina.
A study applying a combined approach using bulk RNAseq, scRNAseq, and microarray RPE transcriptomics was able to draw substantial inferential data pertaining to intercellular communication between the RPE and the choroid. Intercellular communications between RPE cells and stromal elements involved in aging and senescence pertained notably to VEGF, BMP- and tenascin-mediated pathways, i.e., these pathways scored higher when mediating interactions between senescent cell populations. Consistently, AMD-derived patient samples scored higher overall in terms of senescence, and bulk RNAseq data showed a positive correlation in score increase with age.
These findings potentially support employing anti-aging therapies such as senolytic pharmacologic compounds to prevent or ameliorate progression to AMD, as well as underscore the necessity of more rigorous investigation into the interplay of senescence and cell-to-cell communication.
The mTOR pathway is involved in cell growth, survival, and angiogenesis. Dysregulation of mTOR signaling has been implicated in various diseases, including some eye diseases. There is evidence to suggest that mTOR may play a role in the pathogenesis of ARMD, especially in neovascular (wet) ARMD, where abnormal blood vessel growth is a prominent feature. Inhibiting mTOR signaling might reduce this pathological angiogenesis, making it a potential therapeutic target.
In a clinical setting, using published rat studies as a guide, 1mg 3X/week of rapamycin has been found to mitigate the excessive vasculature that causes the blood leakage behind ARMD to acceptable levels. Given the immunosuppressive nature of rapamycin, the patient may be armed with an antibiotic to be taken PRN.
https://ajp.amjpathol.org/article/S0002-9440(12)00357-4/fulltext