Cellular Senescence Is Associated With Human Retinal Microaneurysm Formation During Aging

Abstract

Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.

Lysyl oxidase‐like 2 (LOXL2)‐mediated cross‐linking of tropoelastin

“…Expression of LOXL2 in the wall of small arteries had already been described in Csiszar ( 43 ). More recently, LOXL2 was detected in retina arterioles, with increased expression in growing microaneurysms ( 44 ).…”

The Emerging Role of Senescence in Ocular Disease

“…Though an array of senescence markers has been proposed and widely used in multiple cell types, no single one can reliably identify senescent cells either in vitro or in vivo. The most widely used markers of senescence include the senescence-associated β-galactosidase (SA-β-gal) reactivity [15,20,[35][36][37][38][39], increased expression of the cyclin-dependent kinase (CDK) inhibitor p16INK4a [15,30,[36][37][38][39][40], p21 (CIP1/WAF1) [36-39, 41, 42], p53 [36,37,41,42], induction of SASP factors [14,41,[43][44][45][46][47][48][49][50], mitochondrial DNA modifications [39,[50][51][52][53][54][55][56][57], and chromatin modifications [37,47,58,59] ( Figure 1). The limitation is that even a combination of multiple markers does not truly represent senescence but could also describe long-term cell arrest.…”

“…SA-β-gal positivity of RPE cells has also been reported in the human retina and monkey retina [86]. Neurons, but not neuroglia and blood vessels undergo cellular senescence in the aged human retina [42]. Aging causes loss of retinal neurons, including rod photoreceptors, retinal ganglion cells (RGCs), and rod bipolar cells [82,86,87].…”

“…Retinal microaneurysms overexpress canonical senescence markers, suggesting that cellular senescence is associated with the pathogenesis. Apoptosis also cooccurs with cellular senescence in old-age retinal microaneurysms [42]. The age-related decrease in the anterior segment outflow is largely responsible for the elevated intraocular pressure, one of the factors attributing to the development of glaucoma [89].…”

“…It is well established that not only cell size but also mitochondrial mass increases significantly in senescent cells (Table 3). Senescent cells have been observed in the eye specifically in the neuronal, endothelial, and RPE cells [42,86] and it is critical to understand their participation in energy metabolism during aging as well as the progression of various retinal degenerative diseases. A strong link between mitochondrial metabolism and the senescent state has been proposed [162].…”