Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Abstract

Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies

“…Cellular senescence is an adaptative biological response to a variety of exogenous and endogenous stimuli that arrests cell replication. Despite its importance during development, tissue regeneration, and as a preventive mechanism against tumor proliferation, an accumulation of senescent cells is a driver of the aging process and it is implicated in pathogenesis of several age related diseases, including AMD [ 14 , 15 , 16 ]. Mitochondria play a key role in the regulation of the senescent phenotype.…”

“…In the human aging retina, RPE, ganglion, amacrine, and horizontal cells, and rods acquire characteristics of cellular senescence [ 16 ]. Age related accumulation of senescent RPE cells is marked around drusen, and amyloid-beta (a component of drusen) can induce RPE senescence [ 15 , 16 ].…”

“…In the human aging retina, RPE, ganglion, amacrine, and horizontal cells, and rods acquire characteristics of cellular senescence [ 16 ]. Age related accumulation of senescent RPE cells is marked around drusen, and amyloid-beta (a component of drusen) can induce RPE senescence [ 15 , 16 ]. Moreover, A2E a fluorophore present in lipofuscin (which accumulates in the aging RPE) can also induce cellular senescence by damaging DNA and shortening telomeres [ 17 ].…”

“…Moreover, A2E a fluorophore present in lipofuscin (which accumulates in the aging RPE) can also induce cellular senescence by damaging DNA and shortening telomeres [ 17 ]. Senescence has also been found in retinal and choroidal vascular cells and the consequent vascular dysfunction is associated with the progression of AMD [ 16 ].…”

“…Another key factor of cellular senescence is the senescence-associated secretory phenotype (SASP), wherein senescent cells release growth factors, cytokines, chemokines, proteases, and other molecules that induce inflammation and other AMD-related effects [ 16 , 17 ]. Senescent RPE cells secrete higher levels of MMP-9 and IL-8 which can promote the breakdown of the blood–retinal barrier by increasing tight junction´s degradation and activation of immune cells [ 17 ].…”