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.

Keywords: Cellular senescence; Immune aging; Macular degeneration; Microglia; Neuron; Retinal pigment epithelium; SASP.

Fig. 1

Etiology and consequences of cellular senescence contributing to AMD. Cellular senescence is highly relevant to AMD pathogenesis. A variety of factors—telomere dysfunction, oxidative stress, nutrient signals, DNA damage, and inflammatory cytokines—can activate cellular senescence in both mitotic and post-mitotic cells. Senescent cells display altered metabolic function and autophagy activity, as well as a distinctive proinflammatory secretome, which are all interlinked. These processes directly impose a cause-and-effect on one another, further accelerating their progression. The consequences of chronic cellular senescence, such as increased drusen deposition, increased RPE, choriocapillaris and photoreceptor dysfunction and cell loss, and/or neovascularization, ultimately lead to the advanced disease phenotype of macular degeneration

Fig 2

A schematic diagram of consequences of the senescent retina and induction of SASP during progression of AMD. A healthy retina is an immune-privileged ocular tissue, with active immune regulatory networks and immune cell networks supporting normal retinal cell morphology and function [1, 7]. In contrast, a “senescent” retina has both damaged cells and impaired function with alterations in microglial morphology, migration, and infiltration of systemic immune cells. Additionally, resident neuronal cells (ganglion cells, horizontal cells, amacrine cells, and photoreceptors), RPEs, and microglia/macrophages, enter a senescent state in the senescent retina. Drusen begin to accumulate between the Bruch’s membrane and RPE or in the subretinal space (subretinal drusenoid deposits). The Bruch’s membrane thickens and choriocapillaris has a reduced vascular network alongside thinning and diminishing vessels in the aging choroid. Numerous SASP factors, such as IL-6, IL-12, TNF-α, IFN-γ, and IL-8, are released from the senescent retinal cells. ROS, in tandem with damaged DNA, further promote the age-related decline in RPE and photoreceptors resulting in a feedforward cycle of damage. Signaled by the SASP-chemokines released into the tissue environment, immune cells (monocytes, neutrophils, and T cells) extravasate from the blood vessels, infiltrate the retina, and release SASP components, contributing to a chronic inflammation and other AMD-related pathologies

Fig. 3

Prospective senotherapeutic strategies to subvert AMD progression. (1) Selective elimination or modulation of senescent cells through senolytics such as dasatinib + quercetin, inhibitors of Bcl-2 or BET proteins, chimeric antigen receptor (CAR) T cells, or by modulating neutrophil-induced NETosis, which can redirect immune responses against senescent cells. (2) Modulation of senescence-related signaling networks (senomorphics) to attenuate SASP through, for example, regulating NF-κB, mTOR, and AMPK pathways, or utilizing monoclonal antibodies against SASP factors, such as IL-6. (3) Inhibition of senescence in the eye using cell cycle regulators, p53/Rb sumoylation inhibitors, mitochondria-derived peptides, or lipid mediators. (4) Restoration of cholesterol homeostasis/flux and normal function of macrophages via liver X receptor (LXR) agonists or miR-33 inhibition, which has proved beneficial in the inhibition of retinal degeneration in vivo