A Discussion of Cellular Senescence in Age-Related Macular Degeneration
Cellular senescence is one of the root causes of aging. A small fraction of the large number of cells that become senescent every day fail to self-destruct, and instead linger in tissues to secrete a mix of inflammatory and other harmful signals. This behavior is known as the senescence-associated secretory phenotype, or SASP. The sizable numbers of senescent cells in old tissues have been implicated as a contributing cause of numerous age-related conditions, from lung disease to cardiovascular issues to forms of arthritis. More causal links will be discovered: this is a newly energetic field of research.
As an example of the sort of thinking presently taking place, researchers here discuss a potential role for cellular senescence in macular degeneration, a progressive blindness caused by destruction of retinal tissue. While it seems fairly likely that senescent cells are involved, the question is always whether or not they are involved to a sufficient degree to be an important cause. That seems plausible based on what is known, but it isn't an open and shut case. There is considerable uncertainty, based on the existing evidence. Fortunately, now that senolytic therapies to clear senescent cells are a going concern, there is a fairly rapid way forward to learning more: remove senescent cells in aged animal models of macular degeneration, and see what happens. Someone will get around to that in the next few years, I'd imagine.
Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor, but it is a complex disease in which both genetic and environmental factors play a role. The exact mechanism of its pathogenesis is unknown. Oxidative stress, protein aggregation, and inflammation play a central role in AMD development. Early dry AMD is hardly detectable and usually asymptomatic. Its advanced form, called geographic atrophy (GA), is associated with a massive loss of photoreceptors that evokes central visual loss. A clinical hallmark of wet AMD is the presence of neovascular vessels sprouting from the choriocapillaris into the retina.
It has been proposed that cellular senescence of RPE cells plays a role in the etiology of AMD. It seems that many studies on the role of cell senescence in organismal aging and age-related pathologies support this idea. The exposure of cells to recurrent or chronic nonlethal stress might contribute to an increase in the accumulation of stress-induced senescent cells, thereby accelerating tissue aging. A growing body of evidence proves that persistent DNA damage, especially double-strand breaks (DSBs) and DNA damage response (DDR), are closely associated with cell senescence. Evidence also links DNA damage with inflammation and disease, particularly age-dependent diseases. This is sort of a vicious cycle as DNA damage-dependent senescence can lead to secretion of molecules, which can reinforce senescence and can induce DNA damage and DNA damage-dependent bystander senescence.
Retinal pigment epithelial (RPE) cells in the central retina are quiescent, and when damaged, they can be replaced by their proliferating counterparts at the RPE periphery. Oxidative stress can induce senescence in RPE cells and result in inability of peripheral RPE cells to rescue their central RPE counterparts, which can lead to a massive loss of RPE cells observed in clinically detected AMD. If most of macular peripheral RPE cells are affected by senescence, this mechanism can fail leading to AMD. Senescent RPE will be the source of pathology and have a detrimental impact on surrounding tissue through the senescence-associated secretory phenotype (SASP).
We believe that senescence associates with autophagy and DDR. All these three effects, senescence, autophagy, and DDR, can be provoked by oxidative stress, which is a major factor in AMD pathogenesis. Moreover, aging is the main risk factor of pathogenesis of AMD and can be related to oxidative stress. Inflammation associates with oxidative stress, aging (inflammaging), and AMD. Therefore, it is logical and justified to hypothesize that senescence can play a role in AMD and this process can be influenced or regulated by autophagy and DDR. Consequently, GATA4, as an identified factor to be involved in cell senescence, autophagy, DDR, and inflammation, seems to be a natural candidate to play a major role in the proposed mechanism of AMD pathogenesis. However, this is only a hypothesis, which should be verified, but we tried to show some arguments that this subject is worth further study and development.