Fight Aging!

Senescent cells accumulate with age throughout the body. While their numbers remain a small fraction of all cells in a tissue, even in late life, senescent cells produce an outsized harm to tissue structure and function via a continual, disruptive, pro-growth, pro-inflammatory signaling, the senescence-associated secretory phenotype (SASP). Researchers have demonstrated, in animal models, that senescent cells directly contribute to the onset and progression of many distinct age-related conditions. Further, it has been shown in animal models that clearing senescent cells throughout the body can rapidly reverse pathology in these conditions.

Degeneration of the vasculature is involved in retinopathies, forms of degenerative blindness. In today's open access review, researchers outline what is known of the way in which senescent cells contribute to the degenerative aging of the retina. That senescent cells are involved offers the prospect of using senolytic therapies to selectively remove these cells and their contribution to the disease state. Sadly, few groups are making use of existing low-cost senolytic small molecules in human clinical trials, so while treatments such as the dasatinib and quercetin combination are known to clear senescent cells in humans to about the same degree as in mice, they are not yet widely used. Scores of age-related conditions might be treated or slowed via this approach, but the focus of the industry is on the production and regulatory approval of new senolytics over the years ahead.

Senescent Cells: Dual Implications on the Retinal Vascular System

As we get older, more cells in healthy tissues become senescent. Senescent cells (SCs) are inactive in terms of reproduction, but extremely active in terms of metabolism and potentially inflame the milieu by producing thousands of bioactive molecules. Growth and development are not possible without the presence of SCs due to the critical role of SCs in a variety of biological processes such as embryogenesis, limb generation, wound healing, host immunity, and tumor suppression. However, due to the proinflammatory entity of senescent cells, their chronic accumulation is associated with a gradual decline in tissue function and age-related disorders.

Diseased blood vessels are a common feature in many eye disorders including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Mounting recent evidence has discovered the accumulation of senescent neurons and blood vessels in the retina. However, the underlying mechanisms of senescent cell contribution in retinal vasculopathies are not well defined yet. Here, we reviewed dichotomous implications of SCs at the onset and severity of proliferative retinopathies with a specific focus on the retinal vascular system. In a retinal blood vessel, the senescence phenotype in endothelial cells is associated with lower barrier integrity and increased permeability probably due to the impairment of both adherence and tight junctions.

In retinopathies, the hypoxic/oxidative stress induces cellular senescence in retinal neuronal cells that reside predominantly in the avascular zone. The inflammatory secretome of the cell cycle arrested cell boosts and propagates the senescence phenotype to the surrounding tissues in a paracrine and autocrine manner. Dysregulated angiogenesis is another feature of proliferative retinopathies in which SCs play a role. The presence of angiogenic factors, as a part of the SASP secretome, attracts tip cells of retinal blood vessels to the ischemic area and leads to excessive uncontrolled vascularization in the retina. The newly formed blood vessels are leaky, tortuous, and misdirected and do not properly supply the high energy-demanding tissues of the retina and stimulate the senescence phenotype in surrounding retinal cells.

In the retina, it is vital to bear in mind that all implications of SCs are not detrimental. Immune-mediated clearance of senescent endothelial cells at the late stage of proliferative retinopathies promotes regression of the pathological neovascular tufts and prepares the retina for reparative vascular regression. Recruited mechanisms by retinal immune cells for eliminating stressed endothelial cells are comprehensively described in this review. Finally, senolytics and senomorphics are discussed as two main available therapeutic strategies for eliminating retinal SCs in proliferative retinopathies.