The Impact of Aging on Ocular Diseases: Unveiling Complex Interactions

Abstract

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Aging is an important risk factor for eye diseases. The gradual deterioration of ocular tissue structure and function with age leads to the onset and progression of ocular diseases. During aging, ocular tissues such as the lens, vitreous and retina are affected by age-related changes, such as oxidative stress and protein accumulation in the lens leading to cataract formation, and a decline in retinal pigment epithelial cell function associated with macular degeneration. This article reviews the relationships between aging and ocular diseases, takes age-related macular degeneration, age-related cataracts, glaucoma, diabetic retinal degeneration, and dry eye disease as focal points, analyses the complex interactions between aging and ocular diseases, and describes the therapeutic options and potential targets for age-related ocular diseases.

Figure 1.

The effects of ageing on the eyes. As age increases, the lens thickens and hardens, leading to protein aggregation and clouding, which causes cataracts. The ciliary zonules weaken, the retina degenerates along with optic nerve cells, and retinal blood vessels may sclerose. Additionally, the vitreous becomes cloudy, and intraocular pressure rises. Ageing deteriorates both the structure and function of the eye, heightening susceptibility to various eye diseases.

Figure 2.

Mechanisms associated with aging. Senescence is associated with many mechanisms, including telomere damage and shortening, DNA damage response, cellular senescence, oxidative stress, mitochondrial dysfunction, and activation of signaling pathways. Collectively, these processes contribute to senescence by inducing cell cycle arrest. Accumulation of DNA damage triggers activation of the p53 gene, which in turn induces the expression of the downstream effector p21. This process inhibits cell cycle progression and contributes to cellular senescence. Concurrently, the rise of ROS and the reduction of mitochondrial SIRT3 activate the p38MAPK pathway, which subsequently enhances p53 activity, causing cellular senescence. Additionally, DDR activates GATA4, which subsequently upregulates NF-κB. This activation of NF-κB directly drives cellular senescence. The elevated NF-κB levels increase the transcription of SASP genes during DDR. Both cellular senescence and tissue aging are accelerated by the following increase in SASP factors' translation and release. In senescent cells, the expression of the p16 gene gradually increases, along with changes in the activity of Rb proteins, and this change affects cell cycle progression and leads to cellular senescence. Abbreviation: DDR (DNA damage response); ROS (reactive oxygen species); SASP (senescence-associated secretory phenotype).

Figure 3.

The relationship between ageing and eye diseases. As ageing progresses, there is a notable decline in ocular function. AMD, glaucoma, dry eye syndrome, and DR are commonly associated with this process. These diseases arise from various mechanisms, including cellular ageing, oxidative stress, and the release of inflammatory mediators. Ageing and photostimulation lead to excessive ROS production in the lens epithelium, resulting in ROS accumulation that causes DNA double-strand breaks and oxidative damage. This damage deactivates lens epithelial cells, leading to apoptosis and cataract formation. Additionally, ROS-induced apoptosis of RPE cells fosters CNV, contributing to AMD. ROS also promote apoptosis of TMCs, increasing AH accumulation and IOP, which may result in glaucoma. The density of HCECs gradually decreases and the level of lacrimal secretion decreases with age, resulting in reduced tear film stability and ultimately leading to dry eye. Abbreviation: AGEs (advanced glycation end products); AH (aqueous humor); AL (Axial length); CNV (choroidal neovascularization); HCEC (human corneal endothelial cells); HLE (human lens epithelial cells); IOP (intraocular pressure); NAD (nicotinamide adenine dinucleotide); NADPH (nicotinamide adenine dinucleotide phosphate); PKC (protein kinase C); RAGEs (Receptors for advanced glycation end-products); RGCs (retinal ganglion cells); ROS (reactive oxygen species); RPE (retinal pigment epithelium); TMCs (trabecular meshwork cells); VEGF (vascular endothelial growth factor).

Figure 4.

Aging affects eye diseases and their treatment methods. Aging markers can be divided into primary markers, antagonistic markers and integrative markers. Aggravating them can promote ageing and affect the occurrence of eye diseases. Treatments for age-related eye diseases include medication, surgery, laser therapy, radiation therapy, stem cell therapy, dietary interventions, and regular eye exams. Abbreviation: ARCs (Age-related cataracts); AMD (age-related macular degeneration); DR (Diabetic retinopathy); DED (dry eye disease).