In a recent study, researchers have explored senescence-related proteins and protein interactions in cataracts, a leading cause of visual impairment and blindness in older adults.
Cataracts are characterized by the clouding of the lens in the eye, which leads to impaired vision. Cataracts generally develop slowly and can affect either one or both eyes at the same time. Cataract symptoms typically include faded colors, blurry or double vision, halos around light, trouble with bright lights, and difficulty seeing at night.
By analyzing proteins and their interactions, these researchers aim for a full understanding of this condition, showing that multiple biomarkers associated with aging rise during the formation of cataracts. Typically, p53, a well-known biomarker for the presence of senescent cells, is seen to rise along with transforming growth factor-beta1 (TGF-β1), another biomarker commonly associated with inflammation when encountered in high amounts. During the development of cataracts, the number of senescent cells rises, as this research shows.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.
By the time people reach old age, significant numbers of these senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. These senescent cells are a key process in the progression of aging.
Senescent cells only make up a small number of total cells in the body, but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP is thought to significantly contribute to aging and cancer; thus, targeting senescent cells and removing them has been suggested as a potential solution to this problem.
Senolytics may be a solution
In this study, the researchers chart the interactions between these factors and how they likely encourage the progression of cataracts by increasing the number of senescent cells, and the paper is worth reading to gain a deeper understanding of the mechanisms at play here.
However, regardless of the exact mechanisms at play and the end result of this research, a potential solution to the problem is at hand in the form of senolytics. These drugs may be able to selectively destroy harmful senescent cells in the eyes and thus effectively treat cataracts.
For example, the biotech company UNITY is currently approaching human trials with its candidate UBX1967, and it has macular degeneration and various diabetes-related visual conditions listed for this drug. It may also be the case that UBX1967 or a similar compound could also effectively address cataracts and other senescence-related conditions.
Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53. In lens epithelial cell (HLE B-3) senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1. Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.
Senolytics are now in human trials and, if successful, could be a potential solution to cataracts and many other age-related diseases, as having too many senescent cells causes harmful effects. While understanding the deeper mechanisms and interactions at play here is important, senolytics represent a more immediate answer while this research continues.
 Yan, Y., Yu, H., Sun, L., Liu, H., Wang, C., Wei, X., … & Li, X. (2019). Laminin α4 overexpression in the anterior lens capsule may contribute to the senescence of human lens epithelial cells in age-related cataract. Aging.