From systemic disease to the eye: Why senescence deserves attention in ocular infections.

The global increase in life expectancy has led to a growing elderly population, bringing new challenges in managing infectious diseases. Advancing age is accompanied by progressive dysfunction of both innate and adaptive immunity, resulting in impaired responses to pathogens and elevated morbidity and mortality. Cellular senescence, a state of permanent cell-cycle arrest with extensive molecular and phenotypic changes, including chromatin remodelling and the senescence-associated secretory phenotype (SASP), has emerged as a key factor in this process. Though initially protective as a tumor-suppressive mechanism, senescence becomes maladaptive with age, contributing to inflammaging, immune dysregulation, and heightened susceptibility to infection. In ocular diseases, such as age-related macular degeneration and chronic keratitis, senescent cells in retinal pigment epithelium and corneal tissues drive persistent inflammation and fibrosis, exacerbating vulnerability to opportunistic pathogens. Pathogens can exploit senescent cells through virulence factors and persistent inflammatory responses, thereby promoting chronic infection and even age-related diseases. Conversely, senescent cells and their SASP can intensify infection severity, as shown in viral infections such as SARS-CoV-2 and bacterial pathogens including Streptococcus pneumoniae and Mycobacterium tuberculosis. This reciprocal relationship illustrates how infection accelerates cellular aging while aging predisposes individuals to more severe infections. Emerging therapeutic strategies targeting senescence, including senolytics and senomorphics, hold promise for mitigating infection-related pathology. In parallel, vaccines and immunotherapies tailored to the aging immune system will be crucial for reducing infection burden in older populations. This review integrates current evidence on the bidirectional interplay between senescence and infection, emphasizing its clinical relevance and potential for translational intervention.