Dry eye disease (DED) encompasses a group of diseases characterized by reductions in tear quantity or quality deprive the ocular surface of lubrication and nourishment [1]. Over time, this can lead to impaired vision, ocular inflammation, and corneal epithelial disease. With a global prevalence between 5.7% and 30%, DED is one of the most common ocular conditions, estimated to affect more than 300 million people worldwide 2, 3. Furthermore, risk factors such as older age and the female sex are associated with higher DED incidence rates compared to younger and male populations, respectively 4, 5.

Most DED can be classified as one of two types: evaporative or aqueous-tear-deficient, the latter of which is often more severe. Evaporative DED is linked to dysfunction of the meibomian gland, which is responsible for secreting lipid- and protein-rich oils that form the upper layer of the tear film, functioning to minimize tear evaporation from the ocular surface. Conversely, aqueous-tear-deficient DED is linked to the LG’s ability to produce and secrete the aqueous components of tear film to lubricate and moisten the ocular surface. As such, the health of the LG plays a pivotal role in dictating the onset and severity of DED. Additionally, tear volume and composition are not only affected by tear secretion and evaporation at the ocular surface; they also depend on the extent of tear drainage into the lacrimal sac, which is indirectly regulated by the LG [6].

The aging process is a complex biological phenomenon marked by inflammation and oxidative stress, both of which contribute to tissue damage 7, 8. Sustained exposure to free radicals has been linked to age-related tissue damage 9, 10. The delicate balance between free radical production and antioxidant mechanisms sets the oxidative stress “rheostat” within the ocular microenvironment. In many age-related diseases, such as DED, accumulation of cell injury can induce cellular senescence and thereby impair the immune system’s ability to resolve inflammation. We and others have reported increased oxidative stress markers within the aged LG 11, 12. Furthermore, we have shown that dietary intake of components capable of upregulating the major antioxidant pathway, Nrf2, can ameliorate age-related DED in rodents [12]. Additional age-related changes in the LG include a shift from serous to mucous secretory vesicle production, fibrosis, decreased tear film secretion, and an accumulation of metabolic byproducts such as lipofuscin 13, 14, 15, 16, 17.

Arachidonic acid (AA) is a widely abundant omega-6 (ꞷ-6) polyunsaturated fatty acid (PUFA) and is the precursor to several classes of inflammatory eicosanoids such as prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs). In contrast, ꞷ-3 PUFAs such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) are pro-resolving by nature and serve as precursors to various specialized pro-resolving mediator (SPM) subtypes which exhibit both anti-inflammatory and pro-resolving capabilities (e.g., resolvins [RvDs and RvEs], neuroprotectins [NPDs] and maresins [MaRs]). These ꞷ-3 PUFA-derived bioactive metabolites can restore inflammatory homeostasis in many tissue types, including the eye and brain 18, 19, 20, 21, 22, 23. The balance of ꞷ-3 versus ꞷ-6 PUFAs has been subject of healthy ageing, where higher ratios of ꞷ-3 PUFAs are proposed to support cardiovascular and neuronal health by promoting inflammatory resolution 24, 25. Conversely, lower proportions of ꞷ-3 PUFAs have been reported in the brain for neurodegenerative diseases such as Alzheimer’s disease 18, 19 and in the retina for age-related ocular diseases such as retinitis pigmentosa [26]. Supplementation with ꞷ-3 PUFAs has been shown to alleviate age-related ocular diseases such as age-related macular degeneration (AMD) [27], however, the effects of aging on these lipid mediators in the LG are currently unknown.

Herein, we further probe age-related changes within the LGs of aged mice by evaluating the impact of ageing on lacrimal PUFAs and their bioactive lipid metabolites, which are potent regulators of inflammation.