Mauduit Olivier, Kumar Prashant, Scholand Kaitlin K, Aksan Emre, Schaefer Laura, Abu-Romman Anmar, Delcroix Vanessa, Yu Zhiyuan, Sindikubwabo Aude I, Korstanje Ron, Makarenkova Helen P, de Paiva Cintia S
Department of Molecular Medicine, The Scripps Research Institute, San Diego, CA, USA.
Department of Ophthalmology, Ocular Surface Center, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, USA.
Geroscience. 2025 Jun 28. doi: 10.1007/s11357-025-01748-w.
Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6-7 months and continuing until 10-11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected to calorie restriction compared to ad libitum revealed significant differentially expressed genes (DEGs). Pathways enriched in the upregulated DEGs indicate enhanced circadian rhythm, secretory functions, and lipid metabolism. These findings were confirmed using individual qRT-PCR and western blotting. In contrast, pathways enriched in the downregulated DEGs were associated with immune cell activation, adaptive immune responses, extracellular matrix remodeling, and metalloproteinase activity. Histological sections of calorie-restricted lacrimal glands revealed reduced mononuclear cell infiltration and fewer positive cells for CD4, CD19, and MHC II than in ad libitum lacrimal glands. Calorie restriction also prevented age-related corneal barrier dysfunction and mitigated age-related conjunctival goblet cell loss, hallmarks of dry eye disease. These findings suggest that calorie restriction supports lacrimal gland and ocular surface health by reducing inflammation and extracellular matrix remodeling and by enhancing the lacrimal gland's secretory function.
高龄是干眼症最明显的风险因素之一。干眼症影响着全球数百万人，可能由与年龄相关的泪腺功能障碍引起，这与泪腺分泌细胞功能下降和慢性炎症相关。本研究调查了热量限制对维持泪腺和眼表健康的潜力。成年雌性C57BL/6 J小鼠从6至7个月开始接受40%的热量限制，持续4个月，直至10至11个月。将这些小鼠与自由进食的对照组进行比较。对接受热量限制的小鼠与自由进食的小鼠的泪腺、结膜和角膜进行批量RNA测序，发现了显著差异表达基因（DEGs）。上调的DEGs中富集的通路表明昼夜节律、分泌功能和脂质代谢增强。这些发现通过个体qRT-PCR和蛋白质印迹法得到证实。相比之下，下调的DEGs中富集的通路与免疫细胞激活、适应性免疫反应、细胞外基质重塑和金属蛋白酶活性相关。热量限制组泪腺的组织学切片显示，与自由进食组泪腺相比，单核细胞浸润减少，CD4、CD19和MHC II阳性细胞减少。热量限制还预防了与年龄相关的角膜屏障功能障碍，并减轻了与年龄相关的结膜杯状细胞丢失，这些都是干眼症的特征。这些发现表明，热量限制通过减少炎症和细胞外基质重塑以及增强泪腺的分泌功能来维持泪腺和眼表健康。
