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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\u00a0and ocular surface health. Adult female C57BL\/6\u00a0J mice were subjected to a 40% calorie restriction for 4\u00a0months, starting at 6\u20137\u00a0months and continuing until 10\u201311\u00a0months. 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\u2019s secretory function.<\/jats:p>","DOI":"10.1007\/s11357-025-01748-w","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T23:28:35Z","timestamp":1751066915000},"page":"6157-6176","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the transformative effects of calorie restriction on the lacrimal gland in adult mice"],"prefix":"10.1007","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-5025","authenticated-orcid":false,"given":"Olivier","family":"Mauduit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-9401","authenticated-orcid":false,"given":"Prashant","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-8950","authenticated-orcid":false,"given":"Kaitlin K.","family":"Scholand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0142-4733","authenticated-orcid":false,"given":"Emre","family":"Aksan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1628-2893","authenticated-orcid":false,"given":"Laura","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1478-4200","authenticated-orcid":false,"given":"Anmar","family":"Abu-Romman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6010-9698","authenticated-orcid":false,"given":"Vanessa","family":"Delcroix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0785-9822","authenticated-orcid":false,"given":"Zhiyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3770-2299","authenticated-orcid":false,"given":"Aude I.","family":"Sindikubwabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-1610","authenticated-orcid":false,"given":"Ron","family":"Korstanje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7901-0444","authenticated-orcid":false,"given":"Helen P.","family":"Makarenkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-5494","authenticated-orcid":false,"given":"Cintia S.","family":"de Paiva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,28]]},"reference":[{"key":"1748_CR1","volume-title":"Promoting physical activity and healthy diets for healthy ageing in the WHO European Region","author":"World Health Organization. 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