Liver X Receptors and the Hallmarks of Aging: From Molecular Mechanisms to Therapeutic Opportunities

Liver X Receptors and the Hallmarks of Aging: From Molecular Mechanisms to Therapeutic Opportunities | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 30 October 2025 V1 Latest version Share on Liver X Receptors and the Hallmarks of Aging: From Molecular Mechanisms to Therapeutic Opportunities Authors : Marc Poirot 0000-0002-5711-6624 [email protected] , Julio Buñay , Silia Ayadi , Sandrine Silvente-Poirot , and Philippe De Medina Authors Info & Affiliations https://doi.org/10.22541/au.176184273.34989194/v1 Published Ageing Research Reviews Version of record Peer review timeline 176 views 141 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Aging is the primary risk factor for cardiovascular disease, cancer, neurodegeneration, and other chronic disorders. Therefore, targeting the hallmarks of aging has emerged as a promising strategy to extend healthspan. Liver X receptors (LXRs) are ligand-dependent nuclear receptors that are activated by specific oxysterols and cholesterol derivatives. They are traditionally known as key regulators of cholesterol homeostasis. However, recent evidence reveals that LXRs also influence autophagy, mitochondrial function, epigenetics, senescence, stem cell dynamics, and intercellular communication. This positions LXRs at the crossroads of multiple hallmarks of aging. This review synthesizes current knowledge on endogenous and synthetic LXR ligands, their transcriptional mechanisms, and their effects on the aforementioned hallmarks and age-related pathophysiology. The clinical development of pan-LXR agonists for atherosclerosis has been hindered by side effects, notably hepatic steatosis. Emerging strategies, including LXRβ-selective ligands, selective LXR modulators (SLiMs), and biased agonists such as dendrogenin A, offer ways to separate the protective vascular, metabolic, and neuroprotective effects from adverse outcomes. Additionally, we explore how LXR signaling intersects with the hallmarks of aging and how it can be leveraged to intervene in atherosclerosis, diabetes, cancer, osteoporosis, age-related macular degeneration, and neurodegenerative diseases. Positioning LXRs within the geroscience framework suggests that LXRs may serve as pharmacological hubs to delay aging and its comorbidities. Future work should prioritize isoform-and tissue-selective approaches, metabolite-inspired ligand design, and integration with the hallmarks of aging to unlock the full therapeutic potential of LXRs. Supplementary Material File (poirot et al_preprint lxr ageing v2.pdf) Download 967.04 KB Information & Authors Information Version history V1 Version 1 30 October 2025 Peer review timeline Published Ageing Research Reviews Version of Record 1 Jan 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords age-related diseases aging hallmarks of aging liver-x-receptors oxysterols Authors Affiliations Marc Poirot 0000-0002-5711-6624 [email protected] View all articles by this author Julio Buñay View all articles by this author Silia Ayadi View all articles by this author Sandrine Silvente-Poirot View all articles by this author Philippe De Medina View all articles by this author Funding Information Agence Nationale de la Recherche ANR-24-CE44-4332 Marc Poirot Metrics & Citations Metrics Article Usage 176 views 141 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Marc Poirot, Julio Buñay, Silia Ayadi, et al. Liver X Receptors and the Hallmarks of Aging: From Molecular Mechanisms to Therapeutic Opportunities. Authorea . 30 October 2025. DOI: https://doi.org/10.22541/au.176184273.34989194/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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