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However, the functional role of FGF21 in the aging brain and its influence on lactate homeostasis remains unclear until now. In the study, male C57BL\/6 mice were divided into 2\u2010month\u2010old (control), 20\u2010month (aging), and FGF21\u2010treated aging mice (FGF21). We also examined the MAPK signals and astrocyte\u2010neuron lactate shuttle (ANLS) proteins in wild\u2010type and hydroxycarboxylic acid receptor 1\u2010knockout (HCA1\u2010KO) mice with aging or long\u2010term L\u2010lactate infusion. In a mouse model of aging, neuronal FGF21 expression and ANLS rate were upregulated in hippocampal and cortical regions. Administration of exogenous FGF21 (1\u2009mg\/kg) to aging or lactate\u2010infused mice can significantly improve learning and memory performance and the lactate metabolic microenvironment in an MCT2\u2010dependent manner. Besides, HCA1\u2010KO can significantly abolish both the CREB and MAPK signaling activation in lactate\u2010infused mice, which differs from the scenario of aging mice. Furthermore, in\u00a0vitro aging model further confirmed that p38\u2010mediated FGF21 production and PI3K\u2010mTOR\u2010dependent MCT2 protein translation process, respectively. The increase in levels of FGF21 protein as the brain ages might help neurons cope with age\u2010related neuroinflammation and lactate accumulation in mice. Our findings indicated that the shuttle rate of lactate and its microenvironment are related to neuronal function, which may be one therapeutic target for aging\u2010related cognitive dysfunction.<\/jats:p>","DOI":"10.1111\/acel.70423","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T14:00:54Z","timestamp":1771682454000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Acceleration of Lactate Uptake and Utilization Contributes to Neuroprotective Action of\n                    <scp>FGF21<\/scp>\n                    Involved in Naturally Aging Mice"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3349-8104","authenticated-orcid":false,"given":"Keru","family":"Ji","sequence":"first","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9372-6401","authenticated-orcid":false,"given":"Hongde","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3909-2887","authenticated-orcid":false,"given":"Ruguang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7341-7888","authenticated-orcid":false,"given":"Yutong","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1947-0881","authenticated-orcid":false,"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3462-1879","authenticated-orcid":false,"given":"Hongchang","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Macromolecular Drugs and Large\u2010Scale Manufacturing, School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang China"},{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Metabonomics &amp; 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