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Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D\u2010galactose (D\u2010gal)\u2010induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D\u2010gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high\u2010dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone\u2010binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy\u2010related pathways in ghrelin\u2010treated microglia. Ghrelin altered autophagy\u2010related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin\u2010induced alterations in autophagy\u2010related markers and anti\u2010senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging\u2010related CI, with mechanistic evidence indicating that the modulation of microglial autophagy\u2010related mechanisms through the SHBG\/JNK1\/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging\u2010related CI.<\/jats:p>","DOI":"10.1111\/acel.70732","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:35:04Z","timestamp":1790670904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ghrelin Alleviates Aging\u2010Related Cognitive Impairment by Regulating Autophagy\u2010Related Signaling via the\n                    <scp>SHBG<\/scp>\n                    \/\n                    <scp>JNK1<\/scp>\n                    \/Beclin1 Axis in Microglia"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1146-7808","authenticated-orcid":false,"given":"Lixing","family":"Zhou","sequence":"first","affiliation":[{"name":"The Center of Gerontology and Geriatrics\/National Clinical Research Center for Geriatrics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5101-2579","authenticated-orcid":false,"given":"Ying","family":"Cheng","sequence":"additional","affiliation":[{"name":"The Center of Gerontology and Geriatrics\/National Clinical Research Center for Geriatrics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Center of Gerontology and Geriatrics\/National Clinical Research Center for Geriatrics West China Hospital, Sichuan University  Chengdu 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