{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:13:43Z","timestamp":1788783223307,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Gut hormones govern appetite and postprandial glucose handling, and both functions deteriorate with age \u2014 yet the human literature cannot agree on the direction of the underlying hormonal changes. Incretin secretion is reported both to rise and to fall in older adults; ghrelin to decline, to be unchanged, and to be elevated; and the anorexia of aging is attributed variously to excess satiety signaling and to deficient basal hunger. This mini-review examines these three controversies, identifies the design features that give rise to them, and argues that they are largely reconcilable. Across all three, disputes about magnitude resolve when the outcome measured is instead the fidelity of coupling between nutrient ingestion and hormonal response: elevated GLP-1 coexists with an impaired incretin effect because it is compensation for \u03b2-cell failure, not preserved sensing; ghrelin concentrations may be normal while prandial rhythm is abolished; and older adults with low appetite show exaggerated anorexigenic responses despite unchanged subjective appetite. We further note that the human gut-hormone literature and the rapidly advancing rodent literature on age-related intestinal stem cell misdifferentiation have developed in near isolation, and that they currently disagree on whether the aged gut contains more or fewer enteroendocrine cells. Resolving these controversies requires studies that measure hormone concentrations and functional coupling in the same individuals, as well as longitudinal designs that extend beyond incretins.<\/jats:p>","DOI":"10.3389\/fendo.2026.1952254","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:01:26Z","timestamp":1788782486000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rise or fall? Reconciling contested directions in human gut hormone aging"],"prefix":"10.3389","volume":"17","author":[{"given":"Volodymyr","family":"Mavrych","sequence":"first","affiliation":[{"name":"College of Medicine, Alfaisal University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Shypilova","sequence":"additional","affiliation":[{"name":"School of Medicine, St. Matthew's University","place":["George Town, Cayman Islands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olena","family":"Bolgova","sequence":"additional","affiliation":[{"name":"College of Medicine, Alfaisal University","place":["Riyadh, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00754","article-title":"The regulation of peripheral metabolism by gut-derived hormones","volume":"9","author":"Sun","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1530\/JOE-19-0399","article-title":"Mechanisms controlling hormone secretion in human gut and its relevance to metabolism","volume":"244","author":"Martin","year":"2019","journal-title":"J Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/nu13030883","article-title":"Nutrient-induced cellular mechanisms of gut hormone secretion","volume":"13","author":"Lu","year":"2021","journal-title":"Nutrients"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93306","article-title":"Genetic determinants of circulating GIP and GLP-1 concentrations","volume":"2","author":"Almgren","year":"2017","journal-title":"JCI Insight"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12090790","article-title":"Enteroendocrine hormone secretion and metabolic control: Importance of the region of the gut stimulation","volume":"12","author":"Xie","year":"2020","journal-title":"Pharmaceutics"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1272955","article-title":"Enteroendocrine cell regulation of the gut-brain axis","volume":"17","author":"Barton","year":"2023","journal-title":"Front Neurosci"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2019-01262","article-title":"Longitudinal changes in fasting and glucose-stimulated GLP-1 and GIP in healthy older subjects","volume":"104","author":"Pham","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.dsx.2023.102907","article-title":"Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production","volume":"17","author":"Wang","year":"2023","journal-title":"Diabetes Metab Syndr"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2023.112072","article-title":"Alterations in GLP-1 and PYY release with aging and body mass in the human gut","volume":"578","author":"Jones","year":"2023","journal-title":"Mol Cell Endocrinol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.04.004","article-title":"Impaired incretin secretion and pancreatic dysfunction with older age and diabetes","volume":"63","author":"Geloneze","year":"2014","journal-title":"Metabolism"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00260","article-title":"Older subjects with \u03b2-cell dysfunction have an accentuated incretin release","volume":"103","author":"de Jes\u00fas Garduno-Garcia","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/nu10010002","article-title":"Effect of age on blood glucose and plasma insulin, glucagon, ghrelin, CCK, GIP, and GLP-1 responses to whey protein ingestion","volume":"10","author":"Giezenaar","year":"2017","journal-title":"Nutrients"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac213","article-title":"Loss of the incretin effect in type 2 diabetes: A systematic review and meta-analysis","volume":"107","author":"Grespan","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1042\/CS20150154","article-title":"The regulation of function, growth and survival of GLP-1-producing L-cells","volume":"130","author":"Kuhre","year":"2016","journal-title":"Clin Sci (Lond)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.175r001","article-title":"Plasma ghrelin concentrations in elderly subjects: Comparison with anorexic and obese patients","volume":"175","author":"Rigamonti","year":"2002","journal-title":"J Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-1650","article-title":"Efficacy of ghrelin as a therapeutic approach for age-related physiological changes","volume":"149","author":"Ariyasu","year":"2008","journal-title":"Endocrinology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/83.5.1149","article-title":"Unbalanced serum leptin and ghrelin dynamics prolong postprandial satiety and inhibit hunger in healthy elderly: Another reason for the \"anorexia of aging","volume":"83","author":"Di Francesco","year":"2006","journal-title":"Am J Clin Nutr"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-021656","article-title":"Appetite, food intake, and plasma concentrations of cholecystokinin, ghrelin, and other gastrointestinal hormones in undernourished older women and well-nourished young and older women","volume":"88","author":"Sturm","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2015.220","article-title":"Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1","volume":"21","author":"Fujitsuka","year":"2016","journal-title":"Mol Psychiatry"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.2008.27076","article-title":"Effect of age and frailty on ghrelin and cholecystokinin responses to a meal test","volume":"89","author":"Serra-Prat","year":"2009","journal-title":"Am J Clin Nutr"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.appet.2024.107415","article-title":"Augmented gut hormone response to feeding in older adults exhibiting low appetite","volume":"201","author":"Dagbasi","year":"2024","journal-title":"Appetite"},{"key":"B22","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1093\/ajcn\/69.5.999","article-title":"Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility","volume":"69","author":"MacIntosh","year":"1999","journal-title":"Am J Clin Nutr"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.12.8107","article-title":"Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: Evidence for increased CCK activity as a cause of the anorexia of aging","volume":"86","author":"MacIntosh","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.appet.2010.08.010","article-title":"Effects of nutritional supplementation on the appetite and energy intake responses to IV cholecystokinin in older adults","volume":"55","author":"Tai","year":"2010","journal-title":"Appetite"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s40520-019-01292-6","article-title":"Differences in circulating appetite-related hormone concentrations between younger and older adults: A systematic review and meta-analysis","volume":"32","author":"Johnson","year":"2020","journal-title":"Aging Clin Exp Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1186\/1752-153X-6-31","article-title":"Chromatographic analysis of age-related changes in mucosal serotonin transmission in the murine distal ileum","volume":"6","author":"Parmar","year":"2012","journal-title":"Chem Cent J"},{"key":"B27","doi-asserted-by":"publisher","first-page":"6109","DOI":"10.1038\/s41467-023-41683-y","article-title":"IFN\u03b3-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration","volume":"14","author":"Omrani","year":"2023","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","first-page":"9243","DOI":"10.1038\/s41467-024-53675-7","article-title":"Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction","volume":"15","author":"Yu","year":"2024","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101279","article-title":"Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells","volume":"9","author":"Moorefield","year":"2017","journal-title":"Aging (Albany NY)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnaa018","article-title":"Enteroendocrine dynamics - New tools reveal hormonal plasticity in the gut","volume":"41","author":"Beumer","year":"2020","journal-title":"Endocr Rev"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2025.112607","article-title":"Enteroendocrine cell differentiation: Implications for human disease","volume":"607","author":"Saint-Denis","year":"2025","journal-title":"Mol Cell Endocrinol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2024.171168","article-title":"Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes","volume":"174","author":"Bailey","year":"2024","journal-title":"Peptides"},{"key":"B33","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41467-021-27901-5","article-title":"Robust differentiation of human enteroendocrine cells from intestinal stem cells","volume":"13","author":"Zeve","year":"2022","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107833","article-title":"Labeling and characterization of human GLP-1-secreting L-cells in primary ileal organoid culture","volume":"31","author":"Goldspink","year":"2020","journal-title":"Cell Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.154302","article-title":"Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling","volume":"7","author":"Kim","year":"2022","journal-title":"JCI Insight"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1952254\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:01:26Z","timestamp":1788782486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1952254\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":35,"alternative-id":["10.3389\/fendo.2026.1952254"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1952254","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]},"article-number":"1952254"}}