{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:45:17Z","timestamp":1785840317669,"version":"3.56.0"},"reference-count":97,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R00AG055649"],"award-info":[{"award-number":["R00AG055649"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R56AG079924"],"award-info":[{"award-number":["R56AG079924"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG079924"],"award-info":[{"award-number":["R01AG079924"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008335","name":"Arizona Biomedical Research Commission","doi-asserted-by":"publisher","award":["ADHS-RFGA2022-010-04"],"award-info":[{"award-number":["ADHS-RFGA2022-010-04"]}],"id":[{"id":"10.13039\/100008335","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging, we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient-sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgr\n                    <jats:sup>hep\u2212\/\u2212<\/jats:sup>\n                    ). Liver-specific deletion of the glucagon receptor decreases hepatic AMP kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice but not in Gcgr\n                    <jats:sup>hep\u2212\/\u2212<\/jats:sup>\n                    mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01899-w","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T02:19:23Z","timestamp":1758766763000},"page":"31-53","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice"],"prefix":"10.1007","volume":"48","author":[{"given":"Kassandra R.","family":"Bruner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella R.","family":"Byington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J.","family":"Marx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Vasileva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Temara","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susma","family":"Ghimire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"India J.","family":"Zappia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashika","family":"Shaju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janan","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hallie R.","family":"Wachsmuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thadeus W.","family":"Carlyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Besselsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Drucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A.","family":"Duca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5336-1358","authenticated-orcid":false,"given":"Jennifer H.","family":"Stern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"issue":"6454","key":"1899_CR1","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/366461a0","volume":"366","author":"C Kenyon","year":"1993","unstructured":"Kenyon C, et al. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366(6454):461\u20134.","journal-title":"Nature"},{"key":"1899_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2013.35","volume":"9","author":"GJ Stout","year":"2013","unstructured":"Stout GJ, et al. Insulin\/IGF-1-mediated longevity is marked by reduced protein metabolism. Mol Syst Biol. 2013;9:679.","journal-title":"Mol Syst Biol"},{"issue":"3","key":"1899_CR3","doi-asserted-by":"publisher","first-page":"e1000881","DOI":"10.1371\/journal.pgen.1000881","volume":"6","author":"C Slack","year":"2010","unstructured":"Slack C, et al. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. PLoS Genet. 2010;6(3):e1000881.","journal-title":"PLoS Genet"},{"issue":"5514","key":"1899_CR4","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1126\/science.1057987","volume":"292","author":"M Tatar","year":"2001","unstructured":"Tatar M, et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science. 2001;292(5514):107\u201310.","journal-title":"Science"},{"issue":"5514","key":"1899_CR5","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1126\/science.1057991","volume":"292","author":"DJ Clancy","year":"2001","unstructured":"Clancy DJ, et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science. 2001;292(5514):104\u20136.","journal-title":"Science"},{"issue":"2","key":"1899_CR6","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.celrep.2017.06.048","volume":"20","author":"NM Templeman","year":"2017","unstructured":"Templeman NM, et al. Reduced circulating insulin enhances insulin sensitivity in old mice and extends lifespan. Cell Rep. 2017;20(2):451\u201363.","journal-title":"Cell Rep"},{"issue":"1","key":"1899_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53127-2","volume":"15","author":"C Dos Santos","year":"2024","unstructured":"Dos Santos C, et al. Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice. Nat Commun. 2024;15(1):9063.","journal-title":"Nat Commun"},{"issue":"5","key":"1899_CR8","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.cmet.2008.09.008","volume":"8","author":"C Longuet","year":"2008","unstructured":"Longuet C, et al. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 2008;8(5):359\u201371.","journal-title":"Cell Metab"},{"issue":"12","key":"1899_CR9","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1172\/JCI106445","volume":"49","author":"EB Marliss","year":"1970","unstructured":"Marliss EB, et al. Glucagon levels and metabolic effects in fasting man. J Clin Invest. 1970;49(12):2256\u201370.","journal-title":"J Clin Invest"},{"issue":"2","key":"1899_CR10","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1530\/JOE-19-0201","volume":"243","author":"JH Stern","year":"2019","unstructured":"Stern JH, et al. Obesity dysregulates fasting-induced changes in glucagon secretion. J Endocrinol. 2019;243(2):149\u201360.","journal-title":"J Endocrinol"},{"issue":"4","key":"1899_CR11","doi-asserted-by":"publisher","first-page":"E571","DOI":"10.1152\/ajpendo.00172.2021","volume":"321","author":"NJ Wewer Albrechtsen","year":"2021","unstructured":"Wewer Albrechtsen NJ. The glucose-mobilizing effect of glucagon at fasting is mediated by cyclic AMP. Am J Physiol Endocrinol Metab. 2021;321(4):E571\u20134.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"52","key":"1899_CR12","doi-asserted-by":"publisher","first-page":"54103","DOI":"10.1074\/jbc.M410755200","volume":"279","author":"SR Kimball","year":"2004","unstructured":"Kimball SR, Siegfried BA, Jefferson LS. Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem. 2004;279(52):54103\u20139.","journal-title":"J Biol Chem"},{"issue":"1","key":"1899_CR13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.cmet.2014.03.002","volume":"20","author":"K Burkewitz","year":"2014","unstructured":"Burkewitz K, Zhang Y, Mair WB. AMPK at the nexus of energetics and aging. Cell Metab. 2014;20(1):10\u201325.","journal-title":"Cell Metab"},{"issue":"6","key":"1899_CR14","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1016\/j.celrep.2014.08.006","volume":"8","author":"M Ulgherait","year":"2014","unstructured":"Ulgherait M, et al. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014;8(6):1767\u201380.","journal-title":"Cell Rep"},{"issue":"15","key":"1899_CR15","doi-asserted-by":"publisher","first-page":"3751","DOI":"10.1046\/j.1432-1033.2002.03074.x","volume":"269","author":"U Krause","year":"2002","unstructured":"Krause U, Bertrand L, Hue L. Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur J Biochem. 2002;269(15):3751\u20139.","journal-title":"Eur J Biochem"},{"issue":"5","key":"1899_CR16","doi-asserted-by":"publisher","first-page":"E980","DOI":"10.1152\/ajpendo.00333.2004","volume":"288","author":"AK Reiter","year":"2005","unstructured":"Reiter AK, et al. Repression of protein synthesis and mTOR signaling in rat liver mediated by the AMPK activator aminoimidazole carboxamide ribonucleoside. Am J Physiol Endocrinol Metab. 2005;288(5):E980\u20138.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"7","key":"1899_CR17","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1093\/gerona\/glw064","volume":"71","author":"SI Arriola Apelo","year":"2016","unstructured":"Arriola Apelo SI, et al. Intermittent administration of rapamycin extends the life span of female C57BL\/6J mice. J Gerontol A Biol Sci Med Sci. 2016;71(7):876\u201381.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"7253","key":"1899_CR18","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nature08221","volume":"460","author":"DE Harrison","year":"2009","unstructured":"Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392\u20135.","journal-title":"Nature"},{"issue":"5","key":"1899_CR19","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.celrep.2013.07.030","volume":"4","author":"JJ Wu","year":"2013","unstructured":"Wu JJ, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4(5):913\u201320.","journal-title":"Cell Rep"},{"key":"1899_CR20","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/0065-2571(68)90023-X","volume":"6","author":"RW Butcher","year":"1968","unstructured":"Butcher RW, et al. The role of cyclic AMP in hormone actions. Adv Enzyme Regul. 1968;6:357\u201389.","journal-title":"Adv Enzyme Regul"},{"issue":"4047","key":"1899_CR21","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1126\/science.177.4047.401","volume":"177","author":"EW Sutherland","year":"1972","unstructured":"Sutherland EW. Studies on the mechanism of hormone action. Science. 1972;177(4047):401\u20138.","journal-title":"Science"},{"issue":"12","key":"1899_CR22","doi-asserted-by":"publisher","first-page":"797","DOI":"10.2337\/diab.18.12.797","volume":"18","author":"EW Sutherland","year":"1969","unstructured":"Sutherland EW, Robison GA. The role of cyclic AMP in the control of carbohydrate metabolism. Diabetes. 1969;18(12):797\u2013819.","journal-title":"Diabetes"},{"issue":"4","key":"1899_CR23","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/ng2004","volume":"39","author":"JJ Tong","year":"2007","unstructured":"Tong JJ, et al. Life extension through neurofibromin mitochondrial regulation and antioxidant therapy for neurofibromatosis-1 in Drosophila melanogaster. Nat Genet. 2007;39(4):476\u201385.","journal-title":"Nat Genet"},{"key":"1899_CR24","doi-asserted-by":"publisher","first-page":"12012","DOI":"10.1038\/srep12012","volume":"5","author":"Z Wang","year":"2015","unstructured":"Wang Z, et al. Cyclic AMP mimics the anti-ageing effects of calorie restriction by up-regulating sirtuin. Sci Rep. 2015;5:12012.","journal-title":"Sci Rep"},{"issue":"6083","key":"1899_CR25","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/323068a0","volume":"323","author":"MJ Wakelam","year":"1986","unstructured":"Wakelam MJ, et al. Activation of two signal-transduction systems in hepatocytes by glucagon. Nature. 1986;323(6083):68\u201371.","journal-title":"Nature"},{"key":"1899_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101639","volume":"66","author":"KD Galsgaard","year":"2022","unstructured":"Galsgaard KD, et al. Glucagon receptor antagonism impairs and glucagon receptor agonism enhances triglycerides metabolism in mice. Mol Metab. 2022;66:101639.","journal-title":"Mol Metab"},{"issue":"10","key":"1899_CR27","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/nchembio.209","volume":"5","author":"JW Day","year":"2009","unstructured":"Day JW, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009;5(10):749\u201357.","journal-title":"Nat Chem Biol"},{"issue":"3","key":"1899_CR28","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.cell.2016.09.014","volume":"167","author":"B Finan","year":"2016","unstructured":"Finan B, et al. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell. 2016;167(3):843-857e14.","journal-title":"Cell"},{"issue":"5","key":"1899_CR29","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.jhep.2024.06.003","volume":"81","author":"EJ Lawitz","year":"2024","unstructured":"Lawitz EJ, et al. Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon\/glucagon-like peptide-1 receptor dual agonist, in cirrhosis. J Hepatol. 2024;81(5):837\u201346.","journal-title":"J Hepatol"},{"issue":"7","key":"1899_CR30","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1038\/s41591-024-03018-2","volume":"30","author":"AJ Sanyal","year":"2024","unstructured":"Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037\u201348.","journal-title":"Nat Med"},{"issue":"3","key":"1899_CR31","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1073\/pnas.0237106100","volume":"100","author":"RW Gelling","year":"2003","unstructured":"Gelling RW, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003;100(3):1438\u201343.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"1899_CR32","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.2337\/db11-1605","volume":"62","author":"C Longuet","year":"2013","unstructured":"Longuet C, et al. Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: evidence for a circulating alpha-cell growth factor. Diabetes. 2013;62(4):1196\u2013205.","journal-title":"Diabetes"},{"issue":"1\u20132","key":"1899_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1113\/jphysiol.1949.sp004363","volume":"109","author":"JB Weir","year":"1949","unstructured":"Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949;109(1\u20132):1\u20139.","journal-title":"J Physiol"},{"issue":"6","key":"1899_CR34","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1007\/s10522-022-09996-5","volume":"23","author":"EC Peters","year":"2022","unstructured":"Peters EC, et al. Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice. Biogerontology. 2022;23(6):741\u201355.","journal-title":"Biogerontology"},{"issue":"4","key":"1899_CR35","doi-asserted-by":"publisher","first-page":"E389","DOI":"10.1152\/ajpendo.00078.2022","volume":"323","author":"A Vasileva","year":"2022","unstructured":"Vasileva A, et al. Glucagon receptor signaling at white adipose tissue does not regulate lipolysis. Am J Physiol Endocrinol Metab. 2022;323(4):E389\u2013401.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"9","key":"1899_CR36","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/sj.jhh.1002201","volume":"21","author":"PA Sarafidis","year":"2007","unstructured":"Sarafidis PA, et al. Validity and reproducibility of HOMA-IR, 1\/HOMA-IR, QUICKI and McAuley\u2019s indices in patients with hypertension and type II diabetes. J Hum Hypertens. 2007;21(9):709\u201316.","journal-title":"J Hum Hypertens"},{"issue":"2","key":"1899_CR37","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1152\/jappl.1970.28.2.234","volume":"28","author":"S Lo","year":"1970","unstructured":"Lo S, Russell JC, Taylor AW. Determination of glycogen in small tissue samples. J Appl Physiol. 1970;28(2):234\u20136.","journal-title":"J Appl Physiol"},{"issue":"1","key":"1899_CR38","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.ab.2008.12.020","volume":"387","author":"S Krebs","year":"2009","unstructured":"Krebs S, Fischaleck M, Blum H. A simple and loss-free method to remove TRIzol contaminations from minute RNA samples. Anal Biochem. 2009;387(1):136\u20138.","journal-title":"Anal Biochem"},{"issue":"1","key":"1899_CR39","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/S0304-3940(02)01423-4","volume":"339","author":"C Ramakers","year":"2003","unstructured":"Ramakers C, et al. Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett. 2003;339(1):62\u20136.","journal-title":"Neurosci Lett"},{"issue":"4","key":"1899_CR40","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402\u20138.","journal-title":"Methods"},{"issue":"6","key":"1899_CR41","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.mad.2012.05.001","volume":"133","author":"JH Stern","year":"2012","unstructured":"Stern JH, Kim K, Ramsey JJ. The influence of acute, late-life calorie restriction on whole body energy metabolism in p66Shc(-\/-) mice. Mech Ageing Dev. 2012;133(6):414\u201320.","journal-title":"Mech Ageing Dev"},{"issue":"4","key":"1899_CR42","doi-asserted-by":"publisher","first-page":"E575","DOI":"10.1152\/ajpendo.00171.2021","volume":"321","author":"RL Rodgers","year":"2021","unstructured":"Rodgers RL. The hepatic glucose-mobilizing effect of glucagon is not mediated by cyclic AMP most of the time. Am J Physiol Endocrinol Metab. 2021;321(4):E575\u20138.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"1899_CR43","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2020.111108","volume":"521","author":"M Dadon-Freiberg","year":"2021","unstructured":"Dadon-Freiberg M, Chapnik N, Froy O. REV-erbalpha alters circadian rhythms by modulating mTOR signaling. Mol Cell Endocrinol. 2021;521:111108.","journal-title":"Mol Cell Endocrinol"},{"issue":"6022","key":"1899_CR44","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1126\/science.1198125","volume":"331","author":"D Feng","year":"2011","unstructured":"Feng D, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331(6022):1315\u20139.","journal-title":"Science"},{"key":"1899_CR45","doi-asserted-by":"crossref","unstructured":"Verlande A, et al. Glucagon regulates the stability of REV-ERBalpha to modulate hepatic glucose production in a model of lung cancer-associated cachexia. Sci Adv. 2021;7(26).","DOI":"10.1126\/sciadv.abf3885"},{"issue":"Suppl 1","key":"1899_CR46","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1111\/j.1463-1326.2011.01454.x","volume":"13","author":"CJ Ramnanan","year":"2011","unstructured":"Ramnanan CJ, et al. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab. 2011;13(Suppl 1):118\u201325.","journal-title":"Diabetes Obes Metab"},{"issue":"16","key":"1899_CR47","doi-asserted-by":"publisher","first-page":"6452","DOI":"10.1074\/jbc.R116.771915","volume":"292","author":"H Pan","year":"2017","unstructured":"Pan H, Finkel T. Key proteins and pathways that regulate lifespan. J Biol Chem. 2017;292(16):6452\u201360.","journal-title":"J Biol Chem"},{"issue":"8","key":"1899_CR48","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1038\/s43587-024-00635-x","volume":"4","author":"A Ortega-Molina","year":"2024","unstructured":"Ortega-Molina A, et al. A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan. Nat Aging. 2024;4(8):1102\u201320.","journal-title":"Nat Aging"},{"issue":"20","key":"1899_CR49","doi-asserted-by":"publisher","first-page":"29780","DOI":"10.18632\/oncotarget.8957","volume":"7","author":"D Garcia-Carracedo","year":"2016","unstructured":"Garcia-Carracedo D, et al. Impact of PI3K\/AKT\/mTOR pathway activation on the prognosis of patients with head and neck squamous cell carcinomas. Oncotarget. 2016;7(20):29780\u201393.","journal-title":"Oncotarget"},{"issue":"2","key":"1899_CR50","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1093\/gerona\/gly112","volume":"74","author":"A Diaz-Ruiz","year":"2019","unstructured":"Diaz-Ruiz A, et al. Benefits of caloric restriction in longevity and chemical-induced tumorigenesis are transmitted independent of NQO1. J Gerontol A Biol Sci Med Sci. 2019;74(2):155\u201362.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"7","key":"1899_CR51","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1016\/j.cmet.2023.05.003","volume":"35","author":"E Duregon","year":"2023","unstructured":"Duregon E, et al. Prolonged fasting times reap greater geroprotective effects when combined with caloric restriction in adult female mice. Cell Metab. 2023;35(7):1179-1194e5.","journal-title":"Cell Metab"},{"issue":"6862","key":"1899_CR52","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/35106646","volume":"414","author":"A Bartke","year":"2001","unstructured":"Bartke A, et al. Extending the lifespan of long-lived mice. Nature. 2001;414(6862):412.","journal-title":"Nature"},{"issue":"1","key":"1899_CR53","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1530\/JOE-17-0505","volume":"237","author":"MB Dommerholt","year":"2018","unstructured":"Dommerholt MB, et al. Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage. J Endocrinol. 2018;237(1):59\u201371.","journal-title":"J Endocrinol"},{"issue":"5","key":"1899_CR54","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1093\/gerona\/glp024","volume":"64","author":"MM Masternak","year":"2009","unstructured":"Masternak MM, et al. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci. 2009;64(5):516\u201321.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"6","key":"1899_CR55","first-page":"615","volume":"7","author":"JV Smith","year":"2004","unstructured":"Smith JV, Heilbronn LK, Ravussin E. Energy restriction and aging. Curr Opin Clin Nutr Metab Care. 2004;7(6):615\u201322.","journal-title":"Curr Opin Clin Nutr Metab Care"},{"issue":"10","key":"1899_CR56","doi-asserted-by":"publisher","first-page":"900","DOI":"10.18632\/aging.100700","volume":"6","author":"DS Wiesenborn","year":"2014","unstructured":"Wiesenborn DS, et al. The effect of calorie restriction on insulin signaling in skeletal muscle and adipose tissue of Ames dwarf mice. Aging (Albany NY). 2014;6(10):900\u201312.","journal-title":"Aging (Albany NY)"},{"issue":"3","key":"1899_CR57","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.tem.2009.11.005","volume":"21","author":"RM Anderson","year":"2010","unstructured":"Anderson RM, Weindruch R. Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab. 2010;21(3):134\u201341.","journal-title":"Trends Endocrinol Metab"},{"issue":"5606","key":"1899_CR58","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1126\/science.1078223","volume":"299","author":"M Bluher","year":"2003","unstructured":"Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299(5606):572\u20134.","journal-title":"Science"},{"issue":"11","key":"1899_CR59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0048790","volume":"7","author":"JH Stern","year":"2012","unstructured":"Stern JH, Kim K, Ramsey JJ. The influence of Shc proteins and aging on whole body energy expenditure and substrate utilization in mice. PLoS ONE. 2012;7(11):e48790.","journal-title":"PLoS ONE"},{"issue":"6","key":"1899_CR60","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S1091-255X(98)80053-X","volume":"2","author":"K Brown","year":"1998","unstructured":"Brown K, et al. Cystic glucagonoma: a rare variant of an uncommon neuroendocrine pancreas tumor. J Gastrointest Surg. 1998;2(6):533\u20136.","journal-title":"J Gastrointest Surg"},{"issue":"1","key":"1899_CR61","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s10534-002-0791-y","volume":"10","author":"N Koike","year":"2003","unstructured":"Koike N, et al. Malignant glucagonoma of the pancreas diagnoses through anemia and diabetes mellitus. J Hepatobiliary Pancreat Surg. 2003;10(1):101\u20135.","journal-title":"J Hepatobiliary Pancreat Surg"},{"issue":"9","key":"1899_CR62","first-page":"639","volume":"62","author":"YM Shyr","year":"1999","unstructured":"Shyr YM, et al. Glucagonoma syndrome: a case report. Zhonghua Yi Xue Za Zhi (Taipei). 1999;62(9):639\u201343.","journal-title":"Zhonghua Yi Xue Za Zhi (Taipei)"},{"issue":"1","key":"1899_CR63","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1177\/0192623308329476","volume":"37","author":"RM Anderson","year":"2009","unstructured":"Anderson RM, Shanmuganayagam D, Weindruch R. Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol. 2009;37(1):47\u201351.","journal-title":"Toxicol Pathol"},{"issue":"4","key":"1899_CR64","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1093\/jn\/116.4.641","volume":"116","author":"R Weindruch","year":"1986","unstructured":"Weindruch R, et al. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116(4):641\u201354.","journal-title":"J Nutr"},{"issue":"4538","key":"1899_CR65","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1126\/science.7063854","volume":"215","author":"R Weindruch","year":"1982","unstructured":"Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982;215(4538):1415\u20138.","journal-title":"Science"},{"issue":"6","key":"1899_CR66","doi-asserted-by":"publisher","first-page":"R1340","DOI":"10.1152\/ajpregu.00651.2002","volume":"285","author":"TA Gresl","year":"2003","unstructured":"Gresl TA, et al. Insulin sensitivity and glucose effectiveness from three minimal models: effects of energy restriction and body fat in adult male rhesus monkeys. Am J Physiol Regul Integr Comp Physiol. 2003;285(6):R1340\u201354.","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"issue":"8","key":"1899_CR67","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1093\/gerona\/glt160","volume":"69","author":"A Kuhla","year":"2014","unstructured":"Kuhla A, et al. Lifelong caloric restriction reprograms hepatic fat metabolism in mice. J Gerontol A Biol Sci Med Sci. 2014;69(8):915\u201322.","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"3","key":"1899_CR68","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/mnfr.201400621","volume":"59","author":"F Rusli","year":"2015","unstructured":"Rusli F, et al. A weekly alternating diet between caloric restriction and medium fat protects the liver from fatty liver development in middle-aged C57BL\/6J mice. Mol Nutr Food Res. 2015;59(3):533\u201343.","journal-title":"Mol Nutr Food Res"},{"issue":"37","key":"1899_CR69","doi-asserted-by":"publisher","first-page":"14972","DOI":"10.1073\/pnas.1205983109","volume":"109","author":"Y Lee","year":"2012","unstructured":"Lee Y, et al. Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc Natl Acad Sci U S A. 2012;109(37):14972\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"1899_CR70","doi-asserted-by":"publisher","first-page":"391","DOI":"10.2337\/db10-0426","volume":"60","author":"Y Lee","year":"2011","unstructured":"Lee Y, et al. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes. 2011;60(2):391\u20137.","journal-title":"Diabetes"},{"issue":"8","key":"1899_CR71","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1073\/pnas.1424934112","volume":"112","author":"MY Wang","year":"2015","unstructured":"Wang MY, et al. Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway. Proc Natl Acad Sci U S A. 2015;112(8):2503\u20138.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"1899_CR72","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1007\/s00125-006-0481-3","volume":"50","author":"SL Conarello","year":"2007","unstructured":"Conarello SL, et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia. 2007;50(1):142\u201350.","journal-title":"Diabetologia"},{"issue":"25","key":"1899_CR73","doi-asserted-by":"publisher","first-page":"02278","DOI":"10.1016\/j.jhep.2025.06.011","volume":"S0168-8278","author":"F Long","year":"2025","unstructured":"Long F, Challa TD, Ding L, Sharma AK, Wu C, Ghosh A, No\u00e9 F, Horvath C, Liebisch G, H\u00f6ring M, Wang T, Klug M, Zimmermann T, Pereira MMA, Rist W, Strobel B, Pekcec A, Neubauer H, Wolfrum C. Glucagon controls obesity-specific energy expenditure via persistent cAMP\/PKA signaling. J Hepatol. 2025;S0168-8278(25):02278\u20130. https:\/\/doi.org\/10.1016\/j.jhep.2025.06.011. Epub ahead of print.","journal-title":"J Hepatol."},{"key":"1899_CR74","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15691","volume":"8","author":"M Ogrodnik","year":"2017","unstructured":"Ogrodnik M, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017;8:15691.","journal-title":"Nat Commun"},{"issue":"6598","key":"1899_CR75","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1126\/science.abk0297","volume":"376","author":"V Acosta-Rodriguez","year":"2022","unstructured":"Acosta-Rodriguez V, et al. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL\/6J mice. Science. 2022;376(6598):1192\u2013202.","journal-title":"Science"},{"issue":"10","key":"1899_CR76","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1038\/s42255-021-00466-9","volume":"3","author":"HH Pak","year":"2021","unstructured":"Pak HH, et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nat Metab. 2021;3(10):1327\u201341.","journal-title":"Nat Metab"},{"issue":"26","key":"1899_CR77","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1056\/NEJMra1905136","volume":"381","author":"R de Cabo","year":"2019","unstructured":"de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med. 2019;381(26):2541\u201351.","journal-title":"N Engl J Med"},{"issue":"3","key":"1899_CR78","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1007\/s11357-021-00335-z","volume":"43","author":"E Duregon","year":"2021","unstructured":"Duregon E, et al. Intermittent fasting: from calories to time restriction. Geroscience. 2021;43(3):1083\u201392.","journal-title":"Geroscience"},{"issue":"3","key":"1899_CR79","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1007\/s00394-020-02361-7","volume":"60","author":"JL Dorling","year":"2021","unstructured":"Dorling JL, et al. Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial. Eur J Nutr. 2021;60(3):1633\u201343.","journal-title":"Eur J Nutr"},{"issue":"9","key":"1899_CR80","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S2213-8587(19)30151-2","volume":"7","author":"WE Kraus","year":"2019","unstructured":"Kraus WE, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(9):673\u201383.","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"13","key":"1899_CR81","doi-asserted-by":"publisher","first-page":"5492","DOI":"10.1158\/0008-5472.CAN-07-6721","volume":"68","author":"W Jiang","year":"2008","unstructured":"Jiang W, Zhu Z, Thompson HJ. Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. Cancer Res. 2008;68(13):5492\u20139.","journal-title":"Cancer Res"},{"issue":"11\u201312","key":"1899_CR82","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.mad.2010.09.007","volume":"131","author":"AG Edwards","year":"2010","unstructured":"Edwards AG, et al. Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK. Mech Ageing Dev. 2010;131(11\u201312):739\u201342.","journal-title":"Mech Ageing Dev"},{"issue":"9","key":"1899_CR83","doi-asserted-by":"publisher","first-page":"771","DOI":"10.18632\/aging.100075","volume":"1","author":"OM Palacios","year":"2009","unstructured":"Palacios OM, et al. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY). 2009;1(9):771\u201383.","journal-title":"Aging (Albany NY)"},{"issue":"5","key":"1899_CR84","doi-asserted-by":"publisher","first-page":"E1032","DOI":"10.1152\/ajpendo.00172.2004","volume":"287","author":"AA Gonzalez","year":"2004","unstructured":"Gonzalez AA, et al. Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am J Physiol Endocrinol Metab. 2004;287(5):E1032\u20137.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"11","key":"1899_CR85","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/j.exger.2007.07.003","volume":"42","author":"K To","year":"2007","unstructured":"To K, et al. Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver. Exp Gerontol. 2007;42(11):1063\u201371.","journal-title":"Exp Gerontol"},{"issue":"5","key":"1899_CR86","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.2337\/db11-1180","volume":"61","author":"P Wang","year":"2012","unstructured":"Wang P, et al. Loss of AMP-activated protein kinase-alpha2 impairs the insulin-sensitizing effect of calorie restriction in skeletal muscle. Diabetes. 2012;61(5):1051\u201361.","journal-title":"Diabetes"},{"issue":"25","key":"1899_CR87","doi-asserted-by":"publisher","first-page":"15983","DOI":"10.1073\/pnas.252625599","volume":"99","author":"H Zong","year":"2002","unstructured":"Zong H, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99(25):15983\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7432","key":"1899_CR88","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/nature11861","volume":"493","author":"SC Johnson","year":"2013","unstructured":"Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338\u201345.","journal-title":"Nature"},{"issue":"1","key":"1899_CR89","doi-asserted-by":"publisher","first-page":"E26","DOI":"10.1152\/ajpendo.00555.2019","volume":"319","author":"JE Welles","year":"2020","unstructured":"Welles JE, et al. Glucagon-dependent suppression of mTORC1 is associated with upregulation of hepatic FGF21 mRNA translation. Am J Physiol Endocrinol Metab. 2020;319(1):E26-33.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"1899_CR90","doi-asserted-by":"publisher","first-page":"101080","DOI":"10.1016\/j.molmet.2020.101080","volume":"42","author":"M Winther-Sorensen","year":"2020","unstructured":"Winther-Sorensen M, et al. Glucagon acutely regulates hepatic amino acid catabolism and the effect may be disturbed by steatosis. Mol Metab. 2020;42:101080.","journal-title":"Mol Metab"},{"issue":"19","key":"1899_CR91","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1101\/gad.13.19.2570","volume":"13","author":"M Kaeberlein","year":"1999","unstructured":"Kaeberlein M, McVey M, Guarente L. The SIR2\/3\/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999;13(19):2570\u201380.","journal-title":"Genes Dev"},{"issue":"6825","key":"1899_CR92","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/35065638","volume":"410","author":"HA Tissenbaum","year":"2001","unstructured":"Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410(6825):227\u201330.","journal-title":"Nature"},{"issue":"45","key":"1899_CR93","doi-asserted-by":"publisher","first-page":"15998","DOI":"10.1073\/pnas.0404184101","volume":"101","author":"B Rogina","year":"2004","unstructured":"Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA. 2004;101(45):15998\u20136003.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"1899_CR94","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.cmet.2013.07.013","volume":"18","author":"A Satoh","year":"2013","unstructured":"Satoh A, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013;18(3):416\u201330.","journal-title":"Cell Metab"},{"issue":"10","key":"1899_CR95","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/embor.2011.151","volume":"12","author":"LG Noriega","year":"2011","unstructured":"Noriega LG, et al. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO Rep. 2011;12(10):1069\u201376.","journal-title":"EMBO Rep"},{"issue":"5","key":"1899_CR96","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1210\/er.2018-00117","volume":"39","author":"ME Capozzi","year":"2018","unstructured":"Capozzi ME, et al. Targeting the incretin\/glucagon system with triagonists to treat diabetes. Endocr Rev. 2018;39(5):719\u201338.","journal-title":"Endocr Rev"},{"issue":"7","key":"1899_CR97","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1093\/gerona\/gly023","volume":"73","author":"A Di Francesco","year":"2018","unstructured":"Di Francesco A, et al. Intermittent mTOR inhibition reverses kidney aging in old rats. J Gerontol A Biol Sci Med Sci. 2018;73(7):843\u20134.","journal-title":"J Gerontol A Biol Sci Med Sci"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01899-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-025-01899-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01899-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:03:08Z","timestamp":1773050588000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-025-01899-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,25]]},"references-count":97,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["1899"],"URL":"https:\/\/doi.org\/10.1007\/s11357-025-01899-w","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,25]]},"assertion":[{"value":"16 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors, except for DJD, declare no competing interests. DJD has received consulting fees from Anylam, Amgen, AstraZeneca Inc., Crinetics, Insulet, Kallyope, Metsara, and Pfizer Inc. and speaking fees from Novo Nordisk Inc. Mount Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc., Novo Nordisk, Pfizer, and Zealand Pharmaceuticals Inc. to support preclinical studies in the Drucker laboratory. None of this grant support for DJD is related to studies of glucagon action.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}