{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:35:55Z","timestamp":1792791355784,"version":"4.5.0"},"reference-count":114,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.<\/jats:p>","DOI":"10.3390\/ijms232012325","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:29:46Z","timestamp":1665973786000},"page":"12325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2224-4615","authenticated-orcid":false,"given":"Rosalba","family":"La Grotta","sequence":"first","affiliation":[{"name":"IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Frig\u00e9","sequence":"additional","affiliation":[{"name":"IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1840-3903","authenticated-orcid":false,"given":"Giulia","family":"Matacchione","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences, DISCLIMO, Universit\u00e0 Politecnica delle Marche, Via Tronto 10\/A, 60100 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiola","family":"Olivieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Sciences, DISCLIMO, Universit\u00e0 Politecnica delle Marche, Via Tronto 10\/A, 60100 Ancona, Italy"},{"name":"Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, 60100 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4767-446X","authenticated-orcid":false,"given":"Paola","family":"de Candia","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-3203","authenticated-orcid":false,"given":"Antonio","family":"Ceriello","sequence":"additional","affiliation":[{"name":"IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2959-2658","authenticated-orcid":false,"given":"Francesco","family":"Prattichizzo","sequence":"additional","affiliation":[{"name":"IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16\/15, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41580-021-00411-4","article-title":"Molecular mechanisms of dietary restriction promoting health and longevity","volume":"23","author":"Green","year":"2022","journal-title":"Nat. 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