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Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms.
La Grotta, Rosalba; Frigé, Chiara; Matacchione, Giulia; Olivieri, Fabiola; de Candia, Paola; Ceriello, Antonio; Prattichizzo, Francesco.
  • La Grotta R; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138 Milan, Italy.
  • Frigé C; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138 Milan, Italy.
  • Matacchione G; Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Via Tronto 10/A, 60100 Ancona, Italy.
  • Olivieri F; Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, Via Tronto 10/A, 60100 Ancona, Italy.
  • de Candia P; Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, 60100 Ancona, Italy.
  • Ceriello A; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy.
  • Prattichizzo F; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138 Milan, Italy.
Int J Mol Sci ; 23(20)2022 Oct 14.
Article in English | MEDLINE | ID: covidwho-2071511
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 / Sodium-Glucose Transporter 2 Inhibitors / COVID-19 Type of study: Observational study / Prognostic study / Reviews Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012325

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Diabetes Mellitus, Type 2 / Sodium-Glucose Transporter 2 Inhibitors / COVID-19 Type of study: Observational study / Prognostic study / Reviews Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232012325