Tabriz University of Medical Sciences BioImpacts 2228-5652 16 1 2026 01 04 Mitochondrial and inflammatory mechanisms linking SGLT2 inhibition to cardiac aging: a narrative review of mitohormesis, NLRP3 suppression, and cellular senescence 33987 33987 10.34172/bi.33987 EN Ahmadreza Jodati https://orcid.org/0000-0002-6973-8834 Nasser Safaie Mohammad Aref Rajabi Abbas Afrasiabirad Sajad Khiali Ziba Majidi https://orcid.org/0009-0005-0930-9973 Yousef Faridvand https://orcid.org/0000-0003-1139-3500 Journal Article 10.34172/bi.33987 2026 06 28 2026 08 09 Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular mortality and heart failure hospitalization independently of glycemic status, an effect that has prompted interest in mechanisms beyond glucose lowering. This narrative review examines the hypothesis that part of this benefit reflects favorable modulation of pathways implicated in cardiac aging, namely mitochondrial dysfunction, chronic low-grade inflammation, and cellular senescence. Clinical and preclinical data indicate that SGLT2 inhibition induces a mild catabolic state—marked by glucosuria, reduced insulin, and increased β-hydroxybutyrate (β-OHB)—that is associated with improved myocardial substrate utilization, enhanced mitochondrial calcium handling, and reduced oxidative stress in animal and ex vivo models. β-OHB itself has signaling properties consistent with a mitohormetic response, including histone deacetylase inhibition and suppression of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome assembly, although direct evidence linking these pathways to cardiac mitohormesis in vivo remains limited. Preclinical work further suggests that SGLT2 inhibitors may promote immune-mediated clearance of senescent cells, a mechanism so far demonstrated mainly in progeroid and diabetic rodent models. We argue that these convergent mitochondrial, anti-inflammatory, and senolytic mechanisms provide a plausible—though still largely preclinical and mechanistic rather than clinically proven—basis for the cardioprotective effects of SGLT2 inhibitors observed in randomized trials, rather than evidence that these agents reverse cardiac aging in humans. A recent placebo-controlled trial of a related SGLT2 inhibitor reported increased leukocyte telomere length and cytotoxic T-cell activity after 26 weeks in patients with type 2 diabetes, providing the first direct human evidence for an aging-biomarker effect, yet a Mendelian randomization study using genetic proxies for SGLT2 inhibition found no effect on any of four epigenetic clocks, underscoring that the evidence for a true anti-aging effect remains mixed. Prospective studies incorporating mitochondrial and senescence biomarkers in non-diabetic aging cohorts are needed to test this hypothesis directly.