Mechanistic intersections of empagliflozin and nebivolol in aging-associated redox and inflammatory pathways

Aging is characterized by interconnected disturbances in oxidative stress, chronic inflammation, mitochondrial dysfunction, and nutrient-sensing pathways that collectively contribute to progressive metabolic and vascular decline. Among the central molecular mechanisms implicated in these processes are dysregulation of the AMPK-mTOR-SIRT1 axis, persistent NF-κB activation, impaired Nrf2-mediated antioxidant defense, and mitochondrial redox imbalance. Pharmacological strategies capable of modulating multiple components of this network have therefore gained increasing interest in aging-related research. Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has demonstrated pleiotropic metabolic effects extending beyond glycemic control, including modulation of AMPK signaling, attenuation of oxidative stress, and suppression of inflammatory activation. Nebivolol, a third-generation β₁-selective adrenergic blocker with nitric oxide-mediated vasodilatory properties, has been associated with endothelial protection, vascular redox regulation, and anti-inflammatory activity. Although both agents influence pathways relevant to aging biology, current evidence is derived predominantly from experimental models of cardiovascular or metabolic disease rather than from physiological aging studies. Moreover, direct evidence evaluating their combined effects in aging remains unavailable. This review critically examines the mechanistic roles of empagliflozin and nebivolol within the context of aging-associated metabolic and vascular dysfunction. Particular emphasis is placed on their reported interactions with AMPK-mTOR-SIRT1 signaling, Nrf2-dependent antioxidant responses, NF-κB-mediated inflammation, mitochondrial function, and endothelial homeostasis. In addition, the review discusses current limitations in the evidence base, including the predominance of reductionist experimental approaches, limited translational validation, and the absence of direct combinational investigations. Comparative consideration is also given to established aging-relevant candidates, including metformin, rapamycin, resveratrol, GLP-1 receptor agonists, NAD⁺ modulators, and senolytic strategies, in order to contextualize the potential relevance and limitations of metabolic-vascular pathway modulation in aging research. Rather than proposing definitive evidence of aging-relevant efficacy, the available literature supports a biologically plausible framework in which modulation of metabolic and vascular pathways may influence interconnected mechanisms underlying aging-related decline. Further integrative experimental and translational studies are required to determine whether coordinated targeting of these pathways may provide meaningful therapeutic benefit in aging and age-associated disorders.