Senotherapeutic Potential of Anti-Diabetic Medications: Bridging Type 2 Diabetes and Accelerated Aging.

Abstract

Aging and type 2 diabetes (T2D) are increasingly recognized as interconnected biological processes that share core pathogenic mechanisms, including cellular senescence, mitochondrial dysfunction, chronic low-grade inflammation, impaired autophagy, stem cell exhaustion, dysregulated nutrient sensing, and gut microbiota imbalance. Chronic hyperglycemia and insulin resistance accelerate tissue degeneration across multiple organ systems, thereby establishing T2D as a clinically relevant model of accelerated biological aging. In this context, anti-diabetic medications have attracted growing interest not only as glycemic control agents, but also for their potential to modulate aging biology and delay age-related functional decline. Here, we review the emerging evidence supporting the senotherapeutic properties of metformin, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), alpha-glucosidase inhibitors (AGIs), sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin. These agents have been reported to influence key aging-related pathways, including AMPK, mTOR, SIRT1, NF-κB, ROS/c-JNK, and insulin/IGF-1 signaling, and to exert beneficial effects on cellular senescence, inflammaging, mitochondrial homeostasis, proteostasis, immunosenescence, autophagy, and gut microbiota composition. Despite strong preclinical support, translational relevance remains uncertain due to model heterogeneity, limited randomized clinical evidence, and insufficient long-term follow-up. Clarifying tissue specificity, timing, dose, and patient selection will be essential for determining whether anti-diabetic agents can be safely repurposed as gerotherapeutics.