Metabolic and cannabinoid crosstalk between diabetes mellitus and skin aging: molecular pathways, fibroblast senescence, and therapeutic strategies

Diabetic skin aging represents a clinically accessible model of accelerated systemic aging, sharing core pathogenic pathways with cardio-metabolic diseases such as hypertension and atherosclerosis. This review synthesizes evidence that chronic hyperglycemia induces advanced glycation end-products (AGEs) and oxidative stress, driving dermal fibroblast senescence, extracellular matrix degradation, and a pro-inflammatory secretory phenotype. These mechanisms mirror those implicated in vascular dysfunction. A key focus is the dichotomous role of the endocannabinoid system (ECS) in this process. While cannabinoid receptor 1 (CB1) overactivation may exacerbate metabolic stress, targeted agonism of cannabinoid receptor 2 (CB2) demonstrates protective potential. CB2 activation attenuates oxidative damage and cellular senescence by potentiating the AMPK–SIRT1–Nrf2 axis—a crucial pathway for maintaining vascular and metabolic homeostasis. We propose that pharmacological modulation of the ECS, particularly via CB2-selective ligands, alongside established interventions like metformin and emerging senotherapeutics, offers a novel multi-target strategy. This approach aims not only to restore dermal integrity but also to counteract shared mechanisms of tissue damage across organ systems. By framing diabetic dermopathy within a metabolic-vascular continuum, this review bridges dermatological and cardiovascular research. It highlights fibroblast senescence and ECS dysregulation as convergent therapeutic targets, advocating for integrated strategies that could mitigate both cutaneous and systemic complications of diabetes and related cardio-metabolic syndromes, thereby expanding the therapeutic arsenal against these interconnected conditions.