Systems and Molecular Biology of Longevity and Preventive Medicine: Brain-Energy-Microbiome-Exposome Synergies in Blue Zones and the Cilento Case.

Longevity and healthy aging result from the complex interaction of genetic, epigenetic, microbial, behavioral, and environmental factors. The central nervous system-particularly the cerebral cortex-and the autonomic nervous system (ANS) play key roles in integrating external and internal signals, shaping energy metabolism, immune tone, and emotional regulation. This narrative review examines how the brain-ANS axis interacts with epigenetic regulation, telomere dynamics, the gut microbiome, and the exposome to influence biological aging and resilience. Relevant literature published between 2010 and 2025 was selected through comprehensive database searches (PubMed, Scopus, Google Scholar), with a focus on studies addressing the multisystemic determinants of aging. Emphasis is placed on lifestyle-related exposures, such as diet, physical activity, psychosocial support, and environmental quality, that modulate systemic physiology through neurovisceral pathways. Drawing on empirical findings from classical Blue Zones and recent observational research in the Cilento region of southern Italy, this review highlights how context-specific factors-such as clean air, mineral-rich water, Mediterranean dietary patterns, and strong social cohesion-may foster bioelectric, metabolic, and neuroimmune homeostasis. By integrating data from neuroscience, systems biology, and environmental epidemiology, the review proposes a comprehensive model for understanding healthy longevity and supports the development of personalized, context-sensitive strategies in geroscience and preventive medicine.