Ageing Trajectories: Exposome-Driven Pathobiological Mechanisms and Implications for Prevention from Blue Zones and Italian Longevity Hotspots Such as Cilento and Sicilian Mountain Villages

Ageing is influenced by a complex interplay of genetic, environmental, and lifestyle factors, with increasing evidence highlighting the exposome as a key determinant of healthspan(definition). This review explores the impact of environmental exposures, focusing in particular on pollution, endocrine disruptors, and climate change on the development of age-related diseases such as cardiovascular diseases (CVDs), cancer, and metabolic disorders. Additionally, it examines protective factors that contribute to healthy ageing. A comprehensive literature review was conducted using PubMed, Scopus, and Google Scholar, focusing on studies published between 2000 and 2025. Findings indicate that chronic exposure to pollutants accelerates cellular ageing through mechanisms such as oxidative stress, inflammation, and epigenetic dysregulation. In contrast, longevity hotspots-Blue Zones, Cilento and the mountain villages of Sicily (Sicani and Madonie Mountains)-illustrate how traditional dietary patterns, strong social structures, and reduced environmental toxicity contribute to exceptional health and longevity. Mechanistically, exposome-driven alterations in immune-inflammatory pathways and epigenetic regulation play a central role in modulating ageing trajectories. Understanding these interactions is essential for developing targeted strategies to mitigate harmful exposures and enhance protective factors. This review underscores the urgent need for integrative public health policies that address the environmental determinants of ageing, ultimately promoting a longer and healthier lifespan.