A review on the application of the exposome paradigm to unveil the environmental determinants of age-related diseases

Age-related diseases account for almost half of all diseases among adults worldwide, and their incidence is substantially affected by the exposome, which is the sum of all exogenous and endogenous environmental exposures and the human body's response to these exposures throughout the entire lifespan. Herein, we perform a comprehensive review of the epidemiological literature to determine the key elements of the exposome that affect the development of age-related diseases and the roles of aging hallmarks in this process. We find that most exposure assessments in previous aging studies have used a reductionist approach, whereby the effect of only a single environmental factor or a specific class of environmental factors on the development of age-related diseases has been examined. As such, there is a lack of a holistic and unbiased understanding of the effect of multiple environmental factors on the development of age-related diseases. To address this, we propose several research strategies based on an exposomic framework that could advance our understanding-in particular, from a mechanistic perspective-of how environmental factors affect the development of age-related diseases. We discuss the statistical methods and other methods that have been used in exposome-wide association studies, with a particular focus on multiomics technologies. We also address future challenges and opportunities in the realm of multidisciplinary approaches and genome-exposome epidemiology. Furthermore, we provide perspectives on precise public health services for vulnerable populations, public communications, the integration of risk exposure information, and the bench-to-bedside translation of research on age-related diseases.