ABSTRACT Climate change is a growing public health priority as extreme heat, wildfires, and other natural disasters have led to acute effects on morbidity and mortality; yet, the long-term consequences of extreme heat and wildfires have been sparsely studied. This is due in part to the paucity of studies with longitudinal information on individual- and neighborhood-level factors and fine-scale climate and wildfire data. There is an urgent need to investigate the long-term consequences of extreme heat and wildfires in well-designed studies that include a comprehensive assessment of these exposures and their independent and joint effects on life expectancy, coupled with a critical evaluation of possible mediators (air pollution) and moderators (socioeconomic status, demographics, comorbidities, health behaviors, neighborhood environments, and geography). Furthermore, the biological processes by which climate change affects mortality are not well understood. While evidence of the impact of air pollution on DNA methylation as a measure of epigenetic regulation is accumulating, studies of extreme heat and DNA methylation are sparse. Elucidation of the underlying pathways and the identification of interventions for high-risk groups are needed. To address these gaps, we will conduct a rigorous investigation of the impacts of extreme heat and wildfire smoke on adult life expectancy, leveraging the unique epidemiological resources of the Multiethnic Cohort Study, a large population-based study that includes 112,000 adult men and women from California, who were ages 45-75 at enrollment in 1993-1996 and currently ages 72-103 with strong representation of diverse racial/ethnic and socioeconomic groups. Specifically, we will generate and characterize extreme heat and wildfire smoke for California Multiethnic Cohort participants spanning a 24-year period (Aim 1); assess the impacts of long-term exposures of extreme heat and wildfire smoke on life expectancy (Aim 2); and DNA methylation and epigenetic age (Aim 3). The strengths of this proposal include: 1) the use of state-of-the-art exposure assessment methods to characterize extreme heat, wildfire smoke, and important criteria air pollutants; 2) a large population-based sample with detailed individual- and neighborhood-level data and sufficient power to detect modest effects that are broadly generalizable to similar sex, racial/ethnic, and socioeconomic groups in the US; 3) the assessment of the role of biological pathways (DNA methylation) by which extreme heat and wildfire smoke may operate; and 4) a thorough investigation of effect modification by a variety of factors including modifiable neighborhood environments as well as the mediation of effects by air pollution. Findings from this proposal will expand our understanding of the contribution of long-term extreme heat and wildfire smoke on life expectancy. This knowledge has translational relevance in providing empirical evidence for policy makers and imp...