The goal of this R21 application, “Gestational diabetes and offspring aging and metabolism,” is to examine whether gestational diabetes mellitus (GDM) is linked to adverse offspring metabolism through accelerated molecular aging. In the United States, one in five adolescents has pre-diabetes. Despite their young age, adolescents with glucose intolerance have a high risk of complications. Thus, it is important to understand how events that happen early in life can alter their glucose metabolism. Exposure to GDM while in-utero is an established risk factor for offspring insulin resistance (IR). This phenomenon was first documented in the Pima tribe by Dr. Dabelea, a co-investigator on this application: risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother’s diagnosis. The mechanisms through which this happens are incompletely understood, but have important public health implications for the transmission of diabetes across generations. We propose that one way that maternal dysglycemia might affect offspring glucose metabolism is via alteration of offspring molecular aging pathways, particularly epigenetic age and telomere length. Estimates of epigenetic age, generated from “epigenetic clocks,” are derived from methylation levels at specific CpG sites, and “older” epigenetic age estimates predict mortality. In adults, epigenetic age acceleration (EAA) predicts greater insulin resistance (IR), lower insulin secretion, and diabetes. However, there are no studies of EAA and glucose metabolism in youth. Maternal dysglycemia also has been reported to be linked to shorter telomere length and metabolic syndrome in offspring, but the impact of shortening of telomere length and whether offspring experience aging across these aging mechanisms has not been examined. Therefore, we propose to examine molecular aging and measures of glucose metabolism in a racially diverse cohort, EPOCH, (R01DK068001) which conducted examinations and collected blood samples at ~10 years (range 6-12 years) and ~17 years (range 12-19 years). Using existing EWAS data (R01DK100340), we will calculate EAA in EPOCH offspring. Using existing blood samples, we will measure telomere length using the UCSF Blackburn laboratory. We will examine whether maternal GDM is associated with EAA and telomere shortening in offspring (Aim 1), and whether accelerated epigenetic aging and telomere shortening are associated with glucose metabolism (Aim 2). Our preliminary data support the hypotheses that GDM predicts offspring EAA, which in turn is associated with greater offspring IR and compensatory insulin secretion. Our team is well-positioned to achieve the study aims, due to our familiarity with the cohorts and the resources of the Lifecourse Epidemiology of Adiposity & Diabetes Center. We have an established track record of collaboration. The proposed work is necessary to determine whether targeting aging biomarkers, even...