The rising incidence in early-onset colorectal cancer (CRC diagnosed before 50), has resulted in updated American Cancer Society (ACS) guideline advising average-risk screening begin at age 45, rather than 50. Debates centered around the substantial cost and resources of adding 21 million adults at very low risk to the screening pool, and “further personalize screening strategies” was a priority. Identifying the contributors of the rising incidence are the first steps but thus far an unmet need. Lifestyle factors that preceded and mirrored the rapid rise of early-onset CRC, including obesity, prolong sitting, and poor diet, may play a critical role. Our preliminary data support the importance of obesity and sedentary behaviors and early-onset CRC are more likely to be processed from traditional adenoma-carcinoma sequence compared to CRC diagnosed after age 65. Therefore, investigation into risk factors for early-onset advanced adenoma, the major targets of screening, will illuminate insights of colorectal carcinogenesis at younger ages. Accumulating data suggest that microbial translocation/endotoxemia, which triggers subsequent inflammation and immune response, and augmented by above-mentioned lifestyle factors, might be an emerging pathway. We hypothesized that obesity, prolonged sitting, and poor diet quality increase risk of early-onset advanced adenoma through increasing endotoxemia and inflammation, and contribute to the rise of early-onset CRC. To test these hypotheses, we will leverage lifestyle data collected throughout life course in two well-characterized prospective cohort (Nurses’ Health Study II [NHSII]) and Southern Community Cohort Study (SCCS) with archived pre-diagnostic blood, complemented by decision modeling using the Microsimulation Screening Analysis‐Colon (MISCAN‐Colon), the model used to inform the ACS screening guideline. Specifically, we will first examine prospectively the associations between mid-adulthood and early-life obesity, sedentary behaviors, and diet quality and risk of early-onset advanced adenoma (Aim 1). We will then investigate into the independent and mediating role of pre-diagnostic plasma markers of endotoxemia and inflammation in early-onset neoplasia, leveraging a cost-efficient and reliable proteomic platform. Such profiling will also allow for untargeted discoveries of protein-protein interactions to identify novel networks/targets (Aim 2). Finally, we will conduct a meta-analysis to identify early-onset CRC specific risk factors and quantify the relative risks, and integrate these findings to the MISCAN-Colon to estimate the contributions of secular changes of lifestyle to the rise of early-onset CRC and to improve the simulations used to support the 2018 ACS screening guideline using early-onset CRC specific risk factors/estimates (Aim 3). Our established team, led by an early stage investigator focused on early-onset CRC, and leaders in epidemiology, bioinformatics, biomarker measurement and discoveries, and decision modeling, offers unparalleled expertise. This investigation will illuminate significant insights into the etiology of early-onset CRC and will be a significant step forward to optimal/personalized CRC screening among younger adults.