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De novo lipogenesis (DNL) is a crucial metabolic pathway that convert excess carbohydrates to fatty acids (FA) for energy and storage. Both DNL and the synthesized FA have biologic effects that may affect cardiometabolic risk. Yet, the association between DNL FA and mortality and CVD are not well-established in older adults, especially using serial biomarkers which objectively allow more accurate estimates of long-term FA exposure, as well as changes over time. We investigated the longitudinal association between serial levels of circulating DNL FA and total mortality, cause-specific mortality, and total CVD among 3,869 older U.S. adults (mean age 75 y) free of prevalent CVD at baseline. Levels of plasma phospholipid palmitic (16:0), palmitoleic (16:1n-7), stearic (18:0), and oleic acid (18:1n-9) were quantified at baseline, year 6, and year 13. Outcomes were centrally adjudicated using multiple sources. Risk was assessed in multivariable-adjusted Cox models with time-varying FA and covariates. During 46,974 person-years, 3,227 deaths (including 1,131 from CVD, 2,096 from non-CVD causes) and 1,754 incident total CVD events occurred. After multivariable-adjustment, cumulative levels of 16:0, 16:1n-7 and 18:1n-9 were each positively, while 18:0 was inversely, associated with total mortality (Table). Associations were generally similar for CVD vs. non-CVD mortality, and vs. total incident CVD (not shown). Among non-CVD deaths, associations for dementia and pulmonary deaths were generally similar to total mortality; while only 16:0 and 18:1n-9 were positively associated with cancer mortality. Higher long-term levels of circulating 16:0, 16:1n-7 and 18:1n-9 were positively, while 18:0 was inversely, associated with total mortality in older adults. Novel findings highlight the potential relevance of DNL later in life, and the need for further experimental research and interventions on the relevant underlying physiology and long-term health effects of DNL FA. Findings for FA changes over time to be presented.