Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, is a hallmark of biological aging. We and others have shown that chronic levels of circulating downstream markers of systemic inflammation are associated with age-related disease states, particularly cardiovascular disease, as well as longevity. However, accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, in turn, serve as effective therapeutic targets. Upstream initiation of inflammation in humans is governed primarily by small molecule effectors of arachidonic acid metabolism, termed eicosanoids. These bioactive lipid effectors of both pro- and anti-inflammatory activity include thromboxanes, prostaglandins, lipoxins, and leukotrienes. To date, the interaction between eicosanoid pathways and age-related disease phenotypes remain poorly understood, thus limiting our ability to harness their therapeutic potential. This proposal aims to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual?s propensity for developing or escaping age-related disease. Emerging data suggest that select eicosanoids and genetic polymorphisms in enzymes contributing to their biosynthesis are associated particularly with cardiovascular risk as well as longevity, but comprehensive studies in large cohorts are lacking. Advanced methods using mass spectrometry now allow for the rapid and accurate quantification of >150 upstream eicosanoid mediators representing the multiple enzymatic origins. We will use these methods to comprehensively assay distinct pro- and anti-inflammatory eicosanoids and examine their relation to measures of healthy cardiovascular aging and longevity outcomes in a large cohort of women, enriched with individuals representing the spectrum of risk factor burden as well as a range of achieved lifespans. The goal of this study is to advance our understanding of how upstream inflammatory pathways are related to healthy aging and longevity in women, who continue to outlive men and yet carry a greater burden of chronic disease in later life than men for reasons that remain unclear. Thus, our specific aims are (1) to assess whether circulating eicosanoid mediators of systemic inflammation are associated with longevity in women; and, (2) to evaluate the association between distinct eicosanoid mediators of systemic inflammation and morbidity profiles in women. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in a large, well-phenotyped cohort promises to yield important insights into the determinants of healthy aging and longevity. Importantly, given its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct eicosanoids as well as outcomes.

Public Health Relevance

Chronic inflammation is a hallmark of biological aging, and has been implicated in the development and progression of multiple common chronic diseases of aging. To improve our currently limited understanding of how complex inflammatory pathways interact to promote or prevent human disease, we will study upstream mediators of systemic inflammation in relation to healthy aging and longevity outcomes in the community.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cancer, Heart, and Sleep Epidemiology B Study Section (CHSB)
Program Officer
Ludlam, Shari
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Echouffo-Tcheugui, Justin B; Niiranen, Teemu J; McCabe, Elizabeth L et al. (2018) Lifetime Prevalence and Prognosis of Prediabetes Without Progression to Diabetes. Diabetes Care 41:e117-e118
Fernandes-Silva, Miguel M; Shah, Amil M; Claggett, Brian et al. (2018) Adiposity, body composition and ventricular-arterial stiffness in the elderly: the Atherosclerosis Risk in Communities Study. Eur J Heart Fail 20:1191-1201
Niiranen, Teemu J; Henglin, Mir; Claggett, Brian et al. (2018) Trajectories of Blood Pressure Elevation Preceding Hypertension Onset: An Analysis of the Framingham Heart Study Original Cohort. JAMA Cardiol 3:427-431
Nadruz Jr, Wilson; Claggett, Brian; Henglin, Mir et al. (2018) Widening Racial Differences in Risks for Coronary Heart Disease. Circulation 137:1195-1197
Sengeløv, Morten; Cheng, Susan; Biering-Sørensen, Tor et al. (2018) Ideal Cardiovascular Health and the Prevalence and Severity of Aortic Stenosis in Elderly Patients. J Am Heart Assoc 7:
Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu et al. (2018) CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle. Circ Res 122:88-96
Vasan, Ramachandran S; Xanthakis, Vanessa; Lyass, Asya et al. (2018) Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades. JACC Cardiovasc Imaging 11:1-11
Tobias, Deirdre K; Lawler, Patrick R; Harada, Paulo H et al. (2018) Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women. Circ Genom Precis Med 11:e002157
Henglin, Mir; Stein, Gillian; Hushcha, Pavel V et al. (2017) Machine Learning Approaches in Cardiovascular Imaging. Circ Cardiovasc Imaging 10:
Niiranen, Teemu J; McCabe, Elizabeth L; Larson, Martin G et al. (2017) Risk for hypertension crosses generations in the community: a multi-generational cohort study. Eur Heart J 38:2300-2308

Showing the most recent 10 out of 22 publications