Aging Research Dissertation Award for Marlene Starr:The Role of Adipokines in Age-Related Sensitivity to Sepsis

Aging is characterized by a deteriorated stress response that underlies compromised resistance to such physiological stresses as systemic inflammatory response syndrome and sepsis, clinical conditions in which the inflammatory and coagulant pathways are pervasively activated. Recent evidence suggests that adipokines, adipose tissue-derived signaling proteins including cytokines, coagulation factors and hormones, may play an important role in the inflammatory response. My long term goals are to identify the mechanisms by which adipokines contribute to age-related alterations in inflammatory response and to use this information in the development of therapeutic tools. For these studies I propose to use two widely accepted mouse models of sepsis: (1) acute endotoxemia by injection with bacterial endotoxin lipopolysaccharides (LPS) and (2) acute peritonitis by cecal ligation and puncture (CLP). My central hypothesis is that expression patterns of cytokines and coagulation factors from the adipose tissue are significantly altered with age and that this alteration contributes to age-related sensitivity to sepsis. I intend to achieve these goals in the pursuit of the following three specific aims. In Aim 1, I will determine which adipokines are involved in age-associated differences during systemic inflammation by analyzing mRNA and protein expression in adipose tissues from young and aged mice after LPS injection. In Aim 2, I will use in vitro organ culture techniques and adipose tissue transplantation to understand the mechanisms by which adipokines contribute to this age-associated difference in systemic inflammation. In Aim 3, I will test interventions for improving age-related vulnerability to systemic inflammation through decreases in adipose tissue by surgical removal or dietary restriction. These studies will provide significant insight into the association of the previously neglected adipose organ in inflammatory disorders.