Sepsis is an infection-initiated manifestation of the systemic inflammatory response syndrome that often progresses to septic shock, multiple organ failure with high risks of death. Sepsis is a particularly serious problem in the geriatric population, as the elderly patients with sepsis suffer much higher morbidity and mortality than younger patients. In fact, sepsis is a major cause of death in elderly patients at intensive care units in the US. Although this problem is increasingly recognized, the underlying mechanism(s) responsible for this age-associated vulnerability remain largely unknown. The long-term goal of our research is to determine the mechanisms responsible for the increased septic vulnerability in the aged, and to use this information to develop new treatment strategies for sepsis. The age-associated vulnerability to sepsis is also seen in animal models. We have shown that aged mice suffer significantly higher mortality than young mice in two commonly used models for sepsis;endotoxemia induced by bacterial lipopolysaccharide injection, and an intra-abdominal sepsis induced by cecal ligation and puncture. We have also found that the elevated mortality in aged mice is associated with altered inflammatory and coagulation responses, and increased oxidative damages. Our central hypothesis is that loss of homeostasis in old age leads to excessive inflammation, oxidative damage, and coagulation, contributing to the age-associated vulnerability to sepsis. Our objective in this project is to define the age-associated alterations in pathophysiology and gene expression in the mouse model of sepsis, and to develop strategies to improve the survival of the old mice with sepsis. To achieve these goals, we pursue the following three specific aims: (1) To determine the effects of aging on the pathophysiology of sepsis, (2) To identify the age-associated alterations in gene expression that affects mortality in sepsis, and (3) To test likely strategies for their ability to decrease age-associated mortality in sepsis. The information obtained from this project should provide the basis for new therapeutic strategies to substantially decrease the mortality in elderly patients with sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG025908-06
Application #
7932373
Study Section
Special Emphasis Panel (ZRG1-ASG (01))
Program Officer
Fuldner, Rebecca A
Project Start
2005-05-15
Project End
2012-04-30
Budget Start
2009-09-30
Budget End
2012-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$97,196
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Starr, Marlene E; Saito, Mizuki; Evers, B Mark et al. (2015) Age-Associated Increase in Cytokine Production During Systemic Inflammation-II: The Role of IL-1? in Age-Dependent IL-6 Upregulation in Adipose Tissue. J Gerontol A Biol Sci Med Sci 70:1508-15
Starr, Marlene E; Takahashi, Hitoshi; Okamura, Daiki et al. (2015) Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis. Am J Physiol Heart Circ Physiol 308:H83-91
Starr, Marlene E; Saito, Hiroshi (2014) Sepsis in old age: review of human and animal studies. Aging Dis 5:126-36
Starr, Marlene E; Hu, Yanling; Stromberg, Arnold J et al. (2013) Gene expression profile of mouse white adipose tissue during inflammatory stress: age-dependent upregulation of major procoagulant factors. Aging Cell 12:194-206
Starr, Marlene E; Saito, Hiroshi (2012) Age-related increase in food spilling by laboratory mice may lead to significant overestimation of actual food consumption: implications for studies on dietary restriction, metabolism, and dose calculations. J Gerontol A Biol Sci Med Sci 67:1043-8
Okamura, Daiki; Starr, Marlene E; Lee, Eun Y et al. (2012) Age-dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis. Aging Cell 11:760-9
Wang, Xin; Mandal, Ardhendu K; Saito, Hiroshi et al. (2012) Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/?-catenin signaling pathway. Toxicol Appl Pharmacol 262:11-21
Takahashi, Hitoshi; Okamura, Daiki; Starr, Marlene E et al. (2012) Age-dependent reduction of the PI3K regulatory subunit p85? suppresses pancreatic acinar cell proliferation. Aging Cell 11:305-14
Starr, Marlene E; Ueda, Junji; Yamamoto, Shoji et al. (2011) The effects of aging on pulmonary oxidative damage, protein nitration, and extracellular superoxide dismutase down-regulation during systemic inflammation. Free Radic Biol Med 50:371-80
Starr, Marlene E; Ueda, Junji; Takahashi, Hitoshi et al. (2010) Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood 115:4886-93

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