Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins, including cytokines, coagulation factors and hormones, may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals, we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.

Public Health Relevance

This project is relevant to public health because it will enhance our understanding of the roles of adipose tissue in increased severity of critical illness in the elderly. This project will also provide information for the development of treatments and preventative therapies to decrease incidence rates and deaths related to critical illness in the aged. Preventative therapies will likely result in reduced patient visits and decreased health care costs. The development of effective treatments for systemic inflammation, of which there are currently none available, will be beneficial to elderly patients who suffer from critical illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG039732-02
Application #
8309139
Study Section
Special Emphasis Panel (ZRG1-BDCN-M (02))
Program Officer
Finkelstein, David B
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$304,425
Indirect Cost
$99,425
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; Steele, Allison M; Cohen, Donald A et al. (2016) Short-Term Dietary Restriction Rescues Mice From Lethal Abdominal Sepsis and Endotoxemia and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue. Crit Care Med 44:e509-19
Steele, Allison M; Starr, Marlene E; Saito, Hiroshi (2016) Late Therapeutic Intervention with Antibiotics and Fluid Resuscitation Allows for a Prolonged Disease Course with High Survival in a Severe Murine Model of Sepsis. Shock :
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-1β 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; Steele, Allison M; Saito, Mizuki et al. (2014) A new cecal slurry preparation protocol with improved long-term reproducibility for animal models of sepsis. PLoS One 9:e115705
Shinozaki, Shohei; Chang, Kyungho; Sakai, Michihiro et al. (2014) Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65. Sci Signal 7:ra106
Starr, Marlene E; Saito, Hiroshi (2014) Sepsis in old age: review of human and animal studies. Aging Dis 5:126-36
Mustain, W Conan; Starr, Marlene E; Valentino, Joseph D et al. (2013) Inflammatory cytokine gene expression in mesenteric adipose tissue during acute experimental colitis. PLoS One 8:e83693
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
Tucsek, Zsuzsanna; Gautam, Tripti; Sonntag, William E et al. (2013) Aging exacerbates microvascular endothelial damage induced by circulating factors present in the serum of septic patients. J Gerontol A Biol Sci Med Sci 68:652-60

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