title: Sleep fragmentation and sepsis differentially impact blood-brain barrier integrity and transport of tumor necrosis factor-α in aging.
abstract: The factors by which aging predisposes to critical illness are varied, complex, and not well understood. Sepsis is considered a quintessential disease of old age because the incidence and mortality of severe sepsis increases in old and the oldest old individuals. Aging is associated with dramatic changes in sleep quality and quantity and sleep increasingly becomes fragmented with age. In healthy adults, sleep disruption induces inflammation. Multiple aspects of aging and of sleep dysregulation interact via neuroimmune mechanisms. Tumor necrosis factor-α (TNF), a cytokine involved in sleep regulation and neuroimmune processes, exerts some of its effects on the CNS by crossing the blood-brain barrier (BBB). In this study we examined the impact of sepsis, sleep fragmentation, and aging on BBB disruption and TNF transport into brain. We used the cecal ligation and puncture (CLP) model of sepsis in young and aged mice that were either undisturbed or had their sleep disrupted. There was a dichotomous effect of sepsis and sleep disruption with age: sepsis disrupted the BBB and increased TNF transport in young mice but not in aged mice, whereas sleep fragmentation disrupted the BBB and increased TNF transport in aged mice, but not in young mice. Combining sleep fragmentation and CLP did not produce a greater effect on either of these BBB parameters than did either of these manipulations alone. These results suggest that the mechanisms by which sleep fragmentation and sepsis alter BBB functions are fundamentally different from one another and that a major change in the organism's responses to those insults occurs with aging.
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington School of Medicine, Seattle, WA 98104, United States.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Opp
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington School of Medicine, Seattle, WA 98104, United States.
authors.forename: Amrita
authors.initials: A
authors.lastname: George
authors.affiliation: Department of Anesthesiology & Pain Medicine, University of Washington School of Medicine, Seattle, WA 98104, United States.
authors.forename: Kristyn M
authors.initials: KM
authors.lastname: Ringgold
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, United States; Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, United States.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hansen
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, United States.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Bullock
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, United States; Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, United States. Electronic address: wabanks1@uw.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000375:Aging; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000378:metabolism*; D012890:Sleep; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: Aging; Blood–brain barrier; Sepsis; Sleep; Tumor necrosis factor-α