title: Critical transition in tissue homeostasis accompanies murine lung senescence.
abstract: BACKGROUND
  Respiratory dysfunction is a major contributor to morbidity and mortality in aged populations. The susceptibility to pulmonary insults is attributed to "low pulmonary reserve", ostensibly reflecting a combination of age-related musculoskeletal, immunologic and intrinsic pulmonary dysfunction.
  
  
  RESULTS
  Using a murine model of the aging lung, senescent DBA/2 mice, we correlated a longitudinal survey of airspace size and injury measures with a transcriptome from the aging lung at 2, 4, 8, 12, 16 and 20 months of age. Morphometric analysis demonstrated a nonlinear pattern of airspace caliber enlargement with a critical transition occurring between 8 and 12 months of age marked by an initial increase in oxidative stress, cell death and elastase activation which is soon followed by inflammatory cell infiltration, immune complex deposition and the onset of airspace enlargement. The temporally correlative transcriptome showed exuberant induction of immunoglobulin genes coincident with airspace enlargement. Immunohistochemistry, ELISA analysis and flow cytometry demonstrated increased immunoglobulin deposition in the lung associated with a contemporaneous increase in activated B-cells expressing high levels of TLR4 (toll receptor 4) and CD86 and macrophages during midlife. These midlife changes culminate in progressive airspace enlargement during late life stages.
  
  
  CONCLUSIONS
  Our findings establish that a tissue-specific aging program is evident during a presenescent interval which involves early oxidative stress, cell death and elastase activation, followed by B lymphocyte and macrophage expansion/activation. This sequence heralds the progression to overt airspace enlargement in the aged lung. These signature events, during middle age, indicate that early stages of the aging immune system may have important correlates in the maintenance of tissue morphology. We further show that time-course analyses of aging models, when informed by structural surveys, can reveal nonintuitive signatures of organ-specific aging pathology.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Calvi
authors.forename: Megan
authors.initials: M
authors.lastname: Podowski
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
authors.forename: Shana L
authors.initials: SL
authors.lastname: Metzger
authors.forename: Kaori
authors.initials: K
authors.lastname: Misono
authors.forename: Hataya
authors.initials: H
authors.lastname: Poonyagariyagorn
authors.forename: Armando
authors.initials: A
authors.lastname: Lopez-Mercado
authors.forename: Therese
authors.initials: T
authors.lastname: Ku
authors.forename: Thomas
authors.initials: T
authors.lastname: Lauer
authors.forename: Christopher
authors.initials: C
authors.lastname: Cheadle
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Sharon
authors.initials: S
authors.lastname: McGrath-Morrow
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.forename: Jeremy
authors.initials: J
authors.lastname: Walston
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016923:Cell Death; D006706:Homeostasis; D007136:Immunoglobulins / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000276:immunology; D018384:Oxidative Stress; D010641:Phenotype
chemical_list: D007136:Immunoglobulins