title: Age-associated defect in human TLR-1/2 function.
abstract: The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.
authors.affiliation: Section of Infectious Disease, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
authors.forename: David
authors.initials: D
authors.lastname: van Duin
authors.forename: Subhasis
authors.initials: S
authors.lastname: Mohanty
authors.forename: Venetta
authors.initials: V
authors.lastname: Thomas
authors.forename: Sandra
authors.initials: S
authors.lastname: Ginter
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
authors.forename: Heather G
authors.initials: HG
authors.lastname: Allore
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D051194:Toll-Like Receptor 1 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha