title: Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase.
abstract: Immune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dys-regulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation gene expression mediated by the transcription factor NF-κB is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-κB -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-κB up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dys-regulated basal NF-κB activity may contribute to the mild pro-inflammatory state of aging.
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Arsun
authors.initials: A
authors.lastname: Bektas
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Elin
authors.initials: E
authors.lastname: Lehmann
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Clinical Research Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Madara
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D020123:Sirolimus