Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase

TLDR

Immune impairment and elevated pro‑inflammatory cytokines are hallmarks of human aging, yet the molecular basis of immune dysregulation remains unclear. We show that basal NF‑κB activity in resting CD4⁺ T cells is intrinsically up‑regulated by PI3K signaling driven by metabolic activity, which can be dampened by rapamycin. Older donors exhibit higher NF‑κB‑mediated transcription of pro‑inflammatory cytokines and chemokines, indicating that dysregulated basal NF‑κB contributes to the mild pro‑inflammatory state of aging.

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.