Inflammaging-Driven Stochastic Desynchronization of the Antigen-Presenting Cell Circadian Network as a Mechanism of Age-Related Vaccine Hyporesponsiveness: A Mechanistic Hypothesis

Vaccine efficacy declines substantially with age, yet the precise mechanisms underlying this decline remain incompletely understood. We propose that this inconsistency reflects a fundamental loss of temporal coordination within the antigen-presenting cell network rather than uniform functional decline. Our hypothesis, IACD (Inflammaging-driven APC Circadian Desynchronization), holds that chronic inflammation differentially destabilizes circadian oscillators across DC, Tfh, and B cell populations through NF-kB competition with BMAL1, producing stochastic phase drift and unreliable germinal center initiation. Related work: Sirotin A. (2026). Circadian Gating of p21-Mediated Quiescence. https://doi.org/10.5281/zenodo.20146782