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. Standard explanations invoke global deterioration of immune cell function, but this framing does not account for the observed inconsistency of chronovaccination effects in elderly populations. 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.