Prefrontally Modulated Vagal Tone Inhibits Inflammatory Responses to Prevent Telomere Damage in Healthy Participants

Background Accumulated senescent cells are proposed to be one of the main drivers of age-related pathology through disruption of tissue structure and function. We recently proposed the Neuro-Immuno-Senescence Integrative Model (NISIM; Ask et al., 2018) which relates prefrontally modulated vagal tone and subsequent balance between vagal and sympathetic input to the spleen to inflammatory responses leading to generation of reactive oxygen species and oxidative telomere damage. The NISIM is based on converging evidence and argues for the existence of a prefrontal cortex-autonomic nervous system-spleen (PAS) axis, suggesting that the inflammation that induces reactive oxygen species-generation is downstream of this axis. Aim In this study, we aim to assess inflammation as a mediator in the relationship between prefrontally modulated vagal tone and leukocyte telomere length to test the hypothesis that PAS axis dysregulation accelerates cellular aging. We also assess the relationship between a recently proposed index of vagal immunomodulation (vagal tone/inflammation ratio; NIM index; Gidron et al., 2018) and telomere length, and compare results between the NIM index and vagal tone as predictors of telomere length. Methods This study uses participant data from a large nationally representative longitudinal study since 1974 with a total of 45,000 Norwegian residents so far. A sub-sample of 1372 participants from which vagal tone, C Reactive Protein, and leukocyte telomere length could be obtained were included in the study. Relationships were analyzed with hierarchical multiple linear regression using either vagal tone and C Reactive Protein or the NIM index to predict telomere length. Sleeping problems, tobacco use status, alcohol use status, time since last meal, and symptoms of depression were included as control variables. Results In the mediation analysis, vagal tone was a significant positive predictor of telomere length, while C Reactive Protein was a significant negative predictor of telomere length. This relationship remained significant when individually controlling for some but not all confounding variables. The NIM index was a significant positive predictor of telomere length. This relationship remained significant when controlling for all confounding variables except one. In a reduced dataset excluding all participants where confounders were present, the NIM index remained a significant predictor of telomere length. Conclusion This is the first study suggesting that PAS axis activity is associated with telomere length thus supporting the NISIM. Results indicate that the NIM index is a more sensitive indicator of PAS axis activity than vagal tone and C Reactive Protein in isolation. Clinical relevance and suggestions for future research are discussed.