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

Abstract

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.

Prefrontally modulated vagal neuroimmunomodulation is associated with telomere length

“…It is thus hard to say how the results would have been if CRP type had been specified or if IL-6 had been assessed instead. It is worth mentioning that in the preliminary analyses reported in the preprint for the present study ( Ask and Sütterlin, 2022 , preprint), an association was found between vmHRV and CRP when including participants with vmHRV outside the normal range.…”

“…We would particularly like to thank Leiv Arne Rosseland for help with organizing the study, Christian Tronstad for analysis of IBIs and quantification of HRV indices, and Naomi Azulay for help with detecting outliers in the HRV data. A preprint of this manuscript is available at bioRxiv ( Ask and Sütterlin, 2022 , preprint).…”

Childhood Maltreatment and Leukocyte Telomere Length: Cardiac Vagal Activity Influences the Relation in Older Adults

“…Not only did HRV indices not (cross-sectionally) mediate this association, but they were, for the most part, also not significantly correlated with childhood maltreatment or LTL. This was surprising given the majority of the literature, as limited as it is, has shown lower resting cardiac vagal control in individuals having experienced childhood maltreatment (29–36) as well as those with shorter TL (50,52–55). However, the existing literature has examined the relation between childhood maltreatment or LTL with HRV primarily in younger individuals, often with a focus on female participants, whereas our study included a sex proportional sample of older individuals suffering from chronic disease.…”

“…A few studies have examined the associations between HRV and TL with shorter TL consistently associated with lower resting (HRV) cardiac vagal control (50,(52)(53)(54)(55). However, contradictory results have emerged in the three studies that have examined stress reactivity.…”