Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial

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Summary

Background

Although yoga and meditation have been used for stress reduction with reported improvement in inflammation, little is known about the biological mechanisms mediating such effects. The present study examined if a yogic meditation might alter the activity of inflammatory and antiviral transcription control pathways that shape immune cell gene expression.

Methods

Forty-five family dementia caregivers were randomized to either Kirtan Kriya Meditation (KKM) or Relaxing Music (RM) listening for 12 min daily for 8 weeks and 39 caregivers completed the study. Genome-wide transcriptional profiles were collected from peripheral blood leukocytes sampled at baseline and 8-week follow-up. Promoter-based bioinformatics analyses tested the hypothesis that observed transcriptional alterations were structured by reduced activity of the pro-inflammatory nuclear factor (NF)-κB family of transcription factors and increased activity of Interferon Response Factors (IRFs; i.e., reversal of patterns previously linked to stress).

Results

In response to KKM treatment, 68 genes were found to be differentially expressed (19 up-regulated, 49 down-regulated) after adjusting for potentially confounded differences in sex, illness burden, and BMI. Up-regulated genes included immunoglobulin-related transcripts. Down-regulated transcripts included pro-inflammatory cytokines and activation-related immediate-early genes. Transcript origin analyses identified plasmacytoid dendritic cells and B lymphocytes as the primary cellular context of these transcriptional alterations (both p < .001). Promoter-based bioinformatic analysis implicated reduced NF-κB signaling and increased activity of IRF1 in structuring those effects (both p < .05).

Conclusion

A brief daily yogic meditation intervention may reverse the pattern of increased NF-κB-related transcription of pro-inflammatory cytokines and decreased IRF1-related transcription of innate antiviral response genes previously observed in healthy individuals confronting a significant life stressor.

Introduction

Caring for a frail or demented family member can be a significant life stressor. Older adult caregivers report higher levels of perceived stress and depression, and lower levels of satisfaction with life, joy, vigor, and content than healthy controls (Pinquart and Sörensen, 2003, Miller et al., 2008). Moreover, caregivers show heightened levels of biological markers of inflammation (Wu et al., 1999) and reduced levels of cellular immunity (Kiecolt-Glaser et al., 1991, Damjanovic et al., 2007, Epel et al., 2010, Lovell and Wetherell, 2011). Familial caregivers are often considered to be at risk of stress-related disease and general health decline (Gouin et al., 2008). Some research suggests that psychosocial interventions for dementia caregivers reduce adverse effects of caregiver stress on physical and mental health (Schulz et al., 2002). However, the pathways by which such psychosocial interventions differentially impact biological processes (e.g., inflammation) among caregivers remain poorly understood. Indeed, initial pilot studies suggest that psychosocial interventions delivered to caregivers may potentially improve immune function (Garand et al., 2002, Northouse et al., 2012).

Stress signals interpreted by the central nervous system (CNS) can modulate the expression of immune response genes via the effects of hormones and neurotransmitters on gene transcription control pathways (Irwin and Cole, 2011). Several previous studies have shown that diverse types of significant life adversity such as social isolation (Cole et al., 2007), imminent bereavement (Miller et al., 2008), post-traumatic stress disorder (O’Donovan et al., 2011), chronic loneliness (Cole et al., 2007, Cole et al., 2011), social threat (Cole et al., 2010), and low socioeconomic status (SES) (Miller et al., 2009, Chen et al., 2009, Chen et al., 2010) are associated with an up-regulation of inflammation-related genes under the control of the transcription factor nuclear factor-κB (NF-κB)and a complementary down-regulation of innate antiviral genes targeted by Interferon Response Factors (IRFs) (Irwin and Cole, 2011).

In the context of caregiving stress, one previous genome-wide transcriptional profiling study has shown that monocytes from familial caregivers exhibit heightened expression of genes with response elements for NF-κB and reduced expression of genes with response elements for IRF relative to healthy controls (Miller et al., 2008). These caregivers also showed relative elevations in the inflammatory markers C-reactive protein and interleukin-1 receptor antagonist. This limited literature suggests that psychological stressors experienced by older adult caregivers may alter gene expression that could promote chronic inflammation and undermine antiviral defenses. However, it is unknown whether psychosocial interventions can reverse such changes. This randomized controlled trial is the first to test whether a daily yogic meditation intervention can potentially reverse a pattern of pro-inflammatory and anti-antiviral leukocyte transcriptional alterations that has previously been linked to chronic stress and adversity (Irwin and Cole, 2011).

Meditation practices can lead to improvements in physical and mental health (Grossman et al., 2004, Black et al., 2009, Chiesa and Serretti, 2009). Moreover, initial pilot studies indicate that dementia caregivers who practice meditation show improvement in mental health indices such as depression and anxiety (Waelde et al., 2004, Van Puymbroeck et al., 2007, Pace et al., 2009), which are indices associated with inflammatory markers such as IL-6 (Irwin and Olmstead, 2011). Our recent study showed that meditation increased telomerase activity when compared to a relaxing activity, and it also modulated depression, mental health, and cognition in dementia caregivers (Lavretsky et al., 2012).

Among healthy and depressed older adults, various forms of meditation with movement (e.g., Tai Chi) or without movement (e.g., breath-focused meditation) are shown to improve biological markers of immune function including reduced circulating levels of inflammatory markers (e.g., IL-6, CRP) (Irwin and Olmstead, 2011, Lavretsky et al., 2011, Lavretsky et al., 2012), increased cell-mediated immune response (e.g., varicella-zoster virus (VZV) specific cell-mediated immunity) (Irwin et al., 2003, Irwin et al., 2007, Irwin and Olmstead, 2011), greater rise in antibody titers in response to influenza vaccine (Davidson et al., 2003), greater rise in VZV specific response to vaccine (Irwin et al., 2007) and greater immune cell telomerase activity (Jacobs et al., 2011, Lavretsky et al., 2012). However, the effects of meditation practice on gene expression pathways regulating immune function have not been explored among dementia caregivers.

The present study utilizes an in vivo genomics-based strategy to identify genes that are differentially expressed in immune cells in response to a daily yogic Kirtan Kriya Meditation (KKM) vs. Relaxing Music (RM) listening intervention among family dementia caregivers. The objective is to define upstream transcription-control pathways that mediate the differences in immune cell gene expression profile between treatment groups. We tested the hypothesis that KKM relative to RM would reverse the pattern of increased NF-κB-related transcription of pro-inflammatory cytokines and decreased expression of genes driven by interferon-related transcription factors (i.e., IRF-1), as was previously observed in individuals confronting caregiving stress and other forms of significant life stressors (Cole et al., 2007, Cole et al., 2009, Miller et al., 2008, Miller et al., 2009, Cole, 2008). As such, we hypothesized pre- to post-intervention decreases in expression of NF-κB-related transcripts and increases in expression of IRF-1-related transcripts in KKM relative to RM.

Section snippets

Participants

Over a 12-month study period, a total of 69 family dementia caregivers were screened. Of those screened, 49 were eligible to participate in the study, and four were not interested in participating. Forty-five caregivers were recruited and randomized to the treatment conditions, and 39 completed 8 weeks of the interventions (see Fig. 1 for CONSORT-format flow of participants through the study). Criteria for study inclusion were: (1) being the primary caregivers of an elderly person, (2) being in

Results

Table 1 presents the baseline demographic and clinical characteristics of intervention in 39 intervention completers. Groups were statistically equivalent at baseline across all measures assessed except for BMI; those in the RM vs. KKM condition had a higher mean BMI (M = 29.4 vs. M = 23.5, p = .001, respectively). As reported previously (Lavretsky et al., 2012), the KKM group showed significantly lower levels of depressive symptoms and greater improvement in mental health compared with the RM group,

Discussion

The results of this randomized controlled intervention study show that 8 weeks of structured daily yogic meditation can reverse the pattern of increased expression of NF-κB-associated pro-inflammatory genes and decreased expression of IRF1-associated genes, which were previously observed in healthy individuals confronting caregiving stress and other forms of significant life stressors/adversity (Cole et al., 2007, Cole et al., 2009, Cole, 2008, Miller et al., 2008, Miller et al., 2009). Given

Role of funding source

This work was supported by the Alzheimer's Research and Prevention Foundation grant. Despite contributing training CD audio for Kirtan Kriya the Foundation and Dr Dharma Khlasa did not influence the development of the study design or implementation, or data analyses.

Conflict of interest

H.L. received grant funding from the Forest Research Institute and is a consultant to the Lilly and Dey Pharmaceutical Companies.

Acknowledgments

This work was supported by a Alzheimer's Research and Prevention Foundation grant; and NIH Grants MH077650, MH086481 and AT003480 to H.L., and NIH Grants R01-AG034588; R01-AG026364; R01-CA119159; R01-HL079955; R01 HL095799; P30-AG028748 to MRI; and UCLA CTSI UL1TR000124, and the Cousins Center for Psychoneuroimmunology at the Semel Institute for Neurosciences, and the UCLA Older Americans Independence Center Inflammatory Biology Core to M.R.I.

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