The Journal of IHP

1MeditationImpact on gene expression

By Polina Kapoustina, ND (Cand)

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BackgroundThere is increasing awareness as well as research to show the negative impacts of chronic stress on health. On the other hand, we are just starting to discover what is occurring on a molecular level in a relaxed state. The “relaxation response” (RR) is defined as a physiological and psychological state that is opposite to the stress or fight-or-flight response (Bhasin 2013). The RR can be elicited through multiple mind-body approaches such as yoga, mediation, tai chi, qi gong, progressive muscle relaxation, biofeedback, and breathing exercises (Bhasin 2013). The common thread between these techniques is two-fold: (1) the focus on a word, sound, phrase, repetitive prayer, or movement and (2) the disregard of everyday thought. These two steps are critical in breaking the train of everyday thinking and influencing physiological changes including decreased oxygen consumption and carbon dioxide elimination, changes in blood pressure, heart and respiratory rate, norepinephrine responsiveness, increased heart rate variability, and alterations in cortical and subcortical brain regions (Bhasin 2013).

Practices such as yoga and meditation have been in use for over 5000 years in India (Qu 2013), but there still remain questions around their biological effects on our health as well as how yoga compares to other types of exercise. Recent evidence shows that meditation practices influence our biology through epigenetic changes. Epigenetic changes involve modifications of gene expression and transcription, with the potential to affect virtually any cell in the body through alterations in cell membrane receptor expression and/ or various signaling

factors. Due to these pervasive and far-reaching effects, meditation practices have the potential to modify chronic disease risk and progression, including heart disease, mood disorders, and autoimmune disorders, and cancer. Current studies are looking at how short and long-term meditation practitioners may regulate immunity, metabolic rate, and response to oxidative stress (Ravnik-Glavac 2012). Such new knowledge helps us understand the best therapeutic applications of meditation, and helps reinforce its importance as an intervention for practitioners and patients alike. This paper will examine the current evidence seeking to elucidate the biological effects of meditation practices.

Clinical TrialsDusek et al. (2008) provide evidence that a RR practice results in genomic expression alterations in healthy subjects. Sustained genetic expression alterations were found in both short-term (N2 group) and long-term meditators (M group) when compared to novices (N1). These types of changes are significantly linked to oxidative phosphorylation, antigen processing and presentation, and apoptosis (Dusek 2008). The authors conclude that regular daily practice is recommended for sustained beneficial effects. Ravnik et al. (2012) further show that a higher state of consciousness is associated with significant changes in gene expression and brain waves. Table 1 shows a summary of results from their study that followed two long-term meditators (20+ years experience) for one year. Their results showed that a higher state of consciousness is characterized by both down-regulation and up-regulation of various

AbstractThere is growing evidence to demonstrate that mind-body practices, such as yoga and meditation, can influence our gene expression and in fact counteract cellular damage that may be induced by states of chronic stress. The changes in genetic expression, as a result of doing these mind-body exercises to elicit the “relaxation response,” a physiological and psychological state that is opposite to the fight-or-flight response, play a significant role in reducing the body's inflammation and states of anxiety. Clinically, this applies to a variety of treatment approaches including heart disease, mental health, autoimmune disease and cancer. These findings highlight the importance of a mind-body "prescription" in medicine and provide tangible data to reaffirm the benefits of what has been practiced for centuries in various parts of the globe.

Polina Kapoustina, BA, ND (cand)Canadian College of Naturopathic MedicineClinic Intern, Robert Schad Naturopathic Clinic1255 Sheppard Avenue East, Toronto, Ontario, M2K 1E2

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Reference Method Outcome

Qu 2013 Prospective studyN = 10, male, 18-50 yo, no chronic disease, good psyc health, in Germany, with previous yoga experience (up to 5 yrs)

Sudarshan Kriya (SK) yoga program (postures, breathing, meditation) or control regimen (nature walk with relaxing music) x 4 consecutive days, 6:30-8:30am every day

Peripheral blood mononuclear cells (PBMCs) were isolated from blood sample, taken right before and after the activities, for gene expression profiling experiments. Rapid changes (within 2 hours) were found in PBMCs of yoga group. 97 unique genes were affected in yoga group vs. 24 in control. Hence a yoga program may have additional health benefits as compared to exercise plus simple relaxation. Effects are global and not specific to molecular pathways.

Black 2013 RCTN = 45 familial dementia caregivers

12 mins daily Kirtan Kriya meditation (KKM) or12 mins daily relaxing music (RM) x 8 weeks

Genome-wide transcriptional profiles were collected at baseline and 8-week mark.

Reduced activity of pro-inflammatory NF-kB and increased interferon response factors. The KKM group showed significantly lower levels of depressive symptoms and greater improvement in mental health compared with the RM group following the intervention. In KKM, 65.2% of the participants showed 50% improvement on the Hamilton Depression Rating scale, and 52% showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale. In RM, 31.2% of the participants showed 50% improvement on the Hamilton Depression Rating scale. 19% showed 50% improvement on the Mental Health Composite Summary score of the Short Form-36 scale. These proportions were significantly different across condition (p<0.05).

Bhasin 2013 Prospective (novices) and cross-sectional (long-term practitioners) study N = 52: 26 healthy subjects (in Boston, USA) with no RR experience (N1, N2) AND 26 healthy subjects with experience of 4-20 years (M)

20mins CD of Relaxation Response (RR) activity: yoga/ meditation/ qi gong/ tai chi/ progressive /biofeedback/ breathing exercises or 20mins of health education CD (control) x 8 weeks

Blood was collected immediately prior, immediately after and 15min after activity, isolating total RNA.

FeNO was measured using a rapid response chemoluminescent Nitric Oxide Analyzer.

Instant increases in FeNO after 20-minute RR elicitation among short-term (N2) and long-term (M) practitioners and the sustained increase 15 minutes later in the M group. Long-term RR practitioners have more transcriptional changes as compared to short-term practitioners at rest. Up-regulated long-term changes induced by RR are linked to telomerase stability and maintenance. RR progressively affected energy metabolism and inflammation pathways. Gene sets for CYP450 family, steroid hormones, retinol metabolism, and cell adhesion pathways were up-regulated in M and N2 with greater enrichment in M. Gene sets linked to energy metabolism (electron transport chain, integration of energy metabolism) and insulin secretion pathways were also up-regulated in M compared to N1 and N2.

Ravnik- Glavac 2012 Preliminary cross-sectional study

N = 2 long-term (20+ years) meditation (using Zen, Kriya goa, Kundalini yoga, and Pranayama x 25 min; eyes open or closed) practitioners followed over 1 year. Age 40-50s, Male, Caucasian

EEG – to measure brain frequencies – during rest and meditation, every 50 seconds

Blood sample – control samples (non-meditating days) and test sample (1h and 15 after meditation) – total RNA isolation performed; analyzed transcription differences b/w different states of consciousness via micro array analysis

EEG: Increased signal power in theta (4-7Hz) and alpha (8-12 Hz) brain frequencies during meditation, mainly in parieto-occipital and frontal regions. Genetic analysis: Down regulation of metabolic and cell cycle processes, signaling, protein transport, regulation of gene expression, DNA repair, epigenetic mechanisms. Immune system activity, apoptotic processes were both up and down-regulated, as well as the response to stress. Up-regulation of genes involved in hemoglobin synthesis, transport of oxygen and nitric oxide, significantly enrichment in glutamate transport, ionotropic glutamate receptor activity, and NADH dehydrogenase activity.

Dusek 2008 N= 58 healthy subjects (19 long term practitioners (M); 19 control (N1); 20 newly trained (N2))

Listened to 20mins of RR CD daily for 8 weeks

Blood transcriptional profiles assessed.

Significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress.

Table 1. Human trials demonstrating the use of yoga practice and its affect on gene expression

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genes, including down-regulation of the stress response, up-regulation of genes involved in hemoglobin synthesis, transport of oxygen and nitric oxide, and enrichment in glutamate transport, glutamate receptor activity, and NADH dehydrogenase activity. Brain EEG showed that there was an increase in theta and alpha brain frequencies during a meditative state. This study does have a small sample size and may not apply to novice meditators, but the results are statistically significant and it is at present the only study that has evaluated brain waves. Long-term meditation practitioners were chosen in this case, according to the authors, in order to isolate the expression changes of a higher state of consciousness, however this does not mean that benefits would be absent among novice practitioners.

Bhasin et al. (2013) studied the acute changes in gene expression that took place within a single session of a RR-eliciting practice.

Over an 8-week period, healthy novice subjects were exposed to 20 minutes of any of the following mind-body interventions: yoga/ meditation/ qi gong/ tai chi/ progressive /biofeedback/ breathing exercises. Fractional exhaled nitric oxide (FeNO) samples were collected at three time points during each session to explain the physiological effects of RR including reduction in blood pressure. FeNO is known to play a prominent role in vascular dilatation (Bashin 2013). This study showed that a relaxed state influences various pathways via mitochondrial signaling. Subjects experienced down-regulation of the NF-kB pathway, mitigating oxidative stress, inflammation, and chronic disease vulnerability. Qu (2013) also looked at the immediate changes that occur within two hours of yoga for four consecutive days. This study showed that yogic practices have rapid effects at the molecular level in circulating immune cells.

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Practices such as yoga and meditation have been in use for over 5000 years in India, but there still remain questions around their biological effects

on our health as well as how yoga compares to other types of exercise.

References

Bhasin MK, Dusek JA, Chang BH, Joseph MG, Denninger JW, Fricchione GL, Benson H, Libermann TA. Relaxation response induces temporal tran-scriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS One. 2013 May 1;8(5):e62817.

Black DS, Cole SW, Irwin MR, Breen E, St Cyr NM, Nazarian N, Khalsa DS, Lavretsky H. Yogic meditation reverses NF-κB and IRF-related transcrip-tome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology. 2013 Mar;38(3):348-55.

Dusek JA, Otu HH, Wohlhueter AL, Bhasin M, Zerbini LF, Joseph MG, Benson H, Libermann TA. Genomic counter-stress changes induced by the relaxation response. PLoS One. 2008 Jul 2;3(7):e2576.

Qu S, Olafsrud SM, Meza-Zepeda LA, Saatcioglu F. Rapid gene expression changes in peripheral blood lymphocytes upon practice of a comprehensive yoga program. PLoS One. 2013 Apr 17;8(4):e61910.

Ravnik-Glavač M, Hrašovec S, Bon J, Dreo J, Glavač D. Genome-wide expression changes in a higher state of consciousness. Conscious Cogn. 2012 Sep;21(3):1322-44.

All the studies described thus far have been prospective or cross-sectional. However, a randomized control trial (RCT) conducted in 2013 investigated a unique population group experiencing chronic stress: caregivers of elderly family members with dementia. This was defined as caring for the family member for at least three days per week. Caregivers often report lower levels of satisfaction with life than healthy controls, showing higher markers of inflammation such as C-reactive protein and IL-1 receptor antagonist, and reduced levels of cellular immunity such as interferon (IFN) (Black 2013). This RCT tested whether a daily yogic meditation intervention could reverse a pattern of pro-inflammatory and anti-antiviral leukocyte transcriptional alterations induced by stress. Results showed a reduction in the activity of pro-inflammatory NF-kB and increased interferon response factors (IRF) (Black 2013). The authors concluded that eight weeks of structured daily yogic meditation reversed the pattern of increased NF-κB-associated pro-inflammatory gene expression and decreased expression of IRF1-associated genes.

Future Directions In summary, there is a growing body of evidence to show that

mind-body practices such as yoga and meditation indeed influence our gene expression and counteract cellular damage induced by chronic stress. More questions still remain: are there certain populations or individuals this kind of practice can make a bigger impact? How do we measure one’s progress in clinical practice based on this information (how much, how often, what type of activity and technique, alone or in a group, how advanced)? Could individual genetic backgrounds influence the ability to achieve higher state of consciousness?

Nonetheless, we now know that the changes in genetic expression as a result of doing mind-body exercises to elicit the relaxation response, both over short and long-term, can play a role in general health but also in specific diseases by reducing inflammation, hypertension (via FeNO vasodilation), and influence states of anxiety. The potential to alter gene expression profiles of circulating immune cells toward a less pro-inflammatory profile is impressive. Clinically this could also have significant implications in treatment approaches of autoimmune disease, cancer and chronic infections. These findings highlight the importance of not underestimating a mind-body prescription: the importance of taking time to de-stress and bring one’s awareness to the present moment.