BACKGROUNDMind-body practices that elicit the relaxation response (RR) have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion.METHODS/PRINCIPAL FINDINGSWe assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M), 19 healthy controls (group N(1)), and 20 N(1) individuals who completed 8 weeks of RR training (group N(2)). 2209 genes were differentially expressed in group M relative to group N(1) (p<0.05) and 1561 genes in group N(2) compared to group N(1) (p<0.05). Importantly, 433 (p<10(-10)) of 2209 and 1561 differentially expressed genes were shared among long-term (M) and short-term practitioners (N(2)). Gene ontology and gene set enrichment analyses revealed 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. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N(1) controls, 5 N(2) short-term and 6 M long-term practitioners.CONCLUSIONS/SIGNIFICANCEThis study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring RR and stress related responses in multiple disease settings.