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Barbara L. Fredricksona, Karen M. Grewenb, Kimberly A. Coffeya, Sara B. Algoea, Ann M. Firestinea, Jesusa M. G. Arevaloc, Jeffrey Mac, and Steven W. Colec

To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Pro- moter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (re- duced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-be- ing engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences.

Psychological well-being has been shown to forecast future physical health above and beyond its association with current physical health (1–6), and above and beyond its association with reduced levels of stress, depression, and other negative affective states (2, 3, 5–11). However, the biological basis for this re- lationship remains poorly understood, in part because of a paucity of information regarding the molecular signaling pathways that transduce positive psychological states into somatic physiology (12), and in part because of the multidimensional nature of human well-being (6, 13).
Philosophers have long distinguished two basic forms of well- being: a “hedonic” form representing the sum of an individual’s positive affective experiences, and a deeper “eudaimonic” form that results from striving toward meaning and a noble purpose beyond simple self-gratification (6, 13–16). Both dimensions of well-being are deeply implicated in human biology and evolution (17–24), with hedonic well-being hypothesized to motivate basic physiological and psychological adaptations, and eudaimonic well-being hypothesized to motivate more complex social and cultural capacities (17–19, 25, 26). Although hedonic and eudaimonic well-being are conceptually distinct, they are empirically correlated (14, 27) and can reciprocally influence each other (28, 29). As a result, it has been difficult to determine from observational epidemiology which form of human well-being is most directly related to physical health and longevity (6). It has also been difficult to determine whether hedonic and eudaimonic well-being engage similar biological processes, or whether they
have distinct physiologic consequences (although refs. 13, 30, and 31 provide some initial explorations).

In the present study, we examined the biological implications of hedonic and eudaimonic well-being through the lens of the human genome—a system of ∼21,000 genes that has evolved fundamentally to help humans survive and thrive (i.e., be well) (32). Previous studies have found that circulating immune cells show a systematic shift in basal gene expression profiles during extended periods of stress, threat, or uncertainty (12, 33). This conserved transcriptional response to adversity (CTRA) is characterized by increased expression of genes involved in in- flammation (e.g., proinflammatory cytokines such as IL1B, IL6, IL8, and TNF) and decreased expression of genes involved in type I IFN antiviral responses (e.g., IFI-, OAS-, and MX- family genes) and IgG1 antibody synthesis (e.g., IGJ) (12, 33–35). The CTRA transcriptional program likely evolved to help the im- mune system counter the changing patterns of microbial threat ancestrally associated with changing socioenvironmental con- ditions (e.g., increased risk of wound-related bacterial infection associated with experienced threat or social conflict vs. increased risk of socially mediated viral infection associated with affine social contact) (12, 33, 36). However, in the very different en- vironment of contemporary human society, chronic CTRA ac- tivation by social or symbolic threats may promote inflammation- mediated cardiovascular, neurodegenerative, and neoplastic diseases and impair host resistance to viral infections (12, 33, 37). The present analysis used the CTRA gene expression profile as a high-dimensional molecular reference space in which to map the potentially distinct biological effects of hedonic and eudaimonic well-being.


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