•Chronic stress activates a conserved transcriptional response to adversity (CTRA).•The CTRA involves increased inflammation and decreased antiviral activity.•The CTRA can be assessed at the level of ...mRNA, transcription factors, and cells.•Positive psychological processes can inhibit the CTRA.•The CTRA is associated with cancer and cardiovascular disease.
Gene expression profiling studies of people exposed to chronic threat have identified a Conserved Transcriptional Response to Adversity (CTRA) in circulating immune cells. This physiological pattern is characterized by upregulated expression of genes involved in inflammation and downregulated expression of genes involved in Type I interferon responses. The CTRA is mediated by beta-adrenergic signaling pathways that transduce sympathetic nervous system activity into changes in transcription factor activity and hematopoietic output of myeloid lineage immune cells (monocytes, neutrophils, and dendritic cells). Recent research has begun to identify the CNS processes that regulate peripheral CTRA activity, define its implications for disease, and explore the role of positive psychosocial factors in buffering such effects. The CTRA provides a genomic framework for understanding PNI relationships and connecting macro-level psychosocial processes to the micro-level biology of health and disease.
Recent analyses have discovered broad alterations in the expression of human genes across different social environments. The emerging field of social genomics has begun to identify the types of genes ...sensitive to social regulation, the biological signaling pathways mediating these effects, and the genetic polymorphisms that modify their individual impact. The human genome appears to have evolved specific "social programs" to adapt molecular physiology to the changing patterns of threat and opportunity ancestrally associated with changing social conditions. In the context of the immune system, this programming now fosters many of the diseases that dominate public health. The embedding of individual genomes within a broader metagenomic network provides a framework for integrating molecular, physiologic, and social perspectives on human health.
Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, ...cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology.
When it comes to the pursuit of happiness, popular culture encourages a focus on oneself. By contrast, substantial evidence suggests that what consistently makes people happy is focusing prosocially ...on others. In the current study, we contrasted the mood- and well-being-boosting effects of prosocial behavior (i.e., doing acts of kindness for others or for the world) and self-oriented behavior (i.e., doing acts of kindness for oneself) in a 6-week longitudinal experiment. Across a diverse sample of participants (N = 473), we found that the 2 types of prosocial behavior led to greater increases in psychological flourishing than did self-focused and neutral behavior. In addition, we provide evidence for mechanisms explaining the relative improvements in flourishing among those prompted to do acts of kindness-namely, increases in positive emotions and decreases in negative emotions. Those assigned to engage in self-focused behavior did not report improved psychological flourishing, positive emotions, or negative emotions relative to controls. The results of this study contribute to a growing literature supporting the benefits of prosocial behavior and challenge the popular perception that focusing on oneself is an optimal strategy to boost one's mood. People striving for happiness may be tempted to treat themselves. Our results, however, suggest that they may be more successful if they opt to treat someone else instead.
The Neuroendocrinology of Social Isolation Cacioppo, John T; Cacioppo, Stephanie; Capitanio, John P ...
Annual review of psychology,
2015-Jan-03, Letnik:
66, Številka:
1
Journal Article
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Odprti dostop
Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century. Although the focus of research has been on objective social ...roles and health behavior, the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others. Accordingly, population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior. Human and animal investigations of neuroendocrine stress mechanisms that may be involved suggest that (
a
) chronic social isolation increases the activation of the hypothalamic pituitary adrenocortical axis, and (
b
) these effects are more dependent on the disruption of a social bond between a significant pair than objective isolation per se. The relational factors and neuroendocrine, neurobiological, and genetic mechanisms that may contribute to the association between perceived isolation and mortality are reviewed.
Innate immune responses are regulated by microorganisms and cell death, as well as by a third class of stress signal from the nervous and endocrine systems. The innate immune system also feeds back, ...through the production of cytokines, to regulate the function of the central nervous system (CNS), and this has effects on behaviour. These signals provide an extrinsic regulatory circuit that links physiological, social and environmental conditions, as perceived by the CNS, with transcriptional 'decision-making' in leukocytes. CNS-mediated regulation of innate immune responses optimizes total organism fitness and provides new opportunities for therapeutic control of chronic infectious, inflammatory and neuropsychiatric diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although we generally experience our bodies as being biologically stable across time and situations, an emerging field of research is demonstrating that external social conditions, especially our ...subjective perceptions of those conditions, can influence our most basic internal biological processes—namely, the expression of our genes. This research on human social genomics has begun to identify the types of genes that are subject to social-environmental regulation, the neural and molecular mechanisms that mediate the effects of social processes on gene expression, and the genetic polymorphisms that moderate individual differences in genomic sensitivity to social context. The molecular models resulting from this research provide new opportunities for understanding how social and genetic factors interact to shape complex behavioral phenotypes and susceptibility to disease. This research also sheds new light on the evolution of the human genome and challenges the fundamental belief that our molecular makeup is relatively stable and impermeable to social-environmental influence.
To define the cellular mechanisms of up-regulated inflammatory gene expression and down-regulated antiviral response in people experiencing perceived social isolation (loneliness), we conducted ...integrative analyses of leukocyte gene regulation in humans and rhesus macaques. Five longitudinal leukocyte transcriptome surveys in 141 older adults showed up-regulation of the sympathetic nervous system (SNS), monocyte population expansion, and up-regulation of the leukocyte conserved transcriptional response to adversity (CTRA). Mechanistic analyses in a macaque model of perceived social isolation confirmed CTRA activation and identified selective up-regulation of the CD14⁺⁺/CD16⁻ classical monocyte transcriptome, functional glucocorticoid desensitization, down-regulation of Type I and II interferons, and impaired response to infection by simian immunodeficiency virus (SIV). These analyses identify neuroendocrine-related alterations in myeloid cell population dynamics as a key mediator of CTRA transcriptome skewing, which may both propagate perceived social isolation and contribute to its associated health risks.
functional genomic perspective on human well-being Fredrickson, Barbara L.; Grewen, Karen M.; Coffey, Kimberly A. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2013, Letnik:
110, Številka:
33
Journal Article
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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. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced 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-being 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.
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