Rural-urban disparities in psychosocial functioning in epithelial ovarian cancer patients.

OBJECTIVE: Although rural residence has been related to health disparities in cancer patients, little is known about how rural residence impacts mental health and quality of life (QOL) in ovarian cancer patients over time. This prospective longitudinal study investigated mental health and QOL of ovarian cancer patients in the first-year post-diagnosis. METHOD: Women with suspected ovarian cancer completed psychosocial surveys pre-surgery, at 6 months and one-year; clinical data were obtained from medical records. Histologically confirmed high grade epithelial ovarian cancer patients were eligible. Rural/urban residence was categorized from patient counties using the USDA Rural-Urban Continuum Codes. Linear mixed effects models examined differences in psychosocial measures over time, adjusting for covariates. RESULTS: Although disparities were not observed at study entry for any psychosocial variable (all p-values >0.22), urban patients showed greater improvement in total distress over the year following diagnosis than rural patients (p = 0.025) and were significantly less distressed at one year (p = 0.03). Urban patients had a more consistent QOL improvement than their rural counterparts (p = 0.006). There were no differences in the course of depressive symptoms over the year (p = 0.17). Social support of urban patients at 12 months was significantly higher than that of rural patients (p = 0.04). CONCLUSION: Rural patients reported less improvement in psychological functioning in the year following diagnosis than their urban counterparts. Clinicians should be aware of rurality as a potential risk factor for ongoing distress. Future studies should examine causes of these health disparities and potential long-term inequities and develop interventions to address these issues.

Socioeconomic inequalities in early adulthood disrupt the immune transcriptomic landscape via upstream regulators.

Disparities in socio-economic status (SES) predict many immune system-related diseases, and previous research documents relationships between SES and the immune cell transcriptome. Drawing on a bioinformatically-informed network approach, we situate these findings in a broader molecular framework by examining the upstream regulators of SES-associated transcriptional alterations. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of 4543 adults in the United States. Results reveal a network-of differentially expressed genes, transcription factors, and protein neighbors of transcription factors-that shows widespread SES-related dysregulation of the immune system. Mediational models suggest that body mass index (BMI) plays a key role in accounting for many of these associations. Overall, the results reveal the central role of upstream regulators in socioeconomic differences in the molecular basis of immunity, which propagate to increase risk of chronic health conditions in later-life.

Experiences of racial discrimination and adverse gene expression among black individuals in a level 1 trauma center sample.

Up to 40 % of individuals who sustain traumatic injuries are at risk for posttraumatic stress disorder (PTSD) and the conditional risk for developing PTSD is even higher for Black individuals. Exposure to racial discrimination, including at both interpersonal and structural levels, helps explain this health inequity. Yet, the relationship between racial discrimination and biological processes in the context of traumatic injury has yet to be fully explored. The current study examined whether racial discrimination is associated with a cumulative measure of biological stress, the gene expression profile conserved transcriptional response to adversity (CTRA), in Black trauma survivors. Two-weeks (T1) and six-months (T2) post-injury, Black participants (N = 94) provided a blood specimen and completed assessments of lifetime racial discrimination and PTSD symptoms. Mixed effect linear models evaluated the relationship between change in CTRA gene expression and racial discrimination while adjusting for age, gender, body mass index (BMI), smoking history, heavy alcohol use history, and trauma-related variables (mechanism of injury, lifetime trauma). Results revealed that for individuals exposed to higher levels of lifetime racial discrimination, CTRA significantly increased between T1 and T2. Conversely, CTRA did not increase significantly over time in individuals exposed to lower levels of lifetime racial discrimination. Thus, racial discrimination appeared to lead to a more sensitized biological profile which was further amplified by the effects of a recent traumatic injury. These findings replicate and extend previous research elucidating the processes by which racial discrimination targets biological systems.

The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers. METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression. RESULTS: Greater hope was significantly related to a steeper cortisol slope, ß = -0.193, p = 0.046, and lower night cortisol, ß = -0.227, p = 0.018, plasma IL-6, ß = -0.142, p = 0.033, and ascites IL-6, ß = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol ß = -0.233,p = 0.017 and ascites IL-6, ß = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, ß = 0.211, p = 0.031. CONCLUSIONS: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope.

Affective reactivity to daily stressors and immune cell gene expression in the MIDUS study.

Affective reactivity to stress is a person-level measurement of how well an individual copes with daily stressors. A common method of measuring affective reactivity entails the estimation of within-person differences of either positive or negative affect on days with and without stressors present. Individuals more reactive to common stressors, as evidenced by affective reactivity measurements, have been shown to have increased levels of circulating pro-inflammatory markers. While affective reactivity has previously been associated with inflammatory markers, the upstream mechanistic links underlying these associations are unknown. Using data from the Midlife in the United States (MIDUS) Refresher study (N = 195; 52% female; 84% white), we quantified daily stress processes over 10 days and determined individuals' positive and negative affective reactivities to stressors. We then examined affective reactivity association with peripheral blood mononuclear cell (PBMC) gene expression of the immune-related conserved transcriptional response to adversity. Results indicated that individuals with a greater decrease in positive affect to daily stressors exhibited heightened PBMC JUNB expression after Bonferroni corrections (p-adjusted < 0.05). JUNB encodes a protein that acts as a transcription factor which regulates many aspects of the immune response, including inflammation and cell proliferation. Due to its critical role in the activation of macrophages and maintenance of CD4+ T-cells during inflammation, JUNB may serve as a potential upstream mechanistic target for future studies of the connection between affective reactivity and inflammatory processes. Overall, our findings provide evidence that affective reactivity to stress is associated with levels of immune cell gene expression.

Mindfulness-Based Stress Reduction reduces pro-inflammatory gene regulation but not systemic inflammation among older adults: A randomized controlled trial.

OBJECTIVE: Aging is associated with increased pro-inflammatory gene expression and systemic inflammation, and psychosocial stress may accelerate these changes. Mindfulness interventions show promise for reducing psychosocial stress and extending healthspan. Inflammatory pathways may play a role. In a sample of lonely older adults, we tested whether mindfulness training reduces proinflammatory gene expression and protein markers of systemic inflammation. METHODS: Lonely older adults (65-85 years; N = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or matched Health Enhancement Program (HEP). Blood was drawn pre- and post-intervention and at 3-month follow-up. In peripheral blood mononuclear cells (PBMCs), RNA profiling was used to assess transcriptional regulation by pro-inflammatory NF-kB as well as ß-adrenergic CREB, antiviral IRF, and glucocorticoid receptor (GR) transcription factors. Plasma was assayed for proinflammatory markers IL-6 and CRP. Analyses tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects. RESULTS: MBSR reduced NF-kB (d = .17, p = .028) but did not alter CREB (d = .10, p = .20), IRF (d = .13, p = .086), or GR activity (d = .14, p = .063) relative to HEP over time. Contrary to predictions, there were no time × condition effects of MBSR compared to HEP on reducing circulating IL-6 or CRP. CONCLUSIONS: In lonely older adults, MBSR reduced cellular pro-inflammatory gene regulation in ways that would predict reduced disease risk. However, no similar effect was observed for circulating protein markers of inflammation. These results provide specificity about how mindfulness interventions may impact distinct inflammatory markers among aging adults in ways that may have important implications for healthspan. TRIAL REGISTRATION: Clinical Trials identifier NCT02888600.

Socioeconomic inequalities in young adulthood disrupt the immune transcriptomic landscape via upstream regulators.

Disparities in socio-economic status (SES) predict many immune system-related diseases, and previous research documents relationships between SES and the immune cell transcriptome. Drawing on a bioinformatically-informed network approach, we situate these findings in a broader molecular framework by examining the upstream regulators of SES-associated transcriptional alterations. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of 4,543 adults in the United States. Results reveal a network-of differentially-expressed genes, transcription factors, and protein neighbors of transcription factors- that shows widespread SES-related dysregulation of the immune system. Mediational models suggest that body mass index plays a key role in accounting for many of these associations. Overall, the results reveal the central role of upstream regulators in socioeconomic differences in the molecular basis of immunity, which propagate to increase risk of chronic health conditions in later-life.

Transcendental Meditation practitioners show reduced expression of the Conserved Transcriptional Response to Adversity.

Background and objectives: A recent exploratory study of transcriptional effects of long-term practice of Transcendental Meditation (TM) technologies found evidence for altered expression of genes associated with health and disease. In the present secondary analysis of those data, we test the more specific hypothesis that this sample of long-term practitioners shows a significant reduction in markers of the "Conserved Transcriptional Response to Adversity" (CTRA), an RNA profile characterized by up-regulated inflammation and down-regulated Type I interferon (IFN) activity. Materials and methods: Data come from a previously published study providing genome-wide transcriptional profiles of peripheral blood mononuclear cells (PBMC) from healthy, 38-year practitioners of TM technologies and matched controls (n = 12, mean age 65). The current analysis specifically tests for differential expression of a previously established CTRA indicator gene score, with cross-validation by promoter-based bioinformatic analysis of CTRA-typical differences in transcription factor activity and monocyte subset cellular origins. Results: Compared to controls, the TM group showed lower expression of a pre-specified set of CTRA indicator genes. These effects were accompanied by genome-wide indications of down-regulated pro-inflammatory transcription factor activity (NF-κB, AP-1), up-regulated activity of Interferon Response Factors (IRF) and reduced transcriptional activity of classical monocytes. Conclusions: A sample of long-term practitioners of TM showed reduced CTRA gene expression in PBMC compared to matched controls, supporting the likely value of further research to evaluate causality and specificity of this potential mechanism of health benefits in meditators.

Social network position and the Conserved Transcriptional Response to Adversity in older Koreans.

BACKGROUND: Social connections are crucial to human health and well-being. Previous research on molecular mechanisms in health has focused primarily on the individual-level perception of social connections (e.g., loneliness). This study adopted socio-centric social network analysis that includes all social ties from the entire population of interest to examine the group-level social connections and their association with a molecular genomic measure of health. METHODS: Using socio-centric (global) social network data from an entire village in Korea, we investigated how social network characteristics are related to immune cell gene expression among older adults. Blood samples were collected (N = 53, 65-79 years) and mixed effect linear model analyses were performed to examine the association between social network characteristics and Conserved Transcriptional Response to Adversity (CTRA) RNA expression patterns. RESULTS: Social network positions measured by k-core score, the degree of cohesive core positions in an entire village, were significantly associated with CTRA downregulation. Such associations emerged above and beyond the effects of perceived social isolation (loneliness) and biobehavioral risk factors (smoking, alcohol, BMI, etc.). Social network size, defined as degree centrality, was also associated with reduced CTRA gene expression, but its association mimicked that of perceived social isolation (loneliness). CONCLUSIONS: The current findings implicate community-level social network characteristics in the regulation of individual human genome function above and beyond individual-level perceptions of connectedness.

Socioeconomic Inequalities and Molecular Risk for Aging in Young Adulthood.

Diverse manifestations of biological aging often reflect disparities in socioeconomic status (SES). In this paper, we examine associations between indicators of SES and an mRNA-based aging signature during young adulthood, before clinical indications of aging are common. We use data from wave V (2016-2018) of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of adults aged 33-43 years, with transcriptomic data from a subset of 2,491 participants. Biological aging is measured using 1) a composite transcriptomic aging signature previously identified by Peters et al.'s out-of-sample meta-analysis (Nat Commun. 2015;6:8570) and 2) 9 subsets that represent functional pathways of coexpressed genes. SES refers to income, education, occupation, subjective social status, and a composite measure combining these 4 dimensions. We examine hypothesized mechanisms through which SES could affect aging: body mass index, smoking, health insurance status, difficulty paying bills, and psychosocial stress. We find that SES-especially the composite measure and income-is associated with transcriptomic aging and immune, mitochondrial, ribosomal, lysosomal, and proteomal pathways. Counterfactual mediational models suggest that the mediators partially account for these associations. The results thus reveal that numerous biological pathways associated with aging are already linked to SES in young adulthood.

Human social genomics: Concepts, mechanisms, and implications for health.

The exciting field of human social genomics provides an evolutionarily informed, multilevel framework for understanding how positive and negative social-environmental experiences affect the genome to impact lifelong health, well-being, behavior, and longevity. In this review, we first summarize common patterns of socially influenced changes in the expression of pro-inflammatory and antiviral immune response genes (e.g., the Conserved Transcriptional Response to Adversity), and the multilevel psychological, neural, and cell signaling pathways by which social factors regulate human gene expression. Second, we examine how these effects are moderated by genetic polymorphisms and the specific types of social-environmental experiences that most strongly affect gene expression and health. Third, we identify positive psychosocial experiences and interventions that have been found to impact gene expression. Finally, we discuss promising opportunities for future research on this topic and how health care providers can use this information to improve patient health and well-being.

Reduced Epigenetic Age in Older Adults With High Sense of Purpose in Life.

Psychosocial risk factors have been linked with accelerated epigenetic aging, but little is known about whether psychosocial resilience factors (eg, Sense of Purpose in Life) might reduce epigenetic age acceleration. In this study, we tested if older adults who experience high levels of Purpose might show reduced epigenetic age acceleration. We evaluated the relationship between Purpose and epigenetic age acceleration as measured by 13 DNA methylation (DNAm) "epigenetic clocks" assessed in 1 572 older adults from the Health and Retirement Study (mean age 70 years). We quantified the total association between Purpose and DNAm age acceleration as well as the extent to which that total association might be attributable to demographic factors, chronic disease, other psychosocial variables (eg, positive affect), and health-related behaviors (heavy drinking, smoking, physical activity, and body mass index [BMI]). Purpose in Life was associated with reduced epigenetic age acceleration across 4 "second-generation" DNAm clocks optimized for predicting health and longevity (false discovery rate [FDR] q < 0.0001: PhenoAge, GrimAge, Zhang epigenetic mortality index; FDR q < 0.05: DunedinPoAm). These associations were independent of demographic and psychosocial factors, but substantially attenuated after adjusting for health-related behaviors (drinking, smoking, physical activity, and BMI). Purpose showed no significant association with 9 "first-generation" DNAm epigenetic clocks trained on chronological age. Older adults with greater Purpose in Life show "younger" DNAm epigenetic age acceleration. These results may be due in part to associated differences in health-related behaviors. Results suggest new opportunities to reduce biological age acceleration by enhancing Purpose and its behavioral sequelae in late adulthood.

Black Mothers in Racially Segregated Neighborhoods Embodying Structural Violence: PTSD and Depressive Symptoms on the South Side of Chicago.

This study employs multi-level and mixed-methods approaches to examine how structural violence affects the health of low-income, single Black mothers. We use multilevel regression models to examine how feeling "trapped" in racially segregated neighborhoods with high levels of violence on the South Side of Chicago affects mothers' (N = 69) reports of posttraumatic stress disorder and depressive symptoms. The relationship between feeling "trapped" and variations in expression of mRNA for the glucocorticoid receptor gene NR3C1 using microarray assays was also examined. The regression models revealed that feeling "trapped" significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation. The mothers' voices revealed a nuanced understanding about how a lack of financial resources to move out of the neighborhood creates feelings of being "trapped" in dangerous situations.

Reduced epigenetic age in older adults who volunteer.

BACKGROUND: Volunteering is associated with improved health and well-being outcomes, including a reduced risk of mortality. However, the biological mechanisms underlying the association between volunteering and healthy aging and longevity have not been well-established. We evaluated if volunteering was associated with reduced epigenetic age acceleration in older adults. METHODS: We evaluated associations between volunteering and age acceleration, measured by 13 DNA methylation (DNAm) "epigenetic clocks" in 4011 older adults (Mage=69 years; SDage=10 years) who participated in the Health and Retirement Study. We assessed 9 first-generation clocks (Horvath, Hannum, Horvath Skin, Lin, Garagnani, Vidalbralo, Weidner, Yang, and Bocklandt, which predict chronological age) and 4 second-generation clocks (Zhang, PhenoAge, GrimAge, and DunedinPoAm, which predict future disease or longevity). We quantified the total associations between volunteering and DNAm age acceleration as well as the extent to which these associations might be attributable to potential confounding by individual demographics (e.g., race), social demographics (e.g., income), health factors (e.g., diabetes), and health behaviors (e.g., smoking). RESULTS: Volunteering was associated with reduced epigenetic age acceleration across 6 epigenetic clocks optimized for predicting health and longevity (False Discovery Rate [FDR] q < 0.0001 for epigenetic clocks: PhenoAge, GrimAge, DunedinPoAm, Zhang mortality, Yang mitotic; FDR q < 0.01: Hannum). These associations were mostly independent of demographic and health factors, but substantially attenuated after adjusting for health behaviors. CONCLUSION: Volunteering was associated with reduced epigenetic age acceleration in 6 of 13 (mostly second-generation) epigenetic clocks. Results provide preliminary evidence that volunteering might provide health benefits through slower biological aging and implicate health behaviors as one potential mechanism of such effects.

Socioeconomic inequalities in molecular risk for chronic diseases observed in young adulthood.

Many common chronic diseases of aging are negatively associated with socioeconomic status (SES). This study examines whether inequalities can already be observed in the molecular underpinnings of such diseases in the 30s, before many of them become prevalent. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a large, nationally representative sample of US subjects who were followed for over two decades beginning in adolescence. We now have transcriptomic data (mRNA-seq) from a random subset of 4,543 of these young adults. SES in the household-of-origin and in young adulthood were examined as covariates of a priori-defined mRNA-based disease signatures and of specific gene transcripts identified de novo. An SES composite from young adulthood predicted many disease signatures, as did income and subjective status. Analyses highlighted SES-based inequalities in immune, inflammatory, ribosomal, and metabolic pathways, several of which play central roles in senescence. Many genes are also involved in transcription, translation, and diverse signaling mechanisms. Average causal-mediated effect models suggest that body mass index plays a key role in accounting for these relationships. Overall, the results reveal inequalities in molecular risk factors for chronic diseases often decades before diagnoses and suggest future directions for social signal transduction models that trace how social circumstances regulate the human genome.

Biobehavioral factors predict an exosome biomarker of ovarian carcinoma disease progression.

BACKGROUND: Biobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors. METHODS: Exosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were analyzed by elastic net machine learning to identify a biomarker predicting rapid (≤6 months) versus more extended disease-free intervals following initial treatment. Samples from a second subgroup of 24 patients were analyzed by mixed-effects linear models to determine whether the progression-predictive biomarker varied longitudinally as a function of biobehavioral risk factors (social isolation and depressive symptoms). RESULTS: An RNA-based molecular signature was identified that discriminated between individuals who had disease progression in ≤6 months versus >6 months, independent of clinical variables (age, disease stage, and grade). In a second group of patients analyzed longitudinally, social isolation and depressive symptoms were associated with upregulated expression of the disease progression propensity biomarker, adjusting for covariates. CONCLUSION: These data identified a novel exosome-derived biomarker indicating propensity of ovarian cancer progression that is sensitive to biobehavioral variables. This derived biomarker may be potentially useful for risk assessment, intervention targeting, and treatment monitoring.

Social Genomics of Methamphetamine Use, HIV Viral Load, and Social Adversity.

BACKGROUND: Social genomics has demonstrated altered inflammatory and type I interferon (IFN) gene expression among people experiencing chronic social adversity. Adverse social experiences such as discrimination and violence are linked to stimulant misuse and HIV, conditions that dysregulate inflammatory and innate antiviral responses, leading to increased HIV viral replication and risk of chronic diseases. PURPOSE: We aimed to determine whether methamphetamine (MA) use, unsuppressed HIV viral load (VL) (≥200 c/mL), and experienced intimate partner violence (IPV) (past 12 months) predicted inflammatory and type I IFN gene expression in HIV-positive Black and Latinx men who have sex with men (MSM). METHODS: Participants were 147 HIV-positive Black and Latinx MSM recruited from the mSTUDY, a cohort of 561 MSM aged 18-45 in Los Angeles, CA, of whom half are HIV-positive and substance-using. Transcriptomic measures of inflammatory and type I IFN activity were derived from RNA sequencing of peripheral blood mononuclear cells and matched to urine drug tests, VL, and survey data across two time points 12 months apart. Analysis used linear random intercept modeling of MA use, unsuppressed VL, and experienced IPV on inflammatory and type I IFN expression. RESULTS: In adjusted models, MA use predicted 27% upregulated inflammatory and 31% upregulated type I IFN expression; unsuppressed VL predicted 84% upregulated type I IFN but not inflammatory expression; and experienced IPV predicted 31% upregulated inflammatory and 26% upregulated type I IFN expression. CONCLUSIONS: In Black and Latinx MSM with HIV, MA use, unsuppressed VL, and experienced IPV predicted upregulated social genomic markers of immune functioning.

Social connection and gene regulation during the COVID-19 pandemic: Divergent patterns for online and in-person interaction.

BACKGROUND: Social connection has been linked to reduced disease risk and enhanced antiviral immunity, but it is unclear whether online social connections have similar effects to those previously documented for in-person/offline social relationships, or whether online connections can substitute for in-person social relations when the latter are restricted. We examined this question in the context of the COVID-19 pandemic, focusing specifically on an immune system gene regulation profile known as the conserved transcriptional response to adversity (CTRA), which is characterized by up-regulation of proinflammatory genes and down-regulation of genes linked to innate antiviral responses and antibody production. METHODS: We analyzed CTRA RNA profiles in blood samples from 142 healthy young adults (69% female, 87% white) during the "social distancing" period of the COVID-19 pandemic. Mixed effect linear models quantified the relation of CTRA gene expression to measures of in-person social connection (number of friends, social eudaimonia, loneliness) and online psychosocial connection (online loneliness, perceived social value in online leisure and educational contexts, and internet use) while controlling for demographic and health factors. RESULTS: Multiple indicators of in-person and generalized social connection were associated with lower CTRA gene expression, whereas no measure of online social connection showed any significant association with CTRA gene expression. CONCLUSION: Experiences of in-person social connection are associated with reduced CTRA gene expression during a period of restricted social interaction. In contrast, online social relationships show no such association. Digitally mediated social relations do not appear to substantially offset the absence of in-person/offline social connection in the context of immune cell gene regulation.

The genomic impact of kindness to self vs. others: A randomized controlled trial.

OBJECTIVE: Prosocial behavior has been linked to improved physical health, but the biological mechanisms involved remain unclear. This study tested whether a 4-week kindness intervention could reduce expression of a stress-related immune response gene signature known as the Conserved Transcriptional Response to Adversity (CTRA). METHODS: In a diverse sample of community adults (N = 182), study participants were randomly assigned to perform 3 kind acts for other people, to perform 3 kind acts for themselves, or to list daily activities (control), on one day per week over 4 weeks. CTRA gene expression was measured by RNA sequencing of dried blood spots (DBS) collected at baseline and 5 weeks later (1 week after completing study assignments). Participants' descriptions of their kind acts were coded for protocol adherence and act content. RESULTS: Participants who were randomized to perform kind acts for others showed significant reductions in CTRA gene expression relative to controls. Participants who were randomized to perform kind acts for themselves also showed significant reductions in CTRA gene expression relative to controls, but this pattern emerged only for those who failed to perform the requested self-kind acts (protocol non-adherent). Those who fully adhered to the self-kindness protocol showed no change in CTRA gene expression and did not differ from controls. Act content analyses implicated self-stress-reducing behavior in the paradoxical effects of self-kindness and the physical presence of others in the effects of prosocial behavior. CONCLUSIONS: Prosocial engagement-doing something kind for others rather than oneself-reduces CTRA gene expression. The nature of kind acts and their intended recipient plays a key role in shaping the genomic impact of kindness.