Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability.

OBJECTIVE: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools. METHODS: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (ß) from linear regression, adjusted for BMI and sex, were calculated. RESULTS: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (ß = 0.041, p = 0.002), EFS (ß = 0.696, p = 0.026), and SRS-22r (ß = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (ß = 0.029, p = 0.028) and SRS-22r (ß = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (ß = 0.029, p = 0.037) and SRS-22r (ß = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031). CONCLUSIONS: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.

Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

Family socioeconomic status and child telomere length among the Samburu of Kenya.

Previous research in high-income countries suggests that children from families with lower socioeconomic status (SES) tend to have shorter telomere length - a biomarker of stress and cell aging - than children from families with greater social and economic resources. However, little is known about predictors of child telomere length in low-income settings. Data for the current study are from a sample of 214 Samburu children aged 1-9 years. The Samburu are semi-nomadic pastoralists who live in the Rift Valley of north-central Kenya. Samburu livelihood is based primarily on livestock, and polygynous marriage is common. Drawing on prior ethnographic research, we measured 14 culturally relevant indicators of family SES, including mother's education, head of household's education, whether the child is currently attending school, household spending, mother's employment history, head of household's employment history, mother's perceived wealth, whether the child lives in a modern house, livestock holdings (total, cows, sheep/goats, and camels), mother's wife number, and whether the child lives in a polygynous household. Telomere length was measured in salivary DNA by the quantitative polymerase chain reaction (qPCR) method. Using latent class analysis, we identified four groups of children that are similar based on the 14 indicators of family SES: Lower SES; Middle SES, Traditional; Middle SES, Modern; and Higher SES. SES classes were not significantly associated with child telomere length. In models examining individual indicators of SES, we found that telomere length was 0.57 standard deviations greater for children who lived in families in the lowest quartile of total livestock holdings compared to those in the highest quartile (b = 0.57, p = 0.03). While additional research is needed to identify the mechanisms underlying this counterintuitive finding, the current study highlights the importance of cultural context in shaping the social gradient in health.

Chronic psychosocial and financial burden accelerates 5-year telomere shortening: findings from the Coronary Artery Risk Development in Young Adults Study.

Leukocyte telomere length, a marker of immune system function, is sensitive to exposures such as psychosocial stressors and health-maintaining behaviors. Past research has determined that stress experienced in adulthood is associated with shorter telomere length, but is limited to mostly cross-sectional reports. We test whether repeated reports of chronic psychosocial and financial burden is associated with telomere length change over a 5-year period (years 15 and 20) from 969 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal, population-based cohort, ages 18-30 at time of recruitment in 1985. We further examine whether multisystem resiliency, comprised of social connections, health-maintaining behaviors, and psychological resources, mitigates the effects of repeated burden on telomere attrition over 5 years. Our results indicate that adults with high chronic burden do not show decreased telomere length over the 5-year period. However, these effects do vary by level of resiliency, as regression results revealed a significant interaction between chronic burden and multisystem resiliency. For individuals with high repeated chronic burden and low multisystem resiliency (1 SD below the mean), there was a significant 5-year shortening in telomere length, whereas no significant relationships between chronic burden and attrition were evident for those at moderate and higher levels of resiliency. These effects apply similarly across the three components of resiliency. Results imply that interventions should focus on establishing strong social connections, psychological resources, and health-maintaining behaviors when attempting to ameliorate stress-related decline in telomere length among at-risk individuals.

Justice for all? Beliefs about justice for self and others and telomere length in African Americans.

OBJECTIVE: Believing in justice can protect health. Among marginalized racial minorities however, both endorsing and rejecting beliefs about justice might be critical. The current research examined links between African Americans' beliefs about justice for self and for others and telomere length (TL)-an indicator of biological aging that is increasingly implicated in racial health disparities, with shorter telomeres indicating poorer health. METHOD: Healthy African Americans (N = 118; 30% male; M age = 31.63 years) completed individual differences measures of justice beliefs for self and others and then provided dried blood spot samples that were assayed for TL. RESULTS: We expected that a belief in justice for self would be positively associated with TL, whereas a belief in justice for others would be negatively associated. A significant 3-way interaction with chronological age confirmed this hypothesis-among older African Americans, TL was positively associated with believing in justice for self, but only when this belief was accompanied by a weak endorsement of the belief in justice for others. CONCLUSION: Findings underscore that for racial minorities, health might be best protected when justice beliefs are both endorsed and rebuffed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Socioeconomic Status, Financial Strain, and Leukocyte Telomere Length in a Sample of African American Midlife Men.

BACKGROUND: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced. METHODS: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age. RESULTS: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (χ 2 = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040). CONCLUSION: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.

Childhood adversity, social support, and telomere length among perinatal women.

Adverse perinatal health outcomes are heightened among women with psychosocial risk factors, including childhood adversity and a lack of social support. Biological aging could be one pathway by which such outcomes occur. However, data examining links between psychosocial factors and indicators of biological aging among perinatal women are limited. The current study examined the associations of childhood socioeconomic status (SES), childhood trauma, and current social support with telomere length in peripheral blood mononuclear cells (PBMCs) in a sample of 81 women assessed in early, mid, and late pregnancy as well as 7-11 weeks postpartum. Childhood SES was defined as perceived childhood social class and parental educational attainment. Measures included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, Multidimensional Scale of Perceived Social Support, and average telomere length in PBMCs. Per a linear mixed model, telomere length did not change across pregnancy and postpartum visits; thus, subsequent analyses defined telomere length as the average across all available timepoints. ANCOVAs showed group differences by perceived childhood social class, maternal and paternal educational attainment, and current family social support, with lower values corresponding with shorter telomeres, after adjustment for possible confounds. No effects of childhood trauma or social support from significant others or friends on telomere length were observed. Findings demonstrate that while current SES was not related to telomeres, low childhood SES, independent of current SES, and low family social support were distinct risk factors for cellular aging in women. These data have relevance for understanding potential mechanisms by which early life deprivation of socioeconomic and relationship resources affect maternal health. In turn, this has potential significance for intergenerational transmission of telomere length. The predictive value of markers of biological versus chronological age on birth outcomes warrants investigation.

Telomere length and procedural justice predict stress reactivity responses to unfair outcomes in African Americans.

This experiment demonstrates that chromosomal telomere length (TL) moderates response to injustice among African Americans. Based on worldview verification theory - an emerging psychosocial framework for understanding stress - we predicted that acute stress responses would be most pronounced when individual-level expectancies for justice were discordant with justice experiences. Healthy African Americans (N=118; 30% male; M age=31.63years) provided dried blood spot samples that were assayed for TL, and completed a social-evaluative stressor task during which high versus low levels of distributive (outcome) and procedural (decision process) justice were simultaneously manipulated. African Americans with longer telomeres appeared more resilient (in emotional and neuroendocrine response-higher DHEAs:cortisol) to receiving an unfair outcome when a fair decision process was used, whereas African Americans with shorter telomeres appeared more resilient when an unfair decision process was used. TL may indicate personal histories of adversity and associated stress-related expectancies that influence responses to injustice.

Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.

Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes.

Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002.

Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.

Discrimination, racial bias, and telomere length in African-American men.

BACKGROUND: Leukocyte telomere length (LTL) is an indicator of general systemic aging, with shorter LTL being associated with several chronic diseases of aging and earlier mortality. Identifying factors related to LTL among African Americans may yield insights into mechanisms underlying racial disparities in health. PURPOSE: To test whether the combination of more frequent reports of racial discrimination and holding a greater implicit anti-black racial bias is associated with shorter LTL among African-American men. METHODS: Cross-sectional study of a community sample of 92 African-American men aged between 30 and 50 years. Participants were recruited from February to May 2010. Ordinary least squares regressions were used to examine LTL in kilobase pairs in relation to racial discrimination and implicit racial bias. Data analysis was completed in July 2013. RESULTS: After controlling for chronologic age and socioeconomic and health-related characteristics, the interaction between racial discrimination and implicit racial bias was significantly associated with LTL (b=-0.10, SE=0.04, p=0.02). Those demonstrating a stronger implicit anti-black bias and reporting higher levels of racial discrimination had the shortest LTL. Household income-to-poverty threshold ratio was also associated with LTL (b=0.05, SE=0.02, p<0.01). CONCLUSIONS: Results suggest that multiple levels of racism, including interpersonal experiences of racial discrimination and the internalization of negative racial bias, operate jointly to accelerate biological aging among African-American men. Societal efforts to address racial discrimination in concert with efforts to promote positive in-group racial attitudes may protect against premature biological aging in this population.

Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and Nutrition Examination Survey, 1999-2002.

The purpose of this study was to examine the association between socioeconomic status (SES) and leukocyte telomere length (LTL) - a marker of cell aging that has been linked to stressful life circumstances - in a nationally representative, socioeconomically and ethnically diverse sample of US adults aged 20-84. Using data from the National Health and Nutrition Examination Survey (NHANES), 1999-2002, we found that respondents who completed less than a high school education had significantly shorter telomeres than those who graduated from college. Income was not associated with LTL. African-Americans had significantly longer telomeres than whites, but there were no significant racial/ethnic differences in the association between education and telomere length. Finally, we found that the association between education and LTL was partially mediated by smoking and body mass index but not by drinking or sedentary behavior.

Socioeconomic status and cell aging in children.

Theory suggests that chronic stress associated with disadvantaged social status may lead to acceleration in the rate of decline in physiological functioning. The purpose of this study is to examine the association between parental socioeconomic status (SES) and leukocyte telomere length (LTL), a marker of cell aging, in children. We examined SES and LTL in 70 white and black US children aged 7-13 who participated in the community-based AMERICO (Admixture Mapping for Ethnic and Racial Insulin Complex Outcomes) study. LTL was assessed using the polymerase chain reaction (PCR) method. Parental education was positively associated with child LTL, net of controls for sex, age, race/ethnicity, and family income. Compared to children with at least one college-educated parent, children whose parents never attended college had telomeres shorter by 1,178 base pairs, which is roughly equivalent to 6 years of additional aging. Socioeconomic disparities in cell aging are evident in early life, long before the onset of age-related diseases.

Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women.

Low socioeconomic status (SES) may be associated with accelerated biological aging, but findings relating SES with telomere length have been inconsistent. We tested the hypotheses that shorter telomere length and telomerase activity would be related more robustly to education, an early life indicator of socioeconomic position, than to current indicators of socioeconomic circumstances. Healthy men and women aged 53-76 years from the Whitehall II epidemiological cohort provided blood samples from which telomere length was assessed in 448 and telomerase activity in 416. Educational attainment was classified into four levels, while household income and grade of employment were measured as indicators of current socioeconomic circumstances. Age, gender, blood pressure, glycated hemoglobin, high density lipoprotein cholesterol, smoking, body mass index and physical activity were included as covariates. We found that lower educational attainment was associated with shorter telomere length after controlling statistically for biological and behavioral covariates. Neither household income nor employment grade was related to telomere length. The association between telomere length and education remained significant after adjusting for current socioeconomic circumstances. In men, highest levels of telomerase activity were found in the lowest education group. We conclude that low SES defined in terms of education but not current socioeconomic circumstances is associated with shortened telomeres. Low educational attainment may be an indicator of long-term SES trajectories, and be associated with accumulated allostatic load resulting in telomere shortening. Education may also promote problem-solving skills leading to reduced biological stress responsivity, with favorable consequences for biological aging.