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Item Epigenome-Wide Association Study and Epigenetic Age Acceleration Associated with Cigarette Smoking among Costa Rican Adults(Scientific Reports, Vol. 12 Núm, 2022) Cárdenas, Andrés; Ecker, Simone; Fadadu, Raj P.; Huen, Karen; Orozco, Allan; McEwen, Lisa M.; Engelbrecht, Hannah Ruth; Gladish, Nicole; Kobor, Michael S.; Rosero Bixby, Luis; Dow, William H.; Rehkopf, David H.Smoking-associated DNA methylation (DNAm) signatures are reproducible among studies of mostly European descent, with mixed evidence if smoking accelerates epigenetic aging and its relationship to longevity. We evaluated smoking-associated DNAm signatures in the Costa Rican Study on Longevity and Healthy Aging (CRELES), including participants from the high longevity region of Nicoya. We measured genome-wide DNAm in leukocytes, tested Epigenetic Age Acceleration (EAA) from five clocks and estimates of telomere length (DNAmTL), and examined effect modification by the high longevity region. 489 participants had a mean (SD) age of 79.4 (10.8) years, and 18% were from Nicoya. Overall, 7.6% reported currently smoking, 35% were former smokers, and 57.4% never smoked. 46 CpGs and five regions (e.g. AHRR, SCARNA6/SNORD39, SNORA20, and F2RL3) were differentially methylated for current smokers. Former smokers had increased Horvath’s EAA (1.69-years; 95% CI 0.72, 2.67), Hannum’s EAA (0.77-years; 95% CI 0.01, 1.52), GrimAge (2.34-years; 95% CI1.66, 3.02), extrinsic EAA (1.27-years; 95% CI 0.34, 2.21), intrinsic EAA (1.03-years; 95% CI 0.12, 1.94) and shorter DNAmTL (− 0.04-kb; 95% CI − 0.08, − 0.01) relative to non-smokers. There was no evidence of effect modification among residents of Nicoya. Our findings recapitulate previously reported and novel smoking-associated DNAm changes in a Latino cohort.Item Insurance and other socioeconomic determinants of elderly longevity in a Costa Rican panel(Journal of Biosocial Science: 37(6), 2005) Rosero Bixby, Luis; Dow, William H.; Laclé Murray, AdrianaOfficial figures show that life expectancy in Costa Rica is longer than in the United States (US), in spite of the fact that per capita health expenditure is only one-tenth that of the US. To check whether this is for real and to explore some of its determinants, 900 Costa Ricans aged 60+ were followed from 1984 to 2001. Follow-up household visits were made, deaths were tracked in the national death registry, and survival status in the voting registry was double-checked. In addition, the survivors were contacted in 2002. Two-thirds of the panel had died by December 2001. Kaplan—Meier curves, life tables and Cox regression were used to analyse the panel's survival. Mortality in the panel was slightly higher than the Costa Rican average and similar to that in the US, confirming the exceptional longevity of Costa Ricans. Survival was substantially lower among unmarried men and individuals with limited autonomy at the beginning of the study. The effect of socioeconomic status is weak. Insurance effects seem to be confounded by selection biases.Item Surprising SES gradients in mortality, health, and biomarkers in a Latin American population of adults(Journal of Gerontology: Social Sciences 64B(1), 2009) Dow, William H.; Rosero Bixby, LuisBackground. To determine socioeconomic status (SES) gradients in the different dimensions of health among elderly Costa Ricans. Hypothesis: SES disparities in adult health are minimal in Costa Rican society. Methods. Data from the Costa Rican Study on Longevity and Healthy Aging study: 8,000 elderly Costa Ricans to determine mortality in the period 2000 – 2007 and a subsample of 3,000 to determine prevalence of several health conditions and biomarkers from anthropometry and blood and urine specimens. Results. The ultimate health indicator, mortality, as well as the metabolic syndrome, reveals that better educated and wealthier individuals are worse off. In contrast, quality of life – related measures such as functional and cognitive disabilities, physical frailty, and depression all clearly worsen with lower SES. Overall self-reprted health (SRH) also shows a strong positive SES gradient. Traditional cardiovascular risk factors such as diabetes and cholesterol are not signifi cantly related to SES, but hypertension and obesity are worse among high-SES individuals. Refl ecting mixed SES gradients in behaviors, smoking and lack of exercise are more common among low SES, but high calorie diets are more common among high SES. Conclusions. Negative modern behaviors among high-SES groups may be reversing cardiovascular risks across SES groups, hence reversing mortality risks. But negative SES gradients in healthy years of life persist.Item Stressors over the life course and neuroendocrine system dysregulation in Costa Rica(Journal of Aging and Health XX(X), 2010) Gersten, Omer; Rosero Bixby, Luis; Dow, William H.Objectives: A key aspect of the increasingly popular allostatic load (AL) framework is that stressors experienced over the entire life course result in physiological dysregulation. Although core to AL theory, this idea has been little tested, and where it has been tested, the results have been mixed. Method: The study analyzes the Costa Rican Study on Longevity and Healthy Aging (CRELES), a new, cross-sectional, and nationally representative survey of older Costa Rican men and women (aged between 60 and 109 years). The survey period is between 2004 and 2006, and the survey has a sample size of 2,827 individuals. This article focuses on the relationship between a variety of stressors experienced over the life course and cortisol, dehydroepiandrosterone sulfate (DHEAS), epinephrine, and norepinephrine analyzed separately and in an index. Results: There are some links between certain stressors and worse cortisol levels, but overall, almost all of the stressors examined are not associated with riskier neuroendocrine biomarker profiles. Discussion: More work is needed, in order to establishthe connection between stressors experienced over the life course and resting levels of the neuroendocrine markers.Item Predicting mortality with biomarkers : a population-based prospective cohort study for elderly Costa Ricans(Population Health Metrics 10(1), 2012) Rosero Bixby, Luis; Dow, William H.Background: Little is known about adult health and mortality relationships outside high-income nations, partly because few datasets have contained biomarker data in representative populations. Our objective is to determine the prognostic value of biomarkers with respect to total and cardiovascular mortality in an elderly population of a middle-income country, as well as the extent to which they mediate the effects of age and sex on mortality. Methods: This is a prospective population-based study in a nationally representative sample of elderly Costa Ricans. Baseline interviews occurred mostly in 2005 and mortality follow-up went through December 2010. Sample size after excluding observations with missing values: 2,313 individuals and 564 deaths. Main outcome: prospective death rate ratios for 22 baseline biomarkers, which were estimated with hazard regression models. Results: Biomarkers significantly predict future death above and beyond demographic and self-reprted health conditions. The studied biomarkers account for almost half of the effect of age on mortality. However, the sex gap in mortality became several times wider after controlling for biomarkers. The most powerful predictors were simple physical tests: handgrip strength, pulmonary peak flow, and walking speed. Three blood tests also predicted prospective mortality: C-reactive protein (CRP), glycated hemoglobin (HbA1c), and dehydroepiandrosterone sulfate (DHEAS). Strikingly, high blood pressure (BP) and high total cholesterol showed little or no predictive power. Anthropometric measures also failed to show significant mortality effects. Conclusions: This study adds to the growing evidence that blood markers for CRP, HbA1c, and DHEAS, along with organ-specific functional reserve indicators (handgrip, walking speed, and pulmonary peak flow), are valuable tools for identifying vulnerable elderly. The results also highlight the need to better understand an anomaly noted previously in other settings: despite the continued medical focus on drugs for BP and cholesterol, high levels of BP and cholesterol have little predictive value of mortality in this elderly population.Item Long-term association of economic inequality and mortality in adult Costa Ricans(Social Science & Medicine; Volumen 74, Número 2, 2012) Modrek, Sepideh; Dow, William H.; Rosero Bixby, LuisDespite the large number of studies, mostly in developed economies, there is limited consensus on the health effects of inequality. Recently a related literature has examined the relationship between relative deprivation and health as a mechanism to explain the economic inequality and health relationship. This study evaluates the relationship between mortality and economic inequality, as measured by area-level Gini coefficients, as well as the relationship between mortality and relative deprivation, in the context of a middle-income country, Costa Rica. We followed a nationally representative prospective cohort of approximately 16,000 individuals aged 30 and over who were randomly selected from the 1984 census. These individuals were then linked to the Costa Rican National Death Registry until Dec. 31, 2007. Hazard models were used to estimate the relative risk of mortality for all-cause and cardiovascular disease mortality for two indicators: canton-level income inequality and relative deprivation based on asset ownership. Results indicate that there was an unexpectedly negative association between canton income inequality and mortality, but the relationship is not robust to the inclusion of canton fixed-effects. In contrast, we find a positive association between relative deprivation and mortality, which is robust to the inclusion of canton fixed-effects. Taken together, these results suggest that deprivation relative to those higher in a hierarchy is more detrimental to health than the overall dispersion of the hierarchy itself, within the Costa Rican context.Item The Nicoya region of Costa Rica : a high longevity island for elderly males(Vienna Yearbook of Population Research, Vol 11, 2013) Rosero Bixby, Luis; Dow, William H.; Rehkopf, David H.Reliable data show that the Nicoyan region of Costa Rica is a hot spot of high longevity. A survival follow-up of 16,300 elderly Costa Ricans estimated a Nicoya death rate ratio (DRR) for males 1990–2011 of 0.80 (0.69–0.93 CI). For a 60-yearold Nicoyan male, the probability of becoming centenarian is seven times that of a Japanese male, and his life expectancy is 2.2 years greater. This Nicoya advantage does not occur in females, is independent of socio-economic conditions, disappears in out-migrants and comes from lower cardiovascular (CV) mortality (DRR = 0.65). Nicoyans have lower levels of biomarkers of CV risk; they are also leaner, taller and suffer fewer disabilities. Two markers of ageing and stress—telomere length and dehydroepiandrosterone sulphate—are also more favourable. The Nicoya diet is prosaic and abundant in traditional foods like rice, beans and animal protein, with low glycemic index and high fibre content.Item Longer leukocyte telomere length in Costa Rica's Nicoya Peninsula: A population-based study(Experimental Gerontology; Volumen 48, Número 11, 2013) Rehkopf, David H.; Dow, William H.; Rosero Bixby, Luis; Lin, Jue; Epel, Elissa S.; Blackburn, Elizabeth H.Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.Item A cross-national comparison of 12 biomarkers finds no universal biomarkers of aging among individuals aged 60 and older(Vienna Yearbook of Population Research, vol.14, 2016) Rehkopf, David H.; Rosero Bixby, Luis; Dow, William H.There is uncertainty about whether biological and anthropometric measures that are clinical risk factors for disease are universally associated with chronological age, or whether these correlations vary depending on the social and economic context. The answer to this question has implications for the malleability of biological aging. To examine this issue, we use population-based data on individuals aged 60 and older from the Costa Rican Study on Longevity and Healthy Aging, and temporally consistent data from the United States National Health and Nutrition Examination Survey and the United States Health and Retirement Study. Our analysis focuses on 12 biomarkers that have been shown in the literature to have an association with age, and that occur prior to the clinical manifestation of disease. We find that there are few consistent patterns of association with age when these biomarkers are stratified by gender, country, and level of education. This result suggests that these measures of biological aging are highly context-dependent, and that none of the 12 biomarkers we examined are universal biomarkers of aging. Future research that investigates composite measures of biological age should test newly proposed measures across gender, social class, and country.Item Differential DNA methylation and lymphocyte proportions in a Costa Rican high longevity region(Epigenetics & Chromatin,vol.10(21), 2017) McEwen, Lisa M.; Morin, Alexander M.; Edgar, Rachel D.; MacIsaac, Julia L.; Jones, Meaghan J.; Dow, William H.; Rosero Bixby, Luis; Kobor, Michael S.; Rehkopf, David H.Background: The Nicoya Peninsula in Costa Rica has one of the highest old-age life expectancies in the world, but the underlying biological mechanisms of this longevity are not well understood. As DNA methylation is hypothesized to be a component of biological aging, we focused on this malleable epigenetic mark to determine its association with current residence in Nicoya versus elsewhere in Costa Rica. Examining a population’s unique DNA methylation pattern allows us to differentiate hallmarks of longevity from individual stochastic variation. These differences may be characteristic of a combination of social, biological, and environmental contexts. Methods: In a cross-sectional subsample of the Costa Rican Longevity and Healthy Aging Study, we compared whole blood DNA methylation profiles of residents from Nicoya (n = 48) and non-Nicoya (other Costa Rican regions, n = 47) using the Infinium HumanMethylation450 microarray. Results: We observed a number of differences that may be markers of delayed aging, such as bioinformatically derived differential CD8+ T cell proportions. Additionally, both site- and region-specific analyses revealed DNA methylation patterns unique to Nicoyans. We also observed lower overall variability in DNA methylation in the Nicoyan population, another hallmark of younger biological age. Conclusions: Nicoyans represent an interesting group of individuals who may possess unique immune cell proportions as well as distinct differences in their epigenome, at the level of DNA methylation