Low-serum carotenoid concentrations and carotenoid interactions predict mortality in US adults: the Third National Health and Nutrition Examination Survey

Abstract

Evidence regarding the health benefits of carotenoids is controversial. Effects of serum carotenoids and their interactions on mortality have not been examined in a representative sample of US adults. The objective was to examine whether serum carotenoid concentrations predict mortality among US adults. The study consisted of adults aged ≥20 years enrolled in the Third National Health and Nutrition Examination Survey, 1988 to 1994, with measured serum carotenoids and mortality follow-up through 2006 (N = 13,293). Outcomes were all-cause, cardiovascular disease, and cancer mortality. In adjusted Cox proportional hazards models, participants in the lowest total carotenoid quartile (<1.01 μmol/L) had significantly higher all-cause mortality (mortality rate ratio, 1.38; 95% confidence interval, 1.15-1.65; P = .005) than those in the highest total carotenoid quartile (>1.75 μmol/L). For α-carotene, the highest quartile (>0.11 μmol/L) had the lowest all-cause mortality rates (P < .001). For lycopene, the middle 2 quartiles (0.29-0.58 μmol/L) had the lowest all-cause mortality rates (P = .047). Analyses with continuous carotenoids confirmed associations of serum total carotenoids, α-carotene, and lycopene with all-cause mortality (P < .001). In a random survival forest analysis, very low lycopene was the carotenoid most strongly predictive of all-cause mortality, followed by very low total carotenoids. α-Carotene/β-cryptoxanthin, α-carotene/lutein+zeaxanthin and lycopene/lutein+zeaxanthin interactions were significantly related to all-cause mortality (P < .05). Low α-carotene was the only carotenoid associated with cardiovascular disease mortality (P = .002). No carotenoids were significantly associated with cancer mortality. Very low serum total carotenoid, α-carotene, and lycopene concentrations may be risk factors for mortality, but carotenoids show interaction effects on mortality. Interventions of balanced carotenoid combinations are needed for confirmation.

Figure 1. Continuous Carotenoids and All-Cause Mortality, Third National Health and Nutrition Examination Survey, 1988–1994

Adjusted for demographics (age, sex, race/ethnicity, marital status, education), lifestyle behaviors (alcohol consumption, smoking status, multivitamin/multimineral use, physical activity), biomarkers (body mass index, diastolic blood pressure, systolic blood pressure, total cholesterol, HDL cholesterol, C-reactive protein; models of individual carotenoids included other individual carotenoids), use of blood pressure medication, use of cholesterol-lowering medication, and comorbidities (congestive heart failure, cancer, diabetes, emphysema, stroke) To convert from SI units (µmol/L) to metric (µg/L) divide SI carotenoid concentrations by the following conversion factors: alpha-carotene, beta-carotene, and lycopene = 0.001863; beta-cryptoxanthin= 0.001809; lutein+zeaxanthin = 0.001758. 25, 50, 75, and 95 are labels for the carotenoid 25^th through 95^th percentiles k1 – k5 are labels for locations of carotenoid 1^st through 5^th knots for restricted cubic spline models. The number of knots ranged from 3 to 5 for each carotenoid. CI, confidence interval (shown by dashed lines). P-values from survey-weighted Cox models [31].

Figure 2. Two-Way Carotenoid Interactions and All-Cause Mortality, Third National Health and Nutrition Examination Survey, 1988–1994

Adjusted for demographics (age, sex, race/ethnicity, marital status, education), lifestyle behaviors (alcohol consumption, smoking status, multivitamin/multimineral use, physical activity), biomarkers (body mass index, diastolic blood pressure, systolic blood pressure, total cholesterol, HDL cholesterol, C-reactive protein, other individual carotenoids), use of blood pressure medication, use of cholestero-lowering medication, and comorbidities (congestive heart failure, cancer, diabetes, emphysema, stroke) To convert from SI units (µmol/L) to metric (µg/L) divide SI carotenoid concentrations by the following conversion factors: alpha-carotene, beta-carotene, and lycopene = 0.001863; beta-cryptoxanthin=0.001809; lutein+zeaxanthin = 0.001758. MRR, mortality rate ratio; CI, confidence interval (shown by error bars). P-values from survey-weighted Cox models [31]. Boxed point indicates the reference category (4^th quartile for both carotenoids) Only 13 participants simultaneously had alpha-carotene in the fourth quartile and beta-carotene in the first quartile, among whom 3 deaths occurred, therefore this combination was removed from analyses. Otherwise, the smallest carotenoid combination had 133 participants, and the smallest number of deaths in a carotenoid combination was 19, which are sufficient for the Cox model.