Plasma acylcarnitines and risk of lower-extremity functional impairment in older adults: a nested case–control study (original) (raw)
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Carnitine Serum Levels in Frail Older Subjects
Nutrients
Frailty is an expression that reconciles and condenses loss of autonomy, both physical and cognitive decline and a wide spectrum of adverse outcomes due to aging. The decrease in physical and cognitive activity is associated with altered mitochondrial function, and energy loss and consequently morbidity and mortality. In this cross-sectional study, we evaluated the carnitine levels in frailty status. The mean serum concentrations of total carnitine (TC) were lower in frail elderly subjects than in prefrail ones (p = 0.0006), higher in frail vs. robust subjects (p < 0.0001), and higher in prefrail vs. robust subjects (p < 0.0001). The mean serum concentrations of free carnitine (FC) were lower in frail elderly subjects than in prefrail ones (p < 0.0001), lower in frail vs. robust subjects (p < 0.0001) and lower in prefrail vs. robust subjects (p = 0.0009). The mean serum concentrations of acylcarnitine (AC) were higher in frail elderly subjects than in prefrail ones (p = ...
Plasma acylcarnitine levels increase with healthy aging
Aging, 2020
Acylcarnitines transport fatty acids into mitochondria and are essential for β-oxidation and energy metabolism. Decreased mitochondrial activity results in increased plasma acylcarnitines, and increased acylcarnitines activate proinflammatory signaling and associate with age-related disease. Changes in acylcarnitines associated with healthy aging, however, are not well characterized. In the present study, we examined the associations of plasma acylcarnitines with age (range: 20-90) in 163 healthy, non-diseased individuals from the predictive medicine research cohort (NCT00336570) and tested for gender-specific differences. The results show that long-chain and very long-chain acylcarnitines increased with age, while many odd-chain acylcarnitines decreased with age. Gender-specific differences were observed for several acylcarnitines, e.g., eicosadienoylcarnitine varied with age in males, and hydroxystearoylcarnitine varied in females. Metabolome-wide association study (MWAS) of ageassociated acylcarnitines with all untargeted metabolic features showed little overlap between genders. These results show that plasma concentrations of acylcarnitines vary with age and gender in individuals selected for criteria of health. Whether these variations reflect mitochondrial dysfunction with aging, mitochondrial reprogramming in response to chronic environmental exposures, early pre-disease change, or an adaptive response to healthy aging, is unclear. The results highlight a potential utility for untargeted metabolomics research to elucidate gender-specific mechanisms of aging and age-related disease.
Frontiers in Endocrinology, 2020
The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM. Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD. Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyltetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50). Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.
Lipids, 2013
The prevalence of hypertension in sub-Saharan Africa is increasing rapidly, and treatment remains challenging. Although the use of L-carnitine in treatment has received much attention, studies reporting on physiological L-carnitine levels in hypertensives are limited. Our aim was to determine physiological levels of L-carnitine and acylcarnitines in African and Caucasian men, and to investigate associations between ambulatory blood pressure (BP) and carnitine levels. Participants included 101 African and 101 Caucasian teachers. Ambulatory BP measurements were conducted, and L-carnitine and acylcarnitine levels determined. African men showed significantly higher systolic BP (p \ 0.001), diastolic BP (p \ 0.001) and L-carnitine levels (p = 0.01). In both ethnic groups, partial regression analyses revealed a positive association between BP and L-carnitine, although in Caucasians it was with systolic (r = 0.20, p = 0.045), and in Africans with diastolic BP (r = 0.23, p = 0.023). After adjusting for confounders, an independent positive association between systolic (R 2 = 0.37, b = 0.12, p = 0.041) and diastolic BP (R 2 = 0.39, b = 0.14, p = 0.018) and L-carnitine and longchain acylcarnitines (R 2 = 0.38, b = 0.17, p = 0.005 and R 2 = 0.39, b = 0.15, p = 0.011) were found, independent of ethnicity. Physiological L-carnitine levels were not only higher in Africans than in Caucasians but also above the expected reference range. Despite promising results on L-carnitine (and its short-chain derivatives) in hypertension treatment regimens, our findings paradoxically show that elevated BP is significantly associated with higher physiological L-carnitine and long-chain acylcarnitine levels.
Exacerbation of cardiovascular ageing by diabetes mellitus and its associations with acyl-carnitines
Aging, 2021
Objective: To demonstrate differences in cardiovascular structure and function between diabetic and nondiabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs-1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acylcarnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.
Serum Levels of Acylcarnitines Are Altered in Prediabetic Conditions
PLoS ONE, 2013
Objective: The role of mitochondrial function in the complex pathogenesis of type 2 diabetes is not yet completely understood. Therefore, the aim of this study was to investigate serum concentrations of short-, medium-and long-chain acylcarnitines as markers of mitochondrial function in volunteers with normal, impaired or diabetic glucose control.
Journal of the American Heart Association, 2017
Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris. This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl-, octanoyl-, palmitoyl-, propionyl-, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow-up, 10.0% of the patients died of...
Biomolecules, 2022
Recent studies support that acylcarnitines exert a significant role in cardiovascular disease development and progression. The aim of this metabolomics-based study was to investigate the association of serum acylcarnitine levels with coronary artery disease (CAD) severity, as assessed via SYNTAX Score. Within the context of the prospective CorLipid trial (NCT04580173), the levels of 13 circulating acylcarnitines were accurately determined through a newly developed HILIC-MS/MS method in 958 patients undergoing coronary angiography in the AHEPA University Hospital of Thessaloniki, Greece. Patients presenting with acute coronary syndrome had significantly lower median acylcarnitine C8, C10, C16, C18:1 and C18:2 values, compared to patients with chronic coronary syndrome (p = 0.012, 0.007, 0.018, 0.011 and <0.001, respectively). Among CAD subgroups, median C5 levels were significantly decreased in unstable angina compared to STEMI (p = 0.026), while median C10, C16, C18:1 and C18:2 l...
Impact of an exercise program on acylcarnitines in obesity: a prospective controlled study
Journal of the International Society of Sports Nutrition, 2012
Background: Acylcarnitine (AC) transport dysfunction into the mitochondrial matrix is one of the pathophysiological mechanisms of type 2 diabetes mellitus (DM). The effect of an aerobic exercise (AE) program on this condition in obese subjects without DM is unclear. Methods: A prospective, randomized, longitudinal, interventional study in a University Research Center involved a 10-week AE program in 32 women without DM and a body mass index (BMI) greater than 27 kg/m 2 . (Cases n = 17; Controls n = 15). The primary objective was to evaluate the influence of a controlled AE program on beta-oxidation according to modifications in short, medium, and long-chain ACs. Secondary objectives were to define the behavior of amino acids, and the correlation between these modifications with metabolic and anthropometric markers. Results: The proportion of dropouts was 17% and 6% in controls and cases, respectively. In cases there was a significant reduction in total carnitine (30.40 [95% CI 28.2 to 35.6]) vs. (29.4 [CI 95% 25.1 to 31.7]) p = 0.0008 and longchain AC C14 (0.06 [95% CI 0.05 to 0.08]) vs. (0.05 [95% CI 0.05 to 0.09]) p = 0.005 and in C18 (0.31 [95% CI 0.27 to 0.45]) vs. (0.28 [95% CI 0.22 to 0.32]) p = 0.03. Free fatty acid levels remained without change during the study in both groups.
Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials
Pharmacological Reviews
Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal b-oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabo-lome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. Significance Statement-This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.