Abstract
The pathologic relationship linking obesity and lipid dismetabolism with earlier onset of aging-related disorders, including cardiovascular disease (CVD) and type-2 diabetes (T2D), is not fully elucidate. Chronic inflammatory state, in obese individuals, may accelerate cellular aging. However, leukocyte telomere length (LTL), the cellular biological aging indicator, is elusively linked with obesity. Recent studies indicate that sterol 27-hydroxylase (CYP27A1) is an emerging antiatherogenic enzyme, that, by converting extrahepatic cholesterol to 27-hydroxycholesterol, facilitates cholesterol removal via high-density lipoprotein-cholesterol (HDL-C). We tested the hypothesis that obese subjects who carry at least three copies of CYP27A1 low-hydroxylation (LH) activity genome-wide-validated alleles (rs4674345A, rs1554622A, and rs4674338G) present premature aging, as reflected in shorter LTL and higher levels of CVD/T2D risk factors, including reduced HDL-C. Obese subjects from SPHERE project {n = 1,457; overweight [body mass index (BMI) 25-30 kg/m2] 65.8% and severe-obese (BMI > 30 kg/m2) 34.2%} were characterized for the presence from 0 to 6 LH-CYP27A1 allele copy number. Univariate and multivariable sex-age-smoking-adjusted linear-regression models were performed to compare CVD/T2D risk factors and biological aging (LTL) in relation to the combined BMI-LH groups: overweight-LH: 0-2, overweight-LH: 3-6, severe-obese-LH: 0-2, and severe-obese-LH: 3-6. Higher LTL attrition was found in severe-obese than overweight individuals (p < 0.001). Multivariable model reveals that among severe-obese patients those with LH: 3-6 present higher LTL attrition than LH: 0-2 (p < 0.05). Univariate and multivariable models remarkably show that insulin resistance is higher both in overweight-LH: 3-6 vs overweight-LH: 0-2 (p < 0.001) and in severe-obese-LH: 3-6 vs severe-obese-LH: 0-2 (p < 0.0001), and HDL-C is lower in overweight-LH: 3-6 than overweight-LH: 0-2 (p < 0.05 and p < 001). Finally, most of the well-known (i.e., blood pressure, heart rate, waist to hip, triglycerides, and HDL-C) and novel CVD risk factors [i.e., inflammation markers (C-reactive protein, leukocytes, and chemoattractant protein-1), fibrinogen, and glucose homeostasis (i.e., insulin resistance, and glycated hemoglobin)] are substantially (p < 0.0001) altered in severe-obese-LH: 0-2 vs overweight-LH: 0-2, pointing to the fact that obesity leads to worsen the CVD/T2D risk factor profile. Our study supports evidence that CYP27A1 genetic characterization identifies persons at higher risk to develop CVD and T2D, on which better converge preventive measures, and opens new perspectives on mechanisms that link obesity with aging-related disorders.
Highlights
The dramatic escalation of obesity and overweight prevalence, leading to earlier onset of aging-related cardiovascular disease (CVD), represents an emerging worldwide public health problem [1]
Insulin resistance aFor variables in the original scale, we reported as effect the coefficient beta and 95% confidence intervals (CIs) expressing the change in arithmetic mean of outcome switching from one category to the own reference one [overweight-low hydroxylation (LH): 0–2 or severe-obese LH: 0–2]. bFor log-transformed variables, we reported as effect Δ% = (exp(β) − 1) × 100 and 95% CIs expressing the percent change in geometric mean of variables switching from one category to the own reference one. cCytokines were modeled by means of Tobit regression
We reported as effect the coefficient beta and 95% CIs, expressing the change in arithmetic mean of outcome switching from one category to the own reference one. dOdds ratio (OR) and 95% CIs from adjusted logistic regression for sex, age, and smoking
Summary
The dramatic escalation of obesity and overweight prevalence, leading to earlier onset of aging-related cardiovascular disease (CVD), represents an emerging worldwide public health problem [1]. Mice, lacking in the CYP27A1 with the consequent lessening in 27OHC production, present a failing in estrogen-related cardiovascular protection [14]. 27OHC, Abbreviations: 27OHC, 27-hydroxycholesterol; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; T2D, type-2 diabetes; CYP27A1, sterol 27-hydroxylase; DBP, diastolic blood pressure; ECG, electrocardiogram; ERs, estrogen receptors; HDL-C, high-density lipoprotein-cholesterol; HOMA, homeostasis model assessment; IFNγ, interferon gamma; IL10, interleukin-10; LDL, low-density lipoprotein; LH, low-hydroxylation activity; LTL, leukocyte telomere length; MCP-1, chemoattractant protein-1; MIPα, macrophage inflammatory proteins alpha; SBP, systolic blood pressure; TNFα, tumor necrosis factor alpha; Total-C, total-cholesterol
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