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Background: Cardiovascular disease may be the main reason for stagnant growth in life expectancy in the United States since 2010. The American Heart Association recently released an updated algorithm for evaluating cardiovascular health (CVH)—Life’s Essential 8 (LE8) score. We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. Methods: We included 23 003 nonpregnant, noninstitutionalized participants aged 20 to 79 years who participated in the National Health and Nutrition Examination Survey from 2005 to 2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. The overall CVH was evaluated by the LE8 score (range, 0–100), as well as the score for each component of diet, physical activity, tobacco/nicotine exposure, sleep duration, body mass index, non–high-density lipoprotein cholesterol, blood glucose, and blood pressure. Life table method was used to estimate life expectancy by levels of the CVH. Results: During a median of 7.8 years of follow-up, 1359 total deaths occurred. The estimated life expectancy at age 50 years was 27.3 years (95% CI, 26.1–28.4), 32.9 years (95% CI, 32.3–33.4), and 36.2 years (95% CI, 34.2–38.2) in participants with low (LE8 score Conclusions: Adhering to a high CVH, defined as the LE8 score, is related to a considerably increased life expectancy in US adults, but more research needs to be done in other races and ethnicities (eg, Hispanic and Asian).

Introduction: A previous epigenome-wide association study has causally linked DNA methylation (DNAm) at the SREBF1 gene (cg11024682) with obesity and lipids. However, little is known about whether DNAm at SREBF1 is associated with long-term changes in body adiposity and composition. Hypothesis: We hypothesized that participants with different DNAm at SRBF1 might respond differently to dietary weight-loss interventions on changes in body adiposity and composition. Methods: The current study included 314 individuals with overweight or obese, who participated in POUNDS Lost: a 2-year randomized dietary weight-loss trial. The blood DNAm level was profiled by methylC-capture sequencing at baseline. Regional DNAm at SREBF1 was calculated as the average methylation level over CpGs within ±250 bp of cg11024682. Body composition, including total fat mass (FM), percentage of FM (FM%), total fat-free mass (FFM), percentage of FFM (FFM%), and percentage of trunk fat (TF%) were measured by dual-energy X-ray absorptiometry (DEXA) at baseline, 6 months, and 2 years. Results: Lower regional DNAm at SREBF1 was significantly associated with changes in body composition across 2 years ( Table ). At 6 months, per SD lower regional DNAm at SREBF1 was significantly associated with greater reductions in FM (β [SE] -0.23 [0.07], p=0.002), FM% (-0.30 [0.09], p Conclusions: Overweight and obese individuals with a lower regional DNAm at SREBF1 achieved greater improvement in body composition across the 2-year intervention, independent of concurrent weight loss, suggesting DNAm at SREBF1 is predictive of individuals’ response to treatment.

Introduction: The microRNA-122 (miR-122) is widely involved in the post-transcriptional regulation of glucose and lipid metabolism, and cardiovascular system. Hypothesis: We assessed the hypothesis that decrease in circulating miR-122-5p would be associated with the improvement in cardiovascular health (CVH) score and each component health metric in response to dietary weight-loss interventions. Methods: Circulating miR-122-5p levels were measured at baseline and 6 months among 509 participants with overweight or obesity from the POUNDS LOST trial. We evaluated the CVH score using the newly updated algorithm -life’s essential 8 and calculated the composite score from the available biological health factors (body mass index [BMI], blood lipids, blood glucose, and blood pressure) across the 2-year intervention period. Results: At baseline, lower levels of miR-122-5p were associated with higher CVH scores (PP time*miR-122-5p =0.001). We also found a significant interaction between change in miR-122-5p and dietary fat intake on the 6-months change in CVH ( P = 0.025); a greater decrease in miR-122-5p showed a greater improvement in CVH at 6 months among participants assigned to a low-fat diet. Conclusions: In conclusion, participants with decreased circulating miR-122-5p levels in response to dietary weight-loss interventions had significant improvement in CVH and achieved CVH benefits most strongly when consuming a low-fat diet.

Background: Cardiovascular disease (CVD) may be the main reason for stagnant growth in life expectancy in the US since 2010. The American Heart Association (AHA) recently released updated algorithm for evaluating cardiovascular health (CVH)--life’s essential 8 (LE8) score. Hypothesis: We aimed to quantify the associations of CVH levels, estimated by the LE8 score, with life expectancy in a nationally representative sample of US adults. Methods: We included 23003 adults who participated in the National Health and Nutrition Examination Survey (NHANES) 2005-2018 and whose mortality was identified through linkage to the National Death Index through December 31, 2019. Life table method was used to estimate life expectancy by levels of the CVH. The cause-specific decomposition of the life expectancy differences was evaluated by the Arriaga’s method. Results: During a median of 7.8 years of follow-up, 1359 total deaths occurred (772 in men and 587 in women). The estimated life expectancy at age 50 was 25.5 years (95% CI, 23.8-27.2), 31.2 years (95% CI, 30.4-31.9) and 33.1 years (95% CI, 29.8-36.2) in men with poor, intermediate and ideal CVH, respectively. The corresponding estimated life expectancy at age 50 in women was 29.5 years (95% CI, 27.8-31.1), 34.2 years (95% CI, 33.5-34.9) and 38.4 years (95% CI, 35.4-41.0), respectively. Equivalently, men and women with ideal CVH had an average 7.5 (95% CI, 3.5-11.5) and 8.9 (95% CI, 5.2-12.5) more years of life expectancy at age 50, respectively, compared with their counterparts with poor CVH. In men, on average, 41.8 % of the gained life expectancy at age 50 from adhering to ideal CVH was attributable to reduced CVD death. The corresponding percentage was 44.1 % in women. Similarly significant associations of CVH with life expectancy were observed in Non-Hispanic Whites and Non-Hispanic Blacks but not in Mexican Americans. Conclusions: Adhering to an ideal CVH, defined as the LE8 score, is related to a considerably increased life expectancy in the US adults.

Introduction: Epigenome-wide association studies identified that DNA methylation (DNAm) at the ABCG1 gene (cg06500161) was associated with obesity. However, little is known about whether DNAm at ABCG1 is associated with long-term changes in adiposity and body fat distribution in response to dietary weight-loss interventions. Hypothesis: We hypothesized that participants with varying DNAm at ABCG1 might respond differently to dietary weight-loss interventions on long-term changes in adiposity and body fat distribution. Methods: The current study included 673 participants with overweight/obesity, who were randomly assigned to 1 of 4 diets varying in macronutrient components. Blood DNAm level was profiled by a high-resolution methylC-capture sequencing at baseline. The regional DNAm at ABCG1 was defined as the average methylation level over CpGs within ± 250 bp of cg06500161. Two-year changes in adiposity and Computed Tomography (CT)-measured body fat distribution were calculated. Results: We found that regional DNAm at ABCG1 significantly interacted with dietary protein intake on long-term changes in body weight and waist circumference (WC) at 6 months and 2 years (P-interactionFigure ). Among participants assigned to an average-protein (15%) diet, lower regional DNAm at ABCG1 was associated with greater reductions in body weight and WC at 6 months and 2 years, while opposite associations were found among those assigned to a high-protein (25%) diet. Similar interactions were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (P-interaction Conclusion: Our data indicate that DNAm at ABCG1 interacted with dietary protein intake on long-term changes in adiposity and body fat distribution. Participants with hypomethylation at ABCG1 benefited more in long-term improvement in adiposity and body fat distribution by consuming an average-protein diet.

Introduction: MicroRNA-19 (MiR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). Hypothesis: We assessed the hypothesis that change in circulating miR-19 would be associated with changes in 10-year atherosclerotic CVD (ASCVD) risk and individual cardiovascular risk factors in a dietary weight-loss intervention. Methods: This study included 509 participants with overweight or obesity from the 2-year weight-loss diet intervention study (the POUNDS LOST trial) and with available data on circulating miR-19a/b-3p at baseline and 6 months. The primary outcome was the 6-month change in the ASCVD risk score, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the change in each ASCVD component including blood pressure, lipid profiles, insulin resistance, glucose metabolism, and adiposity measures. Change in habitual physical activity and sleep disturbance were assessed from baseline to 6 months. Results: Circulating miR-19a/b-3p levels significantly decreased during the initial 6-month dietary intervention period (P=0.008, 0.0004, respectively). We found that greater decreases in log-transformed miR-19a/b-3p were related to a greater reduction in ASCVD risk (β[SE]=0.35 [0.13], P=0.01 for miR-19a-3p; β[SE]=0.33 [0.13], P=0.01 for miR-19b-3p) over 6 months. Similar positive associations were observed for changes in diastolic blood pressure with miR-19a/b-3p. Moreover, we found that sleep disturbance was significantly associated with reductions in miR-19a/b-3p from baseline to 6 months (P trend Conclusions: In conclusion, decreased circulating miR-19 levels induced by dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and such associations were more evident in people with no/slight amount of sleep disturbance and an increase in physical activity.

Introduction: The American Heart Association recently introduced an enhanced approach to assess cardiovascular health (CVH): Life’s essential 8 (LE8). Sleep was included as a new component. The current study sought to analyze the relationship between levels of CVH, indicated by the LE8 score, and risks of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD). Hypothesis: We hypothesized that higher CVH, indicated by the LE8 score, was associated with lower risks of CHD, stroke, and CVD; LE8 might also interact with genetic susceptibility. Methods: The current study included 137,794 participants free of CVD from the UK Biobank. CVH was scored at baseline by LE8 (DASH diet score, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure). The LE8 score ranged from 0 to 100; and was categorized as low (0-49), moderate (50-79), and high (80-100). Weighted genetic risk scores (GRS) for CHD and stroke were calculated. Cox proportional hazard model was used to assess the relationship between LE8 and incident CVD outcomes, and potential interaction with age, gender, and GRS. We also compared the performance of LE8 with Life’s Simple 7 (LS7) using Harrell’s C-index. Results: During a median of 10 years, 8,595 CVD cases (6,968 CHD and 1,948 strokes) were documented. A higher LE8 score was associated with remarkably lower risks of CHD, stroke, and CVD (p Conclusions: High level of CVH, defined by LE8, was associated with significantly lower risks of CHD, stroke, and CVD. Such relationships are more pronounced among women, younger adults, and people with a lower genetic predisposition.

Introduction: MicroRNA-21 (MiR-21) is one of the most highly expressed microRNAs in the cardiovascular system and plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Hypothesis: We assessed the hypothesis that circulating miR-21 is associated with the change in overall CVD risk and individual cardiovascular risk factors in response to weight-loss diet interventions. Methods: Circulating miR-21 was measured at baseline and 6 months in 511 participants with overweight or obesity from the 2-year weight-loss diet intervention study, the POUNDS LOST trial. MiR-21-5p is a mature sequence derived from the 5' end of the miR-21 stem-loop precursor and another mature sequence, miR-21-3p, is derived from the 3' end of miR-21. The primary outcome was the change in the global Framingham Risk Score (FRS), which estimates the 10-year probability of a CVD event. Secondary outcomes were the change in the FRS components including systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, insulin, homeostatic model assessment of insulin resistance, gut microbiota metabolites, and adiposity measures. Results: Circulating miR-21-3p levels were positively associated with fasting insulin ( P =0.011), insulin resistance ( P =0.008), and triglycerides ( P =0.003) at baseline. We found that lower pre-intervention expression levels of miR-21-3p and miR-21-5p were related to a greater reduction in FRS (β[SE]=11.020 [5.025], P =0.029 and β[SE]=0.023 [0.008], P =0.005, respectively) over 6 months. The trajectory of the FRS across the 2-year intervention period differed between the patterns of pre-intervention miR-21 ( P time*miR-21-3p =0.002 and P time*miR-21-5p =0.033). Compared to those with a higher level of miR-21, participants with a lower level of miR-21 had a greater decrease in FRS from baseline to 6 months and then increased substantially from 6 months to 2 years. We also found significant interactions between baseline miR-21-5p and dietary fat on change in FRS ( P fat diets* miR-21-5p =0.04). Participants with a lower level of baseline miR-21-5p on the low-fat diet group showed a greater reduction of FRS than those on the high-fat diet at 6 months. In addition, a greater decrease in miR-21-3p rather than miR-21-5p was significantly associated with a greater reduction in body weight (PP =0.002), and improvement in trimethylamine N-oxide ( P =0.011) at 6 months. These associations were attenuated at 2 years of the intervention. Conclusions: In conclusion, decreased circulating miR-21 levels were related to a significant reduction in overall CVD risk and improvement in individual cardiovascular risk factors in response to dietary weight-loss interventions.

Background: MicroRNA (miRNAs) are short non-coding RNAs that play important roles in regulating gene expression. Recently, miR-128-1 was identified as a potential thrifty miRNA that controls energy expenditure, contributing to obesity and metabolic diseases. miR-128-1 is located at the locus harboring the lactase ( LCT ) gene, a hallmark gene of the positive selection and evolutionary adaptation to famine by promoting energy storage. Hypothesis: We investigated whether circulating thrifty miR-128-1 was associated with insulin resistance, adiposity, and energy expenditure among adults with overweight and obesity and tested whether miR-128-1 was associated with changes in these metabolic conditions after low-calorie weight-loss diet interventions. Methods: We included 495 participants from the POUNDS Lost trial with available data on circulating miR-128-1-5p measured at baseline and 6 months after the intervention. The LCT genotype rs4988235, which is responsible for lactase persistence in Europeans, was assessed to analyze the relationship between miR-128-1 and the positive selection at this locus. Outcome measurements included adiposity (weight, waist circumference [WC], and body composition), insulin resistance (HOMA-IR), and energy metabolism. Habitual physical activity was assessed by the Baecke questionnaires; total, leisure time, sport, work index were calculated. Results: The LCT rs4988235 (A) allele was associated with higher levels of miR-128-1 ( p =0.04). Pre-intervention miR-128-1 was significantly and positively associated with HOMA-IR ( p =0.009), insulin ( p =0.008), BMI ( p =0.0002), WC ( p =0.036), and whole-body total % fat mass ( p =0.013), and energy metabolism (resting energy expenditure, oxygen consumption, and carbon dioxide production; p p =0.001) and subscales (leisure index ( p =0.007) and sport index ( p =0.02)). We found significant interactions between miR-128-1 and physical activity on changes in adiposity and insulin resistance at 6 months after the interventions ( P interaction =0.03 for weight; P interaction =0.004 for WC; and P interaction =0.01 for HOMA-IR). Participants with lower levels of physical activity and higher miR-128-1 at baseline responded better to the intervention to improve HOMA-IR at 6 months. There were also significant interactions between changes in miR-128-1 and changes in physical activity on changes in HOMA-IR and energy expenditure. Conclusions: Elevated levels of circulating miR-128-1 were associated with greater adiposity and insulin resistance in adults with overweight and obesity. The thrifty miR-128-1 interacted with physical activity on changes in energy metabolism and insulin sensitivity in response to weight-loss diet interventions.

Background: Bile acids are synthesized from cholesterol in the liver and play pivotal roles in nutrient absorption and metabolic regulation. Altered bile acid metabolism is related to dyslipidemia, and microRNA-34a (miR-34a) may play a pivotal role in the treatment of lipid homeostasis by regulating the bile acid biosynthesis. Hypothesis: We investigated whether weight-loss diet-induced changes in primary and secondary bile acids were associated with the improvements in lipid profiles. We also tested the role of circulating miR-34a in the altered bile acid metabolism in adults with overweight and obesity. Methods: A total of 520 participants of a weight-loss dietary intervention (the POUNDS Lost trial) with data on bile acids and miR-34a were included in the present analysis. Circulating levels of miR-34a and bile acid subtypes (primary and secondary unconjugated bile acids and their taurine-/glycine-conjugates) were measured at baseline and 6 months after the intervention. Outcome measurements were improvements in lipids (triglycerides and cholesterol) in response to the interventions. Results: At baseline, higher levels of primary bile acids (chenodeoxycholate (CDCA), glycocholate (GCA), taurocholate (TCA), and glycochenodeoxycholate (GCDCA) were associated with elevated levels of triglycerides ( P FDR P FDR Conclusions: Changes in the specific primary and secondary bile acid subtypes were related to the improvements in lipid profiles in response to weight-loss diet interventions. Circulating miR-34a might in part contribute to the alterations in the primary bile acid subtypes in obese adults.

Introduction: MicroRNA (miRNAs) are short non-coding RNAs that regulate gene expression at the translational level. Circulating exosomal miRNAs have emerged as novel biomarkers of obesity, insulin resistance, and related metabolic abnormalities. miR-375 has been identified as a regulator of insulin secretion, and miR-375 may also be involved in regulating visceral adiposity and ectopic fat accumulation in the liver. Hypothesis: We aimed to investigate whether changes in circulating miR-375 induced by lifestyle interventions were related to improved visceral adiposity and hepatic fat depot among individuals with abdominal obesity. Methods: This study included adults with abdominal obesity from an 18-month diet and physical activity intervention study (the CENTRAL trial) and with available data on circulating miR-375-3p at baseline (n=222) and 18 months (n=152). Magnetic resonance imaging (MRI) was performed to assess body fat distribution and ectopic fat depots. Outcome measurements included 18-month changes in abdominal (total [TAT], visceral [VAT], deep subcutaneous [DSAT], superficial subcutaneous [SSAT]) adipose tissue area and intrahepatic fat content. Results: At baseline, higher levels of miR-375 were related to lower degrees of BMI ( p =0.0006), waist circumference ( p =0.0008), as well as abdominal adipose tissue area (TAT [ p =0.0024], VAT [ p =0.059], DSAT [ p =0.011], and SSAT [ p =0.0027]). There was a significant increase in circulating miR-375 levels after the 18-month lifestyle interventions ( P by paired t-test < 0.0001). When we analyzed effects (β) of per 1 SD increase in miR-375 changes on the outcomes after adjusting for covariates including baseline levels of miR-375 and BMI, we found that greater increase in miR-375 was associated with larger reductions of VAT (β -8.09 [3.09] cm 2 , p =0.01), as well as DSAT (β -7.87 [2.21] cm 2 , p =0.001) and intrahepatic fat content (β -1.38% [0.5%], p =0.006) at 18 months. Conclusions: Circulating miR-375 levels significantly increased after the long-term lifestyle interventions, and greater increases in miR-375 were related to significant improvements in visceral adiposity and liver fat content that are closely related to insulin resistance in adults with abdominal obesity.

Introduction: Thioredoxin Interacting Protein ( TXNIP ) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes; however, little is known about whether the DNAm level at TXNIP in blood is associated with glycemic changes in response to weight-loss diet interventions. Hypothesis: We hypothesized that participants with varying DNAm level of TXNIP responded differentially to weight-loss diet interventions on glycemic changes. Method: We included 639 overweight and obese participants from Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, who were randomly assigned to 1 of 4 weight-loss diets varying in macronutrient contents. Blood DNAm levels were profiled by a high-resolution methylC-capture sequencing at baseline. We defined regional methylation level of TXNIP as average methylation level over CpGs within 500 bp of cg19693031. Results: Higher regional methylation level at TXNIP was correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (pTXNIP showed significantly different changes in fasting insulin (p-interaction=0.007) and HOMA-IR (p-interaction=0.009) in response to average- vs. high-protein diet intervention at 6 months, independent of weight loss. Among participants with an average-protein diet, higher regional methylation level at TXNIP was associated with a greater reduction of fasting insulin and HOMA-IR at 6 months, while an opposite association was found among those with a high-protein diet. Such difference was attenuated to be nonsignificant at 2 years. Conclusions: DNAm level at TXNIP in blood may modify the effects of diet interventions on changes in glycemic traits, independent of weight loss. Overweight and obese individuals with higher methylation level at TXNIP may benefit more in improving insulin and HOMA-IR by consuming an average-protein diet than a high-protein diet.