Bergstrom, Jaclyn

Abstract Multiple lines of evidence suggest that calorie restriction may slow biological processes related to aging and extend lifespan. To determine whether calorie restriction affects mitochondrial function, we treated fibroblasts from adult donors with serum samples obtained from participants of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study. The CALERIE study enrolled healthy, non-obese middle-aged (average 38y.o) participants to examine the effects of long-term calorie restriction. We studied the serum samples of 177 participants (calorie restriction CR = 121, ad libitum AL = 56) who had specimens available at two timepoints (12 and 24 months). We assessed the basal and maximal mitochondrial respiration of fibroblasts treated with dilute serum for 24 hours. Our results show that the baseline basal and maximal mitochondrial respiration of fibroblasts is positively correlated with the adiposity of the serum donor (R = 0.112, P = 0.137; R = 0.183, P = 0.015, respectively). Interestingly, treatment of fibroblasts with serum collected after 12 months of calorie restriction causes a decrease in both basal and maximal mitochondrial respiration (P = 0.1854; P = 0.0623, respectively). Fibroblasts treated with serum collected after 24 months of calorie restriction exhibited a further reduction in both basal and maximal mitochondrial respiration (P = 0.0174; P = 0.0092, respectively). These findings suggest that the serum of individuals on long term calorie restriction diet comprises factors that can reduce oxidative phosphorylation. This reduction in bioenergetic capacity may align with the theory that calorie restriction leads to a cellular energy-conserving state, which could have implications for cellular aging and metabolism.

Summary Background There are limited data regarding the longitudinal association between MEFIB‐Index (MRE combined with FIB‐4) versus MAST‐Score (MRI‐aspartate aminotransferase) and hepatic decompensation. Aim To examine the longitudinal association between MEFIB‐Index versus MAST‐Score in predicting hepatic decompensation in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI‐PDFF and were followed for hepatic decompensation. Cox‐proportional hazard analyses were used to assess the association between MEFIB‐Index versus MAST‐Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment. Results This meta‐analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB‐Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST‐Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow‐up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB‐Index [HR = 49.22 (95% CI: 6.23–388.64, p < 0.001)] and a positive MAST‐Score [HR = 3.86 (95% CI: 1.46–10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB‐Index ( c ‐statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST‐Score ( c ‐statistic: 0.81, SE = 0.03) ( p < 0.0001) in predicting hepatic decompensation. Conclusion A combination of MRI‐based biomarker and blood tests, MEFIB‐Index and MAST‐Score can predict the risk of hepatic decompensation in patients with MASLD.

Background and Aims: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. Approach and Results: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts (p < 0.05). Conclusions: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

SummaryObjectiveStudies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex‐specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat‐free mass in older women and men enrolled in four similar clinical trials.DesignPooled analyses of data from four double‐blinded, randomized controlled trials.ParticipantsWomen (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months.MeasurementsTwelve‐month changes in BMD, fat mass, fat‐free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin‐like growth factor‐1 (IGF‐1).ResultsWomen on DHEA had increases (mean ± SD; all P < 0.001 vs placebo) in DHEAS (231 ± 164 µg/dL), testosterone (18.6 ± 20.9 µg/dL), (17)estradiol (8.7 ± 11.0 pg/mL) and IGF‐1 (25.1 ± 52.3 ng/mL), and men had increases in DHEAS (269.0 ± 177 µg/dL; P < 0.01), (17)estradiol (4.8 ± 12.2 pg/m; P < 0.01) and IGF‐1 (6.3 ± 41.4 ng/mL; P < 0.05). Women on DHEA had increases in lumbar spine (1.0% ± 3.4%) and trochanter (0.5% ± 3.8%) BMD and maintained total hip BMD (0.0% ± 2.8%); men had no BMD benefit and a decrease in fat mass (−0.4 ± 2.6 kg; all P < 0.01 vs placebo).ConclusionsDehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit‐to‐risk profile for women than oestrogen therapy.