Background: Growth differentiation factor 15 (GDF-15) is a homeostatic cytokine that regulates neural and cardio-metabolic functions, and its release is increased in response to stress, injury, and inflammation. In patients with coronary artery disease and heart failure (HF), three separate meta-analyses have found that elevated circulating GDF-15 was predictive of major adverse cardiovascular events (MACE), but none has evaluated its effects on incident MACE including HF and mortality hazard in type 2 diabetes. Methods: MEDLINE, EMBASE, and Scopus databases were queried. Articles that met the predefined eligibility criteria, including prospective studies that reported adjusted hazard ratios (aHRs), were selected according to the Cochrane Handbook and PRISMA guidelines. Study endpoints were (1) MACE including HF, and (2) all-cause mortality. Different GDF-15 concentration measurements were harmonized using a validated mathematical approach to express log₂-transformed values in per standard deviation (SD). Study heterogeneity (I²), quality, and bias were assessed. Results: 19354 patients in 8 prospective studies were included. In 7 studies that reported 4247 MACE among 19200 participants, the incident rate was 22.1% during a median follow-up of 5.6 years. It was found that four of eight studies included HF decompensation or hospitalization as a component of MACE. In 5 studies that reported all-cause mortality, 1893 of 13223 patients died, at an incidence rate of 15.1% over 5.0 years. Of note, each 1 SD increase of log₂[GDF-15] was associated with aHRs of 1.12 (1.09–1.15, I² = 5%, p < 0.000001) and 1.27 (1.11–1.46, I² = 86%, p = 0.00062) and for MACE and all-cause mortality, respectively. Conclusion: Elevated circulating level of GDF-15 was robustly predictive of MACE in patients with T2D but its prognostic significance in the prediction of mortality requires further studies.

Although recent evidence has revealed that a body shape index (ABSI) is correlated with the incidence of death among different ethnicities, there remains a paucity of studies investigating the impact of ABSI on mortality within the Chinese elderly. Our objective was to ascertain the link between ABSI, as well as its alterations over time, and all-cause mortality among Chinese aged 65 y and above. A total of 3789 participants were enrolled from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Cox regressions and restricted cubic splines were employed to assess the association of ABSI and relative changes with all-cause mortality. When nonlinearity was detected, a restricted cubic spline regression was subsequently conducted to compute hazard ratios and 95% confidence intervals. The median survival time was 46 months, and 1342 individuals (35.4%) were reported to have died. ABSI contributed independently to rising death rates among Chinese old populations according to univariate and multivariate Cox regressions. Statistically significant associations were also found stratified by age, sex, and lifestyle. A U-shaped association of ABSI changes with all-cause mortality (p = 0.027) was observed, indicating that old adults with stable ABSI during the follow-up period experienced the lowest risk of mortality. After multivariable adjustment, participants with a 10% reduction in ABSI changes had an increased 9.4% risk of death, while participants with a 10% rise in ABSI changes had an increased 1.9% risk. ABSI and its changes are predictors for all-cause mortality among the elderly Chinese population, which emphasizes the clinical importance of monitoring ABSI and keeping it stable over time.

Background: Insomnia is one of the most prevalent health concerns and has a major impact on human health and quality of life. Increasing evidence indicates the gut microbiota’s role in sleep regulation through the gut–brain axis. This systematic review aims to summarise current evidence on the role of gut microbiota alterations in insomnia. Methods: We searched PubMed, Embase, and Cochrane Library through November 2024 for case–control studies comparing gut microbiota in insomnia subjects and controls. The primary outcome was changes in microbiota diversity and bacteria taxonomy. Results: We included 15 case–control studies from 14 articles, consisting of 1321 subjects (603 insomnia; 718 controls). Eight studies showed reduced alpha diversity and eleven showed altered beta diversity in insomnia subjects. Depletions of specific taxa such as Lactobacillales (class Bacilli), Faecalibacterium, and Lachnospira and the enrichment of Actinobacteria, Bacteroidales (class Bacteroidia), and several genera, including Streptococcus, Blautia, Lactobacillus, Clostridium, Holdemanella, and Eubacterium hallii, were observed in insomnia subjects. There was a negative association between insomnia severity and abundance of Faecalibacterium and Lachnospira, and positive associations with Blautia. Conclusions: This systematic review identifies specific alterations in gut microbiota among insomnia subjects characterised by taxonomic changes that may serve as promising therapeutic targets for sleep disorders.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7–89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Aims: Available atherosclerotic cardiovascular disease (ASCVD) risk calculators predict acute events suboptimally in the elderly. We aimed to determine if DNA methylation (epigenetic) age acceleration (EAA) was associated with atherogenic inflammageing and predictive of adverse outcomes incremental to SCORE2-OP and PREVENT. Methods: Participants stratified by FRAIL scale (robust/pre-frail/frail) were randomly selected in approximately equal proportions from a parent cohort of 1,400 community-living older adults. Five epigenetic clocks were developed from MethylationEPIC-analysed blood DNA to calculate baseline EAA by regressing chronological age on epigenetic age. Proton-NMR was used to profile serum lipoproteins/lipids and GlycA. The primary outcome was a composite endpoint of incident all-cause mortality, cardiovascular hospitalisation (CVH), and ASCVD/ACS hospitalisation (AAH). Time-to-event analyses were performed. Results: Among epigenetic clocks analysed in 535 individuals aged 60–99y, GrimAge2 EAA (Grim2AA) was most significantly associated with cardiometabolic comorbidities and atherogenic inflammageing. During follow-up of 4.6y, 30 were lost to follow-up while 42 experienced AAH. Cox regression determined that Grim2AA was predictive of CVH (p<0.05) and AAH (p<0.01) but not all-cause mortality. For every one-year increase in Grim2AA, the hazards of CVH and AAH were significantly increased by 6% and 11%, respectively. The predictive performance of AAH by SCORE2-OP and PREVENT was improved by Grim2AA: C-index 0.693 to 0.734 (p<0.05) and 0.682 to 0.725 (p<0.01), respectively. In Kaplan-Meier analysis, the probability of AAH was significantly higher in individuals with Grim2AA ≥0 (acceleration or none) than <0 (deceleration) (p<0.01). Conclusion: Grim2AA may independently predict AAH incremental to SCORE2-OP and PREVENT in older adults.

Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the mature human nervous system, plays a central role in neurodevelopment, emotion regulation, and sensory processing. Many psychiatric drugs act on the GABAergic system, highlighting its importance for healthy brain function. Individual differences in brain and circulating GABA levels have traditionally been attributed to genetic variation. However, several gut bacteria produce neuroactive compounds, including GABA, raising the possibility that microbial variation influences peripheral and central GABA levels and related measures in humans. This relationship remains largely unexplored. In a cross-sectional study of 251 healthy adults, we investigated associations between gut microbiota composition, central and peripheral GABA, and associated features. Brain GABA was quantified using magnetic resonance spectroscopy, blood GABA using enzyme-linked immunosorbent assays, and gut microbiota profiles using absolute and relative abundance measures derived from Flow Cytometry Fluorescent In Situ Hybridisation and 16S rRNA gene sequencing. Motor cortex GABA+ levels were positively associated with greater numbers of Bacteroides/Prevotella bacteria. A similar association was observed for blood GABA, which was additionally associated with greater numbers of lactic acid bacteria, Eubacterium rectale/Clostridium coccoides, and Clostridium histolyticum groups, and with predicted microbial gene pathways involved in GABA, propionate, and butyrate biosynthesis. No association was observed between brain and blood GABA concentrations. These findings provide new evidence for relationships between gut bacterial groups and central and peripheral GABA pools, supporting future longitudinal studies of causal links between gut microbiota and host GABA levels, as well as the potential for future intervention studies to influence GABAergic processing.