Lower serum ferritin levels are associated with worse cognitive performance in aging.

OBJECTIVES: Iron is important for neurogenesis, synaptic development, and neurotransmitter synthesis. Serum ferritin (SF) is a reliable marker for assessing iron stores. Therefore, we evaluated the cognitive function associated with SF levels. We also assessed brain iron content using R2* Magnetic Resonance Imaging (MRI) and its association with SF levels. DESIGN: Data from three cross-sectional observational studies were used. Aging Imageomics (n = 1030) was conducted on aged subjects. Health Imageomics (n = 971) and IR0NMET (n = 175) were conducted in middle-aged subjects. SETTING AND PARTICIPANTS: Participants were enrolled at Dr. Josep Trueta University Hospital facilities. The three cohorts included a total of 2176 subjects (mean age, 52 years; 48% men). MEASUREMENTS: SF levels were measured by standard laboratory methods. Total Digits Span (TDS), and Phonemic Verbal Fluency (PVF) were used to assess executive function. Language function was assessed by semantic verbal fluency (SVF), attention by the Symbol Digit Modalities Test, and memory by the Memory Binding Tests - Total Free Recall and Total Delayed Free Recall. MRI was used to assess the iron content of the brain by R2*. RESULTS: In subjects aged 65 years or older, SF levels were associated with increased TDS (ß = 0.003, p = 0.02), PVF (ß = 0.004, p = 0.01), and SVF (ß = 0.004, p = 0.002) scores. After stratification by sex, these findings were significant only in men, where SF was associated with increased TDS (ß = 0.003, p = 0.01), PVF (ß = 0.004, p = 0.03), and SVF (ß = 0.004, p = 0.009) scores. In middle-aged subjects, SF was also associated with increased SVF scores (ß = 0.005, p = 0.011). Lastly, in men, SF levels were negatively associated with R2*, a surrogate marker of brain iron content, in both the left frontal inferior opercular area (r = -0.41, p = 0.005) and the right frontal inferior opercular area (r = -0.44, p = 0.002). CONCLUSIONS: SF is significantly and positively associated with cognition. In older people with low SF levels, iron supplementation may be a promising therapy to improve cognition.

Gut microbiota links to serum ferritin and cognition.

Iron is required for the replication and growth of almost all bacterial species and in the production of myelin and neurotransmitters. Increasing clinical studies evidence that the gut microbiota plays a critical role in iron metabolism and cognition. However, the understanding of the complex iron-microbiome-cognition crosstalk remains elusive. In a recent study in the Aging Imageomics cohort (n = 1,030), we identified a positive association of serum ferritin (SF) with executive function (EF) as inferred from the semantic verbal fluency (SVF,) the total digit span (TDS) and the phonemic verbal fluency tests (PVF). Here, we explored the potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. Different bacterial species belonging to the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated both with SF and executive function. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with SF, EF, and semantic memory. Other metabolites such as ureidobutyric acid and 19,20-DiHDPA, a DHA-derived oxylipin, were also consistently and negatively associated with SF, EF, and semantic memory, while plasma eicosapentaenoic acid was positively associated. The associations of SF with cognition could be mediated by the gut microbiome through microbial-derived metabolites.

Inflammatory response to bacterial lipopolysaccharide drives iron accumulation in human adipocytes.

The association among increased inflammation, disrupted iron homeostasis, and adipose tissue dysfunction in obesity has been widely recognized. However, the specific impact of inflammation on iron homeostasis during human adipogenesis and in adipocytes remains poorly understood. In this study, we investigated the effects of bacterial lipopolysaccharide (LPS) on iron homeostasis during human adipocyte differentiation, in fully differentiated adipocytes, and in human adipose tissue. We found that LPS-induced inflammation hindered adipogenesis and led to a gene expression profile indicative of intracellular iron accumulation. This was accompanied by increased expression of iron importers (TFRC and SLC11A2), markers of intracellular iron accumulation (FTH, CYBA, FTL, and LCN2), and decreased expression of iron exporter-related genes (SLC40A1), concomitant with elevated intracellular iron levels. Mechanistically, RNA-seq analysis and gene knockdown experiments revealed the significant involvement of iron importers SLC39A14, SLC39A8, and STEAP4 in LPS-induced intracellular iron accumulation in human adipocytes. Notably, markers of LPS signaling pathway-related inflammation were also associated with a gene expression pattern indicative of intracellular iron accumulation in human adipose tissue, corroborating the link between LPS-induced inflammation and iron accumulation at the tissue level. In conclusion, our findings demonstrate that induction of adipocyte inflammation disrupts iron homeostasis, resulting in adipocyte iron overload.

Plasma Lipidomics Profiles Highlight the Associations of the Dual Antioxidant/Pro-oxidant Molecules Sphingomyelin and Phosphatidylcholine with Subclinical Atherosclerosis in Patients with Type 1 Diabetes.

Here, we report on our study of plasma lipidomics profiles of patients with type 1 diabetes (T1DM) and explore potential associations. One hundred and seven patients with T1DM were consecutively recruited. Ultrasound imaging of peripheral arteries was performed using a high image resolution B-mode ultrasound system. Untargeted lipidomics analysis was performed using UHPLC coupled to qTOF/MS. The associations were evaluated using machine learning algorithms. SM(32:2) and ether lipid species (PC(O-30:1)/PC(P-30:0)) were significantly and positively associated with subclinical atherosclerosis (SA). This association was further confirmed in patients with overweight/obesity (specifically with SM(40:2)). A negative association between SA and lysophosphatidylcholine species was found among lean subjects. Phosphatidylcholines (PC(40:6) and PC(36:6)) and cholesterol esters (ChoE(20:5)) were associated positively with intima-media thickness both in subjects with and without overweight/obesity. In summary, the plasma antioxidant molecules SM and PC differed according to the presence of SA and/or overweight status in patients with T1DM. This is the first study showing the associations in T1DM, and the findings may be useful in the targeting of a personalized approach aimed at preventing cardiovascular disease in these patients.