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Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.

Onset and progression of neurodegenerative disorders, including synucleinopathies such as Parkinson's disease, have been associated with various environmental factors. A highly compelling association from a therapeutic point of view has been found between a physically active lifestyle and a significantly reduced risk for Parkinson's disease. Mimicking such conditions in animal models by promoting physical activity, social interactions, and novel surroundings yields in a so-called enriched environment known to enhance adult neurogenesis, increase synaptic plasticity, and decelerate neuronal loss. Yet, the genes that connect beneficial environmental cues to the genome and delay disease-related symptoms have remained largely unclear. To identify such mediator genes, we used a 2 × 2 factorial design opposing genotype and environment. Specifically, we compared wildtype to transgenic mice overexpressing human , a key gene in synucleinopathies encoding alpha-synuclein, and housed them in a standard and enriched environment from weaning to 12 months of age before profiling their hippocampal transcriptome using RNA-sequencing. Under standard environmental conditions, differentially expressed genes were overrepresented for calcium ion binding, membrane, synapse, and other Gene Ontology terms previously linked to alpha-synuclein biology. Upregulated genes were significantly enriched for genes attributed to astrocytes, microglia, and oligodendrocytes. These disturbances in gene activity were accompanied by reduced levels of several presynaptic proteins and the immediate early genes EGR1 and NURR1. Intriguingly, housing transgenic animals in the enriched environment prevented most of these perturbations in gene activity. In addition, a sustained activation specifically in transgenic animals housed in enriched conditions was observed for several immediate early genes including / , and . These findings suggest a compensatory mechanism through an enriched environment-activated immediate early gene network that prevented most disturbances induced by alpha-synuclein overexpression. This regulatory framework might harbor attractive targets for novel therapeutic approaches that mimic beneficial environmental stimuli.

Fat and physical inactivity are the most evident factors in the pathogenesis of obesity, and fat quality seems to play a crucial role for measures of glucose homeostasis. However, the impact of dietary fat quality on brain function, behavior, and sleep is basically unknown. In this study, mice were fed a diet supplemented with either monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) and their impact on glucose homeostasis, locomotion, brain activity, and sleep behavior was evaluated. MUFAs and SFAs led to a significant increase in fat mass but only feeding of SFAs was accompanied by glucose intolerance in mice. Radiotelemetry revealed a significant decrease in cortical activity in SFA-mice whereas MUFAs even improved activity. SFAs decreased wakefulness and increased non-rapid eye movement sleep. An intracerebroventricular application of insulin promoted locomotor activity in MUFA-fed mice, whereas SFA-mice were resistant. In humans, SFA-enriched diet led to a decrease in hippocampal and cortical activity determined by functional magnetic resonance imaging techniques. Together, dietary intake of MUFAs promoted insulin action in the brain with its beneficial effects for cortical activity, locomotion, and sleep, whereas a comparable intake of SFAs acted as a negative modulator of brain activity in mice and humans.

The gut microbiome plays a critical role in metabolism, immunity, and aging. While endurance training has been shown to beneficially modulate the microbiome, the effects of resistance training remain less clear, with some studies reporting minimal changes. This project aims to investigate whether structured resistance training elicits significant changes in gut microbiome composition and diversity in sedentary, healthy adults. 150 participants completed an 8-week supervised resistance training program. Session-level training data, including weights and repetitions, were recorded alongside metrics like load and compliance. Fecal samples were collected throughout the study period at designated timepoints for 16S rRNA gene amplicon sequencing to assess microbiome composition and for metabolomics analyses to evaluate microbial metabolic activity. No differences in microbial diversity were observed, and there were no significant changes in microbial community composition or fecal metabolomics across all participants post-training. However, within-individual microbial community changes significantly correlated with strength improvement, and significantly stronger shifts in beta diversity were observed in participants with high average strength gains compared to those with smaller gains. In these high responders, differential abundance analysis revealed time-dependent microbial changes, with more taxa enriched or depleted by week 8 of training. Notably, Faecalibacterium and Roseburia hominis—both associated with a healthier, anti-inflammatory microbiome—were significantly enriched. Many differentially abundant taxa belonged to the Lachnospiraceae family. Resistance training drives significant, time-dependent gut microbiome changes, particularly in those demonstrating greater improvements in strength. These shifts mirror endurance training effects and may reflect improved overall health. While endurance training has been consistently shown to enhance gut microbiome composition, the effects of resistance training remain less well defined, with findings to date being variable. Our results indicate that resistance training can induce meaningful, time-dependent shifts in the gut microbiome, particularly among sedentary individuals who experience substantial strength gains. Notably, we observed enrichment of key health-associated taxa, including Faecalibacterium and Roseburia hominis, both linked to anti-inflammatory effects and improved gut function. These findings suggest that resistance training may contribute to gut health in conjunction with physical fitness, supporting its broader application in health promotion strategies and future microbiome-focused research.