De Silva, S. | bioRxiv Science

bioRxiv2025

Uncovering Shared and Tissue-Specific Molecular Adaptations to Intermittent Fasting in Liver, Brain, and Muscle

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16-hour daily fasting regimen (IF16) over four months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

molecular biology↗

bioRxiv2024

London taxi drivers leverage regional boundaries to optimise route choices and improve their navigation skill across three decades

The world is defined by boundaries. They segment our experience of time and space, and in virtual environments have been shown to impact navigational choices. Here, we test the impact of boundaries on route choices in a real-world environment (London, UK) with a group of expert navigators: licensed London taxi drivers who are required to memorise the layout of over 26,000 streets to obtain their licence. After presenting photographs of a start location and a goal location, taxi drivers were asked to either accept or reject a third target street as forming part of the direct route or not. Performance increased across the adult life-span period in this group (age: 34 to 67). Taxi drivers were faster and more accurate when the target location formed part of a street network boundary (e.g. streets on the edge of the London neighbourhood Soho). Our results are consistent with taxi drivers exploiting the graph structure of the street network to plan routes, as well as consistent with the formation of hierarchical state representations to reduce the dimensionality of the planning problem. Taken together, we show that navigational skill can improve over decades of exposure and that experts exploit regional boundaries for optimal choices, providing a scaffolding over which to form action plans.

neuroscience↗