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Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation. The authors describe distinct phases of adaptions in the human plasma proteome to 7 days without food, with profound changes occurring only after 2 days.

Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here, we performed a seven-day water-only fast during which 12 volunteers lost an average 5.7kg (±0.8kg) of weight. We performed in-depth characterisation of the temporal trajectories of ˜3,000 plasma proteins measured before, daily during, and after fasting to demonstrate, for the first time, nine distinct proteomic response profiles, with systemic changes evident only after three days of complete calorie restriction. The multi-organ response to complete caloric restriction showed distinct effects of fasting duration and weight loss and was remarkably conserved across volunteers with >1000 significantly responding proteins. The fasting signature was strongly enriched for extracellular matrix (ECM) proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific ECM protein tenascin-R. Using proteogenomic approaches, we estimated the health consequences for 212 proteins that changed during fasting across ˜500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.