Modern intensive care medicine enables survival from previously lethal conditions. Risk of death is mostly attributable to lack of recovery from organ failure. Although intensive care has been practiced for over 6 decades, the understanding of why certain patients recover and others don’t remains very limited. Furthermore, organs and tissues from patients who do not swiftly recover, do not show overt signs of cell death but instead accumulate damaged organelles and protein aggregates and reprogram towards other cell lineages. Accumulation of cell damage can be compared with what occurs during ageing, but much more pronounced and within a much shorter time. Even when patients survive, many continue to suffer from severe morbidity, referred to as the legacy of critical illness. This indicates that acute life-threatening illnesses, and/or the intensive care management, induce “carry-over” effects with long-term consequences with important humane and financial implications. We recently showed that nutrient restriction early during critical illness is an intervention that affects these processes. Nutrient restriction unexpectedly accelerated recovery from organ failure and enhanced rehabilitation far beyond the time window of the intervention. These data radically contradict the traditional dogma that early anabolism is required for recovery from critical illnesses. Also, they raise the hypothesis that pathways which are activated by fasting play a key role. This project is designed to understand the underlying molecular and cellular mechanisms of the damage-induced “reprogramming” and the benefit of nutrient restriction, which is essential in order to develop novel preventive and therapeutic interventions. We hypothesize that activated autophagy and repressed deleterious epigenetic alterations play a major role. The results of these studies are expected to pave the way towards novel effective interventions to prevent/treat the debilitating legacy of critical illness.