Possible role of NAD as mediator of calorie restriction. In calorie excess (A), glucose is oxidized at a high rate by glycolytic enzymes, which sequesters a portion of the available NAD from the common pool. Thus, Sir2 activity is relatively low. In calorie restriction (B) the flow of carbon through glycolysis and the TCA cycle is low, thus increasing available NAD, elevating Sir2-promoted silencing, and promoting a longer life span.