Pathways of calorie restriction leading an increased metabolic rate. Cells are sensitive to energy levels through molecules that detect ATP/AMP and NAD+/NADH ratios. Energy deficiency will activate the enzymes AMPK and SIRT1, which is also activated by NO, and through their respective phosphorylation and deacetylation, the activity of numerous substrates involved in metabolic functions will be modified. One of these is PGC-1α, which activates the transcription factors NRF-1 and -2 and mtTFA. The former two activate nuclear transcription of genes for mitochondrial biogenesis and the latter does the same in the mitochondria. This accounts for an increase in the numbers and size of mitochondria as well as an enhancement in the respiratory rate. All of these changes elevate the oxidative buffer capacity of the cell, augmenting its resistance to conditions of stress.