Calorie or dietary restriction increases the concentrations of metabolic effectors such as nicotinamide adenine dinucleotide (NAD+) and AMP while reducing the concentrations of glucose, amino acids, and lipids. Exogenous administration of nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) or the nicotinamide phosphoribosyltransferase (NAMPT) activator P7C3 can increase NAD+ levels. Calorie restriction also reduces the concentrations of the hormonal effectors' insulin, insulin-like growth factor 1 (IGF1) and growth hormone (GH). These effectors stimulate or inhibit the activity of metabolic sensors such as the sirtuins (SIRTs), AMP kinase (AMPK), target of rapamycin (TOR), insulin–IGF1 signaling (IIS) and forkhead box O (FOXO) transcription factors. Sirtuin-activating compounds (STACs) such as SRT1720 and SRT2104 can directly activate SIRT1, whereas rapamycin is a direct inhibitor of TOR. Metformin indirectly activates AMPK. These metabolic sensors regulate downstream activities such as DNA repair, mitochondrial biogenesis and function, stress resistance, stem cell and telomere maintenance, autophagy, chromatin modifications, reduced inflammation, and translation fidelity. The net effect is to tip the scale in favor of homeostasis and compressed morbidity, resulting in a disease-free, more youthful-like state.