In the recently published review in npj Aging and Mechanisms of Disease, Imai and Guarente have provided a stimulating review about the role of nicotinamide adenine dinucleotide (NAD) in aging. The best known intervention against aging is calorie restriction, which is now recognized to be at the center of aging research. In 2000, Imai et al. published a seminal paper in Nature entitled ‘Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase’. In this paper, they proposed a possible mechanism underlying the benefit of calorie restriction—Sir2 upregulator. Since then, Sir2 family proteins, now called sirtuins, and NAD have attracted researchers’ significant attention for the intervention to promote longevity. The coupling of sirtuin activity and NAD breakdown is a unique mechanism, and the authors portray it with the apt idiom ‘it takes two to tango’. Indeed, as in tango, both sirtuins and NAD are necessary for healthy aging and longevity. When NAD levels decrease with aging, the NAD/sirtuin ‘tango’ falters.