Metabolic homeostasis and interventions that influence nutrient uptake are well-established means to influence lifespan even in higher eukaryotes. Until recently, the molecular mechanisms explaining such an effect remained scantily understood. Sirtuins are a group of protein deacetylases that depend on the metabolic intermediate NAD(+) as a cofactor for their function. For this reason they sense metabolic stress and in turn function at multiple levels to exert proper metabolic adaptation. Among other things, sirtuins can perform as histone deacetylases inducing epigenetic changes to modulate transcription and DNA repair. Recent studies have indicated that beyond sirtuins, the activity of other chromatin modifiers, such as histone acetyl transferases, might also be tightly linked to the availability of their intermediate metabolite acetyl-CoA. We summarize current knowledge of the emerging concepts indicating close crosstalk between the epigenetic machineries able to sense metabolic stress, their adaptive metabolic responses and their potential role in longevity.