Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-B, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADP- ribose) polymerases (PARPs), a crucial and widespread class of NAD+-consuming post-translational protein modifiers. PARPs share a significant number of roles with sirtuins: these enzymes modulate DNA repair, gene expression, and the activities of signalling pathways. We focus on the expanding cross-talk between sirtuins, transcription factors and PARPs, which is a highly promising therapeutic target in a number of age-related neurodegenerative disorders, including the most devastating: Alzheimer's and Parkinson's diseases.