Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review, we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1–7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases. Sirtuins are NAD+-dependent deacetylases and mono-ADP-ribosyl transferases. They regulate various cellular processes, including chromatin structure and transcription, apoptosis and cell survival, DNA repair, energy metabolism, and inflammation. SIRT1 is involved in chromatin structure and transcription, and regulates the activity of various transcription factors. SIRT1 also plays a role in apoptosis and cell survival, and is involved in the regulation of NF-κB, which is a key regulator of inflammation. SIRT1 is also involved in the regulation of energy metabolism, including glucose metabolism and mitochondrial function. SIRT2 is involved in the regulation of cell cycle and apoptosis, and is found in the cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial sirtuins, and are involved in the regulation of mitochondrial function and energy metabolism. SIRT6 is involved in DNA repair and is involved in the regulation of gene expression. SIRT7 is involved in the regulation of RNA polymerase I-mediated transcription and the expression of ribosomal RNA genes. Sirtuins may underlie the beneficial effects of caloric restriction. Caloric restriction is a dietary regimen in which an organism is provided with at least 20% fewer calories than it would naturally consume ad libitum, while maintaining adequate nutrition. Caloric restriction has been shown to extend the lifespan of various organisms, including yeast, fruit flies, nematodes, crustaceans, spiders, and rodents. Caloric restriction is the only non-genetic method that consistently increases maximal lifespan in mammals. It does so not by keeping animals in an unhealthy state for a longer time, but by actually retarding age-related deterioration, such as by decreased collagen elasticity, development of insulin resistance, a decline in immune function, neuro-behavioural impairments and by delaying the onset (and incidence) of age-related diseases such as cancer and auto-immune disorders.Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review, we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1–7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases. Sirtuins are NAD+-dependent deacetylases and mono-ADP-ribosyl transferases. They regulate various cellular processes, including chromatin structure and transcription, apoptosis and cell survival, DNA repair, energy metabolism, and inflammation. SIRT1 is involved in chromatin structure and transcription, and regulates the activity of various transcription factors. SIRT1 also plays a role in apoptosis and cell survival, and is involved in the regulation of NF-κB, which is a key regulator of inflammation. SIRT1 is also involved in the regulation of energy metabolism, including glucose metabolism and mitochondrial function. SIRT2 is involved in the regulation of cell cycle and apoptosis, and is found in the cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial sirtuins, and are involved in the regulation of mitochondrial function and energy metabolism. SIRT6 is involved in DNA repair and is involved in the regulation of gene expression. SIRT7 is involved in the regulation of RNA polymerase I-mediated transcription and the expression of ribosomal RNA genes. Sirtuins may underlie the beneficial effects of caloric restriction. Caloric restriction is a dietary regimen in which an organism is provided with at least 20% fewer calories than it would naturally consume ad libitum, while maintaining adequate nutrition. Caloric restriction has been shown to extend the lifespan of various organisms, including yeast, fruit flies, nematodes, crustaceans, spiders, and rodents. Caloric restriction is the only non-genetic method that consistently increases maximal lifespan in mammals. It does so not by keeping animals in an unhealthy state for a longer time, but by actually retarding age-related deterioration, such as by decreased collagen elasticity, development of insulin resistance, a decline in immune function, neuro-behavioural impairments and by delaying the onset (and incidence) of age-related diseases such as cancer and auto-immune disorders.