The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation.
Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage.
When overexpressed, the NAD-dependent protein deacetylase Sir2 extends the lifespan of both budding yeast and the nematode worm Caenorhabditis elegans. In the worm, this extension of lifespan requires the FOXO transcription factor daf-16. Three recent articles focusing on mammalian homologues of Sir2 and FOXO have highlighted the mechanisms that generate this genetic interaction. Mammalian SIRT1 deacetylates FOXO3 and/or FOXO4, thus attenuating FOXO-induced apoptosis and potentiating FOXO-induced cell-cycle arrest.
In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha.
Silent information regulator two ortholog 1 (SIRT1) is the human ortholog of the yeast sir2 protein; one of the most important regulators of lifespan extension by caloric restriction in several organisms. Dietary polyphenols, abundant in vegetables, fruits, cereals, wine and tea, were reported to stimulate the deacetylase activity of recombinant SIRT1 protein and could therefore be potential regulators of aging associated processes.
The nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sir2 (silent information regulator 2) regulates gene silencing in yeast and promotes lifespan extension during caloric restriction. The mammalian homologue of Sir2 (SirT1) regulates p53, NF-kappaB and Forkhead transcription factors, and is implicated in stress response. This report shows that the cell-cycle and apoptosis regulator E2F1 induces SirT1 expression at the transcriptional level. Furthermore, SirT1 binds to E2F1 and inhibits E2F1 activities, forming a negative feedback loop.
This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators of Sir2/SIRT1 NAD+-dependent deacetylases, extend the lifespans of multiple species in a Sir2-dependent manner and can delay the onset of age-related diseases such as cancer, diabetes and neurodegeneration in model organisms.
The sirtuin 1 protein (SIRT1) is a member of the class III NAD+-dependent histone deacetylases, which are also referred to as the 'sirtuins'. The sirtuins and silent information regulator 1 (SIRT1) in particular, are known to play a role in the response to DNA damage, metabolism, longevity and carcinogenesis. SIRT1 regulates different cellular processes such as proliferation, differentiation and apoptosis through deacetylation of important regulatory proteins such as p53, FOXO3a and NFkappaB.
PURPOSE OF REVIEW: New discoveries focused on mitochondrial metabolism and gene silencing and their regulation by the sirtuin family of protein deacetylases is stimulating new ideas on how to improve geriatric medicine. Information about sertuins in stem cell biology is scarce. We consider recent information on sirtuin 1, its role in aging and metabolism in several species and tissues, and attempt to anticipate how it might influence stem cell aging.
Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals.