Sirt1

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sirt1

SIRT1 is the mammalian orthologue of yeast Sir2, which has emerged as an important regulator of ageing. SIRT proteins catalyze a unique reaction that requires the coenzyme NAD+ (nicotinamide adenine dinucleotide). In this reaction, nicotinamide (NAM) is liberated from NAD+ and the acetyl group of the substrate is transferred to cleaved NAD+ , generating the metabolite O-acetyl-ADP. Due to the NAD+ dependency, SIRTs are thought to constitute one of the functional links between metabolic activity and genome stability and, finally, aging. SIRT1 deacetylates diverse substrates including PGC-1a, p53, forkhead transcription factor (FOXO), NF-kB, Ku70, MyoD17 and histones. Thus it influences gene silencing, apoptosis, stress resistance, senescence, and fat and glucose metabolism. The combination of these cellular functions might contribute to an antiageing effect in mammals although SIRT1 could also limit replicative lifespan after chronic genotoxic stress. On the other hand, SIRT1 activity has also been linked to tumorigenesis. SIRT1 is important for tumour cell growth and survival, possibly due to SIRT1’s antiapoptotic effect. In addition, SIRT1 participates in the silencing of tumour suppressor genes and SIRT1 overexpression has been observed in cancer cells.

SIRT1 transcription is under the control of at least two negative feedback loops that keep its induction tightly regulated during cellular stress. The transcription factor E2F1 can induce SIRT1 expression. Indeed, etoposide-mediated DNA damage causes E2F1-dependent induction of SIRT1 expression. Importantly, E2F1 is also a substrate of SIRT1 and deacetylation of E2F1 inhibits its activity as a transcriptional activator. As well as being a direct effector of SIRT1 deacetylation, p53 can repress SIRT1 transcription through binding to two response elements within the SIRT1 promoter.

SIRT1 is induced by caloric restriction and is a crucial factor in the resistance to stress-induced apoptosis that occurs with ageing. SIRT1 imparts deacetylase activity to a number of targets that are involved in metabolism and energy homeostasis. Deacetylation of the transcription co-activator PGC1α (peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α) by SIRT1 activates gluconeogenic genes and increases hepatic glucose output during the caloric restriction response. In addition, SIRT1 also deacetylates the liver X receptor and downregulates protein-tyrosine phosphatase 1B (PTP1B), leading to an increase in reverse cholesterol transport and decreased insulin resistance, respectively.

In protozoans, SIRT1 has been linked to the extension of lifespan under conditions leading to low NAD+/NADH ratios, which typically occur under caloric restriction. It was later shown that SIRT1 functions as both, a metabolic regulator and as a mediator of cellular stress response. Aberrant regulation of sirtuin activity has potential implications for the etiology and treatment of several human diseases. For example, SIRT1 deacetylase activity has recently been shown to protect against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. In addition, SIRT1 functions in cancer biology are now emerging and it is tempting to speculate, whether an aberrant sirtuin expression pattern would indicate compromised cellular apoptotic pathways. More recently, it was reported that SIRT1 is a potential mediator of chemoresistance, a commonly occurring phenomenon in cancer therapy.