Sirtuins a central regulator in life processes

This Review in Nature 30th July 2009 is a very important review for Nutritionists to appreciate. It suggests that a family of enzymes the sirtuins have a role in governing the control of both metabolism and genetics. This review looks at sirtuin biology, and the role these proteins have in various age-related diseases
The sirtuins are a highly conserved family of NAD+ -dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to a activities that include cellular stress resistance, genomic stability, tumorigenesis and energy metabolism.. .
In 1914, F. Peyton Rous described the beneficial effects of rats placed on a calorie-restricted diet. Over time, however, other scientists demonstrated the benefits of caloric restriction in species ranging from humans to yeast. Studies in yeast showed that the molecular basis of caloric restriction involves a family of NAD+ -dependent enzymes, the sirtuins.
The first described member of the sirtuin family, yeast Sir2 (silent information regulator 2), was originally isolated in a screen for silencing factors. Then , four proteins (named Sir1-Sir4) were shown to be important regulators of silencing at the mating type locus as well as telomeric DNA.
The Sir family are also key regulators of lifespan .
Sir2 also acts as a histone deacetylase, requiring NAD+ as a co-factor.
In yeast and flies, Sir2levels increased following caloric-restriction treatment.
In sirtuins deficient yeast and mice, this extension of lifespan by caloric restriction is abolished.
To date, seven mammalian homologues have been identified. SIRT6 and SIRT7 being nuclear proteins, SIRT3, SIRT4 and SIRTS mitochondrial proteins, and SIRTl and SIRT2 being found both in the nucleus and the cytoplasm, in a cell and tissue-dependent context.
Sirtuins have a role in maintaining genomic integrity . Yeast and mammalian Sir2 has been shown to inhibit recombination of ribosomal DNA, delocalises to sites of DNA breaks and are involved in deacetylating histone proteins and the absence of this activity results in silencing defects, increased genomic instability and sensitivity to DNA damage.
Mammalian SIRT1 also influences genomic stability. SIRTl can deacetylate various factors linked to the repair of DNA damage, SIRTl appears to regulate epigenetic silencing and chromatin modification, and recent evidence suggests this is achieved, at least in part, through direct regulation of modifying enzymes, such as the histone methyltransferase SUV39Hl.
Mammalian sirtuins also appear to have an important role in regulating cellular stress resistance and modulating the threshold for cell death. In part, this increased stress resistance comes from the interaction ‘with the Forkhead box class 0 (FOXO) family of transcription factors. These mammalian transcription factors regulate both energy status and stress resistance, two properties intimately connected to lifespan extension.
In mammals, blood glucose concentration is maintained within a narrow range under a variety of physiological conditions. During starvation, serum glucose control is achieved in part by hepatic gluconeogenesis. Sirtuins have a role in in this physiological adaptation. The peroxisome proliferator-activated receptor gammacoactivator-1α (PGC-lα.) is a known target of SIRTl-dependent deacetylation, and this coactivator also plays a fundamental part in regulating gluconeogenesis and fatty acid oxidation pathways within the liver. The ability of PGC-lα. to modulate these latter two pathways appears to require SIRTl

The sirtuin family has a much broader role in metabolism than the regulation of glucose homeostasis. SIRTl through its regulation of PPAR-y and PGC-lα activity has a significant regulatory role in fat mobilization and fatty acid oxidation The regulation of PGC-la. activity also suggests a role for sirtuins in the generation of new mitochondria, SIRTS, another mitochondrial sirtuin, is an important regulator of the urea cycle.
Why is the sirtuin family a key regulator of so many seemingly varied processes. The common actor is NAD+, linking sirtuin activity to the underlying metabolic state of the cell. Ingested sugar, fat and protein eventually reduce to a single, simple and versatile intermediate, acetylCoA, which also modifies histones and hence regulates gene expression. Acetylation and NAD + -dependent deacetylation are perhaps the most immediate and versatile connection between intracellular energetics and intracellular fate.
Finkel, Deng & Mostoslavsky 2009 Recent progress in the biology and physiology of sirtuins Nature vol 460 pp 587-591

Martin Eastwood
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