A Review of the Sirtuin System, Its Clinical Implications,
and the Potential Role of Dietary Activators Like Resveratrol:
Part 1

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2010 (Sep); 15 (3): 245–263 ~ FULL TEXT

Gregory S. Kelly, ND

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The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.

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From the FULL TEXT Article:

Introduction

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes – SIRT1 to SIRT7 – have been identified. These seven sirtuin genes code for seven distinct sirtuin enzymes that act as deacetylases or mono-ADP-ribosyltransferases. All sirtuin enzymes are dependent on oxidized nicotinamide adenine dinucleotide (NAD+).

Sirtuins are considered to be regulator genes; genes that control other genes. Sirtuins themselves can also be influenced by other genes and respond in an epigenetic manner to a variety of environmental factors. They are hypothesized to play a particularly important role in an organism’s response to certain types of stress and toxicity. Sirtuins regulate reproductive and chronological lifespan in lower organisms (like yeast and bacteria) and appear to affect biological aspects of mammalian diseases of aging. This lifespan and prolongevity regulatory role appears to be most prominent under circumstances that represent a need for cellular adaptation, such as calorie restriction. [1]

Emerging from research on the sirtuins is a growing appreciation that they comprise a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the current state of sirtuin research, including an overview of the mammalian sirtuin system, sirtuin biological functions, and potential clinical implications. Environmental and nutritional factors that influence the sirtuin system are also discussed.

      Overview of the Mammalian Sirtuin System

The first aspect of the sirtuin system to be identified was in the yeast Saccharomyces cerevisiae. This protein was named silent mating type information regulation-2 (Sir2). Sir2 was subsequently found in the fruit fly (Drosophila melanogaster) and the roundworm (Caenorhabditis elegans). In these organisms Sir2 is involved in the regulation of a variety of metabolic pathways including those involved in aging and longevity. In mammals, the first sirtuin gene identified was silent mating type information regulation-2 homolog (SIRT1). It is considered a homologous gene sequence (biologically equivalent gene sequence across species) to Sir2. The product of the SIRT1 gene is the SIRT1 enzyme (also known as NAD+-dependent deacetylase sirtuin-1). Six other sirtuin genes have been identified in mammals, resulting in seven genes – SIRT1 through SIRT7 – that encode for seven sirtuin enzymes in the mammalian sirtuin system. Sirtuins are found in the nucleus, cytoplasm, and mitochondria. Sirtuins are also widely expressed in a variety of tissues.

      Subcellular Location and Tissue Expression

The mammalian sirtuins occupy three different subcellular compartments. SIRT1, -2, -6, -7 are found in the nucleus; SIRT1 and SIRT2 are also found in the cytoplasm. SIRT3, -4, and -5 are found in the mitochondria (Figure 1). [2, 3] In addition to the differences in subcellular localization, the sirtuins are also expressed in varying amounts in different tissues. Of the seven mammalian sirtuins, SIRT1 has been the most extensively studied. It is highly expressed in several brain regions including the hypothalamus, and has been found in the heart, kidney, liver, pancreas, skeletal muscle, spleen, and white adipose. [2, 4] SIRT2 is reported to be the most abundant sirtuin in adipocytes, found in white and brown adipose tissue. It is also highly expressed in the brain and nervous system. [2, 5-9] SIRT3 is found inside the mitochondria in skeletal muscle, brown and white adipose, heart, kidney, liver, and other metabolically active tissues. [2, 10-14] SIRT4, another mitochondrial sirtuin, is expressed in a variety of metabolically active tissues, including the islets of Langerhans in the pancreas. [2, 10, 15] SIRT5, also a mitochondrial sirtuin, is expressed in a variety of tissues including the liver. [2, 10, 16] SIRT6 is broadly expressed, with the highest levels in adipose tissue, skeletal muscle, brain, and heart. [17-19 ] SIRT7 is found in many cells including adipocytes and cardiomyocytes. [20, 21]

      The Sirtuin Enzymes

Sirtuin enzymes are structurally defined by the presence of two central domains that together form a highly conserved (existing in virtually all organisms) central catalytic histidine residue. The sirtuin core is flanked by variable N- and C-terminal extensions that differ among the sirtuins. The central histidine residue structure has been proposed to function as an enzymatic core. [22]

Sirtuins were originally defined as class III histone deacetylases (also called lysine deacetylases), a family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that deacetylate lysine residues on various proteins. Sirtuin-mediated histone deacetylase reactions are specific for acetylated lysines, removing the acetyl group from the acetyllysine residue in a histone and transferring it to the ADP-ribose moiety of NAD+. This reaction cleaves the NAD+ coenzyme resulting in the formation of a deacetylated protein and the release of nicotinamide and 2’-O-acetyl- ADP-ribose (Figure 2). It was later discovered that sirtuins also participate in non-histone deacetylase reactions. These non-histone deacetylations also remove acetyl groups from acetyllysine-modified proteins and transfer them to NAD+, yielding 2’-O-acetyl-ADP-ribose and nicotinamide. [2, 22-25] Further exploration revealed that some members of this enzyme family possess mono-ribosyltransferase (mono-ADP-ribosyltransferases) activity.

Sirtuin-mediated mono-ribosyltransferase reactions transfer the ADP-ribose group from NAD+ to acceptor proteins in a posttranslational modification called ADP-ribosylation. This reaction produces mono-ADP-ribosylated proteins and, similar to the deacetylation reactions, also yields nicotinamide. [10, 23, 26] Table 1 summarizes the mammalian sirtuins, tissue location, and sirtuin enzymes.

      Genetic Variation

Sirtuin genetic variation has been reported. Existing studies have focused primarily on genetic variation of the SIRT1 gene. SIRT1 has a variety of single nucleotide polymorphisms (SNPs) that tag regions of the gene characterized by genetic variation. These include rs12413112, rs1467568, rs2273773, rs3758391, rs3818292, rs7069102, rs730821, and rs7895833. Homozygous, heterozygous, and noncarriers exist for the major alleles of these SNPs. As an example, the three genotypes for several of the SNPs for SIRT1, as well as their population distribution, are listed in Table 2. [27]

Several observational studies have attempted to elucidate whether there are any associations between SIRT1 genetic variation and health. Evidence to date suggests that there might be an

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