The INDIVIDUALIST

A Wiki about biochemical individuality

Nutrigenomics

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Description

Chromosome: 10; Location: 10q21.3

This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.

SIRT1 and the longevity effects of a calorie restricted diet

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of aging. (1)

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. (2)

The demonstrated roles of SIRT1, the mammalian counterpart of the yeast SIR2, reveal that SIRT1 regulates important cellular processes including anti-apoptosis, neuronal protection, cellular senescence, aging and longevity. Based on the observations that SIRT1 is upregulated in tumor cells, the hypothesis is that deregulation of SIRT1 expression may promote tumorigenesis by altering cellular signaling or by inducing modulation of chromatin remodeling leading to promotion of tumorigenesis. Further studies will shed new light on the underlying mechanisms of tumorigenesis mediated by SIRT1.(3)

Calorie restriction increases the life span of many organisms, from yeast to mammals. In yeast, the life span gene affected by calorie restriction is Sir2 (silent information regulator 2). In mammals, Sirt1, an ortholog of Sir2, controls the metabolism of white adipose tissue. Calorie restriction activates Sirt1, and the expressed Sirt1 protein inhibits the action of peroxysome proliferator-activator receptor gamma (PPARgamma), the nuclear receptor that promotes adipogenesis. The effect is lipolysis and loss of fat. Lowering of adiposity appears to be one mechanism whereby calorie restriction affects life span. (4)

Caloric restriction and leanness have been shown to increase longevity in organisms ranging from yeast to mammals. Adipose tissue seems to be a pivotal organ in the aging process and in determination of lifespan. We have recently shown that fat-specific disruption of the insulin receptor gene is sufficient to increase lifespan in FIRKO mice, suggesting that reduced adiposity, even in the presence of normal or increased food intake, can extend lifespan. The model also suggests a special role for the insulin-signaling pathway in adipose tissue in the longevity process. Reduced fat mass has an impact on the duration of life in several other model organisms. In Drosophila, a specific reduction in the fat body through overexpression of forkhead type transcription factor (dFOXO) extends lifespan. Furthermore, sirtuin1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking lifespan to adipose tissue. In the control of human aging and longevity, one of the striking physiological characteristics identified in centenarians is their greatly increased insulin sensitivity even compared with younger individuals. The effect of reduced adipose tissue mass on lifespan could be due to the prevention of obesity-related metabolic disorders including type 2 diabetes and atherosclerosis.(5)

SIRT1(Sir2alpha) deacetylates p53 and promotes survival. (6)

Overexpression of sirt1 induced expression of P-glycoprotein and rendered cancer cells resistant to doxorubicin. (7)

SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence (8)

Abstracts

References

Mechanism of human SIRT1 activation by resveratrol

J Biol Chem. 2005 Apr 29;280(17):17187-95. Epub 2005 Mar 4. Borra MT, Smith BC, Denu JM.

  • The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation ( approximately 8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.

References


1. Bordone L, Guarente L.Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005 Apr;6(4):298-305

2. de Boer VC, de Goffau MC, Arts IC, Hollman PC, Keijer SIRT1 stimulation by polyphenols is affected by their stability and metabolism. J.Mech Ageing Dev. 2006 Apr 5

3. Lim CS. SIRT1: Tumor promoter or tumor suppressor? Med Hypotheses. 2006 Mar 17

4. Wolf G. Calorie restriction increases life span: a molecular mechanism. Nutr Rev. 2006 Feb;64(2 Pt 1):89-92

5. Kloting N, Bluher M. Extended longevity and insulin signaling in adipose tissue.Exp Gerontol. 2005 Nov;40(11):878-83. Epub 2005 Aug 25

6. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W.Negative control of p53 by Sir2alpha promotes cell survival under stress.Cell. 2001 Oct 19;107(2):137-48

7. Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A.Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res. 2005 Nov 15;65(22):10183-7.

8. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 2002 May 15;21(10):2383-96.

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