Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

  title={Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan},
  author={Konrad T. Howitz and Kevin J. Bitterman and Haim Y Cohen and Dudley Lamming and Siva Lavu and Jason G. Wood and Robert E. Zipkin and Phuong Chung and Anne Kisielewski and Li-li Zhang and Brandy Scherer and David A. Sinclair},
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53… 
Alkylresorcinols activate SIRT1 and delay ageing in Drosophila melanogaster
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Sirtuin activators mimic caloric restriction and delay ageing in metazoans
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Sirtuins in mammals: insights into their biological function.
The current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, is described and their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases are discussed.
Studying sirtuin inhibitors with in silico and in vitro approaches
In this thesis, modern computer aided drug design methods have been combined with in vitro methods in the investigation of the properties of sirtuin inhibitors, resulting in the identification of new sirtuins inhibitors and novel insights into sIRTuin inhibitor specificity.
Functional analysis of mitochondrial sirtuins in C. elegans and mammalian cells
All three mitochondrial members of biotin-dependent carboxylases, pyruvate carboxesylase (PC), propionyl-CoA carboxyase (PCC) and methylcrotonyl- coA car boxylases (MCC), as factors interacting with SIR-2.3 and mammalian SIRT4 have conserved functions.
Mechanism of Human SIRT1 Activation by Resveratrol*
It is proposed that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.
Sirtuin Function in Longevity
In this chapter, the historical context of Sirtuin function in yeast is discussed against the backdrop of the catalytic activity that contributes to its prominence in so many research areas and the role as a longevity factor and mediator of the calorie restriction response is discussed.
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  • Biology
    Cold Spring Harbor symposia on quantitative biology
  • 2007
The findings indicate that SIRT1 can influence many of the major diseases of aging, including metabolic diseases like diabetes, neurodegenerative diseases (Alzheimer's and Huntington's), cancer and osteoporosis, and small molecules that alter the activity of Sirt1 (i.e. CR mimetic drugs) offer a new approach to prevent and possibly treat the major Diseases of aging.
Small molecule regulation of Sir2 protein deacetylases
Small molecule regulators that control the activity and functions of this unusual family of protein deacetylases, including sirtuin inhibitors and activators are focused on.


Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
It is concluded that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.
Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1*
It is shown here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of asir2 mutant, demonstrating that silent heterochromatin requires continual Sir2 activity.
Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
In Caenorhabditis elegans, mutations that reduce the activity of an insulin-like receptor (daf-2) or a phosphatidylinositol-3-OH kinase (age-1) favour entry into the dauer state during larval
Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.
These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD, the oxidized form of nicotinamide adenine dinucleotide.
The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases.
Discovery of an intrinsic deacetylation activity for the conserved SIR2 family provides a mechanism for modifying histones and other proteins to regulate transcription and diverse biological processes.
Metabolic Control and Gene Dysregulation in Yeast Aging
  • S. Jazwinski
  • Biology
    Annals of the New York Academy of Sciences
  • 2000
It is now clear that the functional status of chromatin plays an important role in aging, and an optimal level of Ras2p activity is required for maximum longevity.
A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family.
The yeast Sir2 protein, required for transcriptional silencing, has an NAD(+)-dependent histone deacetylase (HDA) activity. Yeast extracts contain a NAD(+)-dependent HDA activity that is eliminated
Paradigms and pitfalls of yeast longevity research
  • D. Sinclair
  • Biology
    Mechanisms of Ageing and Development
  • 2002
The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.
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