The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension

doi:10.1016/j.tips.2004.12.009

Trends in Pharmacological Sciences

Volume 26, Issue 2, February 2005, Pages 94-103

https://doi.org/10.1016/j.tips.2004.12.009 Get rights and content

Acetylation of chromatin-interacting proteins is central to the epigenetic regulation of genome architecture and gene expression. Chemicals that modulate the acetylation of nuclear proteins have proved instrumental in experimental models of several human diseases. Sirtuins represent a new class of evolutionary conserved histone deacetylases, originally identified in yeast, that have emerging pathogenetic roles in cancer, diabetes, muscle differentiation, heart failure, neurodegeneration and aging. In this article, we focus on sirtuins and provide an appraisal of current compounds that either activate or inhibit sirtuin activity, highlighting their therapeutic potential for the treatment of human diseases.

Section snippets

Historical perspective: Sir proteins and silencing of yeast chromatin

Sir1–4 (silent information regulator 1–4) proteins were first shown to be involved in silencing at cell-mating type loci and telomeres in yeast. Subsequent studies showed that Sir2 also participates in the silencing and suppression of recombination at yeast ribosomal DNA (rDNA). Later, additional Sir2 homologues (Hst1–4) that were also involved in silencing were identified 6, 7, 8, 9, 10.

Yeast sirtuins are deacetylases that are involved in a peculiar silencing process. Following the recruitment

New clues: evolutionary conserved, NAD-dependent chromatin remodelling enzymes

Numerous Sir2 homologues have been identified in different organisms 8, 9 (Table 1). Phylogenetic analysis of conserved core sequences in archeans, bacteria, yeasts, plants, protozoans and metazoans reveals that sirtuins can be grouped into five different classes (designated I–IV and U) and are present in all eukaryotes, suggesting ancestral biological functions 16, 17. SIRT1 is the human orthologue of yeast Sir2 and is the best-characterized member among mammalian sirtuins. SIRT1 is a nuclear

Sirtuins and the genetic control of aging: fungi, worms, fruit flies and more?

In 1995, Guarente and colleagues reported that the lifespan of yeast is extended by >30% in the strain mutant Sir4–42, which lacks the C-terminal domain of Sir4 [40]. Importantly, concomitant mutation of sir2 or sir3 suppressed lifespan extension in Sir4–42 mutants [40]. Additional work from the same group demonstrated that deletion of sir3 or sir4 in yeast causes loss of silencing and 20% reduction in lifespan [41]. Similarly, sir2 deletion increases rDNA recombination and shortens lifespan by

An intriguing NAD connection

Several findings show that NAD metabolism (Figure 2) regulates sirtuin functioning [46]. For example, mutation of npt1, the gene encoding yeast nicotinate phosphoribosyl transferase, which participates in NAD re-synthesis, reduces the concentration of intracellular NAD by a factor of 2.5, impairs silencing at telomeres and rDNA and abolishes Sir2-dependent yeast lifespan extension 27, 44, 48. Opposite effects on silencing and longevity are induced by npt1 overexpression [49]. Similarly,

Non-histone targets

Mounting evidence demonstrates that sirtuins also target a substantial number of non-histone proteins. For example, SIRT1 deacetylates the TATA box-binding protein TAF_(I)68, thereby repressing activation of RNA polymerase I [57]. SIRT1 also targets CTIP2 (COUP-TF interacting protein 2) and enhances CTIP2-dependent silencing [58]. Similarly, sirtuin-dependent deacetylation promotes activity of the BCL6 (B-cell lymphoma 6) transcriptional repressor [59]. It is well known that acetylation of p53

Acetyl-ADP-ribose: an orphan metabolite in the midst of metabolic networks

When injected into immature starfish oocytes at concentrations in the range of 0.32–5.00 mM, acetyl-ADP-ribose induces delay and then block of oocyte maturation, whereas at 16 mM acetyl-ADP-ribose quickly triggers oocyte death [32]. The finding that microinjection of human SIRT2 or yeast Hst2 also blocks starfish oocyte maturation and early embryo development [32] suggests that acetyl-ADP-ribose might mediate some of the effects of sirtuins. Evidence that acetyl-ADP-ribose has a short half-life

Therapeutic potential of chemical modulators of sirtuin activity

To date, a significant array of chemical inhibitors and activators of sirtuins have been identified and made available for basic research (Figure 4). Evidence that NAD-dependent deacetylation has a short half-life 11, 12, 13, 14 suggests that these chemicals substantially affect sirtuin signalling (Figure 5). Accordingly, the SIRT1 activator resveratrol decreases acetylation-dependent p53 activation and protects human cells from p53-dependent apoptosis [71]. Similarly, resveratrol suppresses

Acknowledgements

This review is dedicated to the silent teacher. We thank friends for helpful comments.

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Trends in Pharmacological Sciences

The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension

Section snippets

Historical perspective: Sir proteins and silencing of yeast chromatin

New clues: evolutionary conserved, NAD-dependent chromatin remodelling enzymes

Sirtuins and the genetic control of aging: fungi, worms, fruit flies and more?

An intriguing NAD connection

Non-histone targets

Acetyl-ADP-ribose: an orphan metabolite in the midst of metabolic networks

Therapeutic potential of chemical modulators of sirtuin activity

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Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

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Sir2 links chromatin silencing, metabolism, and aging

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Small molecules that regulate lifespan: evidence for xenohormesis

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