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  • Review Article
  • Published:

Sirtuins — novel therapeutic targets to treat age-associated diseases

A Corrigendum to this article was published on 01 June 2009

Key Points

  • Sirtuins (SIRTs) are NAD-dependent deacetylases that have a central role in regulating the cellular proteins and their physiological pathways. Interest in therapeutically targeting this class of enzymes is gaining momentum as more data on their function is becoming available.

  • SIRT1 activators have the potential to mimic many aspects of calorie restriction as the levels of the protein seem to be responsive to such a regimen, and studies in lower organisms show that SIRT1 levels and activity are enhanced under conditions of calorie restriction.

  • Efficacy with potent small-molecule activators of SIRT1 is observed in preclinical models of metabolic, neurodegenerative and inflammatory diseases. The strategy of activation holds promise for drug discovery efforts in multiple therapeutic areas.

  • Evidence of therapeutic value comes from the disease area of type 2 diabetes, in which the field is currently most focused.

  • Currently, clinical trials are being conducted with novel small-molecule SIRT1 activators in a mitochondrial disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and in type 2 diabetes. There is a need for new type 2 diabetes treatments that are not associated with weight gain or cardiovascular risk, and SIRT1 activators are emerging as a promising alternative to existing therapeutics.

Abstract

Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation–deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Here, we discuss current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases, including activation of SIRT1 in type 2 diabetes.

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Figure 1: Chemical structures of SIRT1 activators identified through high-throughput screening.
Figure 2: Sirtuin inhibitors with structural diversity and varying potency described in the literature.
Figure 3: Enzymatic activity, sequence conservation and crystal structure of the human sirtuins.
Figure 4: SIRT1 affects major cellular pathways by either deacetylation of the targets or inhibiting gene transcription.
Figure 5: Multiple target organs in which SIRT1 activators can potentially have effects to treat diseases of ageing.

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Acknowledgements

The authors thank P. Y. Ng and L. Jin for assistance with figures and members of Sirtris Pharmaceuticals for providing valuable feedback on the manuscript.

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Correspondence to Philip D. Lambert.

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All the authors are employees and stockholders of Sirtris Pharmaceuticals, a GSK Company, which is involved in the modulation of sirtuins to treat age-associated diseases.

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DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

colon cancer

COPD

MELAS

multiple sclerosis

Parkinson's disease

type 2 diabetes

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Glossary

Calorie restriction

This is a measure of limited dietary energy intake in which the physiological effects are seen in the form of improved health and ageing by delaying the onset of age-associated diseases. A common diet-restriction regimen used in experimental animals is a 30% reduction in food intake.

Sirtuins

Silent information regulator 2 (Sir2) proteins, sirtuins in short, are proteins that have deacetylase and/or mono-ADP-ribosyl transferase activity. As homologous proteins found in organisms ranging from bacteria to humans, sirtuins regulate important cellular pathways.

Glucose homeostasis

The regulation of glucose levels in the blood by hormonal feedback mechanisms that affect glucose release and uptake in tissues.

PGC1α

Peroxisome proliferator-activated receptor-γ, co-activator 1α is a transcriptional co-activator that regulates genes involved in energy metabolism. This protein interacts with transcription factors, nuclear receptors, cyclic AMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). PGC1α is a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis.

Sirtuin-activating compounds

Sirtuin-activating compounds are chemical entities that activate the deacetylase function of sirtuins.

NAD+-dependent deacetylation

An enzymatic reaction in which an acetyl group is removed from lysine side chains of proteins or peptides cleaving NAD, which acts as a co-substrate, in the process.

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Lavu, S., Boss, O., Elliott, P. et al. Sirtuins — novel therapeutic targets to treat age-associated diseases. Nat Rev Drug Discov 7, 841–853 (2008). https://doi.org/10.1038/nrd2665

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