Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds

Key Points

  • Sirtuins are a critical component of evolutionarily conserved longevity pathways. Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacylases that promote longevity and healthy ageing.

  • Sirtuin-activating compounds (STACs) bind to and allosterically modulate the affinity of SIRT1 for NAD+ and protein substrates, resulting in increased activity.

  • Increasing NAD+ levels through various strategies can enhance the activity of all sirtuins and improve metabolic function and increase longevity.

  • Sirtuin overexpression and treatment with naturally occurring and synthetic STACs improves metabolic function and increases longevity in mice.

  • More than 50 clinical trials are currently evaluating the safety and physiological activity of naturally occurring and synthetic STACs for treating human disease.

Abstract

The sirtuins (SIRT1–7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.

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Figure 1: Nutrient-responsive signalling pathways that maintain health and extend lifespan.
Figure 2: Localization, enzymatic activity and modulation of sirtuins by small molecules.
Figure 3: The allosteric activation mechanism of SIRT1.
Figure 4: Sirtuin activation and its disease relevance.

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Acknowledgements

The authors thank M. B. Schultz for suggestions and edits and are grateful for financial support from the National Institute on Aging, the National Institutes of Health, the Paul F. Glenn Foundation for Medical Research, Edward Schulak, and Ovaxon.

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Correspondence to David A. Sinclair.

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D.A.S. is a consultant to and/or inventor on patents licensed to GlaxoSmithKline, Ovascience, MetroBiotech, Arc Bio, and Liberty BioSecurity. M.S.B. is a consultant for Ovascience.

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Glossary

Replicative ageing

In yeast, the number of daughter cells produced by a mother cell before senescence.

Redox reactions

Oxidation–reduction (redox) reactions involving the transfer of electrons between two chemical species.

Hepatic steatosis

Also known as fatty liver, is a term used to describe the accumulation of fat in the liver cells.

Allosteric activation

Activation of an enzyme by binding of a ligand, which enhances the binding of substrates at other binding sites.

K m

Michaelis constant, which reflects the affinity of an enzyme for its substrate. The Km is measured as the substrate concentration at which the reaction rate is half of its maximum rate.

K-type allosteric activation

Refers to the major type of allosteric activation, in which the main feature that is altered is the Michaelis constant (Km).

HOMA index

The homeostatic model assessment (HOMA) index is a clinical measure used to predict the function of pancreatic β-cells and insulin resistance.

Bioavailability

The degree and rate at which a substance is absorbed and is made available at the site of physiological activity.

EC50

The concentration of substrate that elicits a half-maximal enzymatic response.

Plaque-type psoriasis

The most common form of the disease, which is manifested as raised, red patches covered with a silvery white build-up of dead skin cells or scale.

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Bonkowski, M., Sinclair, D. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol 17, 679–690 (2016). https://doi.org/10.1038/nrm.2016.93

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