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.
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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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.
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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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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