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Sirtuins as regulators of metabolism and healthspan

Key Points

  • Sirtuins regulate protein function by NAD+-dependent post-translational modification, thereby representing a metabolic sensor.

  • Compounds activating sirtuins could be used to treat age-associated mitochondrial diseases.

  • Activation of SIRT1 improves metabolism and global health in organisms ranging from Caenorhabditis elegans to humans.

  • The role of sirtuins in natural longevity is debated, but it is widely accepted that sirtuins have a role in the maintenance of metabolic health.

Abstract

Since the beginning of the century, the mammalian sirtuin protein family (comprising SIRT1–SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.

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Figure 1: Regulation of sirtuin expression and activity.
Figure 2: Sirtuins mediate metabolic responses in several tissues during different physiological challenges.
Figure 3: Overview of the role of sirtuins in the regulation of pathways involved in glucose metabolism.
Figure 4: Overview of the role of sirtuins in the regulation of lipid metabolism.

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Acknowledgements

The authors apologize to colleagues whose original work could not be cited owing to space limitations. The authors thank team members of the Auwerx laboratory for discussions. R.H.H. is supported by a Rubicon fellowship of the Netherlands Organization for Scientific Research (NWO), and E.P. is funded by the Academy of Finland and the Finnish Cultural Foundation. The work in the Auwerx laboratory is supported by grants of the École Polytechnique Fédérale de Lausanne, Faculty of Life Science, the European Union Ideas programme (ERC-2008-AdG-23118), the Velux Stiftung and the Swiss National Science Foundation (31003A-124713 and 31003A-125487).

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Glossary

Caloric restriction

A reduction of caloric intake (typically 20–50% less than average) that has been shown to increase lifespan in a variety of organisms.

Nutriceutical

A food product that provides health benefits.

ADP-ribosyltransferases

Enzymes that transfer an ADP-ribose group on a protein target.

Demalonylate

The act of removing a malonyl group from a specific Lys residue of a target protein.

Desuccinylate

The act of removing a succinyl group from a specific Lys residue of a target protein.

Ketone bodies

Metabolic energy units derived from fat breakdown. Ketone bodies serve to fuel the brain in times of low blood glucose concentrations.

Tricarboxylic acid cycle

(TCA cycle). Also known as Krebs cycle. Acetyl-CoA derived from glucose or fat breakdown is further metabolized to offer reduced energy equivalents that are used by mitochondrial oxidative phosphorylation to generate ATP.

Oxidative phosphorylation

(OXPHOS). Mitochondrial enzymatic chain of events by which ATP is generated.

Reactive oxygen species

(ROS). Oxygen radicals that are produced as by-products of oxidative phosphorylation in mitochondria. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

Steatosis

A condition characterized by abnormal accumulation of lipids within the cell.

K m

(Michaelis constant). Enzymatic property describing the substrate concentration at which the enzyme works at half-maximal capacity.

Hyperinsulinaemia

A condition that occurs when there is excess insulin in the circulation.

Fasting hypoglycaemia

A condition during fasting that occurs when circulating glucose levels are abnormally low.

Insulinoma cells

Tumour cells derived from pancreatic β-cells that secrete insulin.

Single-nucleotide polymorphisms

Naturally occurring single nucleotide variations in a DNA sequence. The most common type of genetic polymorphism.

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Houtkooper, R., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13, 225–238 (2012). https://doi.org/10.1038/nrm3293

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