Summary

• Introduction.
• Sirtuins and Gene Silencing.
• Sirtuins Activity.
• Sirtuins and Senescence.

Introduction

• Silent information regulator (SIR).
• Crossroads of nutrient sensing and stress regulation.
  • Responds to energy and nutrients.
  • Controls cellular health.
• Regulates adaptive response to energy availability.
  • Silences genes.
  • Repairs DNA.
• Senses biological stress in the environment.
  • DNA damage, change in temperature, a lack of nutrients.
• Activity driven by multiple factors.
  • NAD+, polyphenols, quality and quantity of nutrients.
• May play a role in health or lifespan extension.
  • Potentially mediates positive effects of fasting / caloric restriction.
  • Debate around relevant studies / confounding factors.

Sirtuins Affect Many Pathways

• Involved in many regulatory functions, including:
  • Metabolism.
  • Inflammation.
  • Genome stability.
  • Cell cycle.
  • Insulin secretion.
  • Fatty acid oxidation.
• Plays a role in:
  • Promoting insulin sensitivity.
  • Modulating circadian rhythms.
  • Improving genome stability.
  • Suppressing tumors.
  • Reducing inflammation.
  • Protecting against neurodegenerative diseases.
  • Controlling anxiety.

Sirtuins and Gene Silencing

• Controls which genes to turn on and off during adversity.
  • Evolved for survival during adversity.
• Silences genes by removing acetyl groups from histones.
  • Histones are DNA-protein complexes that the DNA inside every cell is wound up in. (see “The Epigenetics Revolution“)
  • When histones have an acetyl group, DNA can be transcribed.
  • When the acetyl group is removed, gene expression stops.

Sirtuins Activity

• NAD+
  • NAD+ plays a key role in metabolism.
    • NAD+ involved in turning nutrients into energy (see “NAD” write-up).
  • Sirtuins can only remove acetyl groups in the presence of NAD+.
  • Sirtuins “consume” NAD+.
    • Unlike redox reactions, no NADH is formed, so there is no “cycling”.
    • Sirtuins “cleave” NAD+ to form nicotinamide (NAM, a form of vitamin B3).
    • NAM switches off sirtuins (negative feedback loop).
    • NAM has to be recycled to reform NAD+, or removed.
• Polyphenols.
  • Reveratrol (subject to debate).
  • Pterostilbene.
    • Found in blueberries.
• Nutrients.
  • Changes in nutrient availability or quality affect sirtuin activity.

Sirtuins and Senescence

• Loss of the mitochondrial sirtuins can induce a senescence response.
• Low NAD+/NADH ratios promote cellular senescence at least in part by limiting glycolysis and ATP production.