So what does epigenetics have to do with ageing? The Sir2 protein is the link. Epigenetics encrypts regions of the genome (our total DNA) as a means of long-term control. Every cell in our body can conceivably express any gene on its DNA template. But that doesn’t mean we want the keratin gene (which makes hair and nails) switched on in white blood cells. So, epigenetic tools like Sir2 keep DNA packaged up as chromatin, encrypting it over many cell generations, so that genes remain active or silenced. It’s like another layer of control over DNA, different but complementary to genetic instruction, embodied in the ensemble of DNA and packaging proteins.

In yeast, Jasper Rine and colleagues first showed that Sir2 silences regions of the genome with the help of other Sir proteins. By removing chemical (acetyl) groups from histones, it keeps chromatin compact, hiding it from gene expression machinery. But it needs NAD+, a metabolite that helps convert food into energy. This dependence on NAD+ provides a credible link between Sir2 and metabolism. The pathway has yet to be worked out, with an inevitable level of disagreement and active debate between research groups, but current thinking suggests that the stress stimulus of calorie restriction activates Sir2 either through increasing the cellular NAD+/NADH ratio, or by activating a stress response gene called PNC1.

What are the knock-on effects of increasing Sir2 that could affect lifespan? In yeast it is about guarding against errors that occur when a DNA copy is made for a daughter cell. Repetitive stretches of DNA (such as rDNA) often misalign like a broken zipper, forming tucks in the DNA strand that loop out and actually pinch off. The Sir2 compaction of chromatin at rDNA repeat regions keeps chromatin locked up, limiting misalignment of repetitive DNA. But with lower levels of Sir2, misalignment is more frequent leading to a build-up of extrachromosomal loops, which age cells, probably by mopping up essential nuclear factors.