How does all this yeast talk translate in other animals, or us? Studies on worms, flies and now even mice and monkeys conclusively earmark Sirtuins (Sir2 and related genes) as key mediators of the longevity effect caused by calorie restriction. But of course, nothing is so simple, least of all in mammals. Ageing brings all manner of disorders: cancer, tissue degeneration, which in neuronal tissues can cause diseases such as Alzheimer’s or Parkinson’s. There is also greater risk of cardiovascular conditions, stroke and diabetes, often owing to an overall increase in body fat with age. And metabolic efficiency is reduced, while more and more cells become suicidal (apoptotic). In mammals, therefore, halting the ageing process must involve a multitude of physiological processes. How do the Sirtuins manage all that?

From what we know, the modus operandum for SirT1 (mammalian version of Sir2) is more complex in mammals than yeast. While the protein removes acetyls from histones, it also targets many other cellular proteins, feeding into many pathways to delay ageing. High-levels can inhibit p53, a well-known tumour-suppressor gene, Ku70 and forkhead proteins, lowering apoptosis. This is fine for neurons, which don’t normally divide and replenish themselves, but for fast-replicating cells, this is hazardous.

Slowing apoptosis means we can’t so easily get rid of rogue cancer cells. Other SirT1-induced hormone changes may counter this risk, we don’t yet know for sure. Just to cause confusion, SirT1 can increase apoptosis in some immune system cells (through its target NF-kappaB) which curbs damaging inflammation. It can also mobilise fat stores by inhibiting the PPAR-gamma receptor. This effect, coupled with lower insulin production, increased insulin sensitivity and insulin growth factor 1 (IGF-1), can delay age-related diseases often associated with obesity, such as diabetes and various heart and circulatory conditions.

There are six other known Sirtuin proteins in humans in addition to SirT1. SirT4, 5 6 and 7 are little studied, but so far, SirT2 and SirT3 seem to extend lifespan. They lower the output of free radicals, which improves the running of energy powerhouses (mitochondria) within cells, and boosts stress resistance by increased oxidative damage repair and neuroprotective function. All this is but a taster of the many different pathways that the Sirtuins feed into.

As for the epigenetics of Sirtuins, it’s early days yet, but Danny Reinberg’s lab (New York University Medical School) has shown that SirT1 is involved in locking DNA away in a compact form of chromatin called heterochromatin. It was also a component detected in deregulated epigenetic machinery gone awry during prostate cancer progression. SirT2 comes into play when chromosomes need to condense before cell division.