The only physiological manipulation that is currently known to extend mammalian lifespan is dietary restriction. In worms, flies and mammals reduced activity in the core insulin/IGF signalling pathway increases lifespan.
This pathway converges on the protein kinase mTOR, which serves as ‘master switch’ in eukaryotic metabolism and growth. When mTOR is active it represses autophagy and promotes anabolic metaboIism, including protein synthesis.
When mTOR is inactive (e.g. during nutrient starvation) or inhibited, cells switch to a catabolic mode; autophagy is activated to recycle proteins and organelles and protein synthesis is repressed (Figure 1, right).
In a landmark study Harrison and co-workers demonstrated that pharmacological inhibition of mTOR, with the drug rapamycin, extended the lifespan of mice, even when administered relatively late in life (Harrison et al. Nature. 2009; 460:392-395)