Scientific investigation of mechanisms that determine lifespan can be divided into three general approaches. The first approach (the comparative method) began over a century ago comparing species differing greatly in maximum longevity and implicated a role for the speed of metabolism in determining the length of life . The second approach commenced after the 1930s investigated the mechanisms whereby “calorierestriction” extended lifespan . The third approach gained popularity in the 1990s and centred on genetic mutations that significantly extend longevity . There has been little overlap between these three approaches. The paper by Shmookler Reis et al. in this issue  is significant in that it advances our understanding by combining the genetic mutants approach with recent insights from the first approach.