Calorie restriction (CR) increases life span in yeast independently of Sir2. Lamming et al. (Reports, 16 September 2005, p. 1861) recently proposed that Sir2-independent life-span extension by CR is mediated by the Sir2 paralogs Hst1 and Hst2. Contradictory to this, we find that CR greatly increases life span in cells lacking Sir2, Hst1, and Hst2, which suggests that CR is not mediated by Sir2, Hst2, or Hst1.