Dietary change without caloric restriction maintains a youthful profile in ageing yeast

Abstract

Caloric restriction increases lifespan and improves ageing health, but it is unknown whether these outcomes can be separated or achieved through less severe interventions. Here we show that an unrestricted galactose diet in early life minimises change during replicative ageing in budding yeast, irrespective of diet later in life. Lifespan and average mother cell division rate are comparable between glucose and galactose diets, but markers of senescence and the progressive dysregulation of gene expression observed on glucose are minimal on galactose, showing these to be associated rather than intrinsic aspects of the replicative ageing process. Respiration on galactose is critical for minimising hallmarks of ageing, and forced respiration during ageing on glucose by over-expression of the mitochondrial biogenesis factor Hap4 also has the same effect though only in a fraction of cells. This fraction maintains Hap4 activity to advanced age with low senescence and a youthful gene expression profile, whereas other cells in the same population lose Hap4 activity, undergo dramatic dysregulation of gene expression and accumulate fragments of chromosome XII (ChrXIIr), which are tightly associated with senescence. Our findings support the existence of two separable ageing trajectories in yeast. We propose that a complete shift to the healthy ageing mode can be achieved in wild-type cells through dietary change in early life without restriction.