An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast

Vacuolar acidity in yeast is shown to decline with age, and preventing this decrease suppresses mitochondrial dysfunction and extends the lifespan of yeast. This manuscript identifies mitochondrial dysfunction due to increasing vacuolar pH as a determinant of lifespan in the yeast Saccharomyces cerevisiae. Vacuolar acidity is shown to decline over time, but the pH is reset in newborn cells with full lifespan potential. Calorie restriction increases vacuolar acidity via conserved nutrient-sensing pathways and both promotes lifespan extension and suppresses mitochondrial dysfunction. Alterations in acidity appear to impair mitochondrial function via a reduction of amino acid storage in the vacuolar lumen. These findings point to a potential mechanism by which amino acid and glucose limitation may converge to regulate lifespan. Mitochondria have a central role in ageing. They are considered to be both a target of the ageing process and a contributor to it1. Alterations in mitochondrial structure and function are evident during ageing in most eukaryotes2, but how this occurs is poorly understood. Here we identify a functional link between the lysosome-like vacuole and mitochondria in Saccharomyces cerevisiae, and show that mitochondrial dysfunction in replicatively aged yeast arises from altered vacuolar pH. We found that vacuolar acidity declines during the early asymmetric divisions of a mother cell, and that preventing this decline suppresses mitochondrial dysfunction and extends lifespan. Surprisingly, changes in vacuolar pH do not limit mitochondrial function by disrupting vacuolar protein degradation, but rather by reducing pH-dependent amino acid storage in the vacuolar lumen. We also found that calorie restriction promotes lifespan extension at least in part by increasing vacuolar acidity via conserved nutrient-sensing pathways3. Interestingly, although vacuolar acidity is reduced in aged mother cells, acidic vacuoles are regenerated in newborn daughters, coinciding with daughter cells having a renewed lifespan potential4. Overall, our results identify vacuolar pH as a critical regulator of ageing and mitochondrial function, and outline a potentially conserved mechanism by which calorie restriction delays the ageing process. Because the functions of the vacuole are highly conserved throughout evolution5, we propose that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.