Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae

Following cessation of growth, yeast cells remain viable in a non-dividing state for a period of time known as the chronological life span (CLS). Autophagy is a degradative process responsible for amino acid recycling in response to nitrogen starvation and amino acid limitation. We have investigated the role of autophagy during chronological aging of yeast grown in glucose minimal media containing different supplemental essential and non-essential amino acids. Deletion of ATG1 or ATG7, both of which are required for autophagy, reduces CLS, whereas deletion of ATG11, which is required for selective targeting of cellular components to the vacuole for degradation, does not reduce CLS. The non-essential amino acids isoleucine and valine, and the essential amino acid leucine, extend CLS in autophagy-deficient as well as autophagy-competent yeast. This extension is suppressed by constitutive expression of GCN4, which encodes a transcriptional regulator of general amino acid control (GAAC). Consistent with this, GCN4 expression is reduced by isoleucine and valine. Furthermore, elimination of the leucine requirement extends CLS and prevents the effects of constitutive expression of GCN4. Interestingly, deletion of LEU3, a GAAC target gene encoding a transcriptional regulator of branched side chain amino acid synthesis, dramatically increases CLS in the absence of amino acid supplements. In general, this indicates that activation of GAAC reduces CLS whereas suppression of GAAC extends CLS in minimal medium. These findings demonstrate important roles for autophagy and amino acid homeostasis in determining CLS in yeast.