Autophagy and aging--importance of amino acid levels

Melendez et al. [Science 301 (2003) 1387] have recently shown that the increased longevity of Caenorhabditis elegans mutants with defective Daf-2 protein, i.e. an insulin receptor analog, involves increased autophagy. Autophagy increases the free amino acid pool and is in certain cells essential for survival at times of limited amino acid availability. In addition, autophagy plays an important role in the turnover of proteins and organelles including mitochondria. The autophagic activity is sensitive to changes in physiological conditions, i.e. it is strongly inhibited by an increase in amino acid concentrations or in insulin receptor signaling. In line with this fact, clinical studies indicate that autophagy mainly occurs at times of low plasma amino acid and insulin concentrations in the post-absorptive (fasted) state, and that the post-absorptive amino acid-sensitive protein catabolism may be taken as a bona fide indicator of autophagic activity. The increased longevity of insulin receptor mutants or of organisms subjected to calorie restriction may, therefore, be attributed to an increase in autophagic activity. Importantly, the autophagic activity decreases with age. Recent studies suggest that this decrease may result from an age-related increase in post-absorptive amino acid levels and/or from an increase in baseline insulin receptor signaling. If so, it is potentially reversible.