Figure 2.

Failure of macroautophagy in aging. Possible causes and consequences of the failure of macroautophagy in old organisms are depicted in this schematic model (brown boxes). (a) The accumulation of autophagic vacuoles with age could result from the inability of lipofuscin-loaded lysosomes to fuse with autophagic vacuoles and degrade the sequestered content. (b) In addition, the formation of autophagosomes in old cells might be reduced because of the inability of macroautophagy enhancers (such as glucagon) to induce full activation of this pathway. The stimulatory effect of glucagon is compromised in old cells because of maintained negative signaling through the insulin receptor (IR) even under basal conditions (i.e. in the absence of insulin). Maintained insulin signaling would activate mTOR, a known repressor of macroautophagy. (c) Inadequate turnover of organelles, such as mitochondria, in aging cells could increase levels of free radicals that generate protein damage and (d) could also potentiate the inhibitory signaling through the insulin receptor. (e) An age-dependent decline in macroautophagy can also result in energetic compromise of the aging cells.