Fig. 7. Working model of ER stress activation in old human beta cells.

Up-regulation of the beta cell transcriptional output increases protein translation and folding demands. To meet this increased demand, beta cells increase amino acid transport and metabolism. This is also associated with activation of the amino acid starvation response that stimulates autophagy. This process is impaired and leads to accumulation of lipofuscin bodies. Higher protein synthesis overloads the ER and triggers ER stress response pathways, which are compromised. This likely contributes to activation of other beta cell aging–dependent pathways, including senescence. Unresolved ER stress phenotype, combined with compromised expression of identity TFs, creates a chronic ER stress state that undermines beta cell structure function that could lead toward secretory failure and/or death.