Hallmarks of Aging: An Autophagic Perspective

Abstract

Autophagy is a major protein turnover pathway by which cellular components are delivered into the lysosomes for degradation and recycling. This intracellular process is able to maintain cellular homeostasis under stress conditions, and its dysregulation could lead to the development of physiological alterations. The autophagic activity has been found to decrease with age, likely contributing to the accumulation of damaged macromolecules and organelles during aging. Interestingly, failure of the autophagic process has been reported to worsen aging-associated diseases, such as neurodegeneration or cancer, among others. Likewise, it has been proposed in different organisms that maintenance of a proper autophagic activity contributes to extending longevity. In this review, we discuss recent papers showing the impact of autophagy on cell activity and age-associated diseases, highlighting the relevance of this process to the hallmarks of aging. Thus, understanding how autophagy plays an important role in aging opens new avenues for the discovery of biochemical and pharmacological targets and the development of novel anti-aging therapeutic approaches.

Keywords: ROS; aging; autophagy; hallmarks of aging; mitophagy.

Figure 1

Different types of autophagy pathways in mammals. Macroautophagy: extension of a specialized membrane (phagophore) surrounds molecules and organelles, forming a double membrane vesicle called autophagosome. Finally, the fusion of autophagosomes with lysosomes leads to cargo degradation. Chaperone-mediated autophagy (CMA): proteins containing a KFERQ motif are delivered to lysosome via cytosolic HSC70 chaperone complex. The receptor lysosome-associated membrane protein type 2A (LAMP2A) is necessary for substrate translocation into the lysosomal lumen, where the degradation occurs. Microautophagy: invagination of the lysosomal membrane engulfs cytosolic cargo in small vesicles for its degradation inside.

Figure 2

Mitophagy protects cancer cell from apoptosis. Different stimuli could drive an activation of mitochondrial dysregulation, triggering signaling pathways involved in activation of pro-apoptotic proteins (BAK and BAX). This results in MOM damage and the consequent cytochrome c and SMAC release to the cytoplasm, activating intrinsic apoptotic pathway.

Figure 3

Schematic representation of aging-related disorders in autophagy and redox imbalance.