Autophagy and aging

Abstract

Autophagy is a critical quality control pathway that is conserved across diverse systems ranging from simple unicellular organisms like yeast to more complex systems, for instance mammals. Although, the fundamental role of autophagy is to maintain cellular quality control through lysosomal degradation of unwanted proteins and organelles, recent studies have mapped several new functions of this pathway that range from fuel utilization, cellular differentiation to protection against cell death. Given the importance of this pathway in maintaining cellular homeostasis, it has been considered that compromised autophagy could contribute to several of the commonly observed age-associated pathologies including neurodegeneration, reduction of muscle mass, cardiac malfunction, excessive lipid accumulation in tissues and glucose intolerance. The present chapter describes the two best-characterized autophagy pathways—macroautophagy and chaperone-mediated autophagy, and discusses how changes in these pathways associate with age-associated disorders. Understanding how to maintain “clean cells” by activation of autophagy could be an attractive strategy to maintain healthspan in aged individuals.

Fig. 3.1

Steps in the macroautophagy pathway. Macroautophagy is a cellular quality control mechanism that requires greater than 30 Atg gene products to deliver cytosolic cargo to lysosomes for their degradation. Starvation or stressors activate macroautophagy by increasing the interaction of Beclin1 with additional proteins to generate the Class III phosphoinositide 3-kinase (PI3K) complex, which gives rise to PI3Ps to recruit ATG proteins (e.g., ULK1) for autophagosome formation. Activation of ATG7 (E1-like ligase) forms the ATG5-ATG12 conjugate, which binds to ATG16L1 to form the ATG5-ATG12-ATG16L1 complex. ATG5-ATG12-ATG16L1 facilitates lipidation of cytosolic LC3-I into autophagosome membrane-bound LC3-II. LC3-II-positive autophagosomes engulf cargo and target it to lysosomes, wherein a battery of hydrolases degrades cargo into amino- and fatty acids. A tight regulatory crosstalk between the nutrient sensor mTOR and ULK1 orchestrates autophagy. Green arrows indicate activating steps and red arrows indicate inhibitory steps

Fig. 3.2

Regulation of chaperone-mediated autophagy. Chaperone-mediated autophagy ensues by (1) recognition of substrate by the Hsc70/Co-chaperone complex followed by (2) binding of the substrate to the cytosolic portion of the LAMP-2A receptor. (3) Binding is followed by substrate unfolding, and along with additional regulatory proteins and lysosomal resident Hsc70 (Lys-Hsc70) the unfolded substrate is translocated across the lysosomal membrane substrate via LAMP-2A multimers for their degradation