Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy’s role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.
Different Types of Autophagy
As autophagy has many effects on cellular renovation, it would be reasonable to assume that autophagy can contribute to whole-body rejuvenation. As discussed above, suppression of autophagy causes age-dependent dysfunction in various organs. Interestingly, many regimes that promote longevity, including calorie restriction, TOR suppression, sirtuin activation, and spermidine treatment, are able to induce autophagy. The central question is whether this represents simply a correlation or whether autophagy is indeed one of the key effectors of these regimens. Genetic studies performed in C. elegans have shown that some of the autophagy-related genes are required for life-span extension induced by inhibition of insulin/IGF-like signaling and calorie restriction, although not all autophagy-related genes have a longevity-promoting effect. Likewise, autophagy is also required for life-span extension induced by activation of sirtuins (higher eukaryote homologs of the yeast NAD+-dependent deacetylase Sir2), silencing of TOR, spermidine treatment, and p53 suppression. These data indicate that autophagy is a common downstream effector in various life-prolonging signaling pathways. However, as other autophagy-independent pathways are also known to be important, how much autophagy contributes overall to the longevity effects of each regimen needs further investigation.
How can autophagy prolong life span? One obvious mechanism is the cell-autonomous function of autophagy, which avoids accumulation of toxic proteins (e.g., misfolded or aggregation-prone proteins) and organelles (e.g., damaged mitochondria). Additionally, autophagy could reduce inflammatory cytokine secretion and spontaneous tumor incidence, which may also account for its longevity-promoting effect
Cells routinely replace their contents to stay healthy but also to make morphological and functional changes. In this Review, we discussed diverse physiological and pathological processes from the perspective of “autophagy” as an intracellular renovation system. Such a multidisciplinary view is useful to understand why this “self-eating” system has been conserved throughout evolution, how it could participate in normal cellular regulation as well as pathogenesis of human diseases, and how we can take advantage of it for disease therapy. However, many fundamental questions remain. Even with the recent development of sophisticated research tools, such as Cre-mediated conditional knockout techniques, the physiological role of autophagy still remains unknown in some key organs, such as in the bone, skin, and blood vessels. Additionally, although selective autophagy substrates have been identified, the physiological significance of degradation of each substrate, particularly of ubiquitinated proteins, needs to be examined further.
Critical issues also remain with regard to autophagy in therapeutics and diagnostics. Effective indicators or biomarkers for autophagy activity are not currently available. Such markers are important to determine autophagic activity in the disease setting, particularly when monitoring drug effectiveness during autophagy-modulating therapy. Furthermore, the autophagy-modulating drugs currently available are not strictly specific, and the development of more specific drugs will be required. Likewise, although the upregulation of autophagy could be theoretically beneficial for eliminating aggregate-prone proteins, damaged mitochondria, and intracellular bacteria, how these selective autophagic pathways can be stimulated is another challenging issue. Nonetheless, the reality of autophagy-modulating therapy is now closer than was ever expected or predicted.
Autophagosome Formation and Atg Proteins in Mammalian Cells
Nonselective and Selective Autophagy
Physiological and Pathological Roles of Autophagy