Trends in Genetics
ReviewAutophagy and aging: keeping that old broom working
Section snippets
Cellular quality control, autophagy and aging
All cells rely on surveillance mechanisms, chaperones and proteolytic systems to control the quality of their proteins and organelles and to guarantee that any malfunctioning or damaged intracellular components are repaired or eliminated 1, 2. Molecular chaperones interact with unfolded or misfolded proteins and assist in their folding [3]. However, if the extent of protein damage is too great, or the cellular conditions are not adequate for re-folding, the same molecular chaperones often
Autophagy: the comeback of an old pathway
Lysosomes are organelles fully devoted to degrading diverse macromolecules both from the extracellular environment and from inside the cells [8]. Lysosomes contain the highest cellular concentration of hydrolases (i.e. proteases, lipases, glycases and nucleotidases) in their lumen, in addition to permeases in their membrane for recycling the essential building blocks of the degraded products (e.g. amino acids, fatty acids and cholesterol, sugars, etc.) to the cytosol [9]. In this respect,
Pathophysiology of autophagy
The participation of autophagy in different physiological functions is attributable, in almost all cases, to one of its two main functions: as an energy source or as a mechanism for the removal of unwanted cellular structures [15] (Figure 1). As described earlier, the essential components resulting from macromolecule degradation in lysosomes can be reused not only for the synthesis of new macromolecules but also as cellular fuel. In addition, the unique ability of the lysosomal system to
Basic mechanisms of autophagy
The detailed molecular characterization of autophagy and the improved understanding of the physiological roles for this pathway have also resulted in a growing number of terms to refer to this process. The differences among the autophagic variations reside in the type of cargo, the mechanism for its delivery to lysosomes and the conditions in which that particular process is activated. However, despite the variety of autophagic processes described, they all fall into one of three main types:
Autophagy and aging: before the genetic dissection
A decrease in proteolytic activity has been considered responsible, at least in part, for the accumulation of damaged cellular components in almost all tissues of aging organisms (reviewed in Refs 6, 7, 26). Indeed, age-dependent alterations in the lysosomal system and declined autophagic activity were described long before the molecular basis for this process was fully understood. Most of the early functional studies were performed in the liver, as this was also the organ in which the most
The new connections between autophagy, aging and life span
Genetic screens in yeast (in the case of macroautophagy) and novel biochemical approaches (in the case of CMA) have helped to identify the subset of genes and protein products that participate as effectors and modulators of these autophagic pathways. Manipulations in these genes have confirmed the tight connection between autophagy, life span and aging (Table 1).
The first genetic connection between autophagy and aging was established in the worm Caenorhabditis elegans, an organism extensively
Consequences of autophagic failure in aging
In light of the myriad of physiological functions of autophagy, it is easy to infer that the described age-related decline in autophagic activity will affect normal cell functioning and contribute to different aspects of the aging phenotype. Recent studies using tissue-specific conditional autophagy-knockout mice have confirmed the important role of this catabolic process in the maintenance of cellular homeostasis and proper response to stress 19, 20, 21, 22. Thus far, changes in life span and
Enhancing autophagy as an anti-aging intervention
Autophagy might prevent or decelerate aging by guaranteeing the stability of the cellular proteome and proper organelle turnover. For example, mitochondrial dysfunction, extensively reported to contribute to cellular aging, has been proposed to occur, at least in part, because of the inability of old cells to remove their non-functional mitochondria (reviewed in Refs 59, 60). The recent advances in our understanding of autophagy have motivated a growing interest in developing strategies to
Concluding remarks and future perspectives
Genetic studies both in invertebrate and in mouse models have recently provided strong evidence of interplay between autophagy, health span and aging. The essential role of autophagy in the maintenance of cellular homeostasis and in the forefront of the response to stress positions it as a crucial player in the fight against cellular aging. Nevertheless, the mechanistic studies of the anti-aging effect of autophagy have just taken off. Generalizations have frequently been made in light of
Acknowledgements
I thank my numerous colleagues both in the fields of autophagy and of biology of aging who, through their animated discussions, have helped shape this review. I am in particular debt to Ashish Massey, Fernando Macian and Susmita Kaushik for critically reading the manuscript. Work in my laboratory is supported by NIH/NIA (AG021904, AG031782), NIH/NIDDK (DK041918) and a Glenn Foundation Award. I sincerely apologize to colleagues whose work has not been cited owing to space limitations.
Glossary
- Autophagy
- degradation of any type of intracellular components including protein, organelles or any type of particulate structures (e.g. protein aggregates, cellular inclusions, etc.) in lysosomes.
- Catabolism
- breakdown of macromolecules into their essential components as a result of the coordinate function of different intracellular metabolic pathways. Catabolic processes provide cells with chemical energy and building blocks for the synthesis of new macromolecules.
- Chaperone-mediated autophagy
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