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GUEST EDITORIAL |
Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York.
Address correspondence to Ana Maria Cuervo, MD, PhD, Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: amcuervo{at}aecom.yu.edu
AS part of the continuous search for the mechanism behind the beneficial effect of caloric restriction (CR) in aging, the effect of CR on protein degradation is now being revised in light of the growing interest in intracellular clearance mechanisms.
Two major proteolytic systems, the ubiquitin-proteasome system and the lysosomes, are responsible for the bulk of intracellular degradation (1,2). The contribution of the lysosomal system to the degradation of intracellular components, by what is known as "autophagy" (or cellular self-digestion), has been known for more than 50 years (3). However, the autophagy field has experienced an exponential growth in recent years due, for the most part, to the better molecular characterization of this pathway provided by mutational screenings in yeast (4). The growing number of genes identified as effectors or modulators of autophagy has allowed investigators in this field to directly analyze the consequences of activating or blocking this pathway in cellular and organism physiology. As a result, the intracellular role for autophagy has considerably broadened (2).
Autophagy has been classically perceived as the mechanism that provides cells with amino acids and substrates for energy production when nutrients are scarce (Figure 1). Nutrient deprivation is still the best characterized inducer of autophagy (5). Under these conditions, intracellular components are degraded by lysosomes in a nonselective manner—via macroautophagy—or in a more selective way that targets nonessential intracellular proteins but preserves essential components—via chaperone-mediated autophagy (6). The amino acids and essential components resulting from degradation of cellular structures in lysosomes are utilized for cell fueling. However, more recently, autophagy has been shown to contribute, independently of the nutritional state, to cellular quality control, along with molecular chaperones and the other proteolytic systems (2). Degradation of abnormal or damaged intracellular components (proteins and organelles) by autophagy (Figure 1) avoids their accumulation inside cells and the consequent functional loss observed if these altered structures persisted inside the cell. In addition, the fine-tuned balance between protein synthesis/organelle biogenesis and their clearance by autophagy permits continuous renewal of the proteome and of organelles. In light of these two major functions—as source of energy and in quality control—autophagy has been shown to be necessary for maintenance of cellular homeostasis, clearance of damaged intracellular components, for cellular processes involving major cellular remodeling (such as development or differentiation), and as part of both innate and acquired immunity, because it contributes to the defense against intracellular and extracellular insults, including common pathogens (2).
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The first connections between CR and autophagy were obtained in mammals. In fact, Ettore Bergamini and his colleagues were the first to present data supporting improvement of autophagy during CR in rat liver (13,14). However, it is only recently that the full transcendence of this finding is being fully appreciated. In fact, the growing evidence supporting a critical role for autophagy in both cellular metabolism and cell repair, along with the fact that alterations in autophagy have been identified as important in the pathogenesis of many age related-diseases, including for example neurodegenerative disorders, explains the renewed interest in the changes of this basic cellular process during CR. The participation of autophagy in the life-span extension mediated by CR has now been genetically confirmed as feeding-defective nematode mutants (eat-2) have elevated autophagy, and their longevity-extending phenotype is abolished when essential autophagy genes are mutated (12,15–17). However, at least in worms, although autophagy is required for extension of life span, it is not sufficient, and it likely acts in parallel with other downstream pathways (12).
A possible relation between CR and autophagy was originally inferred because, as mentioned above, nutrient availability is one of the most potent mechanisms for regulation of autophagy. Furthermore, as we learn more about this basic cellular process, essential players and regulators of autophagy are in fact familiar names for the investigators in the CR field. Thus, signaling mechanisms with inputs in autophagy involve insulin-signaling and mTOR, one of the major kinase complexes inside the cell that acts as an energy and nutrient sensor (Figure 1). Mutations in the insulin-signaling pathway increase life span in different organisms (18,19). However, because life span of these mutants still increases in response to CR, it is likely that insulin and CR may influence aging by different mechanisms. In contrast, mutations in the mTOR pathway in C. elegans and Drosophila increase replicative and chronological life span, but these mutants no longer respond to CR-induced increase in life span, thus supporting the idea that attenuation of mTOR signaling is part of the downstream mechanisms involved in the beneficial effects of CR (20,21). The dual regulation of autophagy by insulin-signaling and mTOR, and the fact that autophagy is partially required for increasing life span in mutant worms with altered insulin-signaling or ablated TOR signaling, now places autophagy as a possible common effector of both pathways.
mTOR signals as both a downstream kinase of the insulin-signaling pathway, but also independent of insulin, because it is also activated by nutrients and growth factors (22). Activation of mTOR promotes protein synthesis, cell growth, and ribogenesis, but in addition it represses macroautophagy, quantitatively the most important type of autophagy (23). The autophagic target of TOR has been identified in yeast as one of the novel autophagy-related proteins, but the mammalian target remains to be identified. In this context, repression of mTOR signaling should thus lead to activation of autophagy.
The potent inhibitory effect of insulin on autophagy has been extensively characterized (24). In fact, the glucagon/insulin balance constitutes the major regulator of liver autophagy in vivo. Thus, during feeding, the high levels of circulating insulin represses autophagy, whereas in the postabsortive period (fasting), down-regulation of insulin signaling along with the increased blood levels of glucagon activate autophagy. It was previously reported that the inhibitory effect of insulin on autophagy does not change with age (25). However, in this issue of the Journal, Bergamini's group, using a more physiological concentration range of this hormone, identifies a decrease in the insulin-mediated autophagic attenuation with age (26). Expanding on their previous observations on the changes in the hormonal regulation of autophagy in aging, they confirm the inability of glucagon to fully activate autophagy in old rodent livers. Interestingly, of the two types of CR shown to slow down aging, only one of them restores the inhibitory insulin response, whereas both CR regimens fully return the stimulatory effect of glucagon on autophagy to the values observed in the young animals (26). Thus, the so-far-underestimated regulatory role of glucagon on autophagy is now revealed to be highly relevant in the decreased activity of this pathway with age. However, it is likely that alterations in the insulin-signaling pathway with age are still behind the inability of glucacon to stimulate autophagy. Thus, the described increase in the basal insulin-independent signaling through the insulin receptor (27) may be the reason why glucagon cannot exert its fully activating effect on autophagy.
Restoration of normal autophagic activity by CR should be beneficial at different levels. On one hand, it would contribute to a better preservation of the cellular energetic balance, as it guarantees proper recycling of essential components that can be reutilized for the synthesis of new macromolecules. Furthermore, due to the critical role of autophagy in cellular quality control, maintenance of adequate autophagy activity should help to prevent the accumulation of altered intracellular components, observed in almost all tissues in old organisms. In this respect, studies in mouse models with impaired autophagy in different organs have revealed that basal autophagy—active independently of the nutritional status—is essential for preservation of cellular homeostasis, and its blockage leads to degeneration and cell death (28–30). These findings may be of particular relevance for protein conformational disorders common in elders, such as neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease). Thus, the late onset of these pathologies has been attributed in part to a failure of the quality control systems with age, and pharmacological activation of autophagy in some of these disorders has already proven effective in ameliorating symptoms (31). Although future studies are required, the fact that CR has been shown to delay the onset of symptoms in animal models for some of these diseases should be good motivation to investigate the contribution of the restored autophagic function to the observed beneficial effects. Lastly, because renewal of organelles is required to maintain functionality, and this continuous turnover is exclusive responsibility of autophagy (32), the improvement in autophagic activity in old organisms during CR could prevent, or at least slow down, the functional deterioration with age of intracellular organelles, such as mitochondria, a critical player in aging.
These are exciting times for the autophagic field. As we learn more about this essential cellular process, it becomes clear that findings in this area will have major implications for our understanding of cellular physiology and pathology, and by extension of aging. Of course, the "arrows" connecting aging, caloric restriction, and autophagy will undoubtedly be complex and branched. The anti-aging effect of autophagy may depend on the interplay of this cellular process with concurrent or parallel pathways also known to modulate aging. Furthermore, because only some of the types of autophagy are conserved throughout evolution, we should be ready for species differences in the anti-aging effect of autophagy. Although the ultimate goal should be to identify and correct the defects that lead to declined autophagic activity with age, the development of efficient methods to stimulate autophagy in different organisms should provide, in the short run, a better understanding of the contribution of failure of this surveillance system to the phenotype of aging.
References
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