ReviewAutophagy and ageing: Insights from invertebrate model organisms
Highlights
► We survey recent findings in invertebrates elucidating molecular links between autophagy and the regulation of ageing. ► We discuss the involvement of autophagy in signalling pathways, genetic manipulations and pharmacological treatments that promote longevity. ► We consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.
Introduction
Ageing is a complex process characterized by the progressive accumulation of damage to molecules, cells, tissues and organs that eventually leads to overall functional decline and increased vulnerability to disease and death. Although, stochastic and environmental factors undoubtedly contribute to the ageing process, intrinsic genetic determinants also modulate both lifespan and healthspan. During the past two decades, many studies in simple model organisms such as Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster have culminated in the delineation of several signalling pathways that influence ageing (Bishop and Guarente, 2007a, Giannakou and Partridge, 2007, Guarente and Kenyon, 2000, Kenyon, 2010). Numerous genetic manipulations and treatments that influence the lifespan of diverse organisms interface with metabolism, nutrient sensing and stress response pathways.
Macroautophagy (hereafter, referred to as autophagy) is an evolutionarily conserved self-eating process by which cytoplasmic components including macromolecules and organelles are sequestered into double-membrane vesicles, the autophagosomes, and then delivered to lysosomes for degradation (Fig. 1; Yang and Klionsky, 2010). Autophagy-related genes (ATG) are highly conserved among eukaryotes. Functional analyses in invertebrate and mammalian models have revealed multiple roles for autophagy in various physiological contexts. A basal level of constitutive autophagy is crucial for routine clearance of the cytosol under normal conditions. Basal autophagy is critical for protein and organelle homeostasis and quality control in post-mitotic differentiated cells such as neurons. In addition, autophagy becomes activated in response to low nutrient availability, providing a source of nutrients and energy. Autophagy is also triggered as an adaptive response to a broad range of other extracellular or intracellular stressors such as hypoxia, heat, reactive oxygen species (ROS) and accumulation of damaged cytoplasmic components (Levine and Klionsky, 2004). Suppression of autophagy by knockout or knockdown of essential autophagy genes triggers apoptosis or necrosis in cells that would otherwise survive under stress conditions (reviewed in Kourtis and Tavernarakis, 2009, Mathew et al., 2009).
Autophagy may proceed as a non-selective catabolic process for bulk segregation and digestion of portions of the cytoplasm in the lysosome, but also, in certain cases, it can selectively target proteins and organelles such as mitochondria (mitophagy), ribosomes (ribophagy), peroxisomes (pexophagy), and endoplasmic reticulum (ER; reticulophagy), thus contributing to their turnover (reviewed in He and Klionsky, 2009, Yang and Klionsky, 2010). Autophagy appears to serve primarily a cytoprotective function by maintaining nutrient and energy homeostasis during starvation or by degrading damaged cellular components and invasive pathogens. Paradoxically, although autophagy is a predominantly homeostatic mechanism, it can also play a role in cell death, which is not restricted to developmental programmed cell death but extends to cell death that occurs in many pathological conditions. Excessive autophagy induced by extreme conditions, such as toxins and necrosis-triggering insults, might cause uncontrollable degradation or sequestration of cells contents into autophagosomes resulting in undesirable cell death if not properly regulated (reviewed in Kourtis and Tavernarakis, 2009, Samara and Tavernarakis, 2008, Yang and Klionsky, 2010).
Beyond its functions at the cellular level, autophagy has also been implicated in the regulation of whole organism healthspan and lifespan. Accumulating findings indicate that clearing cellular damage by autophagy is a common denominator of different lifespan – influencing pathways in diverse organisms including yeast, worms, flies and mammals (Bjedov et al., 2010, Giannakou and Partridge, 2007, Hansen et al., 2008, Hars et al., 2007, Levine and Kroemer, 2008, Toth et al., 2008). Here, we review recent research developments that highlight the interaction of autophagy with several evolutionarily conserved mechanisms linked to longevity. We focus on multicellular invertebrate model organisms such as C. elegans and D. rosophila, which have contributed important insights into the mechanisms of ageing. Further, we discuss the role of autophagy as an adaptive mechanism by which an organism responds to environmental fluctuations to preserve homeostasis and maintain functionality during ageing.
Section snippets
The process of autophagy
Although autophagy was initially identified in mammals, genetic studies in yeast provided fundamental insights into the molecular machinery involved in autophagic degradation (Huang and Klionsky, 2002). These studies identified many ATG that encode proteins involved in the induction of autophagy, the formation, expansion and maturation of autophagosomes and in the retrieval of autophagic proteins from mature autophagosomes (Klionsky, 2005, Klionsky et al., 2003). Conventional autophagy
Insulin/IGF-1 signalling
Reduced activity of the insulin/IGF-1 signalling pathway (IIS) extends lifespan in C. elegans, Drosophila and other multicellular organisms, establishing its evolutionarily conserved role during ageing (Fontana et al., 2010, Kenyon, 2005, Kenyon, 2010). In C. elegans, mutations in the insulin/IGF-1 receptor orthologue DAF-2 double animal lifespan. Likewise, mutations affecting the conserved phosphatidylinositol-3 kinase PI(3)K/AKT/PDK kinase cascade that acts downstream of DAF-2 also extend
Environmental/cellular stress signals induce autophagy-mediated lifespan extension
Living organisms need to cope with multiple different environmental or chemical stressors (food deprivation, temperature shifts, UV irradiation, oxidation agents, etc.). Therefore, strategies that confer resistance to diverse stress stimuli are crucial for survival. In several cases, resistance to stress has been linked to longevity (Johnson et al., 2002, Kourtis and Tavernarakis, 2011). Stress resistance is often studied in two different contexts: survival after acute stress and adaptation to
Pharmacological induction of lifespan extension through autophagy stimulation
Apart from rapamycin (discussed above), many other pharmacological interventions influence longevity or stress resistance in diverse species, through activation of the autophagic machinery. Resveratrol is a plant polyphenol, member of a polyphenol class known as flavonols. It is found in grape berry skin, red wine, knotweed, peanuts and other plants, and displays anti-oxidative and free-radical scavenging properties. It has been studied extensively for its anti-inflammatory (Zhang et al., 2010
Concluding remarks
The process of ageing is driven by the gradual, lifelong accumulation of a wide assortment of molecular and cellular damage that eventually results in frailty and disease (Kirkwood, 2005, Kirkwood, 2008). Autophagy is a cellular housekeeper involved in the elimination of injured or dysfunctional organelles, protein aggregates and intracellular pathogens. These functions are vital for protection against damage associated with ageing and age-associated diseases (Levine and Kroemer, 2008).
Acknowledgements
Work in the authors’ laboratory is funded by grants from the European Research Council (ERC), the European Commission Framework Programmes, and the Greek Ministry of Education.
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These authors contributed equally.