Autophagy and ageing: Insights from invertebrate model organisms

Abstract

Ageing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, 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.