Autophagy as a promoter of longevity: insights from model organisms

Abstract

Autophagy is a conserved process that catabolizes intracellular components to maintain energy homeostasis and to protect cells against stress. Autophagy has crucial roles during development and disease, and evidence accumulated over the past decade indicates that autophagy also has a direct role in modulating ageing. In particular, elegant studies using yeasts, worms, flies and mice have demonstrated a broad requirement for autophagy-related genes in the lifespan extension observed in a number of conserved longevity paradigms. Moreover, several new and interesting concepts relevant to autophagy and its role in modulating longevity have emerged. First, select tissues may require or benefit from autophagy activation in longevity paradigms, as tissue-specific overexpression of single autophagy genes is sufficient to extend lifespan. Second, selective types of autophagy may be crucial for longevity by specifically targeting dysfunctional cellular components and preventing their accumulation. And third, autophagy can influence organismal health and ageing even non-cell autonomously, and thus, autophagy stimulation in select tissues can have beneficial, systemic effects on lifespan. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy.

Fig. 1 |. The macroautophagy process.

A schematic depicting the process and main regulatory machinery of macroautophagy (referred to as autophagy) is shown. The conserved metabolic sensors and longevity determinants mTOR and AMP-activated kinase (AMPK) are the main regulators of autophagy, with mTOR acting as an inhibitor and AMPK as an activator. When autophagy is induced, cytoplasmic material (the autophagic cargo) is engulfed by double membranes, starting from the formation of a cup-shaped structure called the phagophore to the sequestration into double-membrane vesicles, called autophagosomes, which subsequently fuse with acidic lysosomes and form autolysosomes, where cargo is degraded. Autophagy is a multistep process that includes (1) initiation, (2) membrane nucleation and phagophore formation, (3) phagophore expansion, (4) fusion with the lysosome, and (5) degradation, which correspondingly are regulated by multiple proteins, referred to as autophagy-related proteins (ATGs). ATGs assemble into several complexes: the Unc-51-like kinase 1 (ULK1; Atg1 in yeasts) initiation complex, the class III PI3K nucleation complex and the phosphatidylinositol 3-phosphate (PI3P)-binding complex, which directs the distribution of the machinery that enables autophagosome formation, and includes the ATG12 and the microtubule-associated protein light chain 3/γ-aminobutyric acid receptor-associated proteins (LC3/GABARAPs; Atg8 in yeasts) conjugation systems (for simplicity, only LC3 is noted in the figure). In the ATG12 conjugation system, ATG12 is attached to ATG5, which is then attached to ATG16L1 (Atg16 in yeasts), followed by dimerization (not shown) and interaction with the PI3P-binding complex (formed by WD repeat domain phosphoinositide-interacting proteins (WIPIs; Atg18 in yeasts) and zinc-finger FYVE domain-containing protein 1 (DFCP1). The ATG12-ATG5-ATG16L1 complex then promotes conjugation of LC3 (or GABARAP), whereby LC3 is cleaved by the protease ATG4 to form LC3-I, which is then conjugated with phosphatidylethanolamine (PE) to form LC3-II. This conjugate is incorporated into pre-autophagosomal and autophagosomal membranes, where LC3 can interact with cargo receptors, which harbour LC3-interacting motifs (LIRs). Membranes for phagophore expansion are delivered, at least in part, by ATG9-containing vesicles. For simplicity, only the names of vertebrate ATGs are shown. VPS15, PI3K regulatory subunit 4 (also known as PIK3R4 in humans); VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3 (also known as PIK3C3 in humans).

Fig. 2 |. Selective types of autophagy linked to organismal ageing.

A schematic summarizing selective types of autophagy linked to pathologies of ageing in model organisms. In these selective types of autophagy, autophagosomes recruit mitochondria (mitophagy), lipid droplets (lipophagy), aggregate-prone proteins (aggrephagy) and lysosomes (lysophagy). This is generally mediated by so-called autophagy receptors that bridge the cargo and the autophagy machinery (some examples of autophagy receptors that have been indicated to function in the context of ageing are depicted, but most likely other receptors are involved). Consequences of deficiencies in these types of selective autophagy and their links to age-related diseases are listed. Note that while this figure illustrates possible links between forms of selective autophagy and diseases, it is very challenging to demonstrate causality for the selective autophagy in disease in a direct sense, as opposed to links or associations. For example, PTEN-induced putative protein kinase 1 (PINK1), which is mutated in a rare form of recessive Parkinsonism, has been implicated in stress-induced mitophagy in tissue-culture models, leading to the assumption that loss of PINK1 causes disease via defects in mitophagy. However, recent work suggests that loss of PINK1 in mice does not affect mitophagy, thus challenging the model. ALS, amyotrophic lateral sclerosis; BNIP3L, BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3-Like; CMA, chaperone-mediated autophagy; LC3, microtubule-associated protein light chain 3; NBR1, next to BRCA1 gene 1 protein; ROS, reactive oxygen species.