Autophagy and the hallmarks of aging

Abstract

Autophagy, an essential cellular process that mediates degradation of proteins and organelles in lysosomes, has been tightly linked to cellular quality control for its role as part of the proteostasis network. The current interest in identifying the cellular and molecular determinants of aging, has highlighted the important contribution of malfunctioning of autophagy with age to the loss of proteostasis that characterizes all old organisms. However, the diversity of cellular functions of the different types of autophagy and the often reciprocal interactions of autophagy with other determinants of aging, is placing autophagy at the center of the aging process. In this work, we summarize evidence for the contribution of autophagy to health- and lifespan and provide examples of the bidirectional interplay between autophagic pathways and several of the so-called hallmarks of aging. This central role of autophagy in aging, and the dependence on autophagy of many geroprotective interventions, has motivated a search for direct modulators of autophagy that could be used to slow aging and extend healthspan. Here, we review some of those ongoing therapeutic efforts and comment on the potential of targeting autophagy in aging.

Keywords: Aging; Chaperones; Lysosomes; Organelle turnover; Proteolysis; Proteostasis.

Figure. 1.. Types of autophagy pathways in mammals.

Schematic of the three major types of autophagy in mammals. (a) Macroautophagy is characterized by the sequestration of cargo (proteins, aggregates, organelles, pathogens) inside autophagosomes. In bulk and some forms of selective macroautophagy are depicted. The cargo is degraded in lysosomes upon autophagosome-lysosome fusion. (b) Chaperone-mediated autophagy is characterized by the selective degradation of proteins with KFERQ-motif. The substrates are recognized by HSC70/other chaperones. The protein substrates are degraded in lysosomes upon translocating across the membrane through the receptor multimeric complex (LAMP2A). (c) Microautophagy/Endosomal microautophagy is characterized by the engulfment of the cargo (proteins, aggregates, organelles) by the lysosomal membrane (in microautophagy) or late endosomal membrane (in endosomal microautophagy). The cargo is degraded when the intraluminal membrane is disintegrated giving the lysosomal hydrolases access. Once degraded by the lysosomal hydrolases, the biochemical components are recycled to the cytoplasm. Note: For simplicity, the three pathways are shown to converge on one lysosome; however, the current consensus is that different lysosomal populations cater to different autophagy pathways.

Figure. 2.. Steps in different types of autophagy affected by aging.

Aging-imposed changes have been described in different steps of each of the autophagic pathways and in lysosomes, the compartment where these pathways converge for degradation of cargo.

Figure 3.. Impact of autophagy on hallmarks of aging.

Growing evidence supports bidirectional interactions of the different autophagic pathway with multiple drivers of aging. Here, we illustrate hallmarks of aging affected by changes in autophagic activity and indicate the mechanisms whereby autophagy modulates these processes.

Figure 4.. Modulation of autophagy for geroprotection.

Lifestyle interventions (right) and drugs and natural products under the category of geroprotectors (left) proven to upregulate autophagy and benefit healthspan and lifespan. Geroprotectors with activating effects on macroautophagy are divided in two groups, those that have an effect in multiple cellular processes including autophagy and those designed specifically to target components of autophagy.