Macroautophagy and aging: The impact of cellular recycling on health and longevity

Abstract

Aging is associated with many deleterious changes at the cellular level, including the accumulation of potentially toxic components that can have devastating effects on health. A key protective mechanism to this end is the cellular recycling process called autophagy. During autophagy, damaged or surplus cellular components are delivered to acidic vesicles called lysosomes, that secure degradation and recycling of the components. Numerous links between autophagy and aging exist. Autophagy declines with age, and increasing evidence suggests that this reduction plays important roles in both physiological aging and the development of age-associated disorders. Studies in pharmacologically and genetically manipulated model organisms indicate that defects in autophagy promote age-related diseases, and conversely, that enhancement of autophagy has beneficial effects on both healthspan and lifespan. Here, we review our current understanding of the role of autophagy in different physiological processes and their molecular links with aging and age-related diseases. We also highlight some recent advances in the field that could accelerate the development of autophagy-based therapeutic interventions.

Keywords: AMPK; Aging; Autophagy; C. elegans; Healthspan; Lifespan; Neurodegeneration; mTOR.

Figure 1.. Damage accumulation and the molecular basis of aging.

In everyday life, humans are exposed to many stressors that can damage cellular components. Under normal circumstances, homeostatic mechanisms clear damaged material from the cell, but they can accumulate with time and eventually render the cells non-functional and/or induce a pathogenic state. To counteract these challenging insults, cells have evolved diverse cytoprotective mechanisms that include various types of autophagy. Cellular aging is thus dictated by the balance between the rate of damage infliction/accumulation and repair/clearance.

Figure 2.. Pathways of autophagy-mediated lysosomal degradation.

Autophagy allows the degradation of diverse intracellular components via delivery to the lysosomes. Three types of autophagy exist that are defined by the molecular mechanisms that facilitate cargo delivery: chaperone-mediated autophagy, microautophagy, and macroautophagy. Each autophagy type is specialized to enable the degradation of different cargos, with macroautophagy mediating the disposal of the most diverse array of cytoplasmic components, from proteins to organelles. This review focus on macroautophagy in the context of aging.

Figure 3.. Overview of the molecular events underlying macroautophagy.

Autophagy is a multistep process broadly defined by the formation of a double-membraned vesicle called autophagosome in which cargo is recruited. Autophagosomes originate from the progression and growth of a membranous structure called phagophore. The fusion of autophagosomes with lysosomes, finally allows degradation of the cargo. Prominent examples of the autophagy molecular machinery members implicated in the different steps are shown in the boxes.

Figure 4.. Protective roles of autophagy in promoting cellular and organismal health.

By orchestrating the degradation of potentially harmful cellular components, including protein aggregates, dysfunctional organelles (including mitochondria and lysosomes), cytoplasmic DNA, and pathogens, autophagy plays a major role in maintaining cellular homeostasis. Aging and the development of many age-related diseases correlate with a decline in the rate and/or efficiency of autophagy and recycling of specific types of debris, leading to their accumulation. This can trigger cellular dysfunction, followed by tissue/organismal damage which is frequently amplified by inflammatory signaling leading to different diseases. See text for details.

Figure 5.. Molecular events linked to the age-associated decline in autophagy.

(A) The main steps of macroautophagy are depicted together with the events that may fail during aging and in age-related diseases (indicated with a ‘stop’ sign). These include deregulated nutrient signaling, defects in autophagosome biogenesis and transport, as well as failure to maintain low lysosomal pH and lysosomal proteolytic activity. Shown below are several interventions (B), known to mitigate the age-associated loss of autophagy, such as caloric restriction, exercise, and small molecules, and the pathways by which they are thought to act. See text for details.