Autophagy and the cell biology of age-related disease

Andrew M. Leidal, Beth Levine & Jayanta Debnath

Nature Cell Biology 20. (26 November 2018): 1338-1348.

Macroautophagy (autophagy) is a conserved lysosomal degradation process essential for cellular homeostasis and adaption to stress. Accumulating evidence indicates that autophagy declines with age and that impaired autophagy predisposes individuals to age-related diseases, whereas interventions that stimulate autophagy often promote longevity. In this Review, we examine how the autophagy pathway restricts cellular damage and degeneration, and the impact of these functions towards tissue health and organismal lifespan.

Aging—the time-dependent decline in cellular and tissue function—occurs in all metazoan organisms. Although initially perceived as a progressive, entropy-driven deterioration of tissues towards non-functionality and death, we now understand that the aging process is partly controlled by genetics. Evidence of this relationship emerged from screens in model organisms identifying numerous mutants that either extend lifespan or accelerate age-related decline1. The discovery of these conserved genetic determinants of lifespan revealed aging as a biological programme directed by specific signalling pathways and cellular machineries1. Evidence implicates critical roles for diverse stress response pathways in promoting longevity and healthy aging. These pathways, including autophagy, mitigate environmental pressures and extend lifespan through biological programs that limit tissue damage and promote repair and maintenance1. These cytoprotective programs progressively wane during aging, ultimately compromising tissue function and survival.

Autophagy is a conserved lysosomal degradation pathway essential for cellular homeostasis and adaptation to stress. During stress, autophagy facilitates survival through clearance of damaged molecules and mobilization of intracellular stores of energy and nutrients4. Abundant evidence supports autophagy as a critical regulator of lifespan. Many physiological and pharmacological interventions that extend lifespan, such as caloric restriction (CR) and the mTOR inhibitor rapamycin, induce autophagy5. In contrast, autophagy declines with age and autophagy impairment predisposes to assorted age-related diseases, including neurodegeneration and arthritis. Here, we review the biological pathways through which autophagy mitigates cellular damage during aging and discuss strategies to induce autophagy to combat age-related disease.