What is Known of the Age-Related Decline in Autophagy

Autophagy is the name given to a collection of complex maintenance processes responsible for recycling damaged and excess protein structures in the cell. Upregulation of autophagy is one of the more important responses to cell stress, and is involved in the slowing of aging produced by the practice of calorie restriction. It is reasonable to think that more autophagy means less damage and dysfunction in cells at any given time, and, when sustained over time for all of the cells in an organism, this helps to fend off some modest fraction of the damage and dysfunction of degenerative aging. Various measures of autophagy indicate that its efficiency declines with age, however. As for all complex processes in the cell, aging produces disarray. Why exactly is this the case? Autophagy is sufficiently complicated for current answers to that question to be incomplete, a work in progress.

Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age.

In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.