More Evidence for Defects in the Formation of Autophagosomes to be Important in the Age-Related Decline of Autophagy

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Autophagy is a collection of cellular maintenance processes that act to recycle damaged structures in the cell, thereby maintaining cell health and function. On the one hand, the efficiency of autophagy declines with age, and this loss of function is associated with numerous age-related diseases, particularly of the central nervous system and its population of very long-lived neurons. On the other hand, increased autophagy is an important component of many of the interventions shown to slow aging in short-lived species, such as via calorie restriction. A fair number of research groups are working on ways to upregulate autophagy in our species, but this has been going on for a while with little concrete movement towards the clinic.

Autophagy is a complicated process of multiple steps, and at every step there are plausible proximate causes for a faltering of the system with age. The formation of autophagosomes to encapsulate materials to be recycled can break down, as is the case in today’s open access paper. The mechanisms by which autophagosomes are transported to a lysosome for deconstruction of their contents are degraded. The lysosome itself becomes filled with metabolic waste that it struggles to break down, making it bloated and inefficient.

In the case of defects relating to autophagosomes it is unclear as to why the breakage happens, how it relates to the underlying molecular damage that causes aging. Given this, approaches to therapy tend to focus on overriding proximate changes. Researchers find regulatory systems that can be adjusted in order to force the relevant mechanism to work despite its normal reaction to systemic damage in and around cells. In principle this should always be worse as a strategy than identifying and repairing the damage, but it can produce benefits in some cases. In the example here, researchers find a way to override the failure to form autophagosomes that is observed in old neurons.

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Unlike most of the cells in our body, our neurons are as old as we are: while other cell types are replaced as they wear out, our neurons must last our entire lifetime. The symptoms of disorders such as Alzheimer’s disease and ALS result from neurons in the brain or spinal cord degenerating or dying. But why do neurons sometimes die?

One reason may be that elderly neurons struggle to remove waste products. Cells get rid of worn out or damaged components through a process called autophagy. A membranous structure known as the autophagosome engulfs waste materials, before it fuses with another structure, the lysosome, which contains enzymes that break down and recycle the waste. If any part of this process fails, waste products instead build up inside cells. This prevents the cells from working properly and eventually kills them.

Aging is the major shared risk factor for many diseases in which brain cells slowly die. Could this be because autophagy becomes less effective with age? Researcher isolated neurons from young adult, aging and aged mice, and used live cell microscopy to follow autophagy in real time. The results determined that autophagy does indeed work less efficiently in elderly neurons. The reason is that the formation of the autophagosome stalls halfway through. However, increasing the amount of one specific protein, WIPI2B, rescues this defect and enables the cells to produce normal autophagosomes again.

As long-lived cells, neurons depend on autophagy to stay healthy. Without this trash disposal system, neurons accumulate clumps of damaged proteins and eventually start to break down. The results identify one way of overcoming this aging-related problem. As well as providing insights into neuronal biology, the results suggest a new therapeutic approach to be developed and tested in the future.

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