Autophagy is the name given to a collection of recycling mechanisms involved in cellular maintenance. These processes clear out metabolic waste and break down damaged cellular components so that the parts, proteins and their constituents, can be used elsewhere. The better documented forms of autophagy involve the coordination of (a) systems that flag structures and molecules for recycling, (b) systems that engulf the flagged materials in membranes for delivery to cellular recycling centers, and (c) the recycling structures called lysosomes, packed with enzymes capable of dismantling up most of what they will encounter.

Autophagy fails with age, and this failure is thought to contribute to degenerative aging to some degree; certainly many of the methods of modestly slowing aging in laboratory species appear to at least involve - and in some cases rely upon - increased autophagy. Exactly why does autophagy falter with age, however? There are a lot of answers to that question, of varying degrees of incompleteness, speculation, and supporting evidence. The challenge here, as for everything that goes on inside a cell, is that autophagy is a highly dynamic, enormously complex chain of mechanisms. Failures could be subtle and hard to detect in any one component part, or they could be distributed throughout the system, and there are a lot of pieces to examine. It has taken decades for the modern research community to gather today's comparatively sophisticated, partial picture of what is going on under the hood, and the tools of biotechnology are only now gaining the capacity to do better than this given a reasonable amount of time and funding.

A further consideration is that autophagy is a large enough research space to develop specializations: teams will tend to have more experience in just one aspect of this set of processes. It is, like much of the life sciences, a case of the blind men and the elephant, and intensive, ongoing collaboration is required in order to gain any sort of holistic picture. Many autophagic mechanisms no doubt all become dysfunctional in their own particular ways across the course of aging, and each such chain of cause and effect reaches from the beginning of some form of fundamental molecular damage through numerous stages to reach whatever layer of the onion that any given scientist happens to be investigating. When people publish papers on the age-related decline of autophagy, it is always worth bearing this in mind: it is rare that anyone is working with more than a slice of the whole at one time.

That said, the research here is an example of the sort of approach needed to improve the present understanding of how autophagy works in detail, and thus build a better map of where it runs off the rails over the course of aging. You might compare the report here with, say, the standard SENS view of dysfunctional autophagy resulting from hardy metabolic waste accumulated in lysosomes, or the discovery that loss of autophagy can be restored at least partially through genetic engineering to add more receptors to lysosomes, increasing their ability to receive flagged materials for recycling. The lysosome is just one part of a much larger set of autophagic systems, however, and problems can certainly exist elsewhere - though it has to be said that the findings noted below are consistent with theories placing the whole of the problem in the lysosome, and thus supportive of the SENS approach to therapies.

Scientists Take a Deeper Dive Into Cellular Trash

"Autophagy," which means "self-eating" based on its Greek roots, is the normal physiological process the body's cells use to remove viruses, bacteria, and damaged material from the cell. Autophagy also helps cells "clean house" by recycling building blocks - similar to the way we recycle glass, plastic and metal. In recent years, defective autophagy has been linked to age-related diseases such as cancer, neurodegeneration and heart disease. "Increasingly, researchers are asking whether there is an age-related decline in autophagy and if it's connected to diseases that occur more frequently in older individuals. Exposing how autophagy becomes faulty with age may reveal opportunities for us to therapeutically intervene and correct the process to promote health aging." Autophagy is a dynamic, multi-step process that starts with the formation of a double-membrane sac in the cell cytoplasm called the isolation membrane (IM). These structures engulf cellular material and debris, expanding in size to form vesicles called autophagosomes (APs). Finally, APs fuse with lysosomes to form autolysosomes (ALs) that digest and release the breakdown products for re-use, much like a recycling plant would repurpose incoming trash. "A major challenge with understanding how aging impacts autophagy is that researchers have been capturing a dynamic process with static measurements. Autophagy is most commonly monitored by counting the number of APs, which really only provides a snapshot of the process - similar to how counting the number of garbage trucks on the street doesn't tell you how much garbage is actually being recycled at the plant. And typically older organisms have an increased number of APs, but we don't know exactly why." "We wanted to ask how age impacts autophagy - is it at the beginning of the process by increasing the rate at which APs are formed, or, by analogy, how many garbage trucks are rolling out on the street - or is it at the end of the process by blocking the conversion of APs to ALs, i.e., how much recycling is taking place at the recycling plant. Either one of these scenarios would cause an increased number of APs, but knowing which one would help pinpoint where interventions may be helpful. We found that there is indeed an age-dependent decline in autophagy over time in all tissues examined. We further provide evidence that the increase in APs results from an impairment at a step after APs are made. So basically the autophagy recycling process becomes incomplete with age by stopping somewhere after APs are formed. This research is important because it helps provide time- and site-of-action information for potential future interventions directed at sustaining autophagy to extend lifespan. Our next step will be to perform biochemical research to further pinpoint exactly how autophagy fails to complete its cycle, possibly providing targets to develop specific interventions."

Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging