Recycling for a Longer Healthier Life
By promoting cellular recycling we might be able to significantly prolong our lifespan. A study conducted by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) points in this direction. They have undertaken the first ever comprehensive analysis of this process in a living animal during aging. The cells in our body are continuously going through a process of recycling, similar to the way we recycle glass, plastic and metal. They "clean house" by degrading old or malfunctioning organelles and using the resulting pieces as a source of energy or as building blocks for new organelles. This recycling process is known as autophagy, which means "self-eating" based on its Greek roots. Autophagy serves also as a protective mechanism removing viruses and bacteria.
In recent years, scientist have been asking whether age-associated diseases, such as cancer, neurodegeneration and heart disease, are connected to an age-related decline in autophagy. Exploring why and how autophagy becomes faulty with age, may reveal new therapeutic approaches to promote healthy aging by correcting for any errors in autophagy.
What is autophagy? Autophagy begins with formation of a double-membrane sac in the cell cytoplasm called isolation membrane (IM). These structures expand in size, by engulfing cellular material and debris, 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 is to understand how this process changes with aging. Generally, researchers monitor autophagy by counting the number of APs, which really only provides a snapshot of the process — similar to how counting the garbage trucks on the street doesn't tell you how much garbage is actually being recycled at the factory. Typically, older organisms have more APs than younger ones, but we don't exactly understand why. Based on which stage of the process is influenced the strongest by the aging, we can formulate strategies on how we can effectively intervene and correct the process. For example, it may be that the rate at which APs are formed is increased with age, or by analogy, how many garbage trucks are rolled out on the street — or alternatively, the conversion of APs to ALs may somehow be hindered, i.e., how much recycling is taking place at the recycling plant. Both of these scenarios would lead to an increased number of APs, but knowing which one would help direct our intervention strategy.
The model organism loved by research labs all over the world who study aging and autophagy is C. elegans, a tiny roundworm. C. elegans is a powerful genetic tool, as it shares many anatomical and cellular features with humans, and it has a short lifespan of only 17 days (on average). Its short lifespan allows us to study genes and measure cell traits in just two to three weeks.
Previous studies have suggested that APs increase in numbers with age (Hansen, Walker et al. 2018 DOI: 10.1038/s41580-018-0033-y), but the actual process underlying this change remains somewhat elusive. This has to do with the fact that AP measurements were made under steady-state conditions, which does not reveal what step in the process leads to increased levels. In a recent study, published recently in eLife (Chang T et al. eLife 2017 DOI: 10.7554/eLife.18459), a team of researchers from the Sanford Burnham Prebys Medical Discovery Institute in United States, led by Prof. Malene Hansen went beyond the standard approach of counting APs under steady-state conditions. They counted the numbers of APs and ALs in different body tissues—intestine, muscle, and neurons—at different time points during the adult life of C. elegans, and used chemical blockers to learn more about the dynamics of the process. This research led to the observation that there is indeed an age-dependent decline in autophagy over time in all tissues examined. They further provide evidence that age impairs the recycling process at a step after APs are made.
The importance of these findings lays in valuable time- and site-of-action information, that will facilitate future interventions directed at sustaining autophagy to extend lifespan. Future efforts will be directed at understanding how exactly autophagy fails to complete its cycle. Pinpointing the precise sites where this process falters with age, will provide targets to develop specific interventions that help people live longer, healthier lives.
More information can be found in the core article on which this report is based. Jessica T Chang et al, Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging, eLife (2017). DOI: 10.7554/eLife.18459
Author: Sebastian Florescu, PhD