Posted on Jan 05, 2024, 3 p.m.
Autophagy is a cellular housekeeping process that promotes health by recycling or removing damaged DNA and RNA as well as other “garbage” cellular components (like misfolded proteins) in a degradative process. Autophagy is a key factor in preventing aging and disease of aging, and research has demonstrated how autophagy genes are responsible for prolonged longevity in a range of long-lived organisms.
"While this is very basic research, this work is a reminder that it is critical for us to understand whether we have the whole story about the different genes that have been related to aging or age-related diseases," said Professor Malene Hansen, Ph.D., Buck's chief scientific officer, who is also the study's co-senior author. "If the mechanism we found is conserved in other organisms, we speculate that it may play a broader role in aging than has been previously appreciated and may provide a method to improve life span."
"There had been this growing notion over the last few years that genes in the early steps of autophagy were 'moonlighting' in processes outside of this classical lysosomal degradation," she said. Additionally, while it is known that multiple autophagy genes are required for the increased life span, the tissue-specific roles of specific autophagy genes are not well defined.
To investigate the role autophagy genes play in neurons, the team analyzed Caenorhabditis elegans, specifically inhibiting autophagy genes functioning at each step of the process in the neurons. The researchers found that neuronal inhibition of early-acting but not late-acting autophagy genes extended lifespan. Unexpectedly this lifespan extension was accompanied by a reduction in aggregated protein in the neurons and an increase in the formation of exophers.
"Exophers are thought to be essentially another cellular garbage disposal method, a mega-bag of trash," said Dr. Caroline Kumsta, co-senior author and assistant professor at SBP. "When there is either too much trash accumulating in neurons, or when the normal 'in-house' garbage disposal system is broken, the cellular waste is then being thrown out in these exophers."
Worms that had formed exophers also had reduced protein aggregation and lived significantly longer than those that didn’t, and this process was found to be dependent on protein ATG-16.2. Suggesting a link between this process of this massive disposal process to overall health.
Several new functions were identified for autophagy protein ATG-16.2, including exopher formation and lifespan determination. This led the researchers to speculate that this protein plays some nontraditional and unexpected roles in the aging process. If additional research can confirm the same mechanisms in other organisms, it may provide a method of manipulating autophagy genes to improve neuronal health as well as extend lifespan.
"But first we have to learn more -- especially how ATG-16.2 is regulated and whether it is relevant in a broader sense, in other tissues and other species," Hansen said. The Hansen and Kumsta teams are planning on following up with a number of longevity models, including nematodes, mammalian cell cultures, human blood and mice.
"Learning if there are multiple functions around autophagy genes like ATG-16.2 is going to be super important in developing potential therapies," Kumsta said. "It is currently very basic biology, but that is where we are in terms of knowing what those genes do."
Traditionally, aging and autophagy are linked because of lysosomal degradation, and this may need to expand to include additional pathways which would have to be targeted differently to address the diseases and associated problems.
"It will be important to know either way," Hansen said. "The implications of such additional functions may hold a potential paradigm shift."
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