Novel functions of autophagy genes in ageing and cellular waste disposal

Novel functions of autophagy genes in ageing and cellular waste disposal

Credit: Nature Aging (2024). DOI: 10.1038/s43587-023-00548-1

Age-related decreases in autophagy may be hiding more secrets than scientists had thought. Researchers from the Buck Institute, Sanford Burnham Prebys, and Rutgers University have discovered potential new roles for a number of autophagy genes. These functions may regulate different forms of disposal, such as misfolded proteins, and ultimately impact ageing, according to an article published in the January 4th issue of Nature Ageing.

Professor Malene Hansen, Ph.D., Buck's chief scientific officer and co-senior author of the study, said, "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 ageing or age-related diseases."

"If the mechanism we found is conserved in other organisms, we speculate that it may play a broader role in ageing than has been previously appreciated and may provide a method to improve life span."

These novel findings offer an alternative interpretation of what was previously believed to be happening during autophagy.

Through a multi-step degradative process, autophagy is a cellular "housekeeping" mechanism that recycles or eliminates damaged DNA, RNA, and other cellular components, thereby promoting health. It has been demonstrated to play a significant role in delaying the onset of aging-related illnesses, such as diabetes, cancer, heart disease, and neurodegeneration. Interestingly, studies have revealed that autophagy genes are in charge of many long-lived creatures' extended life spans.

According to the traditional theory, autophagy functions by delivering the cellular "garbage" to be degraded to lysosomes via a vesicle covered by a membrane. Nonetheless, Hansen, who has spent the most of her career researching the function of autophagy in ageing, was interested by a growing body of evidence suggesting that this was not the only mechanism in which autophagy genes may be active.

Over the past few years, there has been an increasing belief that genes involved in the initial stages of autophagy are "moonlighting" in pathways other than the traditional lysosomal degradation process, the speaker stated. Furthermore, it is unclear what functions particular autophagy genes serve in different tissues, despite the fact that it is known that several autophagy genes are necessary for the longer lifespan.

In order to fully explore the function of autophagy genes in neurons—a crucial cell type for neurodegenerative diseases—the group examined the nervous system of Caenorhabditis elegans, a microscopic worm commonly used to simulate the genetics of ageing.

By deliberately blocking autophagy genes that functioned at every stage in the animal's neurones, the researchers discovered that neuronal inhibition of early-acting autophagy genes, but not late-acting ones, increased life span. Prior to her relocation to the Buck Institute in 2021, these preliminary findings were conducted in Dr. Hansen's lab at Sanford Burnham Prebys in La Jolla, California.

Unexpectedly, this expansion in life span was accompanied by an increase in the synthesis of so-called exophers and a decrease in aggregated protein in the neurones (an increase in which is linked to conditions like Huntington's disease). 2017 saw the discovery of these enormous vesicles that protruded from neurones by Rutgers University professor and collaborator Dr. Monica Driscoll.

According to Dr. Caroline Kumsta, co-senior author and assistant professor at SBP, "exophers are thought to be essentially another cellular garbage disposal method, a mega-bag of trash." "When there is either too much trash accumulating in neurones, or when the normal 'in-house' garbage disposal system is broken, the cellular waste is then being thrown out in these exophers."

It's interesting to see that exopherous worms lived noticeably longer and exhibited less protein aggregation. According to Kumsta, this study raises the possibility of a connection between the major disposal event's procedure and general health. The group discovered that a protein known as ATG-16.2 was required for this process.

The autophagy protein ATG-16.2 was shown to have multiple new roles in the study, including exopher production and life span determination. These findings lead the researchers to hypothesise that the protein may have an unexpected and atypical role in the ageing process. Should this identical mechanism be functioning in other creatures, it could offer a means of modifying autophagy genes to enhance neuronal well-being and prolong 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 stated. In the future, the Hansen and Kumsta groups intend to investigate a variety of longevity models, such as worms, mouse models, human blood, and mammalian cell cultures.

"Learning if there are multiple functions around autophagy genes like ATG-16.2 is going to be super important in developing potential therapies," Kumsta stated. "It is currently very basic biology, but that is where we are in terms of knowing what those genes do."

In order to address the diseases and associated issues, the conventional explanation of the connection between autophagy and ageing due to lysosomal degradation may need to be expanded to include additional pathways that would require alternative targeting. "Either way, it will be crucial to know," Hansen stated. "The implications of such additional functions may hold a potential paradigm shift."