Longevity Breakthrough: Researchers Discover Protein Mechanism Tied to Lifespan and Cancer Growth

Researchers at UC Merced (University of California, Merced), Genentech Inc., and the University of Iowa used fruit flies to discover a cellular process common to many organisms.

Their findings could significantly impact our understanding of aging and cancer.

The scientists uncovered a mechanism that allows cells to regulate the amount of protein they produce by adjusting the translation of RNA into proteins.

Department of Molecular and Cell Biology Professor at UC Merced, Fred Wolf, said:

“This mechanism may be responsible for changes in protein translation in stress, cancer, and aging.”

The study and its findings have been published in the journal Nature Communications (citation below).

A Collaborative Journey Between Wolf and Dixit

Prof. Wolf, and fellow study researcher, Dr. Vishva M. Dixit, Genentech Inc. Vice President and Senior Fellow in Physiological Chemistry and Research Biology, have a professional relationship dating back when Wolf was an undergraduate at the University of Michigan in Dixit’s research lab.

They stayed in touch when Dixit went to Genentech and Wolf went to graduate school at Berkeley.

Wolf explained:

“Vishva knew I was an expert in Drosophila (fruit fly) genetics, a resource that was not available at Genentech.”

Using Fruit Flies for Genetic Research

Wolf’s lab normally focuses on studying brain circuits and genes that influence animal behavior, with a particular emphasis on how alcohol affects the brain and the way motivation is represented within it.

He and his team use the fruit fly Drosophila, a popular choice among scientists due to their rapid and abundant reproduction, low cost, and ease of genetic modification for testing ideas. According to Wolf, studies centered on fruit flies have led to the development of many sophisticated tools.

The Role of OTUD6 in Stress and Cancer

Dixit was trying to find out what the function of OTUD6 (a protein) was.

Wolf said:

“He asked us to use the awesome power of the fly model to discover its function, and we took up the challenge. Vishva granted me seed funding to start generating flies with mutations in OTUD6 and testing the mutant flies for any problems they might have.”

“The project really got going when the paper’s first author, Sammy Villa, joined my lab in 2018. Sammy took on the project and his skills in molecular biology and biochemistry were instrumental to the success of the project.”

Investigating OTUD6’s Role Using Mutant Flies

Initially, the researchers were unsure of what to expect. When they created flies that were mutant for OTUD6, they anticipated noticeable changes, such as altered wing shape, an unusual number of wings, or reproductive issues. However, the flies appeared normal.

Wolf said:

“We stressed the flies in as many ways as we could conceive of and found they were susceptible to chemical stress, for example, oxidative stress. This allowed us to search for how OTUD6 contributed to resilience to stress.”

The researchers investigated all proteins interacting with OTUD6 to determine its function and found that it reduced ribosomal protein production by 50%. This modification allows cells to adjust and produce more protein.

• The Team Was Surprised

Wolf said:

“We were quite surprised by the huge impact OTUD6 had on how much protein was made in cells: Making flies mutant for OTUD6 cut protein production in half. That’s a big difference.”

“The amount of protein produced in cells is known to affect how long animals live, with less protein being made correlating with longer lifespan. Our OTUD6 mutants lived twice as long. We think this is because there is less protein being made.”

The level of protein production can significantly influence the development of certain types of cancers.

In many types of cancers that affect humans, OTUD6 levels are higher. Many cancers also have greater protein production.

They currently have no direct evidence for a link, the researchers stressed. However, increased levels of OTUD6 might play a role in cancer cell growth and proliferation.

Cells can adjust their levels of OTUD6 to regulate the amount of protein they produce.

Wolf said:

“It has been known for years that there are two other ways for cells to actively tune how much protein is made, and we think we discovered a third way.”

Exploring the Impact on Lifespan and Cancer Treatment

The research team would like to determine how the cell changes cells’ OTUD6 levels. This could help us understand how this new pathway is activated and potentially lead to novel methods for manipulating protein production, which may positively influence lifespan and even cancer treatment.

Citation:

Villa, S., Dwivedi, P., Stahl, A., Hinkle, T., Rose, C. M., Kirkpatrick, D. S., Tomchik, S. M., Dixit, V. M., & Wolf, F. W. OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress. Nat Commun 15, 6873 (2024). https://doi.org/10.1038/s41467-024-51284-y