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Scripps/Salk Rat Study Lays Out Comprehensive Profile of Long-lived Proteins Implicated in Aging

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A joint effort by The Scripps Research Institute and the Salk Institute for Biological Studies has provided the broadest look yet in vivo of a class of proteins that linger in the body for months or even years, rather then being replaced or refreshed after days or hours like a typical protein.

The study, published in Cell last month, identified a small subset of proteins in the brains of rats with lifespans significantly longer than the typical protein. According to the group, led by Scripps’ John Yates and the Salk Institute's Martin Hetzer, the identification of these molecules could have important implications for understanding the molecular basis of aging.

Jeffrey Savas, one of the study’s first authors and a researcher in Yates’ lab told ProteoMonitor this week that the effort was the first successful analysis of all the long-lived proteins in a particular organ system, and revealed a few surprises, as well as interesting targets for future research.

Overall, the effort identified long-lived proteins across several types, including molecules involved in gene expression, neuronal cell communication, and enzymatic processes.

In a confirmation of earlier work the team published last year in Science, the study also identified long-lived members of the nuclear pore complex, which directs transport of molecules into and out of the nucleus.

A few examples of extremely long-lived proteins and their role in some aspects of aging have been known for decades, Savas said. Crystallin, for example, aggregates in the lens of the eye and plays a role in the development of cataracts.

“The idea [with this study] was maybe there are some other important long-lived proteins than the ones we knew about already,” he said. By identifying more members in this subgroup, the team hoped to sift out targets for future research on the process of aging.

“What we think,” Savas said, “is that at least some of these proteins are actually the drivers of aging. When you die, you have usually a cataclysmic failure of an organ like your heart or your lungs. So we think these proteins, as they linger and get damaged, may eventually lead to a systems-level failure of one critical organ or another.”

To broadly profile the presence of these proteins in the brains of rats, the team used a metabolic pulse-chase labeling approach in which the researchers fed rats a diet containing only the nitrogen isotope 15N from birth through six weeks of age, and then switched them to a diet containing normal 14N.

Looking at tissue from the brains of rats killed at 0, 4, 6, 9, and 12 months after this switch using multidimensional liquid chromatograph-tandem mass spectrometry with a Thermo Finnigan Velos instrument, the group calculated ratios of the abundance of 15N/14N.

The team then used the persistence of 15N peptides as a measure of the lack of degradation, and subsequent longevity, of their corresponding proteins.

Among the proteins the researchers identified as particularly long-lived, were several connected with each other in larger protein complexes, Savas said. A particularly interesting group, he added, make up the very inner scaffold of the nuclear pore complex, the main channel for transporting molecules from the cytoplasm to the nucleus.

“It’s a huge protein complex, like 200 proteins,” Savas said. “And most of the whole thing turns over together over time, except for this very inner core, which we showed in neurons and post-mitotic cells turns over very, very slowly, if at all during [an animal’s] lifespan.”

“So that central channel of this massive complex seems to be maintained together, suggesting there is some mechanism in cells to maintain this over a long time and potentially manage damage to it in special ways.”

How this happens is something the group is now researching in more detail, Savas said. In an interview accompanying the Cell paper, Salk’s Hetzer said that because of the role of the nuclear pore complex and its involvement in the overall stability of the nuclear membrane, it’s longevity makes biological sense.

Instead of turning over the inner core complex regularly with the rest of the nuclear pore proteins, the body may replace bits and pieces of the core individually as needed.

The group also identified long-lived proteins for which there is less direct evidence of why they tend to linger without degrading and being replaced, including a number of soluble proteins, like the enzymes Sirt2, Enpp6, and Cnp1.

How or why these molecules are conserved remains “puzzling,” the study authors wrote, and offers another avenue of future research to try to tease out how these proteins evade turnover, and whether their longevity is due to their presence in larger assemblies, like the nuclear core complex, that need to be maintained over time.

Savas said the team is now following up the Cell study with similar work in organ systems other than the brain, as well as looking at whether long-lived proteins may play some measurable role in neurodegenerative diseases like Alzheimer’s.

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