Long-lived proteins are the key to understanding the mechanisms of aging
The "weakest link" of the aging proteome
LifeSciencesToday based on the materials of the Salk Institute:
The 'weakest link' in the aging proteomeProteins are the main actors who perform the duties in cells provided by the information encoded in our genes.
Most proteins live for only about two days, which guarantees timely replacement of molecules damaged by inevitable chemical modifications with new functional copies.
In an article published in the journal Cell (Toyama et al., Identification of Long-Lived Proteins Reveals Exceptional Stability of Essential Cellular Structures), a group led by scientists from the Salk Institute for Biological Studies and the Scripps Research Institute (TSRI) reports on the identification in the brains of rats of a small subgroup of proteins that have been existing for much longer – more than a year – without replacement. The identification of these proteins may be of great importance for understanding the molecular basis of aging.
The nucleus of a rat brain cell. Each red spot is a separate complex of a nuclear pore, a cellular structure located in the membrane surrounding the nucleus, which is essential for communication between the nucleus and the rest of the cell. Scientists from the Salk Institute are studying long-lived proteins, which are important structural components of these complexes. (Photo: Brandon Toyama, Waitt Advanced Biophotonics Center)"The duration of the protein's existence may make the most significant contribution to cellular aging," says Martin Hetzer, professor of the Laboratory of Molecular and Cellular Biology at the Salk Institute, along with TSRI Professor John Yates, senior author of the study.
"The identification of all long-lived proteins allows us to focus our research on these specific molecules, which may be the weakest link in the aging proteome."
This work is the first comprehensive and objective identification of a long–lived proteome – the entire set of proteins expressed by the genome under these environmental conditions. In a study published last year in the journal Science, Professor Getzer and his colleagues identified long-lived proteins in the cell nucleus.
Long-lived intracellular proteins have recently been associated with age-related defects, starting with a decrease in reproductive abilities and ending with a decrease in the functionality of neurons. Why long-lived proteins exist in a metabolically active cellular environment and how they persist for long periods of time has not been sufficiently studied. Scientists from the Salk Institute and TSRI report on the system-wide identification of rat brain proteins with exceptional longevity. These proteins are ineffectively replenished, despite reliable translation throughout the adult life of the body. Using nucleoporins as a paradigm for the persistence of long-lived proteins, they found that nuclear pore complexes (NPCs) are maintained throughout the life of the cell due to the slow but definable replacement of even their most stable subcomplexes. This preservation, however, is limited, since the levels of some nucleoporins decrease during aging, giving a logical explanation for the observed age-related decline in NPC function. Identification of the long-lived proteome reveals cellular components at increased risk of damage accumulation, linking the existence of long-lived proteins with the process of cellular aging. (Fig. Cell)The system–wide identification of long–lived proteins in the rat brain - a laboratory model of human biology - carried out in a new study expands the data published in Science.
Scientists have found that long-lived proteins include those involved in gene expression, neuron communication and enzymatic processes, as well as components of the nuclear pore complex (NPC), responsible for the entire transport of substances into and out of the nucleus.
In addition, they showed that the NPC undergoes a slow but definable upgrade by replacing small subcomplexes, rather than the entire complex as a whole, which probably helps to avoid the accumulation of damaged components.
"This can be compared to maintaining the condition of a car, when you do not change the whole car, but only the broken parts," comments the lead author of the article Brandon Toyama, a postdoctoral fellow in Professor Getzer's laboratory.
Earlier, Professor Getzer and his colleagues found that a decrease in the function of the nuclear pore complex may represent a general mechanism of aging, leading to age-related defects in the function of the nucleus. Other laboratories have linked protein homeostasis, or internal stability, with a decrease in cell function and, thus, with the development of diseases. The new findings point to cellular components at increased risk of damage accumulation, linking the long duration of protein existence with the process of cellular aging.
"Now that we have identified these long–lived proteins, we can begin to study the mechanism of their damage during aging and what the cell does to compensate for the inevitable damage," adds Toyama.
Professor Getzer's group is currently working to identify the targets involved in the aging process and potential solutions to this problem. "We are starting to think about how to return the functionality of its younger version to the protein," the scientist concludes.
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