Protein is an important component of all cells and tissues of the human body. However, abnormal protein activities in the body may cause problems, such as increasing the risk of cancer and making people age faster.

On July 28, a research report titled "Rewiring of the ubiquitinated proteome determines aging in C. elegans" was published in the top journal Nature, revealing the relationship between excessive protein accumulation and longevity.

Researchers from the University of Cologne in Germany found that those shorter-lived Caenorhabditis elegans often face protein removal dysfunction as they age, leading to protein deposition in the body, and if gene therapy or chemical drugs are deployed to accelerate protein decomposition, it can help the nematodes to extend their lifespan by up to 1/5.

There are tens of thousands of proteins that perform various functions in eukaryotic cells. The endogenous proteins have a certain lifespan and will be degraded when they arrive. Ubiquitination (Ub: is one of the ways to guide protein degradation, which can label different types of proteins so that they can be recognized and degraded by corresponding enzymes in the cell. This process is reversible and can be reversed by deubiquitinating enzymes (DUBs).

Although ubiquitination is involved in the regulation of almost all life activities, it is still unclear how this process affects aging. Therefore, researchers started with Caenorhabditis elegans and tried to explore the potential relationship between ubiquitination and aging.

By comparing young nematodes (5 days after birth) with old nematodes (15 days after birth), the researchers found that the ubiquitination of old nematodes was generally reduced, and 350 Ub peptides were up-regulated and 1,813 Ub peptides were down-regulated, which provides evidence for the relationship between aging and the ubiquitination process.

In order to further evaluate the age-related changes in ubiquitination, the researchers performed the western blot analysis. The results showed that compared with young or long-lived nematodes, old wild-type nematodes expressed higher or even equivalent ubiquitin-encoding genes, indicating that the decrease in ubiquitination is not caused by less ubiquitin expression or changes in conversion rate. Is there a mysterious power that affects the ubiquitination process of proteins? In further analysis, the researchers finally found the factor that caused the reduction of ubiquitination-deubiquitinating enzyme (DUB). In old wild-type nematodes, the expression level of DUB was significantly up-regulated, and treatment with the broad-spectrum DUB inhibitor PR-619 was sufficient to save the hypoubiquitination level and prolong the lifespan of the nematodes.

Although there does not seem to be a direct correlation between protein abundance and ubiquitination levels, the researchers found that 192 less ubiquitinated proteins accumulated in elderly nematodes, which is due to decreased ubiquitination level which hinders the recognition and degradation of proteins by the proteasome (

After genetic engineering, the researchers found 10 age-related disorders proteasome targets, namely IFB-2, EPS-8, RPL-4, M01G12.9, C46C2.2, F54D1.6, DDI-1, LEC-1, HSP-43, and USP-5, among which, HSP-43 and USP-5 are important genes for cell viability. Knockout of these two genes leads to a shortening of the nematodes' lifespan, while the knockout of the other 8 genes is enough to extend the lifespan.

It is worth noting that the knockout of IFB-2 or EPS-8 has the greatest impact on lifespan, and the knockout of a single gene can help nematodes extend their lifespan by up to 21%. IFB-2 is only specifically expressed in intestinal cells, and the increase of this gene may lead to the loss of intestinal integrity. As a substrate of intracellular signaling pathways, the increase in EPS-8 expression will over-activate the RAC pathway, causing excessive remodeling and polymerization of actin, thereby affecting the lifespan, muscle function, and mobility of the organism.

According to the leader of the study, David Vilchez of the Center for Molecular Medicine at the University of Cologne, Germany, "Our research results bring potential new methods to delay aging and improve the quality of life of the elderly, especially between aging and ubiquitin-modified proteins. This will have a significant impact on other research on aging, ubiquitination, and other cellular processes in the future."

There are still problems to be solved, such as the mechanism that causes DUB to increase with age, and whether this change in ubiquitination with age can also be observed in more complex organisms such as mice and primates.

In general, this study reveals that during the aging process, the overall deubiquitination of tissues will affect the degradation of proteins and thus damage the lifespan

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