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Do People Age Like Yeast, Worms, and Flies? New Protein Interaction Network Suggests Yes

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With the help of some traditional scientific research surrogates for humans, researchers have created a protein interaction network that could provide clues into human aging and diseases associated with aging.

In a study published March 13 in the online journal PLoS Genetics, researchers drew upon genetic information about aging and longevity in invertebrates such as yeast, nematodes, and fruit flies to create a protein interaction network of human homologs of proteins that affect longevity in invertebrates, as well as proteins that interact with those homologs.

The study revealed that such model organisms have more in common with humans when it comes to the aging process than had been previously known, and that "the broad patterns underlying genetic control of life span in invertebrates is highly relevant to human aging and longevity," its authors wrote.

The network comprises 175 human homologs of proteins known to increase the life span of yeast, nematode, or fly through a loss of function, as well as an additional 2,163 human proteins that interact with these homologs. In total, the network of 2,338 unique proteins consists of 3,271 binary connections.

In the study, the authors said that though genome-wide studies have led to the identification of approximately 200 genes that when knocked out or mutated can increase the lifespans of model organisms such as yeast, nematodes, and fruit flies, whether and how this knowledge of longevity genes in such organisms translates to humans "has yet to be fully established."

Their study, however, indicates that the human homologs of invertebrate longevity genes and human genes encoding proteins that interact with the homolog proteins change in their expression levels during aging in human tissues.

According to an author of the study, the potential benefit of the work isn't that it would result in some monumental leap in human longevity. Rather, it could provide a basis for further research into age-related diseases such as cancers or neurodegenerative ailments.

"The fact of the matter is that lifespan is limited by age-associated disease … and when you think about targets, I don't really think about increasing lifespans per se but rather delaying the appearance of age-related disease, which will increase your quality of life," Robert Hughes, the corresponding author of the PLoS Genetics article, and assistant professor at the Buck Institute for Age Research, told ProteoMonitor this week.

He and his colleagues are using the network they've created to study the role proteins in the network may have in such diseases, he added.

The interaction network was built based on a database of human protein interactions created by Salt Lake City firm Prolexys Pharmaceuticals using yeast two-hybrid screens. Containing more than 114,000 unique binary interactions between fragments of human proteins, Hughes said the extensiveness of the database was a primary reason for the approach he and his co-researchers took.

They opted not to build a protein interaction network of invertebrate proteins first and then translate it to a human equivalent because "I kind of wanted to look [at the Prolexys database] first just because of the scale of what was represented," Hughes said.

The researchers took all the human homologs of the invertebrate aging genes and found all the proteins in the database that interact with them, resulting in a "putative human longevity protein interaction map," Hughes said.

While there has been no genome-wide study of genes that modulate lifespan in humans, another author on the paper, Simon Melov, an associate professor and director of the genomics core lab at the Buck Institute, had a dataset showing genetic changes in the muscle biopsies of individuals in their 20s and those in their 60s.

"And we just asked this following question: 'If you look at these human homologs of … genes that are known to modulate lifespan in invertebrates, do they have a tendency to change in their transcript levels during aging in humans?'" Hughes said.

The answer was "overwhelmingly yes," he said. That indicated to him and his colleagues that the human homologs of the invertebrate aging genes were changing their expression levels during human aging in muscles.

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"This demonstrated that these invertebrate genes really do have some sort of broad relevance to human aging," Hughes said. Looking at the proteins that interacted with the human homolog proteins, they also saw that they "were significantly changing during human aging."

While Hughes emphasized that he and has co-researchers' study doesn't prove that the proteins in their interaction network modulate aging, "they're clearly responsive to human aging."

Hubs

One of the key findings of the study is that the average longevity protein had 19 connections, compared to an average of 14 connections for proteins, in general, suggesting that longevity proteins serve as "hubs" or interfaces among groups of proteins.

The finding was a direct consequence of the proteomics approach they took, Hughes said.

"One interpretation of being a hub … is that [these proteins] tend to be involved in critical processes in the cellular network," he said. "The way that I interpret it is that these aging genes are at the center of a lot of action in the cell or allowing diverse processes or components of the cell to talk to each other."

Other categories of proteins have been observed to have high connection levels, or node degrees, Hughes said. In yeast, for example, a higher connection level is associated with essential genes encoding proteins. Highly conserved proteins and large proteins also tend to have high node degrees.

"But I can tell you that … this enrichment of high-node-degree proteins among aging genes doesn't appear to be driven by any of those features. So it seems to be a special feature," he added.

One protein of particular interest to the researchers is Tor, a signal transducing protein that couples cellular physiology and rates of protein synthesis and degradation to nutrient and growth-factor signaling, among other things. Hughes and his colleagues showed in the PLoS Genetics paper that a number of the Tor-interacting proteins in their interaction network "could modulate lifespan in C. elegans," he said, "and we're mining the network for novel players in the Tor pathway."

In follow-up validation work, Hughes and his team are using cell and model organism assays to show that features of the network are connected to the pathways they are implicated in due to their interaction with certain proteins.

Another planned follow-up is to explore whether SNPs in the candidate genes for human aging can be associated with changes in human lifespans, he added.

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