Abstract
We have mapped a protein interaction network of human homologs of proteins that modify longevity in invertebrate species. This network is derived from a proteome-scale human protein interaction Core Network generated through unbiased high-throughput yeast two-hybrid searches. The longevity network is composed of 175 human homologs of proteins known to confer increased longevity through loss of function in yeast, nematode, or fly, and 2,163 additional human proteins that interact with these homologs. Overall, the network consists of 3,271 binary interactions among 2,338 unique proteins. A comparison of the average node degree of the human longevity homologs with random sets of proteins in the Core Network indicates that human homologs of longevity proteins are highly connected hubs with a mean node degree of 18.8 partners. Shortest path length analysis shows that proteins in this network are significantly more connected than would be expected by chance. To examine the relationship of this network to human aging phenotypes, we compared the genes encoding longevity network proteins to genes known to be changed transcriptionally during aging in human muscle. In the case of both the longevity protein homologs and their interactors, we observed enrichments for differentially expressed genes in the network. To determine whether homologs of human longevity interacting proteins can modulate life span in invertebrates, homologs of 18 human FRAP1 interacting proteins showing significant changes in human aging muscle were tested for effects on nematode life span using RNAi. Of 18 genes tested, 33% extended life span when knocked-down in Caenorhabditis elegans. These observations indicate that a broad class of longevity genes identified in invertebrate models of aging have relevance to human aging. They also indicate that the longevity protein interaction network presented here is enriched for novel conserved longevity proteins.
Highlights
Genetic modulation of life span is mediated through proteins, and the mechanisms that allow this control must necessarily involve the interaction of multiple proteins
We show that human homologs of invertebrate longevity genes change in their expression levels during aging in human tissue
We show that human genes encoding proteins that interact with human longevity homolog proteins are changed in expression during human aging
Summary
Genetic modulation of life span is mediated through proteins, and the mechanisms that allow this control must necessarily involve the interaction of multiple proteins. Modulations of the levels in a single protein have been found that provide robust increases in life-span for an organism [1,2], but contributions from many genes are expected to dictate longevity in all organisms. This idea is supported by an investigation of yeast protein-protein interaction networks that found that proteins related to aging have a significantly higher connectivity than expected by chance [3]. A second group found that their computational model suggested aging genes have more connections in interaction networks, and that this may be useful in identifying new aging genes [4]. A useful way to identify novel genes with roles that affect life span is to identify their gene product’s interactions with known agingassociated proteins
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
