A Human Protein Interaction Network Shows Conservation of Aging Processes between Human and Invertebrate Species

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.

The system capacity view of aging and longevity

“…This is consistent with the fact that aging and lifespan regulators are frequently hubs in the molecular interaction networks [49][50][51], and the fact that pleiotropic genes and genes regulating general stress tolerance in many physiological components or processes, such as daf-16, are key regulators of aging and longevity.…”

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…S3, Supporting information; Tables 1 and S5, Supporting information). Of the 50 genes identified in either the CHARGE or Random gene sets, only 4 – atl‐1 (Suetomi et al ., 2013), atm‐1 (Ventura et al ., 2009), daf‐21 (Horikawa et al ., 2015), and tag‐322 (Bell et al ., 2009) – were previously reported to affect lifespan in C. elegans , while the remaining 46 are novel.…”

A Protein Interaction Network for Ecm29 Links the 26 S Proteasome to Molecular Motors and Endosomal Components

“…Genome-wide Yeast Two-hybrid Screens-High throughput genome-wide yeast two-hybrid screens using human brain libraries were performed as described (35)(36)(37). Briefly, cDNAs were generated from poly(A)ϩ human brain RNA by reverse transcription using random oligonucleotides with a common 5Ј sequence, second strand synthesis, and ligation of an oligonucleotide to the 5Ј-end.…”