A modular network model of aging

Many fundamental questions on aging are still unanswered or are under intense debate. These questions are frequently not addressable by examining a single gene or a single pathway, but can best be addressed at the systems level. Here we examined the modular structure of the protein–protein interaction (PPI) networks during fruitfly and human brain aging. In both networks, there are two modules associated with the cellular proliferation to differentiation temporal switch that display opposite aging‐related changes in expression. During fly aging, another couple of modules are associated with the oxidative–reductive metabolic temporal switch. These network modules and their relationships demonstrate (1) that aging is largely associated with a small number, instead of many network modules, (2) that some modular changes might be reversible and (3) that genes connecting different modules through PPIs are more likely to affect aging/longevity, a conclusion that is experimentally validated by Caenorhabditis elegans lifespan analysis. Network simulations further suggest that aging might preferentially attack key regulatory nodes that are important for the network stability, implicating a potential molecular basis for the stochastic nature of aging. Synopsis Aging is a prominent factor associated with many complex human diseases. Genetic mutants have implicated a large number of different biological processes in the aging process of both human and model organisms. However, some fundamental questions on aging remain unanswered, because they require a systems level view of the process (Kirkwood, 2005; Sinclair, 2005; Hekimi, 2006). Through integrating protein–protein interaction (PPI) networks with gene expression profiles during human brain and fruitfly aging, we first extracted subnetworks that are ‘active’ during aging. Genes in these active subnetworks aggregate into a small number of network modules. In both human brain and fruitfly aging networks, there are two modules associated with the cellular proliferation to differentiation of temporal switch, which display opposite aging‐related, possibly reversible changes in expression. In fruitfly aging network, another couple of modules are associated with the oxidative‐reductive metabolic temporal switch and display opposite linear, possibly irreversible change with age. The transcriptional relationships among these modules can be modified by caloric restriction in fruitfly. The topology of the aging network is rela