A modular network model of aging

Abstract

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 proteinprotein 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.

Gene expression‐based drug repurposing to target aging

“…Downregulated genes were enriched in synaptic functions and biosynthetic processes (FDR‐corrected p  < 0.05), whereas differentiation and proliferation‐related categories showed enrichment for the upregulated genes (FDR‐corrected p  < 0.05). These results are consistent with the findings of earlier brain aging transcriptome studies (Lu et al, 2004; Naumova et al, 2012; Xue et al, 2007). Oddly, ossification‐related biological processes also showed significant enrichment for the upregulated genes.…”

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

“…At present, it is difficult to determine whether preventative and therapeutic strategies (such as calorie restriction) have beneficial effects in humans because there are no validated biomarkers that can serve as surrogate markers of aging (Matkovic et al 1990). To have the "phenome of aging" (Xue et al 2007) much better defined, we propose using the musculoskeletal aging phenotypes as an example and starting point.…”

Understanding biological functions through molecular networks

“…We have found that genes inside the aging-related subnetworks aggregate into several modules related to cellular temporal switches [74]. Two modules of a switch not only correspond to two alternative cellular states, but also assume opposite expression changes during aging.…”

“…Two modules of a switch not only correspond to two alternative cellular states, but also assume opposite expression changes during aging. Such modules are connected through concerted transcriptional regulation and extensive PPIs, with genes connecting these modules through PPIs more likely to affect network stability and organism lifespan [74].…”