The Molecular Landscape of Premature Aging Diseases Defined by Multilayer Network Exploration.

Abstract

Premature Aging (PA) diseases are rare genetic disorders that mimic some aspects of physiological aging at an early age. Various causative genes of PA diseases have been identified in recent years, providing insights into some dysfunctional cellular processes. However, the identification of PA genes also revealed significant genetic heterogeneity and highlighted the gaps in this understanding of PA-associated molecular mechanisms. Furthermore, many patients remain undiagnosed. Overall, the current lack of knowledge about PA diseases hinders the development of effective diagnosis and therapies and poses significant challenges to improving patientcare. Here, a network-based approach to systematically unravel the cellular functions disrupted in PA diseases is presented. Leveraging a network community identification algorithm, it is delved into a vast multilayer network of biological interactions to extract the communities of 67 PA diseases from their 132 associated genes. It is found that these communities can be grouped into six distinct clusters, each reflecting specific cellular functions: DNA repair, cell cycle, transcription regulation, inflammation, cell communication, and vesicle-mediated transport. That these clusters collectively represent the landscape of the molecular mechanisms that are perturbed in PA diseases, providing a framework for better understanding their pathogenesis is proposed. Intriguingly, most clusters also exhibited a significant enrichment in genes associated with physiological aging, suggesting a potential overlap between the molecular underpinnings of PA diseases and natural aging.