Abstract
Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as FN1, APP, CREBBP, EGFR playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, TNF-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and −18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.
Highlights
As we age, physiological functions deteriorate, and these changes lead our organism to become vulnerable and to express age-associated disorders[1]
Systems biology, often referred as network biology[5], has emerged over the last years as a novel paradigm in the field of big data biology aiming to improve our understanding of system-level molecular interactions underlying complex cellular processes, which lead to organ dysfunction; and eventually to clinical expression
We contribute both: to improve the understanding of the biology of frailty using different network biology analysis, and in therapeutics through network pharmacology analysis discovering novel possible targets and compounds that could be useful in this condition
Summary
Physiological functions deteriorate, and these changes lead our organism to become vulnerable and to express age-associated disorders[1]. Network analysis is the newest available approach to the analysis of the system as a whole, aiming to elucidate the molecular mechanisms of complex age-related diseases and conditions such as frailty[7].
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