Systems biology and network pharmacology of frailty reveal novel epigenetic targets and mechanisms

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.

Implementing Precision Medicine in Human Frailty through Epigenetic Biomarkers

“…These can result in gene expression silencing in DNA repair and anti-inflammatory genes [ 31 ]. It has also been suggested that other genes participating in the maintenance of muscle and nervous systems processes, chromatin remodeling, and transcription control may also be affected [ 32 ]. It has been proposed that these global changes in DNA methylation are associated with the incomplete restoration of epigenetic patterns after DNA replication or DNA repair [ 33 ], which contribute to the accumulation of epimutations in the bulk DNA.…”

“…The main interventions developed to date to improve frailty-related health outcomes include lifestyle/behavioral factors: exercise, nutrition, multicomponent interventions, individually-tailored geriatric care models and cognitive health maintenance [ 32 , 100 ]. Among them, exercise is considered the most effective intervention in preclinical and clinical models of frailty [ 103 , 104 ].…”

European Respiratory Society statement on frailty in adults with chronic lung disease

“…Still, some existing drugs affect multiple pathways involved in frailty including apoptosis, proteolysis, muscle proliferation and inflammation, e.g. existing antirheumatic agents modulate both the glucocorticoid receptor and ACE-involved targets [143]. Other novel anabolic agents such as selective androgen receptor modulators [144], and ghrelin mimetics are still under investigation to tackle muscle and bone loss [139].…”

Biomarkers of Frailty: miRNAs as Common Signatures of Impairment in Cognitive and Physical Domains

“…A critical role of these small molecules has been documented relative to the frailty-associated phenotypes, i.e., in muscle development and homeostasis [ 64 ], but also in neuronal processes such as brain development, synaptic plasticity, and learning and memory functions [ 65 ]. A study of network biology, by analyzing the interactome of frailty-related genes, prioritized 10 miRNA markers indirectly associated with frailty through the association of their targets [ 66 ]. To date, only three studies directly evaluated changes in blood plasma miRNAs in frail/non frail subjects [ 67 , 68 , 69 ].…”