The molecular mechanisms underlying these interactions could be explained by their possible relationship with alterations in mitochondrial function, as reported by Gaare and collaborators in They demonstrated that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influenced the risk of PD and proposed that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis 34 , which could establish a relationship between mitochondrial dysfunction —characteristic of PD— and alterations in DNA metabolism.
Cluster 5 includes genes related to signaling and maintenance processes whose primary targets are the muscle and nervous system. It is well established that the lack of trophic inputs during adulthood leads to loss of physical function mediated by the loss of cell populations in different tissues. An example of this is the age-related reduced signaling of IGF-2, that leads to inefficient muscle regeneration.
Ikemoto-Uezumi et al. The ability to detect a decrease in the content of trophic factors or in the efficiency of the signaling pathways responsible for processing their stimulus could be promising for the timely detection of frailty. Overall, these findings support the statement of Neal S.
Some agents could be used because of their impact in inflammation e. Moreover, endocrine pathways are also potential targets for pharmacological treatment, as shown by the estrogen-receptor blocker raloxifene; that is well-known for its impact on the treatment of osteoporosis and some types of cancer. Oxidative stress could also be halted by some of the candidate molecules found in the analysis; such as the epigallocatechin gallate present in chocolate. Further research must be assessed on the matter of repurposing drugs taking advantage of quantitative systems pharmacology QSP , a novel tool useful to simulate drug efficacy pharmacokinetics and pharmacodynamics and toxicity for model-based design of treatment schedules to facilitate pharmaceutical development Drug repurposing has been shown to bring therapeutic alternatives for those conditions that still lack an effective treatment Our results, suggest that anti-rheumatic agents could have the potential to ameliorate the progression of frailty and even halt the burden it poses on older adults.
Finally, there are some interesting, albeit toxic compounds, that may interact with some of the most druggable targets GR and ACE, such as Bisphenol A well-known endocrine disruptor chemical ; which is present in several plastic bottles and metal cans linings that have shown to alter the epigenome. Also, arsenate, the most common form of inorganic arsenic and a widespread pollutant found in water, cigarettes, food, and air, that has been correlated with neurotoxic effects, high levels of DNA methylation and different types of cancer Altogether, these results suggest adverse environmental implications of frailty.
Our work highlights the potential that new methodologies could bring to the field of aging. Frailty in particular has shown to be a special case on the dynamics of a network of networks. Different levels, from the molecular to the clinical expression, seem to be related and understanding their mechanics, could improve knowledge both on causes and potential interventions.
In conclusion, our results show several signaling pathways: apoptosis, inflammation, Notch, and chemokine signaling that play a significant role in the biology of frailty and may be considered as central hubs for this condition. Additionally, epigenetics may play a significant role in the development of frailty, highlighting the role of environmental factors such as pollution that could lead to the clinical expression of this problem.
Finally, there may be some drugs that could be repurposed in order to be used in frailty, such as anti-rheumatic agents. However, further studies are needed to validate drug efficacy and toxicity before they could be implemented in clinical practice. Cytoscape software 37 v 3. Initially, we used a mirror version of GeneMANIA 38 a prediction server that finds functionally similar genes using a wealth of genomics and proteomics on Cytoscape 39 to obtain novel genes related by physical interactions, shared common signaling pathways and co-expression information of frailty-related genes Fig.
For the second step, we used BisoGenet 40 plug-in for Cytoscape to build a structural biological analysis based on PPI and miRNA-Protein interaction network analysis using as seeds input values only frailty-related genes 14 , 15 Fig. Node degree defined as the number of neighbors connected directly to a node. Since the frailty index is a ratio of the number of deficits that an individual has accumulated divided by all deficits measured, we performed a search for the relationship between deficits associated with frailty and those already mentioned genes. There is a reasonable consensus on what the conceptual definition of frailty is; however, an operational definition has been a matter of debate that persists to our days 2.
We chose the frailty index, since Mitnitski et al. In addition, it has shown that deficits interact as a network 46 , 47 with particular characteristics that allow to approach this problem with a systems biology paradigm. The interest was to have a high number of features related to frailty in order to search for them in different databases; the frailty index suits this goal. An exhaustive search of the different deficits that have been used to integrate a frailty index was done, departing from the first table provided by the creators of this tool, and enriched with other frailty indexes used by Mitniski et al.
In order to relate already mentioned genes and deficits, it was developed a weighted socio-matrix or weighted adjacency matrix through the relation of original papers linking deficits with genes performed only on human samples or clinical studies on Pubmed over the last 15 years linking deficits with genes. The term socio-matrix is a square matrix where a number one indicates a tie between two nodes and a number zero indicates no tie.
The convention is that rows indicate the starting node and columns the receiving node. In a weighted socio-matrix, like the one it was used, edge weights are included, and the number ones in the socio-matrix are substituted by the weights publications indicating the strength of a tie. Associations between deficits on the one hand and between genes on the other were not considered; hence, we used zeros in the corresponding entries.
Networks were then built, and their nodes correspond to deficits or genes, and their edges are obtained from the weighted publications socio-matrix. Isolated vertices were eliminated. Centrality measures were calculated i. Since there are weights associated with each edge according to the socio-matrix, weighted centrality measures were calculated as well Supplementary Fig.
To identify clustering formation k-cores maximal subgraph, where each vertex is connected to at least k other vertices in the subgraph were obtained Fig. For the same purpose, community detection algorithms were used walktrap, edge betweenness, spin-glass, fast greedy, label propagation, leading eigenvector, and Louvain , and we chose the clusters obtained through the Louvain algorithm since it provided one of the most significant modularity values and better interpretability. For statistical analyses, software R was used igraph, Intergraph, statnet, and tnet libraries.
Once identified the most critical nodes on the deficit-gene network Fig. Then a novel network to identify chemical targets drugs or toxicants that could interact somehow with the most druggable nodes was used by using the CTD Fig. The network was created by using Cytoscape v 3. Chen, X. Frailty syndrome: an overview. Aging 9 , — Cesari, M. Partridge, L. Facing up to the global challenges of ageing. Nature , 45—56 Dato, S. Frailty phenotypes in the elderly based on cluster analysis: a longitudinal study of two Danish cohorts.
Advances in Pharmacology: Volume 44
Evidence for a genetic influence on frailty. Age Dordr. Afendi, F. Biomed Res. Valenzuela, J. Health and disease phenotyping in old age using a cluster network analysis.
Hopkins, A. Network pharmacology: the next paradigm in drug discovery. Fotis, C.
Network-based technologies for early drug discovery. Drug Discov. Today 23 , — Waring, M. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov 14 , — Zhao, R. Planta Med 85 , 14—23 Hart, T. Molecular Aspects of Medicine Biology of frailty: Modulation of ageing genes and its importance to prevent age-associated loss of function.
Aspects Med. Hangelbroek, R. Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness. Fedarko, N.https://sicarderup.tk
Cellular and Molecular Pharmacology (UCL, Brussels, Belgium)
The biology of aging and frailty. Franceschi, C. Inflammaging and Garb-aging. Trends Endocrinol. Pal, S. Epigenetics and aging. Bellizzi, D.
Global DNA methylation in old subjects is correlated with frailty. Collerton, J. Biogerontology 15 , — Breitling, L. Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Epigenetics 8 , 21 Laboratories, P. Epigenetic regulation of ageing. Hake, S. Expression patterns and post-translational modifications associated with mammalian histone H3 variants.
In this context, propolis and geopropolis represent a promising source of bioactive compounds for pharmacological research [ 1 , 14 — 18 , 21 , 28 , 29 ]. Propolis has been extensively studied, and in the last decades, propolis has aroused scientific attention and many reports have been published concerning its broad spectrum of pharmacological activities and its bioactive components [ 14 , 15 , 18 , 28 ].
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At present, the biological activities reported for propolis include antibacterial [ 30 — 32 ], antioxidant [ 31 , 33 ], antiparasitic [ 34 — 38 ], antifungal [ 39 — 41 ], antiviral [ 42 ], local anaesthetic [ 43 ], anti-inflammatory [ 44 , 45 ], immunomodulatory [ 46 , 47 ], antitumor [ 48 — 50 ], and antiproliferative activity on cancer cell growth [ 50 — 54 ], among others.
There are remarkable differences in the biological activities of propolis from dissimilar geographical origin, and those mainly depend on the qualitative and quantitative variations of its characteristic chemical constituents, which are provided by botanical sources.